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Anti‐Compression and Anti‐Angiogenic Therapy for Breast Cancer
Author(s) -
Jiang Amanda,
Mammoto Tadanori,
Jiang Elisabeth,
Ingber Donald,
Mammoto Akiko
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.284.2
Subject(s) - angiogenesis , cancer research , breast cancer , tumor progression , wnt signaling pathway , vascular endothelial growth factor , medicine , cancer , tumor microenvironment , hif1a , signal transduction , biology , microbiology and biotechnology , tumor cells , vegf receptors
Anti‐angiogenic therapy has been a potential therapeutic strategy for various types of cancer because deregulated angiogenesis contributes to tumor progression. However, current anti‐angiogenic therapy has problems such as rebound tumor growth and resistance to the therapy. Recently, we have shown that physical compaction ‐ the process in which cells gather and pack together‐ induces brain tumor progression by changing the expression of a major angiogenic factor, vascular endothelial growth factor (VEGF). Here we show that physical compaction of E771 mammary tumor tissues also compresses blood vessels and the inhibition of collagen crosslinking using lysyl oxidase (LOX) inhibitor, which disrupts collagen structure and suppresses tumor cell compaction, decreases expression of VEGFR2, suppresses tumor angiogenesis, and breast cancer growth in mice. Knockdown of Wnt co‐receptor low‐density lipoprotein receptor‐related protein (LRP5) suppresses VEGFR2 expression in endothelial cells in vitro and tumor angiogenesis and breast cancer progression are inhibited in Lrp5 knockout mice in an orthotopic mouse E771 breast cancer model in vivo. Importantly, inhibition of LRP5 and LOX has synergistic inhibitory effects on breast cancer progression. These findings suggest that tumor micromechanical environment and chemical LRP5 signaling exhibit crosstalk and inhibit breast cancer growth more efficiently through a VEGF‐VEGFR2 signaling. This project is supported by Boston Children's Hospital Career Development Award and Department of Defense.