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Principles of Neoplasia And Growth
Disorders
Dr: Wael H Mansy, MD
Assistant Professor
Clinical Pharmacy Department-College of Pharmacy
King Saud University
Study objectives
• List the main characteristics of benign and malignant
tumors.
• Describe the nomenclature used for various types of
tumors.
• Discuss tumor metastasis. How do tumors facilitate
their own spread? What are some common sites of
metastasis for tumors?
• Define oncogenesis. Discuss some of the theories of
how it might occur. List some viruses that are
oncogenic, as well as the cancers they may cause.
• What is a carcinogen? List some substances that are
carcinogenic.
• List the local and systemic effects of cancer.
• Define cancer cachexia. Why might it occur?
• Describe the system by which tumors are “staged.”
• What are tumor cell markers? How are they used
clinically?
• Discuss the various treatment options for cancer.
Include the draw-backs of each.
The term neoplasm refers to an abnormal mass of tissue
in which the growth exceeds and is uncoordinated with that
of the normal tissues.
Unlike normal cellular adaptive processes such as
hypertrophy and hyperplasia, neoplasms do not obey the
laws of normal cell growth.
They serve no useful purpose, they do not occur in
response to an appropriate stimulus and they continue to
grow at the expense of the host.
Cell Cycle
The process of cell growth and division is called the
cell cycle.
It is divided into four phases:
1-G1, the postmitotic phase, during which DNA synthesis
ceases while RNA and protein synthesis and cell growth
take place;
2-S the phase during which DNA synthesis occurs, giving
rise to two separate sets of chromosomes;
3-G2 phase: the premitotic phase, during which RNA
and protein synthesis continues;
4-M: the phase of cell mitosis or cell division.
5-G0 phase: is a resting or quiescent phase in which
nondividing cells reside.
The entry into and progression through the various
stages of the cell cycle are controlled by cyclins,
cyclin-dependent kinases, and cyclin-dependent
kinase inhibitors
oNormal tissue renewal and repair involves cell
proliferation, differentiation and apoptosis.
oProliferation, or the process of cell division, is an
inherent adaptive mechanism for cell replacement when
old cells die or additional cells are needed.
oDifferentiation is the process of specialization whereby
new cells acquire the structure and function of the cells
they replace.
oApoptosis is a form of programmed cell death that
eliminates senescent cells, cells with damaged DNA, or
unwanted cells.
Body cells can be divided into two large groups: the
well differentiated neurons and cells of skeletal and
cardiac muscle that rarely divide and reproduce.
The progenitor or parent cells that continue to divide
and reproduce, such as blood cells, skin cells, and liver
cells.
A third category of cells are the stem cells that
remain quiescent until there is a need for cell
replenishment, in which case they divide, producing
other stem cells and cells that can carry out the
functions of differentiated cells.
Stem cells have two important properties, those of selfrenewal and potency.
Self-renewal means that the stem cells can undergo
numerous mitotic divisions while maintaining an
undifferentiated state.
The term potency is used to define the differentiation
potential of stem cells.
A neoplasm, benign or malignant, represents a new
growth.
■ Benign neoplasms are well-differentiated tumors
that resemble the tissues of origin but have lost the
ability to control cell proliferation. They grow by
expansion, are enclosed in a fibrous capsule, and do
not cause death unless their location is such that it
interrupts vital body functions.
■ Malignant neoplasms are less welldifferentiated tumors that have lost the ability
to control both cell proliferation and
differentiation.
They grow in a disorganized and
uncontrolled manner to invade surrounding
tissues, have cells that break loose and travel
to distant sites to form metastases, and
inevitably cause suffering and death unless
their growth can be controlled through
treatment.
Cancer Cell Characteristics
Cancer cells are characterized by two main
features: (1) abnormal and rapid proliferation; and
(2) loss of differentiation so that they do not
exhibit normal features and properties of
differentiated cells, and hence are more similar to
embryonic cells.
ANAPLASIA
Means loss of cell differentiation in cancerous tissue.
In undifferentiated cancer cells both the cells and nuclei
display variations in size and shape, a condition referred to as
pleomorphism.
Their nuclei are variable in size and bizarre in shape, their
chromatin is coarse and clumped, and their nucleoli are often
considerably larger than normal.
Some cancers display only slight anaplasia, whereas
others display marked anaplasia.
The cytologic/histologic grading of tumors is based
on the degree of differentiation and the number of
proliferating cells.
The closer the tumor cells resemble comparable
normal tissue cells, both morphologically and
functionally, the lower the grade.
Accordingly, on a scale ranging from grades I to IV,
grade I neoplasms are well differentiated and grade IV
are poorly differentiated and display marked
anaplasia.
Cancer Cell Characteristics
1-Genetic Instability.
• Most cancer cells exhibit a characteristic called
genetic instability that is often considered to be a
hallmark of cancer.
• It is thought that cancer cells have a “mutation
phenotype” with genetic instability that
contributes to the development and progression of
cancer.
Characteristics of genetic instability include
aneuploidy, in which chromosomes are lost or
gained; intrachromosomal instability, which
includes insertions, deletions, and amplifications;
microsatellite instability, which involves short,
repetitive sequences of DNA; and point mutations.
2-Growth Factor Independence
• *The ability to proliferate even in the absence of growth
factors. This characteristic is often observed when cancer cells
are propagated in cell culture.
• *The addition of serum, which is rich in growth factors, is
unnecessary for the cancers to proliferate.
• *Breast cancer cells that do not express estrogen receptors are
an example. These cancer cells grow even in the absence of
estrogen, Some cancer cells may produce their own growth
factors and secrete them into the culture medium, whereas
others have abnormal receptors or signaling proteins
• Q: Give at least 3 examples of Cancer Growth Factors?
3- Cell Density–Dependent
Inhibition
• Cancer cells often lose cell density–dependent inhibition.
• cells often stop growing when they come into contact with
each other e.g wound healing
• Cancer cells, however, tend to grow rampantly without
regard for adjacent tissue.
• Possible explanations of this include growth factor
independence, oxidative mechanisms, and alterations in
interactions between cell adhesion and cell growth
signaling pathways (e.g., surface integrin receptors,
mitogen-activated protein [MAP] kinase, and focal
adhesion kinase [FAK] phosphorylation)
4- Cell Cohesiveness and Adhesion
 The reduced tendency of cancer cells to stick together.
 These cells appear in the surrounding body fluids or
secretions and often can be detected using cytologic methods.
 cadherins are adhesion molecules that link one cell with
adjacent cell.
 In some cancers, E-cadherin appears to play an important role
in the lack of cohesiveness of cancer cells and the increased
tendency for cancer cells to break free and migrate into the
surrounding tissues.
5- Anchorage Dependence.
• Cancer cells also differ from their normal counterparts in
attaining anchorage independence.
• Normal epithelial cells must be anchored to either
neighboring cells or the underlying extracellular matrix to
live and grow. If these cells become detached, they often
undergo a type of apoptosis known as anoikis.
• Cancer cells, however, frequently remain viable and
multiply without normal attachments to other cells and the
extracellular matrix.
6- Cell-to-Cell Communication
• Impaired cell-to-cell communication may interfere
with formation of intercellular connections and
responsiveness to membrane derived signals.
• For example, changes in gap junction proteins
which enable cytoplasmic continuity and
communication between cells, have been
described in some types of cancer.
7- Life Span.
• Cancer cells differ from normal cells by being immortal,
with an unlimited life span.
• cancer cells may divide an infinite number of times, hence
achieving immortality.
• Most cancer cells maintain high levels of telomerase, an
enzyme that prevents telomere shortening.
• Telomeres are short, repetitive nucleotide sequences at
outermost extremities of chromosome arms
• Telomeres shorten with each cell division. When length is
diminished sufficiently, chromosomes can no longer
replicate, and cell division will not occur.
8- Antigen Expression
• Cancer cells also express a number of cell surface
molecules or antigens that are immunologically identified
as foreign.
• Many transformed cancer cells revert to embryonic
patterns of gene expression and produce antigens that are
immunologically distinct from the antigens that are
expressed by cells of the well-differentiated tissue from
which the cancer originated.
• Tumor antigens may be clinically useful as markers to
indicate the presence, recurrence, or progressive growth of
a cancer.
9- Production of Enzymes,
Hormones, and Other Substances.
• Cancer cells may produce substances that
normal cells of the tissue of origin either do
not produce or secrete in lesser amounts.
• Cancer cells may also assume hormone
synthesis or production and secretion of
procoagulant substances that affect clotting
mechanisms.
10- Cytoskeletal Changes.
• Finally, cancer cells may show cytoskeletal
changes and abnormalities.
• These may involve the appearance of
abnormal intermediate filament types or
changes in actin filaments and microtubules
that facilitate invasion and metastasis.
Invasion and metastasis
Pathophysiology
Invasion and metastasis
• Unlike benign tumors, which grow by expansion and usually
are surrounded by a capsule, cancer spreads by direct
invasion and extension, seeding of cancer cells in body
cavities, and metastatic spread through the blood or lymph
pathways.
• Most cancers synthesize and secrete enzymes that break
down proteins and contribute to the infiltration, invasion, and
penetration of the surrounding tissues.
• The lack of a sharp line of demarcation separating
them from the surrounding tissue makes the
complete surgical removal of malignant tumors
more difficult than removal of benign tumors.
• Often it’s necessary for the surgeon to excise some
of the normal tissues surrounding the cancerous
tumor to make sure that the remaining tissues will
be cancer free.
• The seeding of cancer cells into body cavities occurs when a tumor
sheds cells into these spaces. Most often, the peritoneal cavity is
involved, but other spaces such as the pleural cavity, pericardial cavity,
and joint spaces may be involved.
• Similar to tissue culture, tumors in these sites grow in masses and are
often associated with fluid accumulation (e.g. ascites, pleural effusion).
•
The seeding of cancers is often a concern during the surgical removal
of cancers where it is possible inadvertently to introduce free cancer
cells into a body cavity such as the peritoneal cavity
• The term metastasis is used to describe the development of a
secondary tumor in a location distant from the primary tumor.
• Because metastatic tumors frequently retain many of the
characteristics of the primary tumor from which they were
derived, it’s usually possible to determine the site of the primary
tumor from the cellular characteristics of the metastatic tumor.
• Some tumors tend to metastasize early in their developmental
course, whereas others do not metastasize until later.
• Occasionally, a metastatic tumor will be found far advanced
before the primary tumor becomes clinically detectable e.g
Hypernephroma (malignant tumors of the kidney)
• To metastasize, a cancer cell must be able to break loose
from the primary tumor, invade the surrounding
extracellular matrix, gain access to a blood vessel, survive
its passage in the bloodstream, emerge from the
bloodstream at a favorable location, invade the
surrounding tissue, begin to grow, and establish a blood
supply.
• Metastasis occurs through the lymph channels (i.e.,
lymphatic spread) and the blood vessels (i.e., hematogenic
spread).
Lymphatic Spread
•
In many types of cancer, the first evidence of disseminated
disease is the presence of tumor cells in the lymph nodes
that drain the tumor area.
• When metastasis occurs by the lymphatic route, the tumor
cells lodge first in the initial lymph node that receives
drainage from the tumor site.
• The cancer cells may spread from more distant lymph
nodes to the thoracic duct, and then gain access to the
vasculature.
•
Cancer cells also may gain access to the vasculature from
the initial node and more distant lymph nodes through
tumor-associated blood vessels infiltrating the tumor mass.
• The term sentinel node is used to describe the initial
lymph node to which the primary tumor drains.
•
lymphatic spread and therefore extent of disease may be
determined through lymphatic mapping and sentinel lymph
node biopsy.
• Once the sentinel lymph node has been identified, it is
examined to determine the presence or absence of cancer
cells.
Hematologic Spread
• The blood-borne cancer cells may enter the venous flow
that drains the site of the primary neoplasm.
• Cancer cells may also enter tumor-associated blood
vessels that either infiltrate the tumor or are found at the
periphery of the tumor.
• Before entering the general circulation, venous blood
from the gastrointestinal tract, pancreas, and spleen is
routed through the portal vein to the liver. The liver is
therefore a common site for metastatic spread of cancers
that originate in these organs.
• Although the site of hematologic spread usually is related
to vascular drainage of the primary tumor, some tumors
metastasize to distant and unrelated sites.
• One explanation is that cells of different tumors tend to
metastasize to specific target organs that provide suitable
microenvironments containing substances such as
cytokines or growth factors that are needed for their
survival e.g. transferrin, a growth-promoting substance
isolated from lung tissue, has been found to stimulate the
growth of malignant cells that typically metastasize to the
lungs.
• Considerable evidence suggests that cancer cells capable of
metastasis secrete enzymes that break down the
surrounding extracellular matrix, allowing them to move
through the degraded matrix and gain access to a blood
vessel.
• Once in the circulation, the tumor cells are vulnerable to
destruction by host immune cells. Some tumor cells gain
protection from the antitumor host cells by aggregating and
adhering to circulating blood components, particularly
platelets, to form tumor emboli.
• Tumor cells that survive their travel in the circulation must
be able to halt their passage by adhering to the vessel wall.
Tumor cells express various cell surface attachment factors
such as laminin receptors that facilitate their anchoring to
laminin in the basement membrane.
• After attachment, the tumor cells secrete proteolytic
enzymes such as type IV collagenase that degrade the
basement membrane and facilitate the migration of the
tumor cells through the capillary membrane into the
interstitial area, where they subsequently establish growth
of a secondary tumor.
• Once in the distant tissue site, the process of metastatic tumor
development depends on the establishment of blood vessels and
specific growth factors that promote proliferation of the tumor cells.
Tumor cells as well as other cells in the microenvironment secrete
factors that enable the development of new blood vessels within the
tumor, a process termed angiogenesis.
Q: Enumerate at least 2 angiogenic factors?
• The presence of stimulatory or inhibitor growth factors correlates with
the site-specific pattern of metastasis. For example, a potent growthstimulating factor has been isolated from lung tissue, and stromal cells
in bone have been shown to produce a factor that stimulates growth of
prostatic cancer cells.
Tumor growth
• Once cells have an adequate blood supply, the rate of tissue growth
in normal and cancerous tissue depends on three factors:
1) The number of cells that are dividing through the cell cycle.
2) The duration of the cell cycle.
3) The number of cells that are being lost relative to the number of
new cells being produced.
• One of the reasons cancerous tumors often seem to grow so rapidly
relates to the size of the cell pool that is actively engaged in
cycling.
• cancer cells do not die on schedule and growth factors prevent cells
from exiting the cycle cell and entering the G0 phase. Thus, a
greater percentage of cells are actively engaged in cycling than
occurs in normal tissue.
Tumor growth
• The ratio of dividing cells to resting cells in a tissue mass is called
the growth fraction. The doubling time is the length of time it
takes for the total mass of cells in a tumor to double. As the
growth fraction increases, the doubling time decreases.
• When normal tissues reach their adult size, equilibrium between
cell birth and cell death is reached. Cancer cells, however,
continue to divide until limitations in blood supply and nutrients
inhibit their growth. When this happens, the doubling time for
cancer cells decreases.
• a tumor usually is undetectable until it has doubled 30 times and
contains more than 1 billion cells. At this point, it is
approximately 1 cm. After 35 doublings, the mass contains more
than 1 trillion cells, which is a sufficient number to kill the host.
Etiology of Cancer
• The causes of cancers are very diverse and complex. It is
useful to discuss causation in terms of
(1)The genetic and molecular: mechanisms that are involved
and that characterize the transformation of normal cells to
cancer cells.
(2) The external and more contextual factors such as age,
heredity, and environmental agents that contribute to the
development and progression of cancer. Together, both
mechanisms contribute to a multidimensional web of
causation by which cancers develop and progress over
time.
Genetic and Molecular Basis of
Cancer
Genetic and Molecular Basis of
Cancer
The molecular pathogenesis of most cancers is
thought to originate with genetic damage or
mutation with resultant changes in cell physiology
that transform a normally functioning cell into a
cancer cell
Cancer-Associated Genes
• Most cancer-associated genes can be
classified into two broad categories based
on both increases the risk for cancer
• 1) gene over-activity
• 2) gene under-activity
Cancer-Associated Genes
• The category associated with gene over-activity is
proto-oncogenes (which are normal genes that
become cancer-causing oncogenes if mutated )
Proto-oncogenes encode for normal cell proteins
such as growth factors, growth factor receptors and
transcription factors
• The category associated with gene under-activity
comprises the tumor suppressor genes .
Cancer-Associated Genes
• Tumor suppressor genes include
1) retinoblastoma (RB) gene (which normally prevents cell
division ): Loss of RB activity may accelerate the cell
cycle and lead to increased cell proliferation.
2) the TP53 gene (which normally becomes activated in
DNA-damaged cells to initiate apoptosis ) : inactivity of
TP53 may increase the survival of DNA-damaged cells.
Genetic Events Leading to
Oncogene Formation or Activation
I-Point mutation : a common event is a in which there
is a single nucleotide base change due to an insertion,
deletion, or substitution.
 An example of an oncogene caused by point mutations is
the ras oncogene, which has been found in many cancers
• Members of the ras proto-oncogene family are important
signal-relaying proteins that transmit growth signals to
the nucleus, so activation of the ras oncogene can
increase cell proliferation.
Genetic Events Leading to
Oncogene Formation or Activation
II-Chromosomal translocations have traditionally
been associated with cancers such as Burkitt lymphoma
and chronic myelogenous leukemia (CML).
In Burkitt lymphoma, the myc proto-oncogene, which
encodes a growth signal protein, is translocated from its
normal position on chromosome 8 to chromosome 14,
placing it at the site of an immunoglobulin gene.
in CML The outcome of the translocation is the appearance
of the so-called Philadelphia chromosome involving
chromosomes 9 and 22 and the formation of an abnormal
fusion protein that promotes cell proliferation
Genetic Events Leading to
Oncogene Formation or Activation
III-Gene amplification: Multiple copies of
certain genes may lead to over-expression,
with higher-than-normal levels of proteins
that increase cell proliferation. For example,
the human epidermal growth factor
receptor-2 (HER-2/neu) gene is amplified in
up to 30% of breast cancers.
Genetic Events Leading to Loss of
Tumor Suppressor Gene Function
Tumor
suppressor genes inhibit
the
proliferation of cells in a tumor. When this
type of gene is inactivated, a genetic signal
that normally inhibits cell proliferation is
removed, thereby causing unregulated
growth to begin
• TP53 gene located on the short arm of
chromosome 17, it codes for the p53 protein,
which functions as a suppressor of tumor
growth.
• Mutations in the TP53 gene have been
implicated in the development of lung, breast,
and colon cancer
• The TP53 gene also appears to initiate
apoptosis in radiation- and chemotherapydamaged tumor cells. Thus, tumors that retain
normal TP53 function are more likely to
respond to such therapy than tumors that carry
a defective TP53 gene.
Genetic Events Leading to Loss of
Tumor Suppressor Gene Function
• the malfunction of tumor suppressor genes
may require “two hits” to contribute to total
loss of function, as suggested by the two-hit
hypothesis of carcinogenesis
• The first “hit” may be a point mutation in an
allele of a particular chromosome; later, a
second “hit” occurs that involves the
companion allele of the gene
Genetic Events Leading to Loss of
Tumor Suppressor Gene Function
• In persons carrying an inherited mutation, such as
a mutated RB allele, all somatic cells are perfectly
normal, except for the increased risk of developing
cancer.
• That person is said to be heterozygous at the gene
locus. Cancer develops when a person becomes
homozygous for the mutant allele, a condition
referred to as loss of heterozygosity
Epigenetic Mechanisms
• In addition to mechanisms that involve DNA and
chromosomal structural changes, there are molecular and
cellular mechanisms, termed epigenetic mechanisms, that
involve changes in the patterns of gene expression without
a change in the DNA
• Epigenetic mechanisms may “silence” genes, such as
tumor suppressor genes, so that even though the gene is
present, it is not expressed and a cancer-suppressing
protein is not made.
Epigenetic Mechanisms
• Genes silenced by hypermethylation can be
inherited, and epigenetic silencing of genes
can be considered a first “hit” in the two-hit
hypothesis described previously.
• The epigenetic mechanisms that alter
expression of genes associated with cancer
are under intensive investigation, as are
hypomethylating drugs to prevent or treat
cancer.
Molecular and Cellular Pathways
There are numerous molecular and cellular mechanisms with a
endless of associated pathways and genes that are known or
suspected to facilitate the development of cancer. Here is some
examples from the author of the text book .
1- DNA Repair Defects.
2- Defects in Growth Factor Signaling Pathways.
3- Evasion of Apoptosis.
4- Evasion of Cellular Senescence.
5- Development of Sustained Angiogenesis.
6- Invasion and Metastasis.
1- DNA Repair Defects
Genetic mechanisms that regulate repair of
damaged DNA have been implicated in the
process of oncogenesis
(Fig. 8-7)
NEXT SLID
DNA Repair Defects (Fig. 8-7)
DNA Repair Defects
The DNA repair genes affect cell proliferation and
survival indirectly through their ability to repair
nonlethal damage in proto-oncogenes, tumor
suppressor genes and genes that control apoptosis.
These genes is the principal targets of genetic damage
occurring during the development of a cancer.
Genetic damage may be caused by the action of
chemicals, radiation, or viruses.
2- Defects in Growth Factor
Signaling Pathways
Definition : A relatively common way in
which cancer cells gain autonomous growth
is through mutations in genes that control
growth factor signaling pathways.
Growth Factor Signaling
Pathways Under Normal Conditions
Note : Cell proliferation involves the binding of a growth
factor to its receptor on the cell membrane .
Activation of the growth factor receptor on the inner
surface of the cell membrane .
Transfer of the signal across the cytosol to the nucleus
by signal-transducing proteins (as second messengers) .
Induction and activation of regulatory factors that
initiate DNA transcription, and entry of the cell into the
cell cycle (Fig. 8-8)
Growth Factor Signaling
Pathways Under Normal Conditions
Many of the proteins involved in the signaling
pathways that control the action of growth factors
exert their effects through kinases, enzymes that
phosphorylate proteins.
• In CML, mutation in a proto-oncogene controlling
tyrosine kinase activity occurs, causing
unregulated cell growth and proliferation
• Q: What is the name of this proto-oncogene?
3-Evasion Of Apoptosis
The failure of cancer cells to undergo apoptosis in a normal manner may
be due to a number of problems :
• There may be altered cell survival signaling .
• Over active Ras proteins .
• TP53 mutations .
• Down-regulation of death receptors.
• Stabilization of the mitochondria .
• Inactivation Of Proapoptotic Proteins (E.G., Methylation Of Caspase8).
• Overactivity of nuclear factor kappa B (Nf-êb) .
• Heat-shock Protein Production.
• Failure Of Immune Cells To Induce Cell Death.
Evasion Of Apoptosis
Example : the high levels of the antiapoptotic protein Bcl-2 that
occur secondary to a chromosomal translocation in certain
B-cell lymphomas. The mitochondrial membrane is a key regulator
of the balance between cell death and survival. Proteins in the Bcl2 family reside in the inner mitochondrial membrane
and are either proapoptotic or antiapoptotic. Because apoptosis is
considered a normal cellular response to DNA damage, loss of
normal apoptotic pathways may contribute to cancer by
enabling DNA-damaged cells to survive.
Facts
27 Alterations in apoptotic and antiapoptotic
pathways, genes, and proteins have been
found in many cancers.
4- Evasion Of Cellular
Senescence
• It is another normal cell response to DNA damage.
• As cancer cells are characterized by immortality due to high levels
of telomerase that prevent cell aging and hence senescence (aging),
thus high levels of telomerase and prevention of telomere shortening
may also contribute to cancer and its progression.
• Because senescence is considered to be a normal response to DNA
damage in cells as well as a tumor suppressor mechanism.
5- Development of Sustained
Angiogenesis
Angiogenesis is the physiological process involving the
growth of new blood vessels from pre-existing vessels.
Even with all the aforementioned genetic abnormalities,
tumors cannot enlarge unless angiogenesis occurs and
supplies them with the blood vessels necessary for
survival.
it is required for continued tumor growth & metastasis
The molecular basis for the angiogenic switch is unknown
The normal TP53 gene seems to inhibit angiogenesis by inducing
the synthesis of an antiangiogenic molecule called
thrombospondin-1 .
With mutational inactivation of both TP53 alleles (as occurs in
many cancers), the levels of thrombospondin-1 drop markedly,
tilting the balance in favor of angiogenic factors.
Angiogenesis is also influenced by hypoxia and release of
proteases that are involved in regulating the balance between
angiogenic and antiangiogenic factors.
Facts
Because of the crucial role of angiogenic factors in tumor
growth, much interest is focused on the development of
antiangiogenesis therapy.
Antiangiogenesis therapy is showing synergistic antitumor
actions when combined with conventional forms of
chemotherapy in the treatment of certain cancers
Q: Enumerate two antiagiogenic drugs and their uses?
Invasion and Metastasis
Finally, multiple genes and molecular and cellular pathways are
known to be involved in invasion and metastasis.
There is evidence that cancer cells with invasive properties are
actually members of the cancer stem cell population discussed
previously.
This evidence suggests that genetic programs that are normally
operative in stem cells during embryonic development may
become operative in cancer stem cells, enabling them to detach,
cross tissue boundaries, escape death by anoikis ( is a form
of programmed cell death which is induced by anchorage-dependent cells detaching
from the surrounding extracellular matrix (ECM)), and colonize new tissues.
The MET protooncogenewhich is expressed in
both stem cells and cancer cells, is a key regulator
of invasive growth.
Recent findings suggest that adverse conditions
such as tissue hypoxia, which are commonly
present in cancerous tumors, trigger this invasive
behavior by activating the MET tyrosine kinase
receptor.
Q:What is the main protein synthesized by MET
gene?
Role of the Microenvironment
The microenvironment of the cancer cell consists of
multiple cell types including :
-Macrophages, fibroblasts, endothelial cells, variety of
immune and inflammatory cells, the extracellular
matrix, and the primary signaling substances such as
cytokines, chemokines and hormones.
-The essential steps needed for tumor growth and
metastasis, such as angiogenesis and metastatic
tumor survival, depend on the microenvironment.
Carcinogenesis
The process by which carcinogenic (cancer-causing)
agents cause normal cells to become cancer cells is
hypothesized to be a multistep mechanism that can
be divided into three stages:
• initiation
• promotion
• progression
(Fig. 8-9)
Initiation
involves the exposure of cells to appropriate doses of a
carcinogenic agent that makes them susceptible to malignant
transformation.
The carcinogenic agents can be:
• Chemical.
• physical.
• Biologic.
and produce irreversible changes in the genome of a previously
normal cell.
Fact
The cells most susceptible to mutagenic alterations are those that
are actively synthesizing DNA.
Promotion
involves the induction of unregulated accelerated growth in already
initiated cells by various chemicals and growth factors.
Promotion is reversible if the promoter substance is removed.
Facts
 Cells that have been irreversibly initiated may be promoted even
after long latency periods.
 Many chemical carcinogens are called complete carcinogens
because they can initiate and promote neoplastic
transformation.
Q: Give 2 examples of complete carcinogens?
Progression
is the process whereby tumor cells acquire
malignant phenotypic changes :
 promote invasiveness.
 metastatic competence.
 autonomous growth tendencies.
 increased karyotypic instability.
Host and Environmental Factors
Host and Environmental Factors
The cancer is not a single disease, it is reasonable to assume
that it does not have a single cause. More likely, cancer occurs
because of interactions among multiple risk factors or repeated
exposure to a single carcinogenic agent. Among the traditional
risk factors that have been linked to cancer are heredity, hormonal
factors, immunologic mechanisms, and environmental
agents such as chemicals, radiation, and cancer-causing viruses.
More recently, there has been interest in obesity as a risk factor
for cancer.
Heredity
*A hereditary predisposition to approximately 50 types of cancer has been
observed in families.
*Breast cancer, for example, occurs more frequently in women whose
grandmothers, mothers, aunts, or sisters also have experienced a breast
malignancy.
*Two tumor suppressor genes, called BRCA1 (breast cancer susceptibility
gene1) and BRCA2 (breast cancer susceptibility gene2) have been implicated
in genetic susceptibility to breast cancer.
*Individuals carrying a BRCA mutation have a lifetime risk (if they live to the
age of 85 years) of 80% for developing breast cancer. The lifetime risk for
developing ovarian cancer is 10% to 20% for carriers of BRCA2 mutations
and 40% to 60% for BRCA1 mutations.
• Several cancers exhibit an autosomal dominant inheritance pattern that
greatly increases the risk of developing a tumor.
• Retinoblastoma, a rare childhood tumor of the retina, is an example of
a cancer that follows an autosomal dominant inheritance pattern.
Approximately 40% of retinoblastomas are inherited, and carriers of
the mutant RB tumor suppressor gene have a 10,000-fold increased
risk for developing retinoblastoma, usually with bilateral involvement.
The inherited mutation is usually a point mutation occurring in a single
allele of a tumor suppressor gene.
Hormones
Hormones have received considerable research attention with respect to
cancer of the breast, ovary, and endometrium in women and of the
prostate and testis in men.
Although the link between hormones and the development of cancer is
unclear, it has been suggested that it may reside with the ability of
hormones to drive the cell division of a malignant phenotype.
Because of the evidence that endogenous hormones affect the risk of these
cancers, concern exists regarding the effects on cancer risk if the same
or closely related hormones are administered for therapeutic purposes.
Immunologic Mechanisms
• The central concept, known as the immune surveillance hypothesis,
first proposed by Paul Ehrlich in 1909, postulates that the immune
system plays a central role in resistance against the development of
tumors.
• In addition to cancer–host interactions as a mechanism of cancer
development, immunologic mechanisms provide a means for the
detection, classification, and prognostic evaluation of cancers and as a
potential method of treatment.
• Cancer might be associated with impairment or decline in the
surveillance capacity of the immune system.
1-Cancer incidence increases in people with immunodeficiency diseases
e.g. association of Kaposi sarcoma with AIDS.
2-Cancer incidence increases in those with organ transplants who are
receiving immunosuppressant drugs.
3-Cancer incidence increases in the elderly, in whom there is a known
decrease in immune activity.
• It has been shown that most tumor cells have molecular
configurations that can be specifically recognized by
immune T cells or by antibodies and hence are termed
tumor antigens.
The most relevant tumor antigens fall into two categories:
1-Unique, tumor specific antigens found only on tumor cells
2-Tumor-associated antigens found on tumor cells and normal
cells.
• Quantitative and qualitative differences permit the use of
tumor-associated antigens to distinguish cancer cells from
normal cells.3
Chemical carcinogens
Chemical carcinogens can be divided into two groups:
(1) direct-reacting agents, which do not require activation in the body to
become carcinogenic.
(2) indirect-reacting agents, called procarcinogens or initiators, which
become active only after metabolic conversion.
Direct- and indirect-acting initiators form highly reactive species (i.e.,
electrophiles and free radicals) that bind with the nucleophilic
residues on DNA, RNA, or cellular proteins.
• The action of these reactive species tends to cause cell mutation or
alteration in synthesis of cell enzymes and structural proteins in a
manner that alters cell replication and interferes with cell regulatory
controls
Cont,
•
The carcinogenicity of some chemicals is augmented by agents called
promoters that, by themselves, have little or no cancer-causing ability. It is
believed that promoters exert their effect by changing the expression of genetic
material in a cell, increasing DNA synthesis, enhancing gene amplification.
•
Exposure to many chemical carcinogens is associated with lifestyle risk
factors, such as smoking, dietary factors, and alcohol consumption.
•
Cigarette smoke contains both procarcinogens and promoters. It is directly
associated with lung and laryngeal cancer and has been linked with cancers of
the mouth, nasal cavities, pharynx, esophagus, pancreas, liver, kidney, uterus,
cervix, and bladder, and with myeloid leukemias.
• Chewing tobacco or tobacco products increases the risk of cancers of
the oral cavity and esophagus. It has been estimated that 30% of all
cancer deaths and 87% of lung cancer deaths in the United States are
related to tobacco.36 Not only is the smoker at risk, but others
passively exposed to cigarette smoke are at risk.
• Environmental tobacco smoke has been classified as a “group A”
carcinogen based on the U.S. Environmental Protection Agency’s
system of carcinogen classification. Each year, about 3000
nonsmoking adults die of lung cancer as a result of environmental
tobacco smoke.
• There is strong evidence that certain elements in the diet
contain chemicals that contribute to cancer risk.
• Most known dietary carcinogens occur either naturally in
plants (e.g., aflatoxins) or are produced during food
preparation.
• The effects of carcinogenic agents usually are dose
dependent—the larger the dose or the longer the duration
of exposure.
• List of carcinogens at page 175.
Radiation
• The effects of ionizing radiation in carcinogenesis have been well
documented in atomic bomb survivors, and in industrial workers,
scientists, and physicians who were exposed during employment.
Malignant epitheliomas of the skin and leukemia were significantly
elevated in these populations.
• The type of cancer that developed depended on the dose of radiation,
the sex of the person, and the age at which exposure occurred.For
example, children exposed to ionizing radiation in utero have an
increased risk for developing leukemias and childhood tumors,
particularly 2 to 3 years after birth. This latency period for leukemia
extends to 5 to 10 years if the child was exposed after birth and to 20
years for certain solid tumors
• The association between sunlight and the development of skin cancer
has been reported for more than 100 years.
• Ultraviolet radiation plays a role causing skin cancer primarily on the
areas of skin more frequently exposed to sunlight (e.g., the head and
neck, arms, hands, and legs), a higher incidence in light-complexioned
individuals who lack the ultraviolet-filtering skin pigment melanin, and
the fact that the intensity of ultraviolet exposure is directly related to
the incidence of skin cancer, as evidenced by higher rates occurring in
Australia and the American Southwest.
Oncogenic Viruses
Four DNA viruses have been implicated in human cancers:
the human papillomavirus (HPV), Epstein-Barr virus (EBV), hepatitis B
virus (HBV), and human herpesvirus-8 (HHV8).
HHV-8, which causes Kaposi sarcoma in persons with AIDS.
• There are over 60 genetically different types of HPV. Some types (i.e.,
types 1, 2, 4, 7) have been shown to cause benign squamous
papillomas (i.e., warts).
• HPVs also have been implicated in squamous cell carcinoma of the
cervix and anogenital region. HPV types 16 and 18 and, less
commonly, HPV types 31, 33, 35, and 51 are found in approximately
85% of squamous cell carcinomas of the cervix and presumed
precursors (i.e., severe cervical dysplasia and carcinoma in situ).
• EBV is a member of the herpes virus family. It has been implicated in
the pathogenesis of four human cancers: Burkitt lymphoma,
nasopharyngeal cancer, B-cell lymphomas in immunosuppressed
individuals such as those with AIDS, and in some cases of Hodgkin
lymphoma.
• HBV is the etiologic agent in the development of hepatitis B, cirrhosis,
and hepatocellular carcinoma. There is a significant correlation
between elevated rates of hepatocellular carcinoma worldwide and the
prevalence of HBV carriers.
Cont,
• Although there are a number of retroviruses (RNA viruses) that cause
cancer in animals, human T-cell leukemia virus-1 (HTLV-1) is only
known retrovirus to cause cancer in humans.
• HTLV-1 is associated with a form of T-cell leukemia that is endemic
in parts of Japan and some areas of the Caribbean and Africa, and is
found sporadically elsewhere, including the Unit States.
Cont,
There probably is not a single body function left unaffected by the
presence of cancer.
Because tumor cells replace normally functioning parenchymal tissue, the
initial manifestations of cancer usually reflect the primary site of
involvement.
For example, cancer of the lung initially produces impairment of
respiratory function; as the tumor grows and metastasizes, other body
structures become affected.
Tissue Integrity
Cancer disrupts tissue integrity. As cancers grow, they compress and
erode blood vessels, causing ulceration and necrosis along with frank
bleeding and sometimes hemorrhage.
One of the early warning signals of colorectal cancer is blood in the stool.
Cancer cells also may produce enzymes and metabolic toxins that are
destructive to the surrounding tissues. Usually, tissue damaged by
cancerous growth does not heal normally.
Instead, the damaged area persists and often continues to grow; a sore that
does not heal is another warning signal of cancer.
Cancer has no regard for normal anatomic boundaries; as it grows, it
invades and compresses adjacent structures. Abdominal cancer, for
example, may compress the viscera and cause bowel obstruction.
Cont,
The development of effusions (i.e., fluid)
in the pleural, pericardial, or peritoneal spaces may be the presenting sign
of some tumors.
Direct involvement of the serous surface seems
to be the most significant inciting factor,
although many other mechanisms, such as obstruction of lymphatic flow,
may play a role.
• The production of glucose (gluconeogenesis) from lactate
uses adenosine triphosphate (ATP) and is very energy
inefficient, contributing to the hypermetabolic state of
cachectic patients.
• Another mechanism for the increasing energy expenditure
in cachectic persons is the increased expression of
mitochondrial uncoupling proteins that uncouple the
oxidative phosphorylation process, so that energy is lost as
heat.
• Although the mechanisms of the cancer anorexia–cachexia
syndrome remain incompletely understood, they are probably
multifactorial, resulting from a persistent inflammatory response in
conjunction with production of specific cytokines and catabolic
factors by the tumor.
from synthesis of albumin
to acute-phase proteins such as C-reactive protein, fibrinogen, and
α1-antitrypsin .
• The acute-phase response is known to be activated by cytokines
such as tumor necrosis factor-α (TNF-α) and IL-1 and IL-6,
suggesting that they may also play a role in cancer cachexia.
•
• High serum levels of these cytokines have been observed in persons
with cancer, and their levels appear to correlate with progression of the
tumor.
• TNF-α, secreted primarily by macrophages in response to tumor cell
growth or gram negative bacterial infections, was the first cytokine
associated with cachexia and wasting to be identified.
Fatigue and Sleep Disorders
• Fatigue and sleep disturbances are two of the most
frequent side effects experienced by persons with
cancer.
• Persons with cancer report poor sleep quality,
disturbed initiation and maintenance of sleep,
insufficient sleep, nighttime awakening, and
restless sleep.
Anemia
•
Paraneoplastic Syndromes
• In addition to signs and symptoms at the sites of
primary and metastatic disease, cancer can produce
manifestations in sites that are not directly affected
by the disease.
• Such manifestations are collectively referred to as
paraneoplastic syndromes.
• Some of these manifestations are caused by the
elaboration of hormones by cancer cells, and others
from the production of circulating factors that
produce
hematopoietic,
neurologic,
and
dermatologic syndromes (Table1).
•Some paraneoplastic syndromes are associated with the production
of circulating mediators that produce hematologic complications.
• The symptomatic paraneoplastic neurologic disorders
are relatively rare, with the exception of the LambertEaton myasthenic syndrome, which affects about 3%
of persons with small cell lung cancer; and
myasthenia gravis, which affects about 15% of people
with thymoma.
• A wide variety of cutaneous syndromes is associated with
malignancies and may precede, be concurrent with, or follow the
discovery of cancer.
• Among the paraneoplastic dermatologic disorders is acanthosis
nigricans, characterized by pigmented hyperkeratoses that occur in
skin flexures, particularly the axillary and perineal areas.The lesions
may be accompanied by pruritus.
• The condition is usually associated with adenocarcinomas of the
gastrointestinal tract, particularly gastric carcinoma, but may be
associated with a variety of adenocarcinomas, including lung, breast,
ovarian, and even hematologic cancers.
• The pathogenesis of these lesions is uncertain.
Screening
• Screening represents a secondary prevention measure for
the early recognition of cancer in an otherwise
asymptomatic population.
• It requires a test that will specifically detect early cancers
or pre-malignancies, is cost effective, and results in
improved therapeutic outcomes.
• More sensitive screening methods such as tumor markers
are being developed for these forms of cancer.
Cancers for which current screening or early detection has led
to improvement in outcomes include:
1-Cancer of the breast (breast self-examination and
mammography)
2-Cancer cervix (Pap smear).
3-Colo-rectal cancer (rectal examination, fecal occult blood
test, and flexible sigmoidoscopy and colonoscopy)
4-Cancer prostate (prostate specific antigen [PSA] testing and
transrectal ultrasonography).
Diagnosis
1-Tumour Markers.
2-Cytologic and Histologic Methods:
a-Pap smear.
b-Tissue biopsy.
c-Immuno-histochemistry.
d-Microarray Technology.
3-Staging and Grading of Tumors
Tumour Markers
• Tumor markers are antigens expressed on the surface of
tumor cells or substances released from normal cells in
response to the presence of tumor.
• Tumor markers are used for screening, establishing
prognosis, monitoring treatment, and detecting recurrent
disease.
• The serum markers that have proved most useful in clinical
practice are human chorionic gonadotropin (hCG), CA125, PSA, α-fetoprotein (AFP), carcinoembryonic antigen
(CEA), and CD blood cell antigens.
• See table page 182
• As diagnostic tools, tumor markers have limitations.
Nearly all markers can be elevated in benign conditions,
and most are not elevated in the early stages of
malignancy.
• Hence, tumor markers have limited value as screening
tests. Furthermore, they are not in themselves specific
enough to permit a diagnosis of a malignancy, but once a
malignancy has been diagnosed and shown to be
associated with elevated levels of a tumor marker, the
marker can be used to assess response to therapy.
A-Pap Smear
• The Pap test is a cytologic method used for detecting
cancer cells.
• It consists of a microscopic examination of a properly
prepared slide by a cytotechnologist or pathologist for the
purpose of detecting the presence of abnormal cells.
• Although the Pap test is widely used as a screening test for
cervical cancer, it can be performed on other body
secretions, including nipple drainage, pleural or peritoneal
fluid, and gastric washings.
B-Tissue Piopsy
• involves the removal of a tissue specimen for microscopic
study.
• Biopsies are obtained in a number of ways, including
needle biopsy; endoscopic methods, such as
bronchoscopy or cystoscopy, which involve the passage of
an endoscope through an orifice and into the involved
structure; or laparoscopic methods.
• In some instances, a surgical incision is made from which
biopsy specimens are obtained.
• Excisional biopsies are those in which the entire tumor is
removed.
• A quick frozen section may be done to determine the nature of a mass
lesion or evaluate the margins of an excised tumor to ascertain that the
entire neoplasm has been removed.
• Fine-needle aspiration is another approach that is widely used. The
procedure involves aspirating cells and attendant fluid with a smallbore needle.
• The method is most commonly used for assessment of readily palpable
lesions in sites such as the thyroid, breast, and lymph nodes.
• Modern imaging techniques have also enabled the method to be
extended to deeper structures such as the pelvic lymph nodes and
pancreas.
C-Immunohistochemistry
• Immunohistochemistry involves the use of antibodies to
facilitate the identification of cell products or surface
markers.
• Antibodies against intermediate filaments have proved
useful because tumor cells often contain intermediate
filaments characteristic of their tissue of origin.
• WHY? Because certain anaplastic carcinomas, malignant
lymphomas, melanomas, and sarcomas look very similar
under the microscop & In cases in which the origin of the
metastasis is obscure & to detect molecules that have
prognostic or therapeutic significance e.g. detection of
estrogen receptors on breast cancer cells.
D-Microarray technology
• Microarray technology is a collection of microscopic DNA
spots attached to a solid surface. It is used to measure the
expression levels of large numbers of genes
simultaneously or to genotype multiple regions of a
genome.
• DNA arrays are now commercially available to assist in
making clinical decisions regarding breast cancer
treatment.
• Can be used for predicting prognosis and response to
therapy, examining tumor changes after therapy, and
classifying hereditary tumors.
Staging and Grading
• The two basic methods for classifying cancers are grading
according to the histologic or cellular characteristics of the
tumor and staging according to the clinical spread of the
disease.
• Grading of tumors involves the microscopic examination
of cancer cells to determine their level of differentiation
and the number of mitoses. Cancers are classified as grades
I, II, III, and IV with increasing anaplasia or lack of
differentiation.
• The clinical staging of cancer using TNM system of the
American Joint Committee on Cancer (AJCC) is used by
most cancer facilities.
• the “TNM” system includes a description of tumor size
(T), involvement of lymph nodes (N) and metastasis (M).
• The time of staging is indicated as clinical–diagnostic
staging (cTNM), postsurgical resection–pathologic staging
(pTNM), surgical evaluative staging (sTNM), retreatment
staging (rTNM), and autopsy staging (aTNM)
Tumor Staging
• T — Primary tumor (Is there a tumor and if
so how big is it?)
• TX — Primary tumor cannot be assessed
• TO — No evidence of primary tumor
• Tis — Carcinoma in situ
• T1–T4 — Increasing size of tumor
Tumor Staging
• N — Involvement of lymph nodes (Has the tumor
spread to the lymph nodes?)
• NX — Regional lymph nodes cannot be assessed
• NO — No evidence that the tumor has
metastasized to lymph nodes in the region of the
primary tumor
• N1–N3 — Progressive involvement of regional
lymph nodes
Tumor Staging
• M — Distant metastasis (Has the tumor
spread to distant sites in the body?)
• Mx — Distant metastasis cannot be
assessed
• MO — No evidence of distant metastasis
• M1— Single or multiple sites of metastasis
have been located
Cancer Treatment
• The goals of cancer treatment methods fall into three
categories: curative, control, and palliative.
• The most common modalities are surgery, radiation
therapy, chemotherapy, hormonal therapy and biotherapy.
• The treatment of cancer involves the use of a carefully
planned program that combines the benefits of multiple
treatment modalities and the expertise of an
interdisciplinary team of specialists.
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