(Chest. 2002;121:56S-61S.)
© 2002
American College of Chest Physicians
Genetics and Gene Expression in Lymphangioleiomyomatosis*
Giles F. Filley Lecture
Gustavo Pacheco-Rodriguez, PhD;
Arnold S. Kristof, MD;
Linda A. Stevens;
Yi Zhang, PhD;
Denise Crooks, PhD and
Joel Moss, MD, PhD
*
From the Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
Correspondence to: Joel Moss, MD, PhD, Chief, Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Dr, Bldg 10, Room 6 D05, MSC 1590, Bethesda, MD 20892-1590; e-mail: mossj{at}nhlbi.nih.gov
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Abstract
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Lymphangioleiomyomatosis
(LAM) is a disease of unknown etiology that is characterized by the
proliferation of abnormal smooth muscle cells (LAM cells) in the lung,
which leads to cystic parenchymal destruction and progressive
respiratory failure. Recent evidence suggests that the proliferative
and invasive nature of LAM cells may be due, in part, to somatic
mutations in the TSC2 gene, which has been implicated in
the pathogenesis of tuberous sclerosis complex. Here, we describe the
clinical and molecular characteristics of LAM, as well as the efforts
now under way to understand the genetic and biochemical factors that
lead to progressive pulmonary destruction and, ultimately, to lung
transplantation or death.
Key Words: lymphangioleiomyomatosis • tuberous sclerosis complex
Lymphangioleiomyomatosis (LAM), a rare disease that
is characterized by cystic destruction of the lung leading to chronic
respiratory failure, is found primarily in women of childbearing age.
It is a multisystem disorder and is also associated with abdominal
tumors (eg, angiomyolipomas, lymphangioleiomyomas). The lung
cysts and abdominal tumors are characterized by the presence of
abnormal smooth muscle cells (ie, LAM cells). Epidemiologic,
genetic, and molecular studies have demonstrated a link between
sporadic LAM and tuberous sclerosis complex (TSC), an
autosomal-dominant neurocutaneous disorder with variable penetrance
caused by mutations in the TSC1 and TSC2 genes.
Here, we discuss the clinical characteristics of LAM, the association
of LAM and TSC, the morphologic characteristics of abnormal smooth
muscle proliferative lesions, as well as gene and protein abnormalities
that are characteristic of both sporadic LAM and LAM in patients with
TSC.
|
Clinical Characteristics
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LAM is characterized by progressive respiratory failure and
recurrent pneumothoraces.1
The clinical characteristics of
LAM were investigated in three detailed studies.1
2
3
Patients presented with dyspnea due to small airway obstruction and/or
chylous pleural effusion, chronic cough, or acute chest pain resulting
from pneumothorax. Wheezing and hemoptysis occured less commonly, with
26% of patients having evidence of airway hyperreactivity.
Asymptomatic lung disease may be discovered after the diagnosis of
abdominal angiomyolipomas or axial lymphatic masses.4
Symptoms arising from abdominal lesions include flank pain, hematuria,
and abdominal distension. Retroperitoneal lymphatic involvement can
give rise to significant lymphedema and neuropathies.
Physical examination of the lungs most commonly reveals crackles and
decreased breath sounds, which are consistent with parenchymal
destruction or chylous effusion. Wheezing is heard in 14% of patients,
and clubbing is a rare finding. Cardiac examination may provide
evidence of pulmonary hypertension secondary to chronic respiratory
failure. Abdominal examination may reveal the presence of ascites or
masses, indicating angiomyolipomas or axial lymphatic involvement.
On a chest radiograph, LAM is characterized by an increased number of
interstitial markings in the presence of normal lung volumes or
hyperinflation.5
Although rarely seen on chest radiograph,
thin-walled cysts surrounded by normal parenchyma, which are
pathognomonic of LAM, are easily identified on high-resolution CT
(HRCT) scanning of the chest (Fig 1
).6
7
8
Other diseases, such as eosinophilic granuloma,
benign metastasizing leiomyoma, and Birt-Hogg-Dubé syndrome, need
to be included in the differential diagnosis. In addition, patients
with TSC may have nodular lesions that are independent of LAM-related
cysts, perhaps representing the multifocal micromodular pneumocyte
hyperplasia (MMPH) seen on histopathologic examination. On
abdominal imaging, angiomyolipomas and lymphatic masses can be detected
in patients with sporadic LAM as well as in those with TSC. In patients
with TSC, renal angiomyolipomas are more likely to be bilateral than in
sporadic LAM, and involve a greater proportion of the kidney. Renal
cell carcinomas are seen in patients with TSC, and renal masses should
be investigated appropriately.9
Pulmonary function testing demonstrates an obstructive ventilatory
abnormality, with superimposed restriction in 17% of
patients.2
The diffusing capacity of the lung for carbon
monoxide (DLCO) often is decreased out of proportion to any
abnormalities in spirometry or lung volumes, suggesting a primary
gas-exchange defect.3
In a recent study,10
the rate of decline in DLCO, but not in
FEV1, correlated directly with the histologic
severity of disease and inversely with the time to transplantation.
Similarly, patients often demonstrate hypoxemia at rest or during
exercise, which would not be expected to result from the limited
decrease in ventilatory lung function.10
11
Hypoxemia in
the absence of ventilatory or cardiac limitation has been documented by
cardiopulmonary exercise testing. Finally, 26% of patients with LAM
responded significantly to therapy with bronchodilators, indicating a
reversible component in the airways obstruction.
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Pathology
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Gross specimens from open lung biopsies or autopsies contain cysts
throughout the lung parenchyma that are 0.5 to 2.0 cm in
size.12
On microscopic examination, discrete foci of
abnormal smooth muscle cells abut cystic structures lined with
hyperplastic type II pneumocytes. The foci contain centrally located,
small, spindle-shaped cells with larger epithelioid cells at the
periphery, all of which are arranged in haphazard
fashion.13
In addition to LAM cell foci, patients with TSC
may also exhibit MMPH, a feature characterized by ill-defined nodules
consisting of alveoli with hyperplastic type II
pneumocytes.14
Despite clinical findings that are
consistent with airway hyperreactivity, airway inflammation or invasion
by LAM cells has not been demonstrated.
Abnormal smooth muscle cells in LAM cell foci, primarily of the
epithelioid subtype, react with HMB45, a monoclonal antibody that
reacts with gp100, a melanocyte antigen found in
premelanosomes.12
Although the epitope recognized in LAM
cells has not been identified, HMB45 immunoreactivity has become the
hallmark of diagnosis. Consistent with their classification as smooth
muscle cells, LAM cells react with several smooth muscle-specific
antibodies, including those against 
-actin, vimentin, desmin, and
smooth muscle myosin heavy chains I and II.12
By
immunohistochemistry, the intensity of staining for several proteins
involved in cell proliferation (eg, Bcl-2, MCL-1, c-myc, and
proliferating cell nuclear antigen) was greater in LAM cells than in
adjacent lung cells.15
Proliferating cell nuclear antigen
immunoreactivity was highest in spindle-shaped cells, suggesting a
higher rate of proliferation than that of peripheral epithelioid LAM
cells. In tissue sections, apoptosis appeared to be rare among the
abnormal smooth muscle cells in the LAM foci.15
In support
of a role for sex hormones in the pathogenesis of LAM, epithelioid LAM
cells reacted strongly with antibodies to estrogen and progesterone
receptors. In lung biopsies from five patients who had been treated
with medroxyprogesterone, estrogen and progesterone receptor
immunoreactivity was undetectable, which is perhaps a consequence of
the down-regulation of receptors in end-stage disease and/or an effect
of drug treatment.16
Given the absence of immune cells in LAM cell foci, extracellular
matrix destruction and invasion would appear to be due to the abnormal
smooth muscle cells themselves. LAM cells were reactive with antibodies
directed against matrix metalloproteinases MMP-2 and MMP-9,
which is consistent with the presence of proteins involved in
extracellular matrix degradation.17
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Epidemiology
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The clinical characteristics of lung disease in patients with TSC
and LAM are similar to those in patients with sporadic
LAM.18
As a consequence, an epidemiologic link between LAM
and TSC was sought. There are currently approximately 450 women with
LAM in North America, but the true incidence is unknown. In contrast,
the prevalence of TSC is estimated to be approximately 1 in 6,000, with
equal frequency in men and women.19
In retrospective
studies, the prevalence of LAM in patients with TSC was estimated to be
< 4%.20
However, recent studies21
22
23
have
demonstrated that one third of patients with TSC who had no pulmonary
symptoms when screened by HRCT of the chest had pulmonary cysts that
were consistent with LAM (Table 1
, Group 1). In a prospective study
(Table 1 ), newly diagnosed patients (group 1) had normal lung function and more
mild disease on HRCT scans of the chest than did patients with TSC in
whom LAM previously had been diagnosed (group 2).21
In the latter group of patients, FEV1 and
DLCO were inversely proportional to disease severity, as
assessed by HRCT of the chest.
Of 10 men with TSC, none had evidence of LAM, suggesting that, in
addition to genetic factors, hormonal environment may play a role in
the development of cystic lung disease. Unlike lung cysts, nodules were
present equally in male and female patients with TSC, independent of
the presence of LAM, suggesting that MMPH and lung cysts may have
distinct etiologies. The high prevalence of LAM in patients with TSC,
as well as the apparent dissociation of cysts and nodules, indicates
that screening for cystic disease by HRCT of the chest may identify
patients with TSC who are at risk for the development of LAM-related
complications, and who might be candidates for therapy early in the
course of their disease.
Although almost all cases have occurred in premenopausal women,
LAM has been reported in men and postmenopausal
women.24
25
Because the vast majority of cases occur in
women of childbearing age, estrogens are thought to play a role in the
progression of the disease. This hypothesis has been supported by case
reports26
that described a worsening of the disease during
pregnancy, menstruation, and oral contraceptive use. In a nationwide
case-control study, however, the risk of LAM did not increase with the
use of oral contraceptive medications.27
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Molecular Biology of LAM and TSC
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In addition to the epidemiologic association between TSC and LAM,
the identification of gene and protein abnormalities in LAM cells and
angiomyolipomas has strengthened the hypothesis that the two diseases
have a common etiology. Genetic abnormalities were found in the
TSC1 and TSC2 loci on chromosomes 9q34 and 16p13,
respectively.28
Mutations in TSC2 are common in
patients with sporadic LAM as well as in those with TSC and LAM. In
contrast, TSC1 mutations have been found in patients with
TSC, but not in those with sporadic LAM.29
30
The
TSC1 gene encodes hamartin, a 1,164-amino acid protein that
contains a myosin tail-like, intermediate filament, and adenosine
triphosphate synthetase regions, as well as a putative transmembrane
domain. These structural domains predict functions that are consistent
with a role for hamartin in cytoskeletal rearrangement.31
The TSC2 gene encodes tuberin, a 1,359-amino acid protein
that functions as a guanosine triphosphatase-activating protein
for Rap1a and Rab5.32
33
The macromolecular complex that
includes hamartin and tuberin is primarily cytosolic, is regulated by
phosphorylation, and appears to function in multiple tumor-suppressor
roles in cell-cycle control.34
35
|
Global Gene Expression in Sporadic LAM
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To identify and characterize the genes expressed in LAM
proliferative lesions (genomics), we sought to develop cultures of cell
lines in which to characterize the relevant gene products and potential
therapeutic targets (proteomics). Global gene expression in the lungs
of patients with LAM was examined using tissue collected at the time of
lung transplantation. The foci of abnormal smooth muscle cells were
identified in embedded frozen sections and were selected by laser
capture microdissection. After the isolation of messenger RNA from LAM
lesions, reverse transcriptase polymerase chain reaction (PCR) was
performed with specific primers for the transcripts of gp100,
-smooth muscle actin, and SM22. After the reproducibility of the
procedure was established, we assessed global gene expression with
filters representing approximately 4,000 genes. The overall gene
expression of primary pulmonary artery smooth muscle cells was compared
with that of each microdissected LAM sample. The overall gene
expression of LAM proliferative regions correlated best with cells from
angiomyolipomas, and next best with that of smooth muscle cells, but
not of fibroblasts, lung epithelial adenocarcinoma (A549) cells, or the
melanoma cell line Malme 3M, which also reacts with the HMB45 antibody.
The presence of similarities between LAM cells in lung nodules and
angiomyolipomas is consistent with a common origin. These data support
a model of metastatic spread of cells, as defined by the presence of
identical TSC mutations in cells from the two sites.30
A
further evaluation of specific candidate etiologic genes is currently
under way.
|
Long-term Culture and Characterization of LAM Cells
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To establish a cell line in which to study the molecular and
biochemical nature of LAM cells, samples of lung tissue from patients
who have received a diagnosis of LAM were obtained after lung biopsy or
transplantation. Small pieces of tissue were implanted on cell
culture dishes and were grown in serum-supplemented culture media. To
isolate homogeneous cell populations, cells were seeded at low density
and were allowed to form colonies, which then were removed following
capture in a cloning cylinder. The cell lines obtained appeared to
express smooth muscle antigens and reacted with the HMB45
antibody.36
37
Some isolated cell lines have retained
these characteristics for 8 to 10 passages and are currently the
subject of genetic, biochemical, and structural studies.
|
Genetic Characteristics of LAM Cells
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To determine cell clonality, genomic DNA was prepared from
cultured cells or lung tissue, and the methylation patterns of the
human androgen receptor (HUMAR) gene were assessed.38
HUMAR-specific PCR primers amplified HUMAR alleles both in lung cells
or in tissue derived from patients with LAM. Restriction analysis was
carried out using HpaII, an endonuclease that cleaves only
nonmethylated segments. Amplified products were separated on a
gel. When the restriction enzyme HpaII was employed
to digest nonmethylated regions of the HUMAR, only the methylated
allele was amplified, allowing for the assessment of clonality in LAM
cells. Other studies including karyotyping and the identification of
other markers should help to characterize better the cell lines derived
from patients with LAM.39
Mutations in the TSC2 gene, as determined by a loss of
heterozygosity (LOH) at the TSC2 locus, were previously
identified in lung tissue from patients with sporadic
LAM.30
The TSC2 mutations were present in cells
from LAM proliferative lesions but not from healthy lungs, indicating
the contribution of localized mutagenesis in the pathogenesis of
LAM. In addition, mutations were apparently identical in
angiomyolipomas and lung lesions from the same patients, suggesting
that LAM cells may migrate to lymphatic, abdominal, and/or thoracic
organs after arising in a single location. We are currently screening
for LOH at the TSC2 locus in LAM cell lines. To analyze for
this genetic alteration, samples of DNA from LAM cells and the lungs of
patients with LAM were amplified using PCR with specific
oligonucleotide primers for microsatellite loci on chromosome
16p13.3.40
41
An LOH at the TSC2 locus was
present in a cell line derived from a patient with sporadic LAM,
indicating that cultured cells retain genetic characteristics of the
original founder cells. Consistent with a somatic mutagenesis step in
the etiology of LAM, there are clonal cell lines from different tissues
in the same patient that both have and do not have an LOH at the
TSC2 locus.
|
Conclusion
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Single base-pair mutations in the TSC2 gene, and
a putative loss of tumor-suppressor activity, could, in large part,
explain the uncontrolled proliferation of LAM cells. TSC
genes play roles in transcription, signal transduction, cell cycle
control, control of cell growth and proliferation, and cell
adhesion.31
42
43
44
45
The cellular components involved in
metastasis, invasion, and angiogenesis also may be altered in the
abnormal smooth muscle cells found in pulmonary LAM lesions and
angiomyolipomas. In addition to the point mutations previously
identified in the TSC2 gene, chromosomal and gene
alterations leading to these phenotypes may include aneuploidy,
translocations, deletions, and gene amplification.46
The
nature of the macromolecular complex containing hamartin and tuberin,
and their interactions with other cellular proteins, is poorly
understood. Future findings related to the genomics and proteomics of
TSC and LAM using tissue and cell lines derived from patients may shed
light on the cellular processes that lead to the LAM phenotype and will
help to identify molecular targets for therapeutic intervention.
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Acknowledgements
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We thank Dr. Martha Vaughan for constructive
comments and revision of the manuscript.
|
Footnotes
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Abbreviations: DLCO = diffusing
capacity of the lung for carbon monoxide; HRCT = high-resolution
CT; HUMAR = human androgen receptor; LAM =
lymphangioleiomyomatosis; LOH = loss of heterozygosity;
MMPH = multifocal micronodular pneumocyte hyperplasia;
PCR = polymerase chain reaction; TSC = tuberous sclerosis
complex
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Abstract
Clinical Characteristics
