Angiopoietin-2 stimulates breast cancer metastasis through the α5β1 integrin-mediated pathway

Yorihisha Imanishi, Bo Hu*, Michael J. Jarzynka, Ping Guo, Esther Elishaev, Ifat Bar-Joseph, Shi Yuan Cheng

*Corresponding author for this work

Research output: Contribution to journalArticle

131 Citations (Scopus)

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-3β (GSK-3β) 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 α5β1 integrin/integrin-linked kinase (ILK)/Akt, GSK-3β/Snail/ E-cadherin signaling pathway. Inhibition of ILK and the α5β 1 integrin abrogates Ang2 modulation of Akt, GSK-3β, 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.

Original languageEnglish (US)
Pages (from-to)4254-4263
Number of pages10
JournalCancer Research
Volume67
Issue number9
DOIs
StatePublished - May 1 2007

Fingerprint

Angiopoietin-2
Integrins
Breast Neoplasms
Neoplasm Metastasis
Cadherins
Glycogen Synthase Kinase 3
Cell Movement
Neoplasms
Lymph Nodes
Phenotype
Snails
Lymph
Heterografts
Blood Vessels
Intercellular Signaling Peptides and Proteins
Cell Culture Techniques
Phosphorylation
Lung

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Imanishi, Yorihisha ; Hu, Bo ; Jarzynka, Michael J. ; Guo, Ping ; Elishaev, Esther ; Bar-Joseph, Ifat ; Cheng, Shi Yuan. / Angiopoietin-2 stimulates breast cancer metastasis through the α5β1 integrin-mediated pathway. In: Cancer Research. 2007 ; Vol. 67, No. 9. pp. 4254-4263.
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Angiopoietin-2 stimulates breast cancer metastasis through the α5β1 integrin-mediated pathway. / Imanishi, Yorihisha; Hu, Bo; Jarzynka, Michael J.; Guo, Ping; Elishaev, Esther; Bar-Joseph, Ifat; Cheng, Shi Yuan.

In: Cancer Research, Vol. 67, No. 9, 01.05.2007, p. 4254-4263.

Research output: Contribution to journalArticle

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