TGFbeta Primes Breast Tumors for Lung Metastasis Seeding Through Angiopoietin-like 4

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2008 Apr 9

PMID 18394990

Citations 525

Authors

David Padua

Xiang H-F Zhang

Qiongqing Wang

Cristina Nadal

William L Gerald

Roger R Gomis

Joan Massague

Affiliations

Soon will be listed here.

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.

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