Download The LAM cell: what is it, where does it come from, and why does it

Am J Physiol Lung Cell Mol Physiol 286: L690–L693, 2004;
10.1152/ajplung.00311.2003.
Editorial Focus
The LAM cell: what is it, where does it come from, and why does it grow?
G. Finlay
Tupper Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 02111
The LAM Cell: What Is It?
To understand the pathogenesis of LAM, one needs to have
a keen understanding of the nature of the atypical cell so
characteristic of LAM. In 1966, Cornog and Enterline (8)
described the first significant collection of patients with LAM.
These insightful observers postulated that the cell present in
LAM lung was smooth muscle like, lacked the features of a
malignancy, and perhaps shared a common genetic origin.
Indeed, the cells found in LAM are not malignant and stain
positive for smooth muscle markers, ␣-smooth muscle actin,
desmin, and vimentin (9). What is unusual about LAM is that
it is not due to the proliferation of one monoclonal cell type
only but instead due to the infiltration and proliferation of a
phenotypically heterogeneous group of smooth muscle cells,
many of which have myofibroblast- and epithelioid-like features (4). Interestingly, LAM cells are unusually reactive to
mouse monoclonal antibody HMB45 (20a), which reacts with
a glycoprotein (gp100) found in immature melanocytes. However, considerable variability of HMB45 positivity is frequently observed and is not absolutely necessary for the diagnosis of LAM (20a, 30). Although the relevance of HMB45
positivity and its antigen gp100 is as yet unstudied, an inverse
relationship has been described in LAM smooth muscle cells
between immunostaining for HMB45 and proliferating cell
nuclear antigen (PCNA), which is a marker of cell proliferation
(30). Thin, spindle-shaped smooth muscle cells are less likely
to be immunoreactive for HMB45 and more likely to be PCNA
positive. In contrast, larger epithelioid-like smooth muscle
cells are more likely to exhibit positive immunostaining for
HMB45 with poor or no reactivity for PCNA. These observations have led to the hypothesis that LAM cells are a population of smooth muscle cells that at any one point in time may
be in a state of variable differentiation (22). Furthermore, it is
reasonable to postulate that each phenotype is associated with
a cell-specific function, at least in terms of its proliferative
Address for reprint requests and other correspondence: G. Finlay, TuftsNew England Medical Center, NEMC #257, 750 Washington St., Boston, MA
02111 (E-mail: [email protected]).
L690
capacity, which may help to explain why many patients with
LAM have variable responses to therapy and outcomes.
Cornog and Enterline (8) also postulated in 1966 that the
smooth muscle cells may share a common genetic origin. They
noted that pulmonary LAM is histologically indistinct from the
pulmonary lesions observed in tuberous sclerosis complex
(TSC), and recent reports indicate that LAM has a prevalence
as high as 39% in TSC (10, 31, 32). TSC, which is characterized by hamartomatous proliferations in the brain, kidney, skin,
heart, and lung, is caused by germline mutations of either the
TSC1 or TSC2 gene located on chromosomes 9q34 and 16p13,
respectively (18). It is now clear that both of these genes are
tumor suppressor genes encoding hamartin (TSC1) and tuberin
(TSC2) and that the tumors associated with TSC have undergone loss of heterozygosity (LOH), indicating that tumor
development in TSC is associated with the “two-hit” hypothesis of Knudson (5). In 1998, the discovery of LOH of the
TSC2 gene in the angiomyolipomas (AMLs) and lymph nodes
of women who suffer from sporadic LAM heralded a new
wave of investigation of the role of the TSC genes and, in
particular, the TSC2 gene in sporadic LAM (36). Subsequently,
mutational analysis of the 41 coding exons of the TSC2 gene
from LAM patients revealed that germline mutations of the
TSC2 or TSC1 genes are extremely uncommon (1). Additional
analysis of microdissected smooth muscle cells from renal
AMLs and pulmonary LAM lesions revealed that mutations of
the TSC2 gene in renal and pulmonary smooth muscle cells are
not found in surrounding normal kidney or lung (6). Subsequently, single-strand conformation polymorphism (SSCP)
analysis revealed that a spectrum of TSC2 gene mutations
exists in microdissected smooth muscle cells from sporadic
pulmonary LAM (37). These studies support the hypothesis
that LAM is caused by a somatic mutation in the TSC2 gene.
However, mutations of the TSC2 gene were not detected in
every patient. This may be due to limitations of SSCP in the
detection of important mutations, contamination of the microdissected specimen with other pulmonary cells that may not
express mutations of TSC2, or perhaps inconsistencies of
mutations of the TSC2 gene in LAM cells and LAM patients.
Nonetheless, despite these limitations, the available evidence is
convincing for a strong association between somatic TSC2
gene mutations and sporadic LAM.
The LAM Cell: Where Does It Come From?
Studies supporting a causative role for somatic mutations of
the TSC2 gene in sporadic LAM (6, 37) suggest that a normal
resident pulmonary cell undergoes a spontaneous mutation
resulting in aberrant proliferation locally. The question is
which smooth muscle cell underwent such a mutation? In the
lung, smooth muscle is predominantly found in the airway and
vasculature with a small amount in lung interstitium. Based on
the frequent observation of microscopic hemorrhage in LAM
lesions, and the frequent involvement of blood vessels, it has
been hypothesized that LAM cells may be derived from vas-
1040-0605/04 $5.00 Copyright © 2004 the American Physiological Society
http://www.ajplung.org
Downloaded from http://ajplung.physiology.org/ by 10.220.33.5 on May 10, 2017
LYMPHANGIOLEIOMYOMATOSIS (LAM) is a rare disease that affects
females of reproductive age (38). Pathologically, it is characterized by the abnormal proliferation of immature smooth
muscle-like cells that grow aberrantly in the lung. The relentless growth of LAM cells in the pulmonary airway, parenchyma, lymphatics, and blood vessels leads to respiratory
failure and death. Recent progress has been made in understanding more about the pathogenesis of LAM. Studies such as
those published by Yu et al., one of the current articles in focus
(Ref. 42, see page L694 in this issue), deepen our understanding of the disease and facilitate the identification of potential
therapeutic targets aimed at abrogating the aberrant cellular
proliferation characteristic of LAM.
Editorial Focus
L691
The LAM Cell: How Does It Grow?
Investigating LAM at a cellular level has been hampered by
the lack of agreement on what exactly constitutes a LAM cell
and the absence of an animal model of the disease. As previously discussed, the LAM cell is not a single phenotype, but
many phenotypes, with cell-specific protein expression profiles
and differential proliferative capacities. Thus applying the
technique of microdissection to LAM tissue allows the limited
AJP-Lung Cell Mol Physiol • VOL
evaluation of one cell type only. One group of microdissected
cells may behave very differently from 1) microdissected cells
from another LAM lesion within the same patient or 2) microdissected cells from another patient. Furthermore, contamination from nearby cells, influence of stage of disease, and
hormonal therapy may also interfere with the genetic makeup
and phenotype of microdissected pulmonary cells from the
lung. This leads to a lack of standardization in the scientific
approach to the cellular investigation of LAM.
Nonetheless, one recent study clearly demonstrated activation of S6, a ribosomal protein intricately involved in regulating the cell cycle, in smooth muscle cells that were microdissected from LAM lung (19). These cells expressed an aberrant
form of TSC2. Furthermore, reexpression of tuberin, the protein product of TSC2, in LAM-derived smooth muscle cells,
led to reduced proliferation of LAM cells and reduced phosphorylation of S6. This is the first study to suggest that
expression of mutant TSC2 in LAM smooth muscle cells leads
to the aberrant cellular proliferation observed in LAM lung.
Furthermore, the findings in this study parallel the observations
of others investigating TSC2 biology who have noted that
tuberin antagonizes the downstream pathways activated by the
phosphorylation of tyrosine kinase receptors (16, 17, 33, 34).
An explosion of research in the last five years has demonstrated
that tuberin interacts with and binds to TOR (target of rapamycin), a cellular protein that is frequently activated in response to growth factor stimulation. Activation of mammalian
TOR subsequently results in the downstream activation and
phosphorylation of S6 (25). The study by Goncharova et al.
(19) indicates that similar pathways are overactivated in LAM
and suggests that studying the regulation of signaling pathways
by tuberin provides useful insights into how LAM cells grow.
Because of the paucity of LAM tissue and the absence of an
ideal cell line in which to study signaling pathways in LAM,
many investigators have relied on alternative cellular models.
Such models include that described by Yu et al. (42). Renal
AML smooth muscle cells bear remarkable morphological
similarity to pulmonary LAM smooth muscle cells. Yu et al.
describe the development of a cell line from an AML from a
LAM patient that expressed inactivating mutations in both
alleles of the TSC2 gene. Importantly, they demonstrate that
similar to pulmonary LAM cells, the estrogen receptors (ER) ␣
and ER␤ are aberrantly expressed in LAM-derived renal AML
cells. Furthermore, these cells grow in response to hormonal
stimulation, and hormone-mediated growth of LAM-associated
renal AML cell activates potent mediators of cell growth, i.e.,
ERK and c-myc. This study closely parallels findings by other
groups that demonstrated a positive growth response to estrogen in smooth muscle cells that are null for TSC2 and TSC1
genes (14, 26). Yu et al. (42) add to our understanding of the
proliferative effect of estrogen in cells that express dysfunctional TSC proteins that contrasts the inhibitory growth effects
of estrogen frequently observed in vascular smooth cells that
constitutively express tuberin (13, 14). Of even greater significance, Yu et al. also demonstrate that tamoxifen is equal to
estrogen in its potency as an activator of growth of LAMderived AML cells. This observation supports the known fact
that tamoxifen and, in some cases, progesterone, act as both
estrogen agonists and antagonists and raises the question of
whether anti-estrogen therapy is appropriate in LAM. Although estrogen has been implicated in the growth of LAM
286 • APRIL 2004 •
www.ajplung.org
Downloaded from http://ajplung.physiology.org/ by 10.220.33.5 on May 10, 2017
cular smooth muscle. It has been shown that four distinct
phenotypes of smooth muscle exist in the media of bovine
aorta and that each phenotype is associated with a specific gene
expression profile (40). Interestingly, in culture, each smooth
muscle cell phenotype has different proliferative capacities
(15). Similarly, in LAM, distinct smooth muscle cell phenotypes also occur that express markers indicating phenotype
differences in growth potential. These parallel observations
between vascular and LAM smooth muscle cell biology have
led to the hypothesis that the LAM smooth muscle cell may be
derived from vascular smooth muscle that differentiates into a
unique migratory or proliferative phenotype by undergoing a
spontaneous mutation within the vessel wall. However, no
direct evidence supports this theory, leaving it yet to be proven.
LAM is a multisystem disease that is not necessarily limited
to lung involvement but can also involve lymph nodes, kidney,
and colon. Recently, the observation that identical mutations
are shared between the renal and pulmonary lesions in LAM
have led some members of the LAM scientific community to
hypothesize that the pulmonary LAM cell may have originally
metastasized from a distant site (41). AMLs are highly vascular
tumors that occur frequently in LAM (3, 24). They contain
strong vascular and smooth muscle elements with histological
appearances similar to pulmonary LAM and are also immunoreactive to HMB45 (7). AMLs that occur in sporadic pulmonary LAM share identical mutations of the TSC2 gene, indicating that they are genetically related. Karbowniczek et al.
(23) have recently demonstrated five morphologically distinct
vessel phenotypes in renal AML from patients with LAM, four
of which were neoplastic in character, indicating a higher
propensity to metastasize. In addition, smooth muscle cells are
aberrantly found in the lung at autopsy in trauma patients
(personal communication from L. S. Schuger), and on occasion, benign uterine leiomyomata can metastasize to the lung,
resulting in a clinical syndrome similar to LAM (12). Thus it
could be postulated that pulmonary LAM is a rare benign
metastasizing disease.
An alternative, but closely allied, explanation for the aberrant proliferation of immature smooth muscle cells in the lung
is that LAM cells are donor cells from a nonhost source.
Recent studies indicate that cell traffic occurs between the fetus
and mother during pregnancy and that low numbers of cells or
DNA persist in the maternal circulation for years thereafter
(27). This process, known as microchimerism, is more common in diseases that have a female prevalence, such as autoimmune diseases, but can also be found in other conditions,
such as in transplant or transfusion patients, where the source
of nonhost cells is derived from the organ donor or blood (11).
LAM has a predilection to the female sex, but the role of
microchimerism is as yet unstudied in LAM, and the true
source of the LAM cell remains elusive.
Editorial Focus
L692
AJP-Lung Cell Mol Physiol • VOL
REFERENCES
1. Astrinidis A, Khare L, Carsillo T, Smolarek T, Au KS, Northrup H,
and Henske EP. Mutational analysis of the tuberous sclerosis gene TSC2
in patients with pulmonary lymphangioleiomyomatosis. J Med Genet 37:
55–57, 2000.
3. Bernstein SM, Newell JD Jr, Adamczyk D, Mortenson RL, King TE
Jr, and Lynch DA. How common are renal angiomyolipomas in patients
with pulmonary lymphangiomyomatosis? Am J Respir Crit Care Med 152:
2138–2143, 1995.
4. Bonetti F, Pea M, Martignoni G, Zamboni G, and Iuzzolino P. Cellular
heterogeneity in lymphangiomyomatosis of the lung. Hum Pathol 22:
727–728, 1991.
5. Carbonara C, Longa L, Grosso E, Borrone C, Garre MG, Brisigotti
M, and Bigone M. 9q34 loss of heterozygosity in a tuberous sclerosis
astrocytoma suggests a growth suppressor-like activity also for the TSC1
gene. Hum Mol Genet 3: 1829–1832, 1994.
6. Carsillo T, Astrinidis A, and Henske EP. Mutations in the tuberous
sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci USA 97: 6085–6090, 2000.
7. Chan JK, Tsang WY, Pau MY, Tang MC, Pang SW, and Fletcher CD.
Lymphangiomyomatosis and angiomyolipoma: closely related entities
characterized by hamartomatous proliferation of HMB-45-positive smooth
muscle. Histopathology 22: 445–455, 1993.
8. Cornog JL Jr and Enterline HT. Lymphangiomyoma, a benign lesion of
chyliferous lymphatics synonymous with lymphangiopericytoma. Cancer
19: 1909–1930, 1966.
9. Corrin B, Liebow AA, and Friedman PJ. Pulmonary lymphangiomyomatosis. A review. Am J Pathol 79: 348–382, 1975.
10. Costello LC, Hartman TE, and Ryu JH. High frequency of pulmonary
lymphangioleiomyomatosis in women with tuberous sclerosis complex.
Mayo Clin Proc 75: 591–594, 2000.
11. De Pauw L, Toungouz M, and Goldman M. Infusion of donor-derived
hematopoietic stem cells in organ transplantation: clinical data. Transplantation 75: 46S–49S, 2003.
12. Esteban JM, Allen WM, and Schaerf RH. Benign metastasizing leiomyoma of the uterus: histologic and immunohistochemical characterization of
primary and metastatic lesions. Arch Pathol Lab Med 123: 960–962, 1999.
13. Farhat MY, Lavigne MC, and Ramwell PW. The vascular protective
effects of estrogen. FASEB J 10: 615–624, 1996.
14. Finlay GA, Hunter DS, Walker CL, Paulson KE, and Fanburg BL.
Regulation of PDGF production and ERK activation by estrogen is
associated with TSC2 gene expression. Am J Physiol Cell Physiol 285:
C409–C418, 2003.
15. Frid M, Aldashev AA, Dempsey EC, and Stenmark KR. Smooth
muscle cells isolated from discrete compartments of the mature vascular
media exhibit unique phenotypes and distinct growth capabilities. Circ Res
81: 940–952, 1997.
16. Gao X and Pan D. TSC1 and TSC2 tumor suppressors antagonize insulin
signaling in cell growth. Genes Dev 15: 1383–1392, 2001.
17. Gao X, Zhang Y, Arrazola P, Hino O, Kobayashi T, Yeung RS, Ru B,
and Pan D. Tsc tumour suppressor proteins antagonize amino-acid-TOR
signalling. Nat Cell Biol 4: 699–704, 2002.
18. Gomez M, Sampson J, and Whittemore VH. Tuberous Sclerosis Complex. New York: Oxford Univ., 1999.
19. Goncharova EA, Goncharov DA, Eszterhas A, Hunter DS, Glassberg
MK, Yeung RS, Walker CL, Noonan D, Kwiatkowski DJ, Chou MM,
Panettieri RA Jr, and Krymskaya VP. Tuberin regulates p70 S6 kinase
activation and ribosomal protein S6 phosphorylation: a role for the TSC2
tumor suppressor gene in pulmonary lymphangioleiomyomatosis. J Biol
Chem 3: 3, 2002.
20. Hayashi T, Fleming MV, Stetler-Stevenson WG, Liotta LA, Moss J,
Ferrans VJ, and Travis WD. Immunohistochemical study of matrix
metalloproteinases and their tissue inhibitors in pulmonary lymphangioleiomyomatosis. Hum Pathol 28: 1071–1078, 1997.
20a.Hoon V, Thung SN, Kaneko M, and Unger PD. HMB reactivity in renal
angiomyolipoma and lymphangioleiomyomatosis. Arch Path Lab Meth
118: 732–734, 1994.
21. Inoue Y, King TE Jr, Barker E, Daniloff E, and Newman LS. Basic
fibroblast growth factor and its receptors in idiopathic pulmonary fibrosis
and lymphangioleiomyomatosis. Am J Respir Crit Care Med 166: 765–
773, 2002.
286 • APRIL 2004 •
www.ajplung.org
Downloaded from http://ajplung.physiology.org/ by 10.220.33.5 on May 10, 2017
cells in vivo, it has not yet been demonstrated that pulmonary
LAM-derived smooth muscle cells grow in culture in response
to estrogen. However, if one extrapolates from the study of Yu
et al. to the LAM patient, hormone-manipulating agents are
potentially harmful and perhaps caution should be exercised
when prescribing “anti-estrogen” therapy to patients who suffer from LAM.
The aberrant expression of the ER and growth factors and
their receptors in the lungs of LAM patients has received
attention by researchers. Interestingly, immunohistochemical
studies show that IGF binding proteins-2, -4, and -6 are
associated with spindle-shaped LAM cells, whereas type 5 IGF
binding protein is associated with epithelioid LAM cells (39).
Similarly, FGF receptor-2 (FGFR-2; bek) is primarily expressed in LAM smooth muscle cells compared with FGFR-1
(Flg), which is expressed in epithelial cells adjacent to LAM
smooth muscle cells (21). Matsui et al. (29) demonstrated that
ER, localized in the nuclei of epithelioid (nonproliferating)
LAM cells, is downregulated by hormonal therapy. In contrast,
spindle-shaped (proliferating) LAM cells express little ER but
highly express membrane type 1 matrix metalloproteinase
(MT-1 MMP) (29). MT-1 MMP is a membrane-associated
protein that activates MMP-2. MMP-2 is a potent matrixdegrading enzyme that is upregulated in LAM lung (20, 28).
MMPs regulate matrix turnover, but it has also been shown that
MMPs can induce cell growth by the activation of IGF binding
proteins (35). These studies suggest that differential expression
of growth factors and their receptors in LAM may result in
cell-specific functions to exert fibrogenic, proliferative, and
matrix-regulating effects in LAM. The immunohistochemical
analysis of LAM tissue sheds new insights into the potential
roles of ER, growth factors, and MMPs in LAM. However, it
is limiting in terms of translating the role of such proteins into
cellular function. The roles of ER, growth factors, their receptors, and MMPs in LAM-derived cells in culture has not been
studied and would be extremely useful in clarifying the complex role of each individual growth factor in the pathogenesis
of LAM.
In summary, considerable progress has been made in our
understanding of the pathogenesis of LAM. Although the jury
is out on the true source of LAM cells, it is clear that they are
a heterogeneous population of smooth muscle-like cells that
variably exhibit immunoreactivity to HMB45. Evidence suggests that they possess specific functions regarding cell growth
and matrix-degrading capacity and that the growth of at least a
subpopulation of LAM cells is associated with the mutant
expression of the TSC2 gene. Until a deeper understanding of
the exact nature of LAM cells is achieved or until an animal
model becomes available, scientists studying LAM will need to
rely on immunohistochemical analysis of LAM tissue, the
study of LAM-derived smooth muscle cells, renal AMLs, or
other cells expressing aberrant forms of TSC2. However, it
should be realized that limiting studies in LAM to specific
genotypes may ultimately hamper the investigation of the
pathogenesis of this disease. Studies that focus on TSC2 and
TSC1 biology, other potential genetic mutations in LAM, the
function of individual subpopulations of LAM cells, and factors that govern cell growth and matrix degradation all bear
relevance to the pathogenesis of LAM.
Editorial Focus
L693
AJP-Lung Cell Mol Physiol • VOL
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
characteristics of lymphangioleiomyomatosis in patients with tuberous
sclerosis complex. Am J Respir Crit Care Med 164: 669–671, 2001.
Potter CJ, Huang H, and Xu T. Drosophila Tsc1 functions with Tsc2 to
antagonize insulin signaling in regulating cell growth, cell proliferation,
and organ size. Cell 105: 357–368, 2001.
Potter CJ, Pedraza LG, and Xu T. Akt regulates growth by directly
phosphorylating Tsc2. Nat Cell Biol 4: 658–665, 2002.
Rajah R, Nunn SE, Herrick DJ, Grunstein MM, and Cohen P.
Leukotriene D4 induces MMP-1, which functions as an IGFBP protease in
human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol
271: L1014–L1022, 1996.
Smolarek TA, Wessner LL, McCormack FX, Mylet JC, Menon AG,
and Henske EP. Evidence that lymphangiomyomatosis is caused by
TSC2 mutations: chromosome 16p13 loss of heterozygosity in angiomyolipomas and lymph nodes from women with lymphangiomyomatosis.
Am J Hum Genet 62: 810–815, 1998.
Strizheva GD, Carsillo T, Kruger WD, Sullivan EJ, Ryu JH, and
Henske EP. The spectrum of mutations in TSC1 and TSC2 in women with
tuberous sclerosis and lymphangiomyomatosis. Am J Respir Crit Care
Med 163: 253–258, 2001.
Sullivan EJ. Lymphangioleiomyomatosis: a review. Chest 114: 1689–
1703, 1998.
Valencia JC, Matsui K, Bondy C, Zhou J, Rasmussen A, Cullen K, Yu
ZX, Moss J, and Ferrans VJ. Distribution and mRNA expression of
insulin-like growth factor system in pulmonary lymphangioleiomyomatosis. J Investig Med 49: 421–433, 2001.
Weiser-Evans MC, Schwartz PE, Grieshaber NA, Quinn BE, Grieshaber SS, Belknap JK, Mourani PM, Majack RA, and Stenmark KR.
Novel embryonic genes are preferentially expressed by autonomously
replicating rat embryonic and neointimal smooth muscle cells. Circ Res
87: 608–615, 2000.
Yu J, Astrinidis A, and Henske EP. Chromosome 16 loss of heterozygosity in tuberous sclerosis and sporadic lymphangiomyomatosis. Am J
Respir Crit Care Med 164: 1537–1540, 2001.
Yu J, Astrinidis A, Howard S, and Henske EP. Estradiol and tamoxifen
stimulate LAM-associated angiomyolipoma cell growth and activate both
genomic and nongenomic signaling pathways. Am J Physiol Lung Cell
Mol Physiol 286: L694–L700, 2004.
286 • APRIL 2004 •
www.ajplung.org
Downloaded from http://ajplung.physiology.org/ by 10.220.33.5 on May 10, 2017
22. Kalassian KG, Doyle R, Kao P, Ruoss S, and Raffin TA. Lymphangioleiomyomatosis: new insights. Am J Respir Crit Care Med 155: 1183–
1186, 1997.
23. Karbowniczek M, Yu J, and Henske EP. Renal angiomyolipomas from
patients with sporadic lymphangiomyomatosis contain both neoplastic and
non-neoplastic vascular structures. Am J Pathol 162: 491–500, 2003.
24. Kerr LA, Blute ML, Ryu JH, Swensen SJ, and Malek RS. Renal
angiomyolipoma in association with pulmonary lymphangioleiomyomatosis: forme fruste of tuberous sclerosis? Urology 41: 440–444, 1993.
25. Kwiatkowski DJ. Tuberous sclerosis: from tubers to mTOR. Ann Hum
Genet 67: 87–96, 2003.
26. Kwiatkowski DJ, Zhang H, Bandura JL, Heiberger KM, Glogauer M,
el-Hashemite N, and Onda H. A mouse model of TSC1 reveals sexdependent lethality from liver hemangiomas, and up-regulation of p70S6
kinase activity in Tsc1 null cells. Hum Mol Genet 11: 525–534, 2002.
27. Lambert N and Nelson JL. Microchimerism in autoimmune disease:
more questions than answers? Autoimmun Rev 2: 133–139, 2003.
28. Matsui K, Takeda K, Yu ZX, Travis WD, Moss J, and Ferrans VJ.
Role for activation of matrix metalloproteinases in the pathogenesis of
pulmonary lymphangioleiomyomatosis. Arch Pathol Lab Med 124: 267–
275, 2000.
29. Matsui K, Takeda K, Yu ZX, Valencia J, Travis WD, Moss J, and
Ferrans VJ. Downregulation of estrogen and progesterone receptors in
the abnormal smooth muscle cells in pulmonary lymphangioleiomyomatosis following therapy. An immunohistochemical study. Am J Respir Crit
Care Med 161: 1002–1009, 2000.
30. Matsumoto Y, Horiba K, Usuki J, Chu SC, Ferrans VJ, and Moss J.
Markers of cell proliferation and expression of melanosomal antigen in
lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 21: 327–336,
1999.
31. McCormack F, Brody A, Meyer C, Leonard J, Chuck G, Dabora S,
Sethuraman G, Colby TV, Kwiatkowski DJ, and Franz DN. Pulmonary cysts consistent with lymphangioleiomyomatosis are common in
women with tuberous sclerosis: genetic and radiographic analysis. Chest
121: 61S, 2002.
32. Moss J, Avila NA, Barnes PM, Litzenberger RA, Bechtle J, Brooks
PG, Hedin CJ, Hunsberger S, and Kristof AS. Prevalence and clinical