Lymphangioleiomyomatosis and<i>TSC2<sup>-/-</sup></i>Cells

Darling, Thomas N.; Pacheco–Rodriguez, Gustavo; Gorio, Alfredo; Lesma, Elena; Walker, Cheryl L.; Moss, Joel

doi:10.1089/lrb.2009.0031

Cited by 26 publications

(22 citation statements)

References 106 publications

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“…Lymphangioleiomyomatosis (LAM) is a rare destructive lung disease that is etiologically associated with excessive proliferation of LECs (lymphangio) and smooth muscle cells (leiomyoma) throughout the lungs including bronchioles, alveolar septa, perivascular spaces, and parenchyma (Hohman et al 2008;Darling et al 2010;Kristof 2010;Kwiatkowski 2010;Seyama et al 2010). The abnormal proliferation of these two types of cells (LECs and SMCs) in LAM results in both obstruction of airways and tissue fluid drainage, causing pulmonary cyst formation, pneumothorax, and chylous pleural effusion with respiratory failure, needing lung transplantation.…”

Section: Lymphangioleiomyomatosis (Lam)mentioning

confidence: 99%

“…Importantly, LAM patients express a high level of the potent lymphangiogenic factor VEGF-D in their blood serums, which may partly explain the excessive LEC proliferation in their lungs. Because mutations in TSC1/2 lead to abnormal activation of the downstream effector mTOR, rapamycin, a chemical inhibitor for mTOR, was found to be beneficial to some LAM patients (Darling et al 2010;Kristof 2010). Kaposi's sarcoma (KS) is an endothelial cell tumor and the most common neoplasm among HIV-positive individuals .…”

Section: Lymphangioleiomyomatosis (Lam)mentioning

confidence: 99%

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The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

Choi

Lee²,

Hong

2012

Cold Spring Harbor Perspectives in Medicine

122

107

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The blood and lymphatic systems are the two major circulatory systems in our body. Although the blood system has been studied extensively, the lymphatic system has received much less scientific and medical attention because of its elusive morphology and mysterious pathophysiology. However, a series of landmark discoveries made in the past decade has begun to change the previous misconception of the lymphatic system to be secondary to the more essential blood vascular system. In this article, we review the current understanding of the development and pathology of the lymphatic system. We hope to convince readers that the lymphatic system is no less essential than the blood circulatory system for human health and well-being.

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Section: Lymphangioleiomyomatosis (Lam)mentioning

confidence: 99%

Section: Lymphangioleiomyomatosis (Lam)mentioning

confidence: 99%

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

Choi

Lee²,

Hong

2012

Cold Spring Harbor Perspectives in Medicine

122

107

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“…In TSC1 +/-mice a similar phenotype was seen, however, kidney tumors developed with a lower frequency [42]. Germline inactivation of both alleles of TSC1 or TSC2 in mice is lethal [43].…”

Section: Cell Lines As a Model Of Lammentioning

confidence: 66%

LAM cells biology and lymphangioleiomyomatosis

Grzegorek¹,

Drożdż²,

Podhorska-Okołów³

et al. 2013

Folia Histochem Cytobiol.

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Abstract:Progressive lung tissue destruction in lymphangioleiomyomatosis (LAM) occurs as a result of excessive proliferation of LAM cells caused by a mutation in one of the tuberous sclerosis complex suppressor genes, TSC1 or TSC2. These cells show constitutive activation of the mammalian target of rapamycin (mTOR) pathway and many of the mTOR-related kinases such as Akt, Erk, S6K1 and S6. Phenotype of LAM cells differs considerably depending on their microenvironment. LAM cells show differences in morphology, size and expression of various factors depending on their location in the tumor or body fluids. The presence of LAM cells in blood, urine, bronchoalveolar lavage fluid (BALF), and chyle proves their ability to metastasis. Antigens of smooth muscle cells are expressed in most LAM cells. Some of these cells are immunoreactive with HMB-45 antibody, which is used for the immunohistochemical diagnosis of LAM. Receptors for estrogen and progesterone may also be expressed in these cells, which probably is associated with the fact that LAM occurs almost exclusively in women of childbearing age. LAM cells via increased production of metalloproteinases are involved in the destruction of the extracellular matrix, as well as the remodeling and damage of lung tissue. Sporadic LAM occurs extremely rarely. Therefore a good experimental model of this disease is necessary. To date, several animal and human cell lines, which both genetically and phenotypically resemble LAM cells, have been obtained. These cell lines, derived from LAM nodule or an angiomyolipoma, are usually characterized by a mutation of the TSC2 gene, expression of smooth muscle cell antigens such as a-smooth muscle actin (aSMA) or S6K1 and S6 protein hyperphosphorylation. Presently, there is no commercially available cell line representing a good model of LAM. A better understanding of LAM cell biology is necessary for creating a useful model in vitro for further exploration of both LAM pathomechanisms and more general mechanisms of carcinogenesis. (Folia Histochemica et Cytobiologica 2013, Vol. 51, No. 1, 1-10) Abbreviations 4E-BP1 -eukaryotic translation initiation factor 4E-binding protein 1; AKT -protein kinase B; BALF -bronchoalveolar lavage fluid; EGF -epidermal growth factor; EGFR -epidermal growth factor receptor; elF4E -eukaryotic initiation factor-like protein; EMMPRIN -extracellular matrix metalloproteinase inducer; ER -estrogen receptor; ERKextracellular signal-regulated kinase; HIF-1a a a a a -hypoxia-inducible factor 1a; IGF-1 -insulin-like growth factor 1; LAM -lymphangioleiomyomatosis; LOH -loss of heterozygosity; MAPK -mitogen-activated protein kinase; MART-1 -melanoma-associated antigen recognized by T cells; MEFs -mouse embryo fibroblasts; MMPs -matrix metalloproteinases; mTOR -mammalian target of rapamycin; PAI-1 -plasminogen activation inhibitor; PDK1 -phosphoinositide-dependent kinase-1; PGE2 -endogenous prostaglandin E2; PgR -progesterone receptor; PI3K -phosphoinositide 3-kinase; PLG -plasminogen; Rheb -Ras homolog enriched in ...

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“…Although significant progress has been made in characterizing the underlying cause of these conditions and pharmacologically slowing their progression with rapamycin, 23,37 our understanding of their pathogenesis remains incomplete because of the lack of an identified cell of origin. Because the only available bona fide cell lines to study these conditions are AML derived, we elucidated the source of these neoplastic cells by endowing them with TSC2 with the expectation that TSC2 reconstitution can revert the AML cell phenotype to that of its precursor cell type.…”

Section: Discussionmentioning

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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Lymphangioleiomyomatosis andTSC2^-/-Cells

Cited by 26 publications

References 106 publications

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

LAM cells biology and lymphangioleiomyomatosis

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

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Lymphangioleiomyomatosis andTSC2-/-Cells

Cited by 26 publications

References 106 publications

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

LAM cells biology and lymphangioleiomyomatosis

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

Contact Info

Product

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Lymphangioleiomyomatosis andTSC2^-/-Cells