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Cleavage of galectin‐3 by matrix metalloproteases induces angiogenesis in breast cancer
Author(s) -
NangiaMakker Pratima,
Wang Yi,
Raz Tirza,
Tait Larry,
Balan Vitaly,
Hogan Victor,
Raz Avraham
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25254
Subject(s) - angiogenesis , cancer research , galectin 3 , metastasis , biology , matrix metalloproteinase , transfection , tumor progression , endothelial stem cell , microbiology and biotechnology , cancer , immunology , cell culture , in vitro , biochemistry , genetics
Galectin‐3 cleavage is related to progression of human breast and prostate cancer and is partly responsible for tumor growth, angiogenesis and apoptosis resistance in mouse models. A functional polymorphism in galectin‐3 gene, determining its susceptibility to cleavage by matrix metalloproteinases (MMPs)‐2/‐9 is related to racial disparity in breast cancer incidence in Asian and Caucasian women. The purpose of our study is to evaluate ( i ) if cleavage of galectin‐3 could be related to angiogenesis during the progression of human breast cancer, ( ii ) the role of cleaved galectin‐3 in induction of angiogenesis and ( iii ) determination of the galectin‐3 domain responsible for induction of angiogenic response. Galectin‐3 null breast cancer cells BT‐459 were transfected with either cleavable full‐length galectin‐3 or its fragmented peptides. Chemotaxis, chemoinvasion, heterotypic aggregation, epithelial‐endothelial cell interactions and angiogenesis were compared to noncleavable galectin‐3. BT‐549‐H 64 cells harboring cleavable galectin‐3 exhibited increased chemotaxis, invasion and interactions with endothelial cells resulting in angiogenesis and 3D morphogenesis compared to BT‐549‐P 64 cells harboring noncleavable galectin‐3. BT‐549‐H 64 cells induced increased migration and phosphorylation of focal adhesion kinase in migrating endothelial cells. Endothelial cells cocultured with BT‐549 cells transfected with galectin‐3 peptides indicate that amino acids 1–62 and 33–250 stimulate migration and morphogenesis of endothelial cells. Immunohistochemical analysis of blood vessel density and galectin‐3 cleavage in a breast cancer progression tissue array support the in vitro findings. We conclude that the cleavage of the N terminus of galectin‐3 followed by its release in the tumor microenvironment in part leads to breast cancer angiogenesis and progression.