1. TGF[beta] Primes Breast Tumors for Lung Metastasis Seeding through Angiopoietin-like 4
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Padua, David, Zhang, Xiang H.-F., Wang, Qiongqing, Nadal, Cristina, Gerald, William L., Gomis, Roger R., and Massague, Joan
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Transforming growth factors ,Breast cancer ,Metastasis ,Biological sciences - Abstract
To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2008.01.046 Byline: David Padua (1), Xiang H.-F. Zhang (1), Qiongqing Wang (1), Cristina Nadal (5), William L. Gerald (2), Roger R. Gomis (4), Joan Massague (1)(3) Keywords: HUMDISEASE; SIGNALING; CELLBIO 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 TGF[beta] 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 TGF[beta] via the Smad signaling pathway. TGF[beta] 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. Author Affiliation: (1) Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA (2) Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA (3) Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA (4) Oncology Programme, Institute for Research in Biomedicine, 08028 Barcelona, Spain (5) Institut de Malalties Hemato-OncolA[sup.2]giques, Hospital Clinic-IDIBAPS, 08036 Barcelona, Spain Article History: Received 18 October 2007; Revised 11 December 2007; Accepted 30 January 2008 Article Note: (miscellaneous) Published: April 3, 2008
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- 2008