Angiopoietin-2 Stimulates Breast Cancer Metastasis through the α5β1 Integrin-Mediated Pathway

Abstract

Acquisition of a metastatic phenotype by breast cancer cells includes alternations of multigenic programs that permit tumor cells to metastasize to distant organs. Here, we report that angiopoietin-2 (Ang2), a known growth factor, is capable of promoting breast cancer cell invasion leading to metastasis. Analysis of 185 primary human breast cancer specimens that include 97 tumors showing lymph node and/or distant metastasis reveals a significant correlation between the expression of Ang2 and E-cadherin, Snail, metastatic potential, tumor grade, and lymph-vascular invasion during breast cancer progression. Using a xenograft model, we show that overexpression of Ang2 in poorly metastatic MCF-7 breast cancer cells suppresses expression of E-cadherin and induces Snail expression and phosphorylation of Akt and glycogen synthase kinase-3B (GSK-3B) promoting metastasis to the lymph nodes and lung. In cell culture, Ang2 promotes cell migration and invasion in Tie2-deficient breast cancer cells through the A 5 B 1 integrin/integrin-linked kinase (ILK)/Akt, GSK-3B/Snail/ E-cadherin signaling pathway. Inhibition of ILK and the A 5 B 1 integrin abrogates Ang2 modulation of Akt, GSK-3B, Snail, and E-cadherin and Ang2-stimulated breast cancer cell migration and invasion. Together, these results underscore the significant contribution of Ang2 in cancer progression, not only by stimulating angiogenesis but also by promoting metastasis, and provide a mechanism by which breast cancer cells acquire an enhanced invasive phenotype contributing to metastasis.

Tumor Necrosis Factor-Induced Neutrophil Adhesion Occurs Via Sphingosine Kinase-1-Dependent Activation of Endothelial α5β1 Integrin

“…45 Finally, a close association between the angiopoietins and ␣ 5 ␤ 1 has previously been demonstrated in pull-down assays and is suggested to be Tie-2 independent. 47,48 Our study supports these observations with TNF␣-induced neutrophil recruitment being both ␣ 5 ␤ 1 -and Ang-2-dependent and that a relationship with VCAM-1 and ICAM-1, but not ␣ v ␤ 3 , may exist.…”

A Human Monoclonal Anti-ANG2 Antibody Leads to Broad Antitumor Activity in Combination with VEGF Inhibitors and Chemotherapy Agents in Preclinical Models

“…Conversely, Ang1 seems to be expressed constitutively in adults, consistent with a role for Ang1 in blood vessel maintenance and stability (10,22,28). Ang2 may also have additional roles in early stages of tumor growth, promoting the recruitment of Tie2-expressing monocyte populations (29) and through interaction with the α5β1 integrin leading to a stimulation of tumor cell motility and invasion (30).…”

Implications of Different Cancer Stem Cell Phenotypes in Breast Cancer

“…CD29 represents the predominant integrin in mammary epithelial cells in mice, and is aberrantly expressed in human breast carcinomas, contributing to diverse malignant phenotypes, including EMT, metastasis and angiogenesis (82)(83)(84)(85). Moreover, in patients with IBC, high CD29 expression was found to be associated with significantly shorter DFS and OS (86,87).…”