TGFβ Primes Breast Tumors for Lung Metastasis Seeding through Angiopoietin-like 4

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.

Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis

“…36) and matrix metalloproteinases 37 , which were previously implicated in tumour-mediated disruption of endothelium integrity. Notably, angiopoietin-like 4, a matricellular protein endowing breast tumours with the capacity to disrupt lung capillaries and seed pulmonary metastases 35,38 , was absent from our proteomic analysis. In line with this, angiopoietin-like 4 was reported to prevent metastasis of melanoma B16 cells by inhibiting vascular permeability and tumour cell motility 39 .…”

“…34), TGF-b 35 , IL8 (ref. 36) and matrix metalloproteinases 37 , which were previously implicated in tumour-mediated disruption of endothelium integrity.…”

“…All mouse experiments were carried out in accordance with the Institutional Animal Care and the local ethics committee (CIEPAL-Azur agreement NCE/2014-179). Lung microvasculature permeability was determined by the FITC-Dextran extravasation technique as previously described 35 . Briefly, 5-week-old female athymic (nu/nu) mice (Harlan) were intravenously injected with 1205Lu cells (1 Â 10 6 ) resuspended in 100 ml of PBS.…”

Endoglin expression in breast tumor cells suppresses invasion and metastasis and correlates with improved clinical outcome

“…231-ENG cells produced significantly less lung nodules than 231-VEC cells (Figure 6a). Recently, TGF-b activity has been shown to increase the extravasation of breast cancer cells into the lung parenchyma (Padua et al, 2008). To investigate this aspect of the metastatic cascade, the 231-VEC and 231-ENG cell lines were infected with a luciferaseexpressing lentivirus to generate the 231-VEC(Luc) and 231-ENG(Luc) lines.…”

Tamoxifen decreases extracellular TGF-β1 secreted from breast cancer cells — A post-translational regulation involving matrix metalloproteinase activity

“…In breast cancer patients, an increased expression of TGF-β1 has been shown to correlate with metastatic disease and poor prognostic outcome [10][11][12]. Moreover, TGF-β1 activity may prime primary breast tumors for lung metastasis seeding [13].…”