LAM

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General Information

LAM Week

Pulmonary lymphangioleiomyomatosis (LAM), a rare progressive cystic lung disease, afflicts predominantly women1,2.  LAM has been defined as a low-grade, destructive, neoplasm3 that causes holes in the lung, obstruction of lymphatics and spontaneous lung collapse1,2.  A key histologic hallmark of LAM is the presence of nests of smooth muscle-like LAM cells.  In advanced disease, LAM cells infiltrate the airways.  LAM cells are similar to normal smooth muscle cells but also express positivity for the HMB-45 (Human Melanoma Black-45) antibody.  Significance of LAM cell populations with different cell lineage markers and proliferating rates remains to be established.  Estrogen and progesterone receptors have been detected primarily in the nuclei of LAM cells4.  The origin of the LAM cell in the lung is not established 2,5.  Fibrotic tissue is usually not abundant in LAM lesions and lung.  There is no cure for LAM.

LAM cells behave in many ways like metastatic tumor cells6.  Although increased LAM cell migration and invasiveness is abrogated by TSC2 re-expression in experimental study7, the cellular and molecular mechanisms of neoplastic LAM cell transformation and the mechanisms by which these cells lead to the destruction of lung parenchyma remain unknown.  These pathological changes in LAM might be mediated by an imbalance between matrix-degrading metalloproteases (MMPs) and their endogenous inhibitors TIMPs2.  In LAM, the invasive cell phenotype is associated with TIMP-3 downregulation8 and TSC2-dependent upregulation of MMPs9-12

The progressive growth of LAM cells in the lung is associated with mutational inactivation of the Tuberous Sclerosis Complex (TSC1 or TSC2) tumor suppressor genes13-15TSC1 mutations cause a less severe clinical phenotype than do TSC2 mutations16.  The discovery of the TSC1/2 gene function as a negative regulator of the mammalian target of rapamycin complex 1 (mTORC1)17,18 led to successful use of the rapamycin analog sirolimus in clinical trials 19,20 and FDA approval of sirolimus for treatment of LAM.

TSC1 and TSC2 form a tumor suppressor complex and regulate activity of the mammalian target of rapamycin (mTOR) by directly controlling the activity of the small GTPase Rheb via the GTPase-activating protein (GAP) domain of TSC2.  Rheb binds to Raptor and controls the activity of the mTOR complex 1 (mTORC1) that directly phosphorylates p70 S6 kinase (S6K1) and 4E-BP1.  The mTOR forms two physically and functionally distinct multiprotein complexes:  the rapamycin-sensitive mTORC1 and the rapamycin-insensitive mTORC221.  The mTORC1 consists of five proteins among which Raptor positively regulates mTOR activity22-24.  The mTORC2 consists of six proteins including mTOR and Rictor, which defines the activation level of mTORC225-27 and modulates the actin cytoskeleton through Rho GTPases28-30, and Rac1 is required for mTOR activation31.  In TSC2-null and human LAM cells, Rho GTPase activity is required for cell adhesion, motility, proliferation and survival7,32,33.  Loss of TSC1/TSC2 in LAM not only induces uncontrolled LAM cell growth but also increases LAM cell viability.  Upregulation of STAT1 and STAT334-37 and autophagy38 are known mediators of LAM cell viability and survival.

Clinical and histopathological evidence demonstrate the lymphatic involvement in LAM2,39-45.  The prevailing hypothesis is that LAM lesions secrete the lymphangiogenic factor VEGF-D, recruit lymphatic endothelial cells (LECs) that form lymphatic vessels, and induce lung cysts2.  VEGF-D serum levels are increased in LAM46 compared to other cystic lung diseases including pulmonary Langerhans cell histiocytosis, emphysema, Sjögren syndrome or Birt-Hogg-Dubé syndrome47.  VEGF-D levels correlate with the severity of LAM, evaluated as a measure of CT grade, the abundance of chylous effusions and lymphatic involvement48.  VEGF-D is known for its role in cancer lymphangiogenesis and metastasis49-51.  Histopathologically, LAM lesions are surrounded by cells, positive for VEGFR3, and the lymphatic cell markers lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) and podoplanin39,52.  VEGF-D binds to the receptor protein tyrosine kinases VEGFR-2 and VEGFR-349 in humans, and to VEGFR3 in mice51,53.  Surprisingly, knock-out of VEGF-D in mice has little effect on development of the lymphatic system54.  During tumorigenesis, however, VEGF-D promotes formation of tumor lymphatic vessels and facilitates metastatic spread of cancer cells50,51.  Little is known, however, about the role of abnormal lymphatics and VEGF-D in LAM etiology and pathogenesis.

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Four Facts About LAM

  1. Lymphangioleiomyomatosis (LAM) is a progressive disease that predominantly affects women, especially during child bearing years.  Symptoms may include shortness of breath, collapsed lung, chest pain, cough, fatigue and in 40% of patients one or more benign kidney tumors called angiomyolipomas.

  2. Women with LAM may be misdiagnosed with asthma, emphysema, or bronchitis. The diagnosis of LAM can most often be made without surgical lung biopsy using a combination of high resolution CT imaging of the lungs and abdomen, clinical signs and symptoms, serum VEGF-D levels and sometimes transbronchial biopsy.

  3. In May of 2015, the FDA approved Sirolimus as a proven therapy for LAM that can stabilize lung function and improve some measures of quality of life and functional performance. Lung transplant remains the option of last resort for patients with advanced disease.

  4. Median survival in patients with LAM has varied from 10 to 30 years. Most patients have dyspnea on exertion with daily activities by 10 years after symptom onset and many will require supplemental oxygen over that interval.

Last Reviewed: August 2015