Journal
CELL
Volume 133, Issue 1, Pages 66-77Publisher
CELL PRESS
DOI: 10.1016/j.cell.2008.01.046
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Funding
- Howard Hughes Medical Institute Funding Source: Medline
- NCI NIH HHS [P01 CA094060, P01 CA094060-01A10002, R37 CA034610, R37 CA034610-25, P30 CA008748] Funding Source: Medline
- NIGMS NIH HHS [GM07739, T32 GM007739] Funding Source: Medline
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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 TGFb via the Smad signaling pathway. TGFb 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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