Download December 2002 Vol 2 No 12

Nature Reviews Cancer 2, 897-909 (2002); doi:10.1038/nrc949
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December 2002 Vol 2 No 12
preface
Epidemiology of pancreatic cancer
Molecular genetics of pancreatic adenocarcinoma
Pancreatic cancer biology
Future directions
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about the authors
Nature Reviews Cancer 2, 897-909 (2002); doi:10.1038/nrc949
PANCREATIC CANCER BIOLOGY AND GENETICS
Nabeel Bardeesy & Ronald A. DePinho
about the authors
Department of Adult Oncology, Dana–Farber Cancer Institute and Departments of Medicine and
Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
correspondence to: Ronald A. DePinho Correspondence to:[email protected]
Pancreatic ductal adenocarcinoma is an aggressive and devastating disease,
which is characterized by invasiveness, rapid progression and profound
resistance to treatment. Advances in pathological classification and cancer
genetics have improved our descriptive understanding of this disease;
however, important aspects of pancreatic cancer biology remain poorly
understood. What is the pathogenic role of specific gene mutations? What is
the cell of origin? And how does the stroma contribute to tumorigenesis? A
better understanding of pancreatic cancer biology should lead the way to more
effective treatments.
PANCREATIC ADENOCARCINOMA is the fourth leading cause of cancer death in the United
States1. With a 5-year survival rate of only 3% and a median survival of less than 6
months, a diagnosis of pancreatic adenocarcinoma carries one of the most dismal
prognoses in all of medicine2. Due to a lack of specific symptoms and limitations in
diagnostic methods, the disease often eludes detection during its formative stages.
Whipple and colleagues reported the first PANCREATICODUODENECTOMY in 1935 and
surgery has since offered the only possibility of cure, although surgical intervention
alone rarely achieves a curative end point2. For the 15–20% of patients who undergo
potentially curative resection, the 5-year survival is only 20% (Ref. 3). Some
improvements in surgical outcome occur in patients who also receive chemotherapy
and/or radiotherapy, although the impact on long-term survival has been minimal owing
to the intense resistance of pancreatic adenocarcinoma to all extant treatments. So,
management of most patients focuses on palliation.
A recent National Cancer Institute 'think tank' (known as a Progress Review Group)
articulated the crucial questions and challenges facing the field and provided
recommendations to address key unmet needs in the clinical and basic research arenas4
(see Pancreatic Cancer — Agenda for Action in online links box). Many hurdles and
opportunities were noted, and among these were the overarching needs to conduct a
more penetrating analysis of pancreatic cancer biology and to develop refined animal
models of pancreatic adenocarcinoma. The identification of signature gene mutations in
pancreatic adenocarcinoma was recognized as a valuable starting point, providing a
conceptual framework to guide the future analysis of complex aspects of this disease.
How these genetic changes translate into the classical biological features of pancreatic
cancer cells stands as a key area for increased active investigation. It is anticipated that
more sophisticated genetic-engineering strategies will generate refined mouse models
for the systematic dissection of the pathophysiological impact of various genetic
alterations, and elucidation of the complexities of intersecting signalling pathways that
control cellular growth, survival and differentiation. So how can information and
technological advances be integrated to create a 'roadmap' for an improved
understanding of pancreatic cancer biology, and how might such systems lead to more
effective treatments?
Epidemiology of pancreatic cancer
Pancreatic adenocarcinoma is generally thought to arise from pancreatic ductal cells
(Fig. 1; Table 1); however, this remains an area of ongoing study (see below)14, 147. The
aetiology of pancreatic adenocarcinoma remains poorly defined, although important
clues of disease pathogenesis have emerged from epidemiological and genetic studies.
Pancreatic adenocarcinoma is a disease that is associated with advancing age5 — rare
before the age of 40, it culminates in a 40-fold increased risk by the age of 80.
Environmental factors might modulate pancreatic adenocarcinoma risk5. On the genetic
level, numerous studies have documented an increased risk in relatives of pancreatic
adenocarcinoma patients (approximately threefold), and it is estimated that 10% of
pancreatic cancers are due to an inherited predisposition6. As with most cancer types,
important insights have emerged from the study of rare kindreds that show an increased
incidence of pancreatic adenocarcinoma. However, unlike familial cancer syndromes for
breast, colon and melanoma, pancreatic adenocarcinoma that is linked to a familial
setting has a lower penetrance (<10%) and maintains a comparable age of onset to
sporadic cases in the general population. Among the genetic lesions that are linked to
familial pancreatic adenocarcinoma are germline mutations in CDKN2A (which encodes
two tumour suppressors — INK4A and ARF), BRCA2, LKB1 and MLH1 (Ref. 7). The low
penetrance of pancreatic adenocarcinoma that is associated with these germline
mutations might point to a role in the malignant progression of precursor lesions rather
than in the limiting events that control initiation of neoplastic growth from normal
pancreatic cells. With respect to CDKN2A and BRCA2, this notion gains experimental
support from the observation that inactivation of these genes is not detected in
premalignant ductal lesions that are thought to represent early stages of pancreatic
tumorigenesis (see below).
Figure 1 | Anatomy of the pancreas.
The pancreas is comprised of separate functional units that
regulate two major physiological processes: digestion and
glucose metabolism136. The exocrine pancreas consists of
acinar and duct cells. The acinar cells produce digestive
enzymes and constitute the bulk of the pancreatic tissue. They
are organized into grape-like clusters that are at the smallest
termini of the branching duct system. The ducts, which add
mucous and bicarbonate to the enzyme mixture, form a network of increasing size,
culminating in main and accessory pancreatic ducts that empty into the duodenum. The
endocrine pancreas, consisting of four specialized cell types that are organized into compact
islets embedded within acinar tissue, secretes hormones into the bloodstream. The and> -cells regulate the usage of glucose through the production of glucagon and insulin,
respectively. Pancreatic polypeptide and somatostatin that are produced in the PP and> cells modulate the secretory properties of the other pancreatic cell types.>a | Gross anatomy
of the pancreas. b | The exocrine pancreas. c | A single acinus. d | A pancreatic islet
embedded in exocrine tissue.
Table 1 | Types of pancreatic neoplasms
Beyond the above classical tumour-suppressor mutations, additional genetic defects
seem to be operative in rare families in which pancreatic cancer is inherited as an
autosomal-dominant trait with very high penetrance6. A pancreatic cancer syndrome —
so far identified in a single family — has been linked to chromosome 4q32-34 (Ref. 8)
and is associated with diabetes, pancreatic exocrine insufficiency and pancreatic
adenocarcinoma, with a penetrance approaching 100%. Patients with hereditary
pancreatitis, which is associated with germline mutations in the cationic trypsinogen
gene PRSS1, experience a 53-fold increased incidence of pancreatic adenocarcinoma9, 10.
Mutations in PRSS1 cause the encoded enzyme either to be more effectively
autoactivated or to resist inactivation and, consequently, to display deregulated
proteolytic activity. It is assumed that the resulting inflammation promotes
tumorigenesis, in part, by producing growth factors, cytokines and reactive oxygen
species (ROS), thereby inducing cell proliferation, disrupted cell differentiation and
selecting for oncogenic mutations. We speculate that increased cell turnover and ROS
might also lead to increased telomere attrition and dysfunction, setting the stage for
potentially oncogenic genomic instability (see below).
Molecular genetics of pancreatic adenocarcinoma
Signalling pathways and tumour progression. A careful molecular and pathological
analysis of evolving pancreatic adenocarcinoma has revealed a characteristic pattern of
genetic lesions. The field is now faced with the challenge of understanding how these
signature genetic lesions — mutations of KRAS, CDKN2A, TP53, BRCA2 and
SMAD4/DPC4 — contribute to the biological characteristics and evolution of this disease.
The progression model for colorectal cancer has served as a template for relating
sequential, defined mutations to increasingly atypical growth states11. Whether such a
progression series exists for pancreatic adenocarcinoma will draw continued scrutiny in
the years ahead.
The pancreatic-duct cell is generally believed to be the progenitor of pancreatic
adenocarcinoma. As defined in Cubilla and Fitzgerald's classic study12, the increased
incidence of abnormal ductal structures (now designated pancreatic intraepithelial
neoplasia, PanIN)5, 15 in patients with pancreatic adenocarcinoma, and the similar spatial
distribution of such lesions to malignant tumours, are consistent with the hypothesis
that such lesions might represent incipient pancreatic adenocarcinoma. Histologically,
PanINs show a spectrum of divergent morphological alterations relative to normal ducts
that seem to represent graded stages of increasingly dysplastic growth14 (Fig. 2). Cell
proliferation rates increase with advancing PanIN stages, which is consistent with the
idea that these are progressive lesions15. A growing number of studies have identified
common mutational profiles in simultaneous lesions, providing supportive evidence of
the relationship between PanINs and the pathogenesis of pancreatic adenocarcinoma.
Specifically, common mutation patterns in PanIN and associated adenocarcinomas have
been reported for KRAS and for CDKN2A16. In addition, similar patterns of LOSS OF
HETEROZYGOSITY (LOH) at chromosomes 9q, 17p and 18q (harbouring CDKN2A, TP53
and SMAD4, respectively) have been detected in coincident lesions (see below), and
studies have consistently shown an increasing number of gene alterations in highergrade PanINs17-20. Intriguingly, there seems to be an ordered series of mutational events
in association with specific neoplastic stages7.
Figure 2 | Genetic progression model of pancreatic
adenocarcinoma.
Pancreatic intraepithelial neoplasias (PanINs) seem to
represent progressive stages of neoplastic growth that are
precursors to pancreatic adenocarcinomas. The genetic
alterations documented in adenocarcinomas also occur in PanIN
in what seems to be a temporal sequence, although these alterations have not been
correlated with the acquisition of specific histopathological features. The stage of onset of
these lesions is depicted. The thickness of the line corresponds to the frequency of a lesion.
The temporal alterations in telomerase activity and telomere length are by inference from
Refs 62,139 and need further substantiation in PanIN. Normal duct, PanIN-1A/PanIN-1B and
PanIN-3 images reproduced with permission from ref. 14 (2001) Lippincott Williams &
Wilkins; PanIN-2 and adenocarcinoma images kindly provided by Dr Ralph Hruban, Johns
Hopkins University (http://pathology.jhu.adu/pancreas/panin/).
KRAS. The earliest ductal lesions do not usually display genetic alterations. Activating
KRAS mutations are the first genetic changes that are detected in the progression
series, occurring occasionally in histologically normal pancreas and in about 30% of
lesions that show the earliest stages of histological disturbance (Fig. 2; see Ref. 13 and
references therein). KRAS mutations increase in frequency with disease progression,
and are found in nearly 100% of pancreatic adenocarcinomas; they seem to be a virtual
rite of passage for this malignancy21. WAF1 (also known as p21 and CIP1) seems to be
coordinately induced with the onset of KRAS mutations, perhaps due to activation of the
mitogen-activated protein kinase (MAPK) PATHWAY22.
Activating mutations of RAS-family oncogenes produce a remarkable array of cellular
effects, including induction of proliferation, survival and invasion through the stimulation
of several effector pathways (reviewed in Ref. 23). Although the roles of specific KRAS
effector pathways in pancreatic cancer pathogenesis have not been resolved, there is
evidence for an important contribution of AUTOCRINE epidermal growth-factor (EGF)family signalling24-27, 31. This autocrine loop and resulting stimulation of the
phosphatidylinositol 3-kinase (PI3K) PATHWAY is required for transformation of several
cell lineages by RAS-family oncogenes28. Consistent with the existence of such an
autocrine loop, pancreatic adenocarcinomas overexpress EGF-family ligands (such as
transforming growth factor- (TGF- ) and EGF) and receptors (EGFR, ERBB2 (also
known as HER2/neu) and ERBB3)24, 26, 28. EGFR and ERBB2 induction occurs in low-grade
PanINs, indicating that autocrine EGF-family signalling might be operative at the earliest
stages of pancreatic neoplasia29. The functional importance of this pathway is illustrated
by the growth inhibition of pancreatic adenocarcinoma cell lines in vitro and in
xenografts following attenuation of EGFR signalling by blocking antibodies or expression
of dominant-negative EGFR alleles27, 30, 31. Many pathways are likely to contribute to the
pathogenic role of activated KRAS, and a deeper understanding of this oncogenic
programme will be vital for the development of new treatment approaches towards this
disease.
CDKN2A. Germline mutations in the CDKN2A tumour-suppressor gene are associated
with the familial atypical mole-malignant melanoma (FAMMM) syndrome. In addition to
a very high incidence of melanoma, the inheritance of mutant CDKN2A alleles confers a
13-fold increased risk of pancreatic cancer32, 33. Although pancreatic adenocarcinoma
arises in some, but not all, FAMMM kindreds with CDKN2A mutations, there are no clear
genotype–phenotype associations, indicating a modulating role for environmental factors
in disease penetrance34, 35. FAMMM kindreds that harbour mutant loci other than
CDKN2A, such as cyclin-dependent kinase 4 (CDK4) alleles that abrogate INK4A binding
or other uncharacterized loci, do not have increased incidence of pancreatic
adenocarcinoma33, 36.
Loss of CDKN2A function — brought about by mutation, deletion or promoter
hypermethylation — also occurs in 80–95% of sporadic pancreatic adenocarcinomas21.
CDKN2A loss is generally seen in moderately advanced lesions that show features of
dysplasia (Fig. 2). The dissection of the role of CDKN2A has been a fascinating story as
this tumour-suppressor locus, at 9q21, encodes two tumour suppressors — INK4A and
ARF — via distinct first exons and alternative reading frames in shared downstream
exons37. Given this physical juxtaposition and frequent homozygous deletion of 9p21 (in
40% of tumours), many pancreatic cancers sustain loss of both the INK4A and ARF
transcripts, thereby disrupting both the retinoblastoma (RB) and p53 tumoursuppression pathways. INK4A inhibits CDK4/CDK6-mediated phosphorylation of RB,
thereby blocking entry into the S (DNA synthesis) phase of the cell cycle; ARF stabilizes
p53 by inhibiting its>MDM2-dependent proteolysis. INK4A seems to be the more
important pancreatic cancer suppressor at this locus, as germline and sporadic
mutations have been identified that target INK4A, but spare AR>21, 38, 39.
The INK4A transcript displays a highly restricted expression pattern and is dispensable
for normal development and homeostasis40-43. When primary cells are placed into
culture, INK4A-transcript expression is induced, and this seems to be a stress response
to the inappropriate growth environment that is associated with in vitro culture44, 45;
similar INK4A induction is observed in vivo in association with reactive processes43. This
induction by environmental stress and aberrant proliferative signals provides a plausible
basis for the tumour-suppression function of INK4A, although the relationship of this
phenomenon to cancer suppression in vivo is not established. Recent studies have also
implicated INK4A in the cellular response to DNA damage in vivo46, so the absence of
INK4A might also contribute to the chemoresistance of pancreatic adenocarcinoma.
In human fibroblasts, high levels of activated RAS genes induce INK4A, which, in turn,
results in premature senescence47-49 — a presumed defence mechanism against
oncogenic stress. This had been thought to contribute to the coincident mutations of
RAS and CDKN2A in cancer, but numerous observations now indicate that this simple
model might require reconsideration. Notably, KRAS mutations are often detected in
non-neoplastic states, such as chronic pancreatitis, and possibly in normal pancreas50.
Furthermore, several different KRAS mutations might be detected in individual PanIN
lesions16, 51. Loss of INK4A usually occurs only in later stages of pancreatic neoplasia.
These data indicate that, rather than inducing premature senescence, KRAS mutations
confer a survival advantage in vivo. This is corroborated by studies in mouse cells in
which an activated KRAS allele, which is expressed at physiological levels, provokes
immortalization of fibroblasts in vitro or adenoma formation of lung epithelial cells in
vivo52(D. Tuveson and T. Jacks, personal communication). Although loss of INK4A
probably facilitates the oncogenicity of activated RAS alleles, as shown in animal
models53, 54, its occurrence later in pancreatic tumour progression indicates that the
intersection of these pathways might require other events, such as disrupted contacts
with the extracellular matrix or elevations in the level of activated KRAS.
TP53. The TP53 tumour-suppressor gene is mutated, generally by missense alterations
of the DNA- binding domain, in more than 50% of pancreatic adenocarcinomas21. TP53
mutations arise in later-stage PanINs that have acquired significant features of
dysplasia, reflecting the function of TP53 in preventing malignant progression. In
contrast to many other cancer types, there does not seem to be a reciprocal relationship
in the loss of CDKN2A and TP53 (Refs 22,55), which points to non-overlapping functions
for ARF and p53 in pancreatic cancer suppression. TP53 loss probably facilitates the
rampant genetic instability that characterizes this malignancy. These tumours have
profound aneuploidy and complex cytogenetic rearrangements, as well as intratumoral
heterogeneity, which is consistent with ongoing genomic rearrangements57, 144.
Cytogenetic studies have provided evidence that telomere dynamics might contribute to
this genomic instability. Although reactivation of telomerase is crucial to the emergence
of immortal cancer cells, a preceding and transient period of telomere shortening and
dysfunction might also contribute to carcinogenesis by leading to the formation of
chromosomal rearrangements through breakage–fusion–bridge cycles56, 58 (Fig. 3). The
survival of cells with critically short telomeres (crisis), which continue to go through
breakage–fusion–bridge events, is enhanced by inactivation of the p53-dependent DNAdamage response59, allowing the acquisition of oncogenic chromosomal alterations61.
Studies in the telomerase-knockout mouse support this model, as telomere dysfunction
and p53 loss cooperate to promote the development of carcinomas in multiple tissues58.
An analysis of a large series of human pancreatic cancer cell lines revealed that
telomeres were frequently lost from chromosome ends and that anaphase bridging
occurred, indicating that persistent genomic instability is associated with critically short
telomeres60, 61. As these features were observed in both low- and high-grade tumours,
the authors conclude that telomere dysfunction was an early step in the pathogenic
process. Moreover, studies of pancreatic adenocarcinomas revealed that tumours have
shortened telomere length and that the activation of telomerase is a late event61, 62, 139.
Telomere attrition due to increased cell turnover might contribute to the high incidence
of pancreatic adenocarcinomas that are associated with hereditary pancreatitis. To
establish more conclusively the role of crisis in the genesis of pancreatic
adenocarcinoma, it will be of interest to specifically correlate telomere length, p53
status and the onset of genomic instability in PanINs, and to develop pancreatic cancer
models in mouse strains with telomere dysfunction.
Figure 3 | Telomere attrition and genomic instability.
Most human somatic cells lack telomerase activity, hence
telomeres are eroded as cells proliferate. If the proliferative
stimulus is maintained, such as in cells that have sustained
oncogenic mutations, progressive telomere shortening activates
DNA-damage responses, resulting in growth arrest. Loss of these
checkpoint responses, such as by mutation of TP53, allows cells
to continue proliferating, leading to telomere dysfunction and
genomic instability (crisis). Chromosome breakage–fusion cycles
produce severe aneuploidy and chromosomal translocations that
contribute to tumour progression. Telomerase reactivation subsequently stabilizes the
genome and facilitates the immortal growth of the tumour cells. Independent processes also
lead to genomic instability — centrosome defects result in a disorganized mitotic spindle,
which leads to aneuploidy or chromosome breakage; BRCA2 mutations produce genomic
instability by disabling the homologous recombination-based DNA-repair pathway.
BRCA2. Inherited BRCA2 mutations are typically associated with familial breast and
ovarian cancer syndrome, but also carry a significant risk for the development of
pancreatic cancer. Approximately 17% of pancreatic cancers that occur in a familial
setting harbour mutations in this gene64, 65. As is the case for those individuals with
germline CDKN2A mutations, the penetrance of pancreatic adenocarcinoma in BRCA2mutation carriers is relatively low ( 7%) and the age of onset is similar to that of
patients with the sporadic form of the disease. Familial breast cancer alleles other than
BRCA2 do not seem to predispose to pancreatic adenocarcinoma.
Loss of wild-type BRCA2 seems to be a late event in those individuals who inherit
germline heterozygous mutations of BRCA2, which is restricted to severely dysplastic
PanINs and adenocarcinomas65. Although the numbers are small, these patients do not
show an elevated incidence of PanINs. These data are consistent with the possibility that
BRCA2 loss promotes the malignant progression of existing lesions in pancreatic
neoplasia. BRCA2 is necessary for the maintenance of genomic stability by regulating
the homologous-recombination-based DNA-repair processes; consequently, BRCA2
deficiency in normal cells results in the accumulation of lethal chromosomal
aberrations63. The fact that BRCA2 is selectively mutated late in tumorigenesis probably
reflects the need for DNA-damage-response pathways to be inactivated first — for
example, by TP53 mutation — so that the damage incurred can be tolerated.
Chromosomal instability. Defects in the mitotic-spindle apparatus conferred by
centrosome abnormalities might also contribute to the aneuploidy and genomic
instability of pancreatic adenocarcinomas. Centro-some abnormalities are detected in
85% of pancreatic adenocarcinomas, and there is a correlation between levels of such
abnormalities and the degree of chromosomal aberrations66. Overall, the loss of TP53
and BRCA2, and the detection of abnormal mitosis and severe nuclear abnormalities in
PanIN-3 lesions, indicate that genomic instability is initiated at this stage of tumour
progression.
These observations have several implications. First, the detection of clonal genetic
alterations in PanINs and synchronous adenocarcinomas is consistent with the concept
that PanINs are, indeed, neoplastic growths that are precursors to adenocarcinomas.
Although KRAS mutations are an early, and probably necessary, event in the
development of pancreatic adenocarcinoma, their absence in the earliest lesions
indicates that KRAS activation is not responsible for neoplastic initiation. This notion is
supported by the observation of different KRAS mutations between PanINs of the same
individual. One possibility is that the earliest lesions might be non-clonal areas of
aberrant proliferation and altered states of differentiation that are associated with the
replacement of damaged cells and with inflammatory processes. These disruptions in
tissue architecture and induction of cell proliferation could produce a FIELD DEFECT in
which there is significant selection for cells that sustain activating KRAS mutations.
Along these lines, inflammatory stimuli promote the expression of both TGF- and EGFR
in the pancreatic ducts, providing a pathway that could synergize with activated KRAS25.
In addition to the extreme aneuploidy of pancreatic adenocarcinomas, there is a high
degree of genetic heterogeneity within these tumours. For instance, different KRAS
mutations and 9q, 17p and 18q LOH patterns have been observed in adjacent PanINs,
and several KRAS mutations have been detected in the same adenocarcinomas16-18.
Importantly, it seems that there is spatial distribution of genetic heterogeneity17.
Neoplastic foci from adjacent regions tend to show similar mutation patterns, whereas
increasing genetic divergence has been documented in more geographically distant foci.
It seems likely that adenocarcinomas can develop from the clonal progression of one of
several related but divergent lesions. These features might indicate that a key event
beyond the initiation of PanINs is the acquisition of a mutator state that allows initiated
cells to acquire progression-associated genetic lesions. It is tempting to speculate that
this tremendous degree of heterogeneity and ongoing instability lies at the heart of the
resistance of pancreatic tumours to chemotherapy and radiotherapy.
The marked chromosomal abnormalities and the disruptions in DNA-repair processes in
pancreatic adenocarcinoma might reflect the existence of additional loci, the genomic
alterations of which contribute to the malignant progression. This is supported by the
detection of recurrent chromosomal amplifications and deletions by COMPARATIVE
GENOMIC HYBRIDIZATION (CGH) and other cytogenetic methods69, 144. In addition to the
signature losses of 17p, 9p and 18q, deletions of chromosomes 8p and 6q and 4q, and
amplifications of chromosomes 8q, 3q, 20q and 7p, have been consistently reported.
Microsatellite instability. Microsatellite instability is a second mode of genomic
instability that, in contrast to the large-scale alterations that are associated with
chromosomal instability, is characterized by very high mutation rates at small DNA
repeat sequences. This phenotype is caused by mutations in DNA mismatch-repair
genes, including MLH1, MSH2 and MSH6 (Ref. 70) and is associated with hereditary
non-polyposis colon cancer (HNPCC) syndrome. There seems to be an elevated risk of
pancreatic cancer in HNPCC families67, 71. The pancreatic adenocarcinomas in HNPCC
patients show distinct molecular genetic profiles, such as a lower rate of KRAS and TP53
mutation, frameshift mutations in BAX and TGF RII, characteristic histopathology and a
less-aggressive clinical course compared with pancreatic adenocarcinomas that occur
outside of this syndrome68, 72, 73.
SMAD4/DPC4. Another frequent alteration in pancreatic adenocarcinoma is the loss of
SMAD4/DPC4 (Ref. 74), which encodes a transcriptional regulator that is a keystone
component in the TRANSFORMING GROWTH FACTOR- (TGF- )-FAMILY SIGNALLING
CASCADE75. This gene maps to chromosome 18q21 — a region that sustains deletion in
approximately 30% of pancreatic cancers74. The pathogenic role of SMAD4 inactivation
is strongly supported by the identification of inactivating intragenic lesions of SMAD4 in
a subset of tumours. SMAD4 seems to be a progression allele for pancreatic
adenocarcinoma, as its loss occurs only in later-stage PanINs18, 19; moreover, there does
not seem to be a strong predisposition to pancreatic adenocarcinoma in patients that
inherit a germline SMAD4 mutation (that is, in juvenile polyposis syndrome patients).
Loss of SMAD4 is a predictor of decreased survival in pancreatic adenocarcinoma20,
which is consistent with a role for it in disease progression. The mechanism by which
SMAD4 loss contributes to tumorigenesis is likely to involve its role in TFG- -mediated
growth inhibition. TGF> inhibits the growth of most normal epithelial cells by either
blocking the G1–S cell-cycle transition or by promoting apoptosis75. The cellular
responses to TGF- are partially, but not exclusively, SMAD4-dependent76 and,
correspondingly, pancreatic adenocarcinomas show a degree of TGF- resistance. The
roles of TGF- signalling in pancreatic adenocarcinoma pathogenesis are not well
defined. Studies have shown inconsistent effects of this cytokine on cultured cell lines
with respect to cell proliferation rates and dependency on SMAD4 status for TGFresponsiveness77-80. These ambiguous results probably stem from the heterogeneity that
is associated with cancer cell lines and the non-physiological conditions that are
encountered in vitro. It seems that in-depth investigational approaches will be required
to understand the contribution of this signalling pathway to pancreatic cancer biology.
SMAD4 loss is also likely to contribute to tumour progression through effects on
tumour–STROMA interactions (see below).
LKB1/STK11. The Peutz–Jeghers syndrome (PJS), which is caused by LKB1/STK11
mutations, is another familial cancer syndrome that is associated with an increased
incidence of pancreatic adenocarcinoma81. PJS patients are primarily afflicted with
benign intestinal polyposis at a young age85, although advancing age carries an
increased risk of developing gastrointestinal malignancies, including a more than 40-fold
increase in pancreatic adenocarcinoma145. PJS is associated with loci other than LKB1 in
some families; it will be important to evaluate the relative role of the different PJS loci in
pancreatic neoplasia84, 86, 87.
Pancreatic cancer biology
Molecular pathology and cancer genetic studies have provided an outline of the cellular
perturbations that are associated with pancreatic adenocarcinoma; however, the picture
remains static with only correlative links to underlying biology at present. A more direct
mechanistic view of how classical lesions influence pancreatic cancer biology is needed
and some key questions need to be answered. What is the CELL OF ORIGIN of pancreatic
cancer, what are the roles of specific lesions in the tumorigenic programme and how
does the cell(s) of origin's developmental state influence the activity of a cancerrelevant genetic lesion?
Cell lineage studies. Pancreatic adenocarcinoma cells show phenotypic resemblance to
pancreatic-duct cells, displaying cuboidal shape, ductal antigen expression and growth
into tubular structures82. The genetic progression model of pancreatic adenocarcinoma
therefore provides strong support for a ductal origin of this malignancy. This model does
not, however, establish whether the progenitors are a specific cell type that resides
within the ducts. Moreover, the focal expression of non-ductal lineage markers,
including endocrine factors and pancreatic enzymes, indicates that there might be
developmental plasticity of the tumorigenic process (reviewed in Ref. 88). Indeed,
observations from animal-model systems have indicated that there are several routes to
pancreatic adenocarcinoma, indicating that putative pancreatic stem cells and
transdifferentiated endocrine or exocrine cells might be involved.
Parallel observations have been made in rat and hamster carcinogen models83, 89 and in
Trp53-mutant mice that express Tgf- in their acinar cells (Ela-Tgf- )90. In these
models, acinar cells are lost — due to direct damage or apparent TRANSDIFFERENTIATION
— and duct-like tubular complexes emerge and proliferate; these eventually give rise to
pancreatic ductal adenocarcinomas. But different progenitors are thought to give rise to
the tubular complexes — duct cells in the rat model, islet cells or islet-associated stem
cells in the hamster, and de-differentiated acinar cells in Tgf- -transgenic>Trp53mutant mice. A role for islet-associated cells in pancreatic adenocarcinoma is also
indicated by the demonstration that mouse islet-cell cultures that express polyoma virus
middle T oncogene proceed to form pancreatic ductal adenocarcinoma when
transplanted into histocompatible mice91. The complexities in tracing the cell of origin of
pancreatic neoplasia should not be surprising given the close developmental
relationships of the pancreatic cell types and the known propensity of endodermal
lineages to transdifferentiate in vitro and in vivo92(Box 1).
These dynamic cell-lineage relationships fit well with emerging concepts of the plasticity
of differentiation states93. In contrast to previous models that indicate that
differentiation is an irreversible process and that stem cells have a rigidly defined
identity, this revised view proposes that differentiation involves a graded loss of stemcell propensity and that 'stem-cellness' represents a differentiation state rather than a
discrete entity. Implicit in this model is the notion of facultative stem cells —
differentiated cell lineages that have the potential to be stimulated to assume a stemcell role. Based on studies of cell renewal and differentiation, Bonner–Weir94 has argued
persuasively that all or nearly all of the pancreatic-ductal cells are potential facultative
stem cells, with the capacity to differentiate into both endocrine and exocrine lineages.
The adult pancreas is a relatively quiescent organ, with low but measurable levels of cell
division in the acini, ducts and islets95. Increases in proliferation rate can be induced by
certain stimuli, demonstrating the regenerative capacity of this organ. In rats subjected
to partial pancreatectomy, the exocrine and endocrine compartments are regenerated
by both replication of differentiated cells and expansion of multipotent cells from the
pancreatic ducts96, 97. In the latter process (neogenesis), proliferating duct cells give rise
to both endocrine and exocrine structures, recapitulating embryonic development (Fig.
4). Re-entry into the cell cycle is immediately followed by transient induction of Pdx1
expression, a transcription factor that marks multipotent progenitors in the embryonic
pancreas, and loss of expression of differentiated ductal markers. Virtually all the cells of
the ductal epithelium undergo this process of dedifferentiation and expansion, indicating
that the normal, differentiated cells of the ducts have the capacity to transiently become
pluripotent. Comparable processes of pancreatic neogenesis from duct-cell progenitors
are observed in various rodent models of pancreatic damage98-100. Neogenesis from
ductal progenitors might also be relevant to human physiological processes, such as in
new islet formation (nesidioblastosis) that is associated with type I diabetes. Overall,
these observations seem consistent with a general role of the duct cells as facultative
stem cells for pancreatic-cell replacement. Such a proliferating cell with unlimited
replicative potential would be a prime candidate for oncogenic mutation. It is noteworthy
that the paracrine signals that are implicated in the regulation of ductal proliferation in
these models — TGF- /EGF and hepatocyte growth factor (HGF) as initiating factors and
TGF- as an inhibitor — are also engaged during tumorigenesis26, 96, 101.
Figure 4 | Model of relationship of pancreatic regeneration and
tumorigenesis.
a | There is a low rate of cell proliferation in the normal pancreas.
Injury to the organ by various insults results in a prominent
proliferative response. b | This response might involve proliferation of
the duct cells that are associated with disruptions in the basement
membrane (for example, MMP and UPA activity), inflammatory
responses due to cytokine release and reactive oxygen species (ROS)
production, and autocrine/paracrine release of growth factors (for
example, TGF- , HGF and KGF). c | The proliferative response might
result in regeneration of pancreatic tissue and return to quiescence if the stimulus is
attenuated. d | This proliferative arrest is likely to involve INK4A and TGF- /SMAD4
pathways. e | Alternatively, the proliferating ductal cells might incur oncogenic mutations,
such as activated KRAS. f | In the face of this sustained proliferative stimulus, there is
selective pressure for subsequent mutations in growth-inhibitory pathways (such as in
INK4A), leading to PanIN and g) metastatic cancer.
Although it seems that the ducts are a main source for pancreatic neogenesis, each
pancreatic compartment shows the capacity for assuming a dedifferentiated, duct-like
phenotype with multipotent differentiative capacity. Cultured acinar cells undergo
transdifferentiation to ductal cells in the absence of cell division and with associated
reactivation of Pdx1 (Ref. 102). The emerging ductal cells can subsequently
redifferentiate into cells that show features of either exocrine or endocrine lineages that
are consistent with a stem-cell character. Similarly, numerous experiments have shown
the propensity of islet cells for facultative stem-cell behaviour. One prediction of this
developmental plasticity is that tumours that show particular differentiation phenotypes
might not have a unique cell of origin. Experimental studies in mice indicate that this
model might apply to brain tumour pathogenesis, as mutations of Cdkn2a and Egfr in
either neural stem cells or differentiated astrocytes gave rise to malignant gliomas with
indistinguishable tumour phenotypes103. These data indicate that it is the specific genetic
alterations rather than the identity of the target cell that defines the ensuing malignant
phenotype. The highly specific mutational profiles of the different types of pancreatic
cancer indicate that this concept might be relevant to pancreatic neoplasia (Table 1). An
alternative possibility is that the pancreatic-duct cells (in the case of pancreatic
adenocarcinoma) have a particular sensitivity to mutations in these genes. Mouse
models and primary cultures of human pancreatic cells should allow a more direct
experimental analysis of this question.
Tumour–stroma interactions. Heterotypic microenvironmental cellular interactions
seem to be important in the pathogenesis of pancreatic adenocarcinoma. Notably, these
tumours show a marked proliferation of stromal fibroblasts and deposition of
extracellular matrix components such as matrix metalloproteinases and collagens
(desmoplasia)82. The role of this process in cancer pathogenesis remains uncertain, as it
is not well established whether the response is part of the tumorigenic programme or
whether it represents a form of host defence against the tumour. Recent evidence
indicates that the carcinoma cells direct the desmoplastic response and that TGFcontributes to this process104. There are suggestions that SMAD4 loss might be
permissive for these effects, as intestinal tumours in APCMin/+ Smad4+/- mice show moreprominent desmoplastic reactions than those seen in ApcMin/+ Smad4+/+ animals —
notably, Smad4-deficient tumours show increased growth and invasiveness in this
model. Another role for SMAD4 in regulating heterotypic interactions is indicated by
experiments in which Smad4 is reintroduced into some pancreatic adenocarcinoma cell
lines. In these experiments, Smad4 blocks tumorigenic growth in immunodeficient mice
by inhibiting angiogenesis, but does not affect tumour-cell sensitivity to Tgf- 105. These
concepts are consistent with recent studies showing that cancers 'programme' an
oncogenic stroma that, in turn, contributes to tumour growth through paracrine
signalling, angiogenesis and protection from immune attack106, 107.
Mouse models. Mouse models provide tractable genetic systems to dissect the
complexities of evolving cancers in a physiological context (for a review of other animal
models of pancreatic cancer, see Ref. 108). Pancreatic adenocarcinoma is rarely
observed spontaneously or following carcinogen administration in the laboratory mouse,
but genetic engineering has allowed the generation of strains that harbour germline
oncogenic lesions that are found in human pancreatic adenocarcinomas. Early attempts
to model exocrine pancreatic cancer used acinar-specific transgene expression, because
of the availability of promoters that are capable of directing transgene expression to this
compartment. Transgenic mice that express SV40 large T antigen (T Ag)109, 110, activated
HRAS111 or c-Myc112, 113 in the acini using the elastase (Ela) promoter develop acinar-cell
carcinomas, although Ela-Myc tumours progress to mixed acinar-ductal histology.
Transgenic mice expressing TGF- in the acinar cells (Ela-TGF- ) develop acinar-ductal
metaplasia, accompanied by an induction in Egfr expression in the resulting metaplastic
ducts that proliferate due to this autocrine loop. On a Trp53-deficient background, these
metaplastic ducts give rise to pancreatic adenocarcinomas that recapitulate several
features of the human disease, including expression of ductal markers, deletion of the
Cdkn2a locus, and the propensity for invasiveness and metastasis90. Although no Kras
mutations are found in these tumours, the Ela-TGF- mice show constitutive activation
of Ras proteins in their premalignant tubular complexes. The Ela-TGF- mice show
progressive fibrotic lesions of the pancreas and so the relationship of this model to
human pancreatic adenocarcinoma pathogenesis remains unclear. Metallo-thionein-TGF(MT-TGF- ) mice also have acinar TGF- expression and tubular metaplasia, but do
not develop pancreatic adenocarcinoma even in the context of Trp53 and Cdkn2a
deficiency. Instead, these tumour-suppressor mutations cooperate to promote benign
serous cystadenomas (SCA) of the pancreas114. The differences in tumour phenotype of
Ela-TGF- Trp53-/- and MT-TGF- Trp53-/- models could relate to the extinction of
expression of the MT-TGF- transgene in progressive ductal lesions. The absence of a
sustained oncogenic stimulus in the initiated lesions of the MT-TGF- Trp53-/- mice might
then result in a benign, rather than malignant, neoplastic course.
Mouse strains harbouring mutant alleles of the tumour suppressors that are implicated
in pancreatic cancer have been generated; however, pancreatic adenocarcinomas have
not been reported in these animals (Table 2). The rapid onset of sarcomas and
lymphomas in the Trp53-, Ink4a-, Arf- and Ink4a/Arf-mutant mouse strains might
obscure the development of other malignancies. Introduction of the Ink4a-insensitive
mutant Cdk4R24C allele into the mouse germline (knock-in) results in islet-cell
hyperplasia and pancreatic endocrine, but not exocrine, tumours115, 116. A series of
different Brca2-mutant alleles have been generated, resulting predominantly in
embryonic lethality due to defects in DNA repair. In a heterozygous state, these alleles
do not strongly predispose to cancer, and pancreatic adenocarcinomas have not been
reported. The absence of Trp53 is likely to facilitate the cancer susceptibility of Brca2mutant strains by abrogating DNA-damage responses. Finally, heterozygosity of either
Smad4 (Refs 117,118) or Lkb1 (Refs 119–121) results in gastrointestinal polyps. Some
mouse strains with compound mutations of tumour-suppressor genes develop pancreatic
neoplasms of the islets or acini, but adenocarcinoma is not observed 146.
Table 2 | Mouse knockouts of pancreatic adenocarcinoma
tumour suppressors
The phenotypes of these mice do not accord with the susceptibility to pancreatic
adenocarcinoma of humans with inherited mutations in homologous genes. This might
reflect fundamental species-dependent differences in pancreatic tumour-suppression
pathways and/or compensating events during mouse development. As an example of
the 'compensation' phenomenon, Rb-heterozygous mutant mice and Rb-/- chimaeras do
not develop retinoblastoma; however, chimaeras that are derived from Rb-/- p107-/embryonic stem cells are highly prone to these tumours122. Despite these experimental
issues, a large body of evidence indicates that tumour-suppressor gene function can be
modelled in the mouse despite possible alterations in the 'wiring' of signalling
pathways108. The construction of compound-mutant mice and conditional targeting (see
below) should further enhance the use of the mouse in the dissection of key pancreatic
tumour-suppressor mechanisms.
Future directions
Refined mouse models of pancreatic adenocarcinoma. The use of conditional
targeting methods is expected to facilitate the generation of genetically accurate,
pancreatic-cancer-prone mouse strains and allow greater insight into pancreatic cancer
biology (for reviews, see Refs 108,123). Conditional tumour-suppressor alleles, in
conjunction with cell-type-specific expression of CRE RECOMBINASE transgenes, should
circumvent the development of competing malignancies, as well as allow a more-direct
analysis of the cell-of-origin issue. The versatility of such systems can also be expanded
by the generation of mouse strains with tissue-specific expression of the AVIAN
RETROVIRAL RECEPTOR, allowing somatic introduction of oncogenes, or by the use of the
inducible expression systems. A prominent issue in these efforts will be the availability
of suitable promoters to target transgene expression to specific compartments of the
pancreas. Cre recombinase — under the control of the Pdx1 promoter — is effective in
deleting loxp-flanked sequences from the entire pancreatic epithelium, while remaining
inactive in nearly all other tissues124. For targeting of the pancreatic compartments,
highly specific promoters exist for acini (elastase) and -cells >insulin), whereas a
robust pancreatic-duct-specific promoter remains an unmet need in the field.
Inducible mouse cancer models might be well suited to the identification of crucial genes
that regulate tumour maintenance; that is, initiating lesions might or might not be
relevant for sustained tumorigenicity of advanced malignancies that have incurred
numerous subsequent mutations during progression. Studies of transgenic melanoma
and lung adenocarcinoma models directed by inducible HRAS and KRAS alleles,
respectively, have shown that sustained mutant RAS activity is necessary for both the
initiation of tumorigenesis and for maintenance of the transformed state54, 125. In both
systems, extinction of RAS expression results in rapid tumour regression. Expressionprofiling analysis of growing tumours and of those in stages of regression ('RAS-on'
versus 'RAS-off') should give insight into the oncogenic programme that is controlled by
mutant RAS. The application of such concepts to models of pancreatic adenocarcinoma
might allow the elucidation of the molecular basis for oncogenic transformation of the
pancreas and the identification and validation of novel molecular targets for therapy.
The availability of genetically accurate mouse models will afford the opportunity to
evaluate chemotherapeutic agents in a relevant physiological context. The generation of
models with different mutant alleles should uncover the genetics behind
chemotherapeutic responsiveness, as has been done for lymphomas47. Furthermore,
such models will allow the systematic testing of chemopreventive protocols. Recent
studies have indicated that pancreatic adenocarcinomas and PanIN have elevated
expression of cyclooxygenases and lipoxygenases — enzymes that regulate
inflammatory arachidonic-acid signalling126-128. Furthermore, it seems that use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces pancreatic cancer incidence129.
Mouse models of intestinal tumorigenesis have proven useful in demonstrating the
chemopreventive efficacy of NSAIDs and have enabled insight into the mechanistic basis
of these effects (reviewed in Ref. 130).
Gene discovery. Novel genomic and proteomic technologies for global expression
analysis have shown promise in providing a molecular taxonomy of tumours (reviewed
in Ref. 131). Signature profiles have allowed the improved classification of tumour types
and the elucidation of prognostic markers. These methods have recently been used to
study pancreatic adenocarcinoma and have revealed potential new diagnostic markers
and therapeutic targets132-135. As discussed above, the identification of recurrent
chromosomal amplifications and deletions in pancreatic adenocarcinomas indicates that
there are numerous loci involved in the pathogenesis of this malignancy. High-resolution
gene-discovery technologies, coupled with the validation potential of inducible mouse
models, should expand the list of essential targets for more-productive drugdevelopment initiatives.
Another important avenue for pancreatic adenocarcinoma gene discovery might be from
genetic mapping studies of pancreatic-adenocarcinoma-prone kindreds. The genetic
lesions in most of these families have yet to be identified. Segregation analysis of a
large number of kindreds has indicated that susceptibility might be due to autosomaldominant inheritance of a rare allele(s)7. The identification of such an allele would be of
great potential use for the early identification of patients at risk and in understanding
the biology of the disease.
The last decade has seen remarkable progress in fields that are relevant to pancreatic
adenocarcinoma, including cancer genetics, development biology of the pancreas and
genetic engineering in the mouse. There is now unprecedented commitment to
understanding the pathogenesis of pancreatic cancer. The availability of powerful new
technologies and continued contributions of investigators in many related disciplines
provides a measure of optimism towards future progress in treating this disease.
Boxes
Box 1 | Cell differentiation programmes in the pancreas
Despite their distinct morphological and functional
properties, all of the epithelial cells of the endocrine
and exocrine pancreas share a common embryological
origin — the gut endoderm137. The genetic programme
for pancreatic development is characterized by a
hierarchical and combinatorial network of transcription
factors and by the inductive signalling from adjacent
tissues138, 140. The endodermal region that is marked for
pancreatic differentiation is distinguished from adjacent
endoderm by absence of sonic hedgehog (Shh) expression141. The Pdx1 transcription
factor is required for the proliferation and branching of early pancreatic progenitors that
give rise to all pancreatic epithelial cell types, hence the Pdx1-expressing pancreatic
endoderm represents a multipotent pancreatic stem-cell population. Some of the
transcription factors controlling differentiation to endocrine and exocrine lineages are
indicated in the figure.
Many of the transcription factors that regulate pancreatic differentiation also contribute
to the development of other endodermal tissues and/or of separate stages of pancreatic
development142. Moreover, ectopic expression of some of these factors can
reprogramme other endodermal tissues to a pancreatic differentiation phenotype or
alter the differentiation of pancreatic compartments143. This illustrates the importance of
combinatorial activities of a small number of transcription factors in endodermal-cell
specification and reinforces the close interrelation among endodermal cell types. This
conversion of cellular phenotype — metaplasia — also occurs spontaneously during
development and in response to injury, whereby foci of misplaced hepatocytes arise in
the regenerating pancreas92. In addition, transdifferentiation — phenotypic conversion
of differentiated cells — of pancreatic cells in culture is well described. For example,
appropriate culture conditions leads acinar–ductal, islet–ductal and ductal–islet
transdifferentiation of purified cell populations.
Links
DATABASES
Cancer.gov: pancreatic adenocarcinoma
LocusLink: BRCA2 | CDK4 | CDK6 | CDKN2A | EGF | EGFR | ERBB2 | ERBB3 | KRAS |
LKB1 | MDM2 | MLH1 | MSH2 | MSH6 | Pdx1 | PRSS1 | RB | SMAD4 | TGF- | TP53 |
WAF1
OMIM: FAMMM syndrome | hereditary pancreatitis | HNPCC syndrome | Peutz–
Jeghers syndrome
FURTHER INFORMATION
Pancreatic Cancer Agenda for Action
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Niederhuber, J. E., Brennan, M. F. & Menck, H. R. The National Cancer Data Base
report on pancreatic cancer. Cancer 76, 1671-1677 (1995). | PubMed |
Warshaw, A. L. & Fernandez-del Castillo, C. Pancreatic carcinoma. N. Engl. J. Med.
326, 455-465 (1992). | PubMed |
Ahrendt, S. A. & Pitt, H. A. Surgical management of pancreatic cancer. Oncology
16, 725-734; discussion 734, 736-738, 740, 743 (2002).
Kern, S. et al. A white paper: the product of a pancreas cancer think tank. Cancer
Res. 61, 4923-4932 (2001). | PubMed |
Anderson, K. E., Potter, J. D. & Mack, T. M. in Cancer Epidemiology and Prevention
(eds Schottenfeld, D. & Fraumeni, J. J.) 725-771 (Oxford University Press, New
York, 1996).
Lynch, H. T. et al. Familial pancreatic cancer: a review. Semin. Oncol. 23, 251275 (1996). | PubMed |
Jaffee, E. M., Hruban, R. H., Canto, M. & Kern, S. E. Focus on pancreas cancer.
Cancer Cell 2, 25-28 (2002). | Article | PubMed |
Eberle, M. A. et al. A new susceptibility locus for autosomal dominant pancreatic
cancer maps to chromosome 4q32-34. Am. J. Hum. Genet. 70, 1044-1048
(2002).
Linkage mapping of a new familial pancreatic cancer
gene. | Article | PubMed |
Lowenfels, A. B. et al. Hereditary pancreatitis and the risk of pancreatic cancer.
International Hereditary Pancreatitis Study Group. J. Natl Cancer Inst. 89, 442446 (1997). | Article | PubMed |
Whitcomb, D. C. et al. Hereditary pancreatitis is caused by a mutation in the
cationic trypsinogen gene. Nature Genet. 14, 141-145 (1996). | PubMed |
Kinzler, K. W. & Vogelstein, B. Lessons from hereditary colorectal cancer. Cell 87,
159-170 (1996). | PubMed |
Cubilla, A. L. & Fitzgerald, P. J. Morphological lesions associated with human
primary invasive nonendocrine pancreas cancer. Cancer Res. 36, 2690-2698
(1976).
A landmark study providing histological evidence for a ductal cell of origin
for pancreatic adenocarcinoma. | PubMed |
Klimstra, D. S. & Longnecker, D. S. K-ras mutations in pancreatic ductal
proliferative lesions. Am. J. Pathol. 145, 1547-1550 (1994). | PubMed |
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
Hruban, R. H. et al. Pancreatic intraepithelial neoplasia: a new nomenclature and
classification system for pancreatic duct lesions. Am. J. Surg. Pathol. 25, 579-586
(2001). | Article | PubMed |
Klein, W. M., Hruban, R. H., Klein-Szanto, A. J. & Wilentz, R. E. Direct correlation
between proliferative activity and dysplasia in pancreatic intraepithelial neoplasia
(PanIN): additional evidence for a recently proposed model of progression. Mod.
Pathol. 15, 441-447 (2002). | PubMed |
Moskaluk, C. A., Hruban, R. H. & Kern, S. E. p16 and K-ras gene mutations in the
intraductal precursors of human pancreatic adenocarcinoma. Cancer Res. 57,
2140-2143 (1997). | PubMed |
Yamano, M. et al. Genetic progression and divergence in pancreatic carcinoma.
Am. J. Pathol. 156, 2123-2133 (2000). | PubMed |
Luttges, J. et al. Allelic loss is often the first hit in the biallelic inactivation of the
p53 and DPC4 genes during pancreatic carcinogenesis. Am. J. Pathol. 158, 16771683 (2001).
References 16-18 document common mutational profiles in PanINs and
pancreatic adenocarcinomas occurring in the same patient, providing
genetic evidence that PanINs are progenitors of
adenocarcinomas. | PubMed |
Wilentz, R. E. et al. Loss of expression of Dpc4 in pancreatic intraepithelial
neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression.
Cancer Res. 60, 2002-2006 (2000). | PubMed |
Heinmoller, E. et al. Molecular analysis of microdissected tumors and preneoplastic
intraductal lesions in pancreatic carcinoma. Am. J. Pathol. 157, 83-92
(2000). | PubMed |
Rozenblum, E. et al. Tumor-suppressive pathways in pancreatic carcinoma. Cancer
Res. 57, 1731-1734 (1997).
Mutational profile of a large series of pancreatic
adenocarcinomas. | PubMed |
Biankin, A. V. et al. Overexpression of p21(WAF1/CIP1) is an early event in the
development of pancreatic intraepithelial neoplasia. Cancer Res. 61, 8830-8837
(2001). | PubMed |
Shields, J. M., Pruitt, K., McFall, A., Shaub, A. & Der, C. J. Understanding Ras: 'it
ain't over 'til it's over'. Trends Cell Biol. 10, 147-154 (2000). | Article | PubMed |
Korc, M. et al. Overexpression of the epidermal growth factor receptor in human
pancreatic cancer is associated with concomitant increases in the levels of
epidermal growth factor and transforming growth factor alpha. J. Clin. Invest. 90,
1352-1360 (1992). | PubMed |
Barton, C. M., Hall, P. A., Hughes, C. M., Gullick, W. J. & Lemoine, N. R.
Transforming growth factor alpha and epidermal growth factor in human
pancreatic cancer. J. Pathol. 163, 111-116 (1991). | PubMed |
Friess, H. et al. Pancreatic cancer: the potential clinical relevance of alterations in
growth factors and their receptors. J. Mol. Med. 74, 35-42 (1996). | PubMed |
Watanabe, M., Nobuta, A., Tanaka, J. & Asaka, M. An effect of K-ras gene
mutation on epidermal growth factor receptor signal transduction in PANC-1
pancreatic carcinoma cells. Int. J. Cancer 67, 264-268 (1996). | Article | PubMed |
Sibilia, M. et al. The EGF receptor provides an essential survival signal for SOSdependent skin tumor development. Cell 102, 211-220 (2000). | PubMed |
Day, J. D. et al. Immunohistochemical evaluation of HER-2/ neu expression in
pancreatic adenocarcinoma and pancreatic intraepithelial neoplasms. Hum. Pathol.
27, 119-124 (1996). | PubMed |
Wagner, M. et al. Expression of a truncated EGF receptor is associated with
inhibition of pancreatic cancer cell growth and enhanced sensitivity to cisplatinum.
Int. J. Cancer 68, 782-787 (1996). | Article | PubMed |
Overholser, J. P., Prewett, M. C., Hooper, A. T., Waksal, H. W. & Hicklin, D. J.
Epidermal growth factor receptor blockade by antibody IMC-C225 inhibits growth
of a human pancreatic carcinoma xenograft in nude mice. Cancer 89, 74-82
(2000). | Article | PubMed |
Whelan, A. J., Bartsch, D. & Goodfellow, P. J. Brief report: a familial syndrome of
pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor
gene. N. Engl. J. Med. 333, 975-977 (1995). | Article | PubMed |
Goldstein, A. M. et al. Increased risk of pancreatic cancer in melanoma-prone
kindreds with p16INK4 mutations. N. Engl. J. Med. 333, 970-974
(1995). | Article | PubMed |
Goldstein, A. M., Struewing, J. P., Chidambaram, A., Fraser, M. C. & Tucker, M. A.
Genotype-phenotype relationships in U. S. melanoma-prone families with CDKN2A
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
and CDK4 mutations. J. Natl Cancer Inst. 92, 1006-1010
(2000). | Article | PubMed |
Lynch, H. T. et al. Phenotypic variation in eight extended CDKN2A germline
mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone
families: the familial atypical mole melanoma-pancreatic carcinoma syndrome.
Cancer 94, 84-96 (2002). | Article | PubMed |
Borg, A. et al. High frequency of multiple melanomas and breast and pancreas
carcinomas in CDKN2A mutation-positive melanoma families. J. Natl Cancer Inst.
92, 1260-1266 (2000). | Article | PubMed |
Sherr, C. J. The INK4A/ARF network in tumour suppression. Nature Rev. Mol. Cell
Biol. 2, 731-737 (2001). | Article | PubMed |
Liu, L. et al. Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon
and predisposes to melanoma. Nature Genet. 21, 128-132 (1999). | Article
| PubMed |
Lal, G. et al. Patients with both pancreatic adenocarcinoma and melanoma may
harbor germline CDKN2A mutations. Genes Chromosom. Cancer 27, 358-361
(2000). | Article |
Krimpenfort, P., Quon, K. C., Mooi, W. J., Loonstra, A. & Berns, A. Loss of p16Ink4a
confers susceptibility to metastatic melanoma in mice. Nature 413, 83-86
(2001). | Article | PubMed |
Sharpless, N. E. et al. Loss of p16Ink4a with retention of p19Arf predisposes mice to
tumorigenesis. Nature 413, 86-91 (2001).
References 40 and 41 report the phenotypes of Ink4a-knockout
mice. | Article | PubMed |
Zindy, F., Quelle, D. E., Roussel, M. F. & Sherr, C. J. Expression of the p16 INK4a
tumor suppressor versus other INK4 family members during mouse development
and aging. Oncogene 15, 203-211 (1997). | Article | PubMed |
Nielsen, G. P. et al. Immunohistochemical survey of p16INK4A expression in normal
human adult and infant tissues. Lab. Invest. 79, 1137-1143 (1999). | PubMed |
Sherr, C. J. & DePinho, R. A. Cellular senescence: mitotic clock or culture shock?
Cell 102, 407-410 (2000). | PubMed |
Ramirez, R. D. et al. Putative telomere-independent mechanisms of replicative
aging reflect inadequate growth conditions. Genes Dev. 15, 398-403
(2001). | Article | PubMed |
Schmitt, C. A. et al. A senescence program controlled by p53 and p16(INK4a)
contributes to the outcome of cancer therapy. Cell 109, 335-346
(2002). | PubMed |
Zhu, J., Woods, D., McMahon, M. & Bishop, J. M. Senescence of human fibroblasts
induced by oncogenic Raf. Genes Dev. 12, 2997-3007 (1998). | PubMed |
Brookes, S. et al. INK4A-deficient human diploid fibroblasts are resistant to RASinduced senescence. EMBO J. 21, 2936-2945 (2002). | Article | PubMed |
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras
provokes premature cell senescence associated with accumulation of p53 and
p16INK4a. Cell 88, 593-602 (1997).
References 47-49 provide an explanation for the oncogenic cooperation of
activated RAS genes and loss of the INK4A/ARF locus. | Article | PubMed |
Luttges, J. et al. The K-ras mutation pattern in pancreatic ductal adenocarcinoma
usually is identical to that in associated normal, hyperplastic, and metaplastic
ductal epithelium. Cancer 85, 1703-1710 (1999). | Article | PubMed |
Laghi, L. et al. Common occurrence of multiple K-RAS mutations in pancreatic
cancers with associated precursor lesions and in biliary cancers. Oncogene 21,
4301-4306 (2002). | Article | PubMed |
Jackson, E. L. et al. Analysis of lung tumor initiation and progression using
conditional expression of oncogenic K-ras. Genes Dev. 15, 3243-3248
(2001). | Article | PubMed |
Chin, L. et al. Cooperative effects of INK4A and RAS in melanoma susceptibility in
vivo. Genes Dev. 11, 2822-2834 (1997). | PubMed |
Fisher, G. H. et al. Induction and apoptotic regression of lung adenocarcinomas by
regulation of a K-Ras transgene in the presence and absence of tumor suppressor
genes. Genes Dev. 15, 3249-3262 (2001). | Article | PubMed |
Sharpless, N. E. & DePinho, R. A. The INK4A/ARF locus and its two gene products.
Curr. Opin. Genet. Dev. 9, 22-30 (1999). | Article | PubMed |
Maser, R. S. & DePinho, R. A. Connecting chromosomes, crisis, and cancer.
Science 297, 565-569 (2002). | Article | PubMed |
Gorunova, L. et al. Cytogenetic analysis of pancreatic carcinomas: intratumor
heterogeneity and nonrandom pattern of chromosome aberrations. Genes
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
Chromosom. Cancer 23, 81-99 (1998). | Article |
Artandi, S. E. et al. Telomere dysfunction promotes non-reciprocal translocations
and epithelial cancers in mice. Nature 406, 641-645 (2000). | Article | PubMed |
Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and
cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527538 (1999). | PubMed |
Gisselsson, D. et al. Chromosomal breakage-fusion-bridge events cause genetic
intratumor heterogeneity. Proc. Natl Acad. Sci. USA 97, 5357-5362
(2000). | Article | PubMed |
Gisselsson, D. et al. Telomere dysfunction triggers extensive DNA fragmentation
and evolution of complex chromosome abnormalities in human malignant tumors.
Proc. Natl Acad. Sci. USA 98, 12683-12688 (2001).
Evidence for a role of telomere attrition in promoting chromosomal
instability in the progression of pancreatic
adenocarcinoma. | Article | PubMed |
Suehara, N. et al. Telomerase elevation in pancreatic ductal carcinoma compared
to nonmalignant pathological states. Clin. Cancer Res. 3, 993-998
(1997). | PubMed |
Venkitaraman, A. R. Cancer susceptibility and the functions of BRCA1 and BRCA2.
Cell 108, 171-182 (2002). | PubMed |
Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium.
J. Natl Cancer Inst. 91, 1310-1316 (1999). | Article | PubMed |
Goggins, M., Hruban, R. H. & Kern, S. E. BRCA2 is inactivated late in the
development of pancreatic intraepithelial neoplasia: evidence and implications.
Am. J. Pathol. 156, 1767-1771 (2000). | PubMed |
Sato, N. et al. Correlation between centrosome abnormalities and chromosomal
instability in human pancreatic cancer cells. Cancer Genet. Cytogenet. 126, 13-19
(2001). | Article | PubMed |
Aarnio, M., Mecklin, J. P., Aaltonen, L. A., Nystrom-Lahti, M. & Jarvinen, H. J. Lifetime risk of different cancers in hereditary non-polyposis colorectal cancer
(HNPCC) syndrome. Int. J. Cancer 64, 430-433 (1995). | PubMed |
Goggins, M. et al. Pancreatic adenocarcinomas with DNA replication errors (RER+)
are associated with wild-type K-ras and characteristic histopathology. Poor
differentiation, a syncytial growth pattern, and pushing borders suggest RER+.
Am. J. Pathol. 152, 1501-1507 (1998). | PubMed |
Mahlamaki, E. H. et al. Comparative genomic hybridization reveals frequent gains
of 20q, 8q, 11q, 12p, and 17q, and losses of 18q, 9p, and 15q in pancreatic
cancer. Genes Chromosom. Cancer 20, 383-391 (1997). | Article | PubMed |
Peltomaki, P. & de la Chapelle, A. Mutations predisposing to hereditary
nonpolyposis colorectal cancer. Adv. Cancer Res. 71, 93-119 (1997). | PubMed |
Lynch, H. T., Voorhees, G. J., Lanspa, S. J., McGreevy, P. S. & Lynch, J. F.
Pancreatic carcinoma and hereditary nonpolyposis colorectal cancer: a family
study. Br. J. Cancer 52, 271-273 (1985). | PubMed |
Yamamoto, H. et al. Genetic and clinical features of human pancreatic ductal
adenocarcinomas with widespread microsatellite instability. Cancer Res. 61, 31393144 (2001). | PubMed |
Wilentz, R. E. et al. Genetic, immunohistochemical, and clinical features of
medullary carcinoma of the pancreas: a newly described and characterized entity.
Am. J. Pathol. 156, 1641-1651 (2000). | PubMed |
Hahn, S. A. et al. DPC4, a candidate tumor suppressor gene at human
chromosome 18q21.1. Science 271, 350-353 (1996).
Identification of SMAD4/DPC4. | PubMed |
Massague, J., Blain, S. W. & Lo, R. S. TGF- signaling in growth control, cancer,
and heritable disorders. Cell 103, 295-309 (2000). | PubMed |
Sirard, C. et al. Targeted disruption in murine cells reveals variable requirement
for Smad4 in transforming growth factor beta-related signaling. J. Biol. Chem.
275, 2063-2070 (2000). | Article | PubMed |
Jonson, T. et al. Altered expression of TGF- receptors and mitogenic effects of
TGF- in pancreatic carcinomas. Int. J. Oncol. 19, 71-81 (2001). | PubMed |
Dai, J. L. et al. Transforming growth factor-beta responsiveness in DPC4/SMAD4null cancer cells. Mol. Carcinog. 26, 37-43 (1999). | Article | PubMed |
Giehl, K., Seidel, B., Gierschik, P., Adler, G. & Menke, A. TGF- 1 represses
proliferation of pancreatic carcinoma cells which correlates with Smad4independent inhibition of ERK activation. Oncogene 19, 4531-4541
(2000). | Article | PubMed |
Rowland-Goldsmith, M. A., Maruyama, H., Kusama, T., Ralli, S. & Korc, M. Soluble
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
type II transforming growth factor-beta (TGF-beta) receptor inhibits TGF-beta
signaling in COLO-357 pancreatic cancer cells in vitro and attenuates tumor
formation. Clin. Cancer Res. 7, 2931-2940 (2001). | PubMed |
Hemminki, A. et al. A serine/threonine kinase gene defective in Peutz-Jeghers
syndrome. Nature 391, 184-187 (1998). | Article | PubMed |
Solcia, E., Capella, C. & Kloppel, G. Tumors of the Pancreas (ed. Rosai, J.) (Armed
Forces Institute for Pathology, Washington DC, 1995).
Pour, P. M. The role of langerhans islets in pancreatic ductal adenocarcinoma.
Front Biosci. 2, d271-282 (1997). | PubMed |
Boardman, L. A. et al. Genetic heterogeneity in Peutz-Jeghers syndrome. Hum.
Mutat. 16, 23-30 (2000). | Article | PubMed |
Cooper, H. S. in Pathology of the Gastrointestinal Tract (eds Ming, S.-C. &
Goldman, H.) 819-853 (Wiliams & Wilkens, Baltimore, 1998).
Olschwang, S. et al. Peutz-Jeghers disease: most, but not all, families are
compatible with linkage to 19p13.3. J. Med. Genet. 35, 42-44 (1998). | PubMed |
Olschwang, S., Boisson, C. & Thomas, G. Peutz-Jeghers families unlinked to
STK11/LKB1 gene mutations are highly predisposed to primitive biliary
adenocarcinoma. J. Med. Genet. 38, 356-360 (2001). | Article | PubMed |
Klimstra, D. S. in Pancreatic Cancer: Advances in Molecular Pathology, Diagnosis
and Clinical Management (eds Sarkar, F. S. & Duggan, M. C.) 21-48 (Eaton
Publishing, Natick, Massachusetts, 1998).
Jimenez, R. E. et al. Immunohistochemical characterization of pancreatic tumors
induced by dimethylbenzanthracene in rats. Am. J. Pathol. 154, 1223-1229
(1999). | PubMed |
Wagner, M. et al. A murine tumor progression model for pancreatic cancer
recapitulating the genetic alterations of the human disease. Genes Dev. 15, 286293 (2001).
The first description of a genetically defined mouse model of pancreatic
adenocarcinoma. | Article | PubMed |
Yoshida, T. & Hanahan, D. Murine pancreatic ductal adenocarcinoma produced by
in vitro transduction of polyoma middle T oncogene into the islets of Langerhans.
Am. J. Pathol. 145, 671-684 (1994). | PubMed |
Tosh, D. & Slack, J. M. How cells change their phenotype. Nature Rev. Mol. Cell
Biol. 3, 187-194 (2002). | Article | PubMed |
Blau, H. M., Brazelton, T. R. & Weimann, J. M. The evolving concept of a stem cell:
entity or function? Cell 105, 829-841 (2001). | Article | PubMed |
Bonner-Weir, S. & Sharma, A. Pancreatic stem cells. J. Pathol. 197, 519-526
(2002). | Article | PubMed |
Elsasser, H.-P., Adler, G. & Kern, H. F. in The Pancreas: Biology, Pathobiology and
Disease (Raven Press Ltd, New York, 1993).
Bonner-Weir, S., Stubbs, M., Reitz, P., Taneja, M. & Smith, F. E. in Pancreatic
Growth and Regeneration (ed. Sarvetnick, N.) (Karger Landes Systems, Basel,
Switzerland, 1997).
Sharma, A. et al. The homeodomain protein IDX-1 increases after an early burst
of proliferation during pancreatic regeneration. Diabetes 48, 507-513
(1999). | PubMed |
Vinik, A. I., Pittenger, G. L., Rafaeloff, R., Rosenberg, L. & Duguid, W. in
Pancreatic Growth and Regeneration. (ed. Sarvetnick, N.) 183-217 (Karger Landes
Systems, Basel, 1997).
Scoggins, C. R. et al. p53-dependent acinar cell apoptosis triggers epithelial
proliferation in duct-ligated murine pancreas. Am. J. Physiol. Gastrointest. Liver
Physiol. 279, G827-G836 (2000). | PubMed |
Kritzik, M. R. et al. PDX-1 and Msx-2 expression in the regenerating and
developing pancreas. J. Endocrinol. 163, 523-530 (1999). | PubMed |
Arnush, M. et al. Growth factors in the regenerating pancreas of -interferon
transgenic mice.>Lab. Invest. 74, 985-990 (1996). | PubMed |
Rooman, I., Heremans, Y., Heimberg, H. & Bouwens, L. Modulation of rat
pancreatic acinoductal transdifferentiation and expression of PDX-1 in vitro.
Diabetologia 43, 907-914 (2000). | Article | PubMed |
Bachoo, R. M. et al. Epidermal growth factor receptor and Ink4a/Arf. Convergent
mechanisms governing terminal differentiation and transformation along the
neural stem cell to astrocyte axis. Cancer Cell 1, 269-277
(2002). | Article | PubMed |
Lohr, M. et al. Transforming growth factor- 1 induces desmoplasia in an
experimental model of human pancreatic carcinoma. Cancer Res. 61, 550-555
(2001). | PubMed |
105. Schwarte-Waldhoff, I. et al. Smad4/DPC4-mediated tumor suppression through
suppression of angiogenesis. Proc. Natl Acad. Sci. USA 97, 9624-9629
(2000). | Article | PubMed |
106. Bissell, M. J. & Radisky, D. Putting tumours in context. Nature Rev. Cancer 1, 4654 (2001). | Article | PubMed |
107. Olumi, A. F. et al. Carcinoma-associated fibroblasts direct tumor progression of
initiated human prostatic epithelium. Cancer Res. 59, 5002-5011
(1999). | PubMed |
108. Van Dyke, T. & Jacks, T. Cancer modeling in the modern era: progress and
challenges. Cell 108, 135-144 (2002). | PubMed |
109. Ornitz, D. M., Hammer, R. E., Messing, A., Palmiter, R. D. & Brinster, R. L.
Pancreatic neoplasia induced by SV40 T-antigen expression in acinar cells of
transgenic mice. Science 238, 188-193 (1987). | PubMed |
110. Glasner, S., Memoli, V. & Longnecker, D. S. Characterization of the ELSV
transgenic mouse model of pancreatic carcinoma. Histologic type of large and
small tumors. Am. J. Pathol. 140, 1237-1245 (1992). | PubMed |
111. Quaife, C. J., Pinkert, C. A., Ornitz, D. M., Palmiter, R. D. & Brinster, R. L.
Pancreatic neoplasia induced by Ras expression in acinar cells of transgenic mice.
Cell 48, 1023-1034 (1987). | PubMed |
112. Sandgren, E. P., Quaife, C. J., Paulovich, A. G., Palmiter, R. D. & Brinster, R. L.
Pancreatic tumor pathogenesis reflects the causative genetic lesion. Proc Natl Acad
Sci USA 88, 93-97 (1991).
113. Sandgren, E. P. et al. Transforming growth factor alpha dramatically enhances
oncogene-induced carcinogenesis in transgenic mouse pancreas and liver. Mol.
Cell Biol. 13, 320-330 (1993). | PubMed |
114. Bardeesy, N. et al. Obligate roles for p16(Ink4a) and p19(Arf)-p53 in the
suppression of murine pancreatic neoplasia. Mol. Cell Biol. 22, 635-643
(2002). | Article | PubMed |
115. Sotillo, R. et al. Wide spectrum of tumors in knock-in mice carrying a Cdk4 protein
insensitive to INK4 inhibitors. EMBO J. 20, 6637-6647 (2001). | Article | PubMed |
116. Rane, S. G. et al. Loss of Cdk4 expression causes insulin-deficient diabetes and
Cdk4 activation results in -islet cell hyperplasia.>Nature Genet. 22, 44-52
(1999). | Article | PubMed |
117. Xu, X. et al. Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric
polyposis and cancer in mice. Oncogene 19, 1868-1874 (2000). | Article
| PubMed |
118. Takaku, K. et al. Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice.
Cancer Res. 59, 6113-6117 (1999). | PubMed |
119. Jishage, K. et al. Role of Lkb1, the causative gene of Peutz-Jegher's syndrome, in
embryogenesis and polyposis. Proc. Natl Acad. Sci. USA 99, 8903-8908
(2002). | PubMed |
120. Miyoshi, H. et al. Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous
knockout mice. Cancer Res. 62, 2261-2266 (2002). | PubMed |
121. Bardeesy, N. et al. Loss of the Lkb1 tumour suppressor provokes intestinal
polyposis but resistance to transformation. Nature 419, 162-167 (2002). | Article
| PubMed |
122. Robanus-Maandag, E. et al. p107 is a suppressor of retinoblastoma development
in pRb-deficient mice. Genes Dev. 12, 1599-1609 (1998). | PubMed |
123. Jonkers, J. & Berns, A. Conditional mouse models of sporadic cancer. Nature Rev.
Cancer 2, 251-265 (2002). | Article | PubMed |
124. Gu, G., Dubauskaite, J. & Melton, D. A. Direct evidence for the pancreatic lineage:
NGN3+ cells are islet progenitors and are distinct from duct progenitors.
Development 129, 2447-2457 (2002). | PubMed |
125. Chin, L. et al. Essential role for oncogenic Ras in tumour maintenance. Nature
400, 468-472 (1999). | Article | PubMed |
126. Hennig, R. et al. 5-lipoxygenase and leukotriene b(4) receptor are expressed in
human pancreatic cancers but not in pancreatic ducts in normal tissue. Am. J.
Pathol. 161, 421-428 (2002). | PubMed |
127. Maitra, A. et al. Cyclooxygenase 2 expression in pancreatic adenocarcinoma and
pancreatic intraepithelial neoplasia: an immunohistochemical analysis with
automated cellular imaging. Am. J. Clin. Pathol. 118, 194-201 (2002). | PubMed |
128. Tucker, O. N. et al. Cyclooxygenase-2 expression is up-regulated in human
pancreatic cancer. Cancer Res. 59, 987-990 (1999). | PubMed |
129. Anderson, K. E., Johnson, T. W., Lazovich, D. & Folsom, A. R. Association between
nonsteroidal anti-inflammatory drug use and the incidence of pancreatic cancer. J.
Natl Cancer Inst. 94, 1168-1171 (2002). | Article | PubMed |
130. Oshima, M. & Taketo, M. M. COX selectivity and animal models for colon cancer.
Curr. Pharm. Des. 8, 1021-1034 (2002). | PubMed |
131. Ramaswamy, S. & Golub, T. R. DNA microarrays in clinical oncology. J. Clin. Oncol.
20, 1932-1941 (2002). | PubMed |
132. Argani, P. et al. Discovery of new markers of cancer through serial analysis of
gene expression: prostate stem cell antigen is overexpressed in pancreatic
adenocarcinoma. Cancer Res. 61, 4320-4324 (2001). | PubMed |
133. Iacobuzio-Donahue, C. A. et al. Discovery of novel tumor markers of pancreatic
cancer using global gene expression technology. Am. J. Pathol. 160, 1239-1249
(2002). | PubMed |
134. Rosty, C. et al. Identification of hepatocarcinoma-intestine-pancreas/pancreatitisassociated protein I as a biomarker for pancreatic ductal adenocarcinoma by
protein biochip technology. Cancer Res. 62, 1868-1875 (2002). | PubMed |
135. Han, H. et al. Identification of differentially expressed genes in pancreatic cancer
cells using cDNA microarray. Cancer Res. 62, 2890-2896 (2002). | PubMed |
136. Githens, S. in The Pancreas: Biology, Pathobiology and Disease (eds Liang, V. &
Go, W.) 21-55 (Raven Press Ltd, New York, 1993).
137. Slack, J. M. Developmental biology of the pancreas. Development 121, 1569-1580
(1995). | PubMed |
138. Kim, S. K. & Hebrok, M. Intercellular signals regulating pancreas development and
function. Genes Dev. 15, 111-127 (2001). | Article | PubMed |
139. Kobitsu, K. et al. Shortened telomere length and increased telomerase activity in
hamster pancreatic duct adenocarcinomas and cell lines. Mol. Carcinog. 18, 153159 (1997). | Article | PubMed |
140. Edlund, H. Organogenesis: pancreatic organogenesis developmental mechanisms
and implications for therapy. Nature Rev. Genet. 3, 524-532 (2002). | Article
| PubMed |
141. Hebrok, M., Kim, S. K. & Melton, D. A. Notochord repression of endodermal Sonic
hedgehog permits pancreas development. Genes Dev. 12, 1705-1713
(1998). | PubMed |
142. Wells, J. M. & Melton, D. A. Vertebrate endoderm development. Annu. Rev. Cell
Dev. Biol. 15, 393-410 (1999). | Article | PubMed |
143. Shen, C. N., Slack, J. M. & Tosh, D. Molecular basis of transdifferentiation of
pancreas to liver. Nature Cell Biol. 2, 879-887 (2000). | Article | PubMed |
144. Harada, T. et al. Interglandular cytogenetic heterogeneity detected by
comparative genomic hybridization in pancreatic cancer. Cancer Res 62, 835-839
(2002). | PubMed |
145. Giardiello, F. M. et al. Very high risk of cancer in familial Peutz-Jeghers syndrome.
Gastroenterology 119, 1447-1453 (2000). | PubMed |
146. Clarke, A. R., Cummings, M. C. & Harrison, D. J. Interaction between murine
germline mutations in p53 and APC predisposes to pancreatic neoplasia but not to
increased intestinal malignancy. Oncogene 11, 1913-1920 (1995). | PubMed |
147. Meszoely, I. M., Means, A. L., Scoggins, C. R. & Leach, S. D. Developmental
aspects of early pancreatic cancer. Cancer J. 7, 242-250 (2001). | PubMed |
Figure 1 | Anatomy of the pancreas. The pancreas is comprised of separate functional units that regulate
two major physiological processes: digestion and glucose metabolism136. The exocrine pancreas consists of
acinar and duct cells. The acinar cells produce digestive enzymes and constitute the bulk of the pancreatic
tissue. They are organized into grape-like clusters that are at the smallest termini of the branching duct
system. The ducts, which add mucous and bicarbonate to the enzyme mixture, form a network of increasing
size, culminating in main and accessory pancreatic ducts that empty into the duodenum. The endocrine
pancreas, consisting of four specialized cell types that are organized into compact islets embedded within
acinar tissue, secretes hormones into the bloodstream. The - and> -cells regulate the usage of glucose
through the production of glucagon and insulin, respectively. Pancreatic polypeptide and somatostatin that
are produced in the PP and> -cells modulate the secretory properties of the other pancreatic cell types.>a |
Gross anatomy of the pancreas. b | The exocrine pancreas. c | A single acinus. d | A pancreatic islet
embedded in exocrine tissue.
Figure 2 | Genetic progression model of pancreatic adenocarcinoma. Pancreatic intraepithelial
neoplasias (PanINs) seem to represent progressive stages of neoplastic growth that are precursors to
pancreatic adenocarcinomas. The genetic alterations documented in adenocarcinomas also occur in PanIN in
what seems to be a temporal sequence, although these alterations have not been correlated with the
acquisition of specific histopathological features. The stage of onset of these lesions is depicted. The
thickness of the line corresponds to the frequency of a lesion. The temporal alterations in telomerase activity
and telomere length are by inference from Refs 62,139 and need further substantiation in PanIN. Normal
duct, PanIN-1A/PanIN-1B and PanIN-3 images reproduced with permission from ref. 14 (2001) Lippincott
Williams & Wilkins; PanIN-2 and adenocarcinoma images kindly provided by Dr Ralph Hruban, Johns Hopkins
University (http://pathology.jhu.adu/pancreas/panin/).
Figure 3 | Telomere attrition and genomic instability. Most human somatic cells lack telomerase
activity, hence telomeres are eroded as cells proliferate. If the proliferative stimulus is maintained, such as
in cells that have sustained oncogenic mutations, progressive telomere shortening activates DNA-damage
responses, resulting in growth arrest. Loss of these checkpoint responses, such as by mutation of TP53,
allows cells to continue proliferating, leading to telomere dysfunction and genomic instability (crisis).
Chromosome breakage–fusion cycles produce severe aneuploidy and chromosomal translocations that
contribute to tumour progression. Telomerase reactivation subsequently stabilizes the genome and facilitates
the immortal growth of the tumour cells. Independent processes also lead to genomic instability —
centrosome defects result in a disorganized mitotic spindle, which leads to aneuploidy or chromosome
breakage; BRCA2 mutations produce genomic instability by disabling the homologous recombination-based
DNA-repair pathway.
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Figure 4 | Model of relationship of pancreatic regeneration and tumorigenesis. a | There is a low
rate of cell proliferation in the normal pancreas. Injury to the organ by various insults results in a prominent
proliferative response. b | This response might involve proliferation of the duct cells that are associated with
disruptions in the basement membrane (for example, MMP and UPA activity), inflammatory responses due to
cytokine release and reactive oxygen species (ROS) production, and autocrine/paracrine release of growth
factors (for example, TGF- , HGF and KGF). c | The proliferative response might result in regeneration of
pancreatic tissue and return to quiescence if the stimulus is attenuated. d | This proliferative arrest is likely
to involve INK4A and TGF- /SMAD4 pathways. e | Alternatively, the proliferating ductal cells might incur
oncogenic mutations, such as activated KRAS. f | In the face of this sustained proliferative stimulus, there is
selective pressure for subsequent mutations in growth-inhibitory pathways (such as in INK4A), leading to
PanIN and g) metastatic cancer.
Table 1 | Types of pancreatic neoplasms
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