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PMID: 18394990 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4.

Cell ·Vol. 133 ·No. 1 ·2008-04-04 ·Pages 66-77

Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR, Massagué J

Abstract

Cells released from primary tumors seed metastases to specific organs by a nonrandom process, implying the involvement of biologically selective mechanisms. Based on clinical, functional, and molecular evidence, we show that the cytokine TGFbeta in the breast tumor microenvironment primes cancer cells for metastasis to the lungs. Central to this process is the induction of angiopoietin-like 4 (ANGPTL4) by TGFbeta via the Smad signaling pathway. TGFbeta induction of Angptl4 in cancer cells that are about to enter the circulation enhances their subsequent retention in the lungs, but not in the bone. Tumor cell-derived Angptl4 disrupts vascular endothelial cell-cell junctions, increases the permeability of lung capillaries, and facilitates the trans-endothelial passage of tumor cells. These results suggest a mechanism for metastasis whereby a cytokine in the primary tumor microenvironment induces the expression of another cytokine in departing tumor cells, empowering these cells to disrupt lung capillary walls and seed pulmonary metastases.

MeSH Terms
Angiopoietin-Like Protein 4 Angiopoietins Animals Breast Neoplasms/metabolism,pathology Cell Line, Tumor Cell Movement Endothelial Cells/cytology Female Gene Expression Profiling Humans Intercellular Junctions Intercellular Signaling Peptides and Proteins/metabolism Lung Neoplasms/metabolism,secondary Mice Mice, Inbred NOD Mice, SCID Neoplasm Transplantation Neoplasms, Experimental Oligonucleotide Array Sequence Analysis Signal Transduction Transforming Growth Factor beta/metabolism Transplantation, Heterologous Tumor Cells, Cultured
Chemicals
ANGPTL4 protein, human Angiopoietin-Like Protein 4 Angiopoietins Intercellular Signaling Peptides and Proteins Transforming Growth Factor beta
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Padua David
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Zhang Xiang H-F
Wang Qiongqing
Nadal Cristina
Gerald William L
Gomis Roger R
Massagué Joan
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2008.01.046
Published
2008-04-04
Pages
66-77
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC2390892
Subset
IM
Grants
NIGMS NIH HHS · GM07739 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · R37 CA034610-25 · United States
NCI NIH HHS · P30 CA008748 · United States
NCI NIH HHS · P01 CA094060 · United States
NCI NIH HHS · P01 CA094060-01A10002 · United States
NIGMS NIH HHS · T32 GM007739 · United States
NCI NIH HHS · R37 CA034610 · United States
Corrections
CommentIn
PMID: 18394984
External Links
PubMed source DOI: 10.1016/j.cell.2008.01.046 PMC Full Text View journal details
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