Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis

Crooks, Denise; Pacheco–Rodriguez, Gustavo; DeCastro, Rosamma; McCoy, J. Philip; Jian, Wang; Kumaki, Fumiyuki; Darling, Thomas N.; Moss, Joel

doi:10.1073/pnas.0407971101

Cited by 175 publications

(134 citation statements)

References 27 publications

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“…Further, LAM cells were identified in blood and other body fluids (ie, urine, chylous pleural effusions, ascites). 17 These data are consistent with the metastatic spread of LAM cells among organs.…”

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confidence: 80%

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Serum Vascular Endothelial Growth Factor-D Levels in Patients With Lymphangioleiomyomatosis Reflect Lymphatic Involvement

Glasgow

Avila

Lin

et al. 2009

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confidence: 80%

“…Plasma levels of osteopontin (a protein that binds to CD44) were higher in LAM patients than in healthy volunteers, 23 and LAM cells from blood or chyle can be characterized for TSC2 LOH. 17 These, in addition to VEGF-D, may aid in the difficult diagnosis of a patient who presents with only cystic lung disease.…”

Section: Discussionmentioning

confidence: 99%

Serum Vascular Endothelial Growth Factor-D Levels in Patients With Lymphangioleiomyomatosis Reflect Lymphatic Involvement

Glasgow

Avila

Lin

et al. 2009

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106

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“…We also found that estrogen treatment enhances the survival of intravenously injected cells in the peripheral blood. These data are of particular interest because circulating LAM cells can be detected in the blood and pleural fluid of women with LAM (35). Our data provide a rationale for the potential use of circulating cells as a quantitative and rapid biomarker of response to targeted therapy in women with LAM.…”

Section: Discussionmentioning

confidence: 97%

Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells

Robb

Morrison

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

154

198

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Lymphangioleiomyomatosis (LAM) is an often fatal disease primarily affecting young women in which tuberin (TSC2)-null cells metastasize to the lungs. The mechanisms underlying the striking female predominance of LAM are unknown. We report here that 17-␤-estradiol (E2) causes a 3-to 5-fold increase in pulmonary metastases in male and female mice, respectively, and a striking increase in circulating tumor cells in mice bearing tuberin-null xenograft tumors. E 2-induced metastasis is associated with activation of p42/44 MAPK and is completely inhibited by treatment with the MEK1/2 inhibitor, CI-1040. In vitro, E 2 inhibits anoikis of tuberin-null cells. Finally, using a bioluminescence approach, we found that E 2 enhances the survival and lung colonization of intravenously injected tuberin-null cells by 3-fold, which is blocked by treatment with CI-1040. Taken together these results reveal a new model for LAM pathogenesis in which activation of MEKdependent pathways by E 2 leads to pulmonary metastasis via enhanced survival of detached tuberin-null cells.L AM, the pulmonary manifestation of tuberous sclerosis complex (TSC), affects women almost exclusively (1). LAM affects 30Ϫ40% of women with TSC (2, 3). In a Mayo Clinic series, LAM was the third most frequent cause of TSC-related death, after renal disease and brain tumors (4). LAM can also occur in women who do not have germline mutations in TSC1 or TSC2 (sporadic LAM). LAM cells from both TSC-LAM and sporadic LAM carry inactivating mutations in both alleles of the TSC1 or TSC2 genes (5). The protein products of TSC1 and TSC2, hamartin and tuberin, respectively, form heterodimers (6, 7) that inhibit the small GTPase Ras homologue enriched in brain (Rheb), via tuberin's highly conserved GTPase activating domain. In its active form, Rheb activates the mammalian target of rapamycin (mTOR) complex 1 (TORC1), which is a key regulator of protein translation, cell size, and cell proliferation (8). Evidence of TORC1 activation, including hyperphosphorylation of ribosomal protein S6, has been observed in tumor specimens from TSC patients and LAM patients (9-11). Independent of its activation of mTOR, Rheb inhibits the activity of B-Raf and C-Raf/Raf-1 kinase, resulting in reduced phosphorylation of p42/44 MAPK (12-14), but the impact of the Raf/MEK/ MAPK pathway on disease pathogenesis is undefined.LAM is characterized pathologically by widespread proliferation of abnormal smooth muscle cells and by cystic changes within the lung parenchyma (1). About 60% of women with the sporadic form of LAM also have renal angiomyolipomas. The presence of TSC2 mutations in LAM cells and renal angiomyolipoma cells from women with sporadic LAM, but not in normal tissues, has led to the hypothesis that LAM cells spread to the lungs via a metastatic mechanism, despite the fact that LAM cells have a histologically benign appearance (15,16). Genetic and fluorescent in situ hybridization analyses of recurrent LAM after lung transplantation support this benign metastatic model (16).The female...

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“…Furthermore, it has been postulated that LAM may originate from AML cells that metastasize to the lungs. 14,15 Against this possibility, however, stands the fact that the two conditions are more often seen independently than in combination and that AML affects men and women, whereas LAM rarely affects men. Therefore, currently it is hypothesized that TSC2-deficient cells from a third site may metastasize to both the lung and the kidney in the sporadic form of LAM.…”

mentioning

confidence: 99%

“…Therefore, currently it is hypothesized that TSC2-deficient cells from a third site may metastasize to both the lung and the kidney in the sporadic form of LAM. 16 Despite intense speculation, 14,15,17 the precursor cell from which AML and LAM originate remains unknown. A neural crest cell (NCC) origin has been mostly favored 14,15,17 because of the coexistence of melanocytic and smooth cell markers in the AML and LAM cells, two cell lineages known to arise, partially in the case of smooth muscle cells, from NCCs.…”

mentioning

confidence: 99%

Evidence Supporting a Lymphatic Endothelium Origin for Angiomyolipoma, a TSC2− Tumor Related to Lymphangioleiomyomatosis

Yue

Pacheco

Cheng

et al. 2016

The American Journal of Pathology

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Angiomyolipoma (AML) is a tumor closely related to lymphangioleiomyomatosis (LAM). Both entities are characterized by the proliferation of smooth muscle actin and melanocytic glycoprotein 100 (recognized by antibody HMB-45)epositive spindle-shaped and epithelioid cells. AML and LAM are etiologically linked to mutations in the tsc2 and tsc1 genes in the case of LAM. These genes encode the proteins tuberous sclerosis complex (TSC)-1 and TSC2, which are directly involved in suppressing the mechanistic target of rapamycin cell growth signaling pathway. Although significant progress has been made in characterizing and pharmacologically slowing the progression of AML and LAM with rapamycin, our understanding of their pathogenesis lacks an identified cell of origin. We used an AML-derived cell line to determine whether TSC2 restitution brings about the cell type from which AML arises. We found that AML cells express lymphatic endothelial cell markers consistent with lymphatic endothelial cell precursors in vivo and in vitro. Moreover, on TSC2 correction, AML cells mature into adult lymphatic endothelial cells and have functional attributes characteristic of this cell lineage, suggesting a lymphatic endothelial cell of origin for AML. These effects are dependent on TSC2-mediated mechanistic target of rapamycin inactivation. Finally, we demonstrate the in vitro effectiveness of norcantharidin, a lymphangiogenesis inhibitor, as a potential co-adjuvant therapy in the treatment of AML. (Am J Pathol 2016 http://dx

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Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis

Abstract: loss of heterozygosity ͉ metastasis ͉ CD235a ͉ angiomyolipoma ͉ smooth muscle cells

Cited by 175 publications

References 27 publications

Serum Vascular Endothelial Growth Factor-D Levels in Patients With Lymphangioleiomyomatosis Reflect Lymphatic Involvement

Serum Vascular Endothelial Growth Factor-D Levels in Patients With Lymphangioleiomyomatosis Reflect Lymphatic Involvement

Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells

Evidence Supporting a Lymphatic Endothelium Origin for Angiomyolipoma, a TSC2− Tumor Related to Lymphangioleiomyomatosis

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