Evidence Supporting a Lymphatic Endothelium Origin for Angiomyolipoma, a TSC2(-) Tumor Related to Lymphangioleiomyomatosis.
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)-positive 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.
Department of Pathology, The University of Chicago, Chicago, Illinois.
Michael
M
Yue
Department of Pathology, The University of Chicago, Chicago, Illinois.
Gustavo
G
Pacheco
Department of Pathology, The University of Chicago, Chicago, Illinois.
Tao
T
Cheng
Department of Pathology, The University of Chicago, Chicago, Illinois.
Jefferine
J
Li
Department of Pathology, The University of Chicago, Chicago, Illinois.
Yitang
Y
Wang
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Elizabeth P
EP
Henske
Department of Pathology, The University of Chicago, Chicago, Illinois. Electronic address: lschuger@bsd.uchicago.edu.
Lucia
L
Schuger
D018207:Angiomyolipoma / Q000235:genetics / Q000473:pathology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects; D004729:Endothelium, Lymphatic / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D018192:Lymphangioleiomyomatosis / Q000235:genetics / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
D000903:Antibiotics, Antineoplastic; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus