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Inhibition of αvβ3 integrin reduces angiogenesis, bone turnover, and tumor cell proliferation in experimental prostate cancer bone metastases

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Abstract

The growth of metastatic prostate cancer cells in the bone involves an intimate interaction between the tumor cells and various elements of the bone microenvironment, resulting in increased rate of bone turnover and rapid tumor growth. The αvβ3 integrin has been shown to play an important role in tumor growth and angiogenesis, and is known to be critical to osteoclast formation and activity. This study was designed to examine the role of αvβ3 expressed by cells native to the bone in the growth and pathogenesis of prostate cancer bone metastases. Human prostate cancer cells which do not express αvβ3 or αIIbβ3 integrins were injected directly into human bone fragments previously implanted subcutaneously in SCID mice (SCID-human-bone model). At the same time treatment with anti-β3 antibody fragment (m7E3 F(ab′)2) i.p. at 300 μg/dose 3× per week was initiated and continued for 2 weeks. In this system, m7E3 F(ab′)2 only recognizes human bone-derived αvβ3. Antibody inhibition of αvβ3 integrin in vivo resulted in a specific reduction in the proportion of antigenically-human blood vessels within tumor-bearing bone implants (from 73.5% ± 3.93 in controls to 17.74% ± 5.64 in treated animals). Proliferation of the αvβ3-negative tumor cells was also reduced, although the overall vessel density was maintained by compensating mouse vasculature. Blockage of human bone-derived αvβ3 also significantly reduced the recruitment of osteoclasts in response to tumor cells, as well as degradation of calcified bone tissue. Together these observations confirm the importance of αvβ3 in bone metabolism and angiogenesis, and point to the role of these processes in controlling growth of metastatic prostate cancer cells in the bone.

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Authors and Affiliations

  1. Department of Oncology Research, Centocor, Inc., Malvern, Pennsylvania, USA

    Jeffrey A. Nemeth, Zhao Zhou & Mohit Trikha

  2. Departments of Urology, USA

    Michael L. Cher, Chadwick Mullins & Sunita Bhagat

  3. Pathology, Wayne State University, Detroit, Michigan, USA

    Michael L. Cher

Authors
  1. Jeffrey A. Nemeth
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  2. Michael L. Cher
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  3. Zhao Zhou
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  4. Chadwick Mullins
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  5. Sunita Bhagat
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  6. Mohit Trikha
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Correspondence to Mohit Trikha.

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Nemeth, J.A., Cher, M.L., Zhou, Z. et al. Inhibition of αvβ3 integrin reduces angiogenesis, bone turnover, and tumor cell proliferation in experimental prostate cancer bone metastases. Clin Exp Metastasis 20, 413–420 (2003). https://doi.org/10.1023/A:1025461507027

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