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Molecular Cancer Research
Molecular Cancer Research

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Angiogenesis, Metastasis, and the Cellular Microenvironment

Loss of TGF-β Responsiveness in Prostate Stromal Cells Alters Chemokine Levels and Facilitates the Development of Mixed Osteoblastic/Osteolytic Bone Lesions

Xiaohong Li, Julie A. Sterling, Kang-Hsien Fan, Robert L. Vessella, Yu Shyr, Simon W. Hayward, Lynn M. Matrisian and Neil A. Bhowmick
Xiaohong Li
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Julie A. Sterling
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Kang-Hsien Fan
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Robert L. Vessella
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Yu Shyr
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Simon W. Hayward
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Lynn M. Matrisian
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Neil A. Bhowmick
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DOI: 10.1158/1541-7786.MCR-11-0506 Published April 2012
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Abstract

Loss of TGF-β type II receptor (TβRII, encoded by Tgfbr2) expression in the prostate stroma contributes to prostate cancer initiation, progression, and invasion. We evaluated whether TβRII loss also affected prostate cancer bone metastatic growth. Immunohistologic analysis revealed that TβRII expression was lost in cancer-associated fibroblasts in human prostate cancer bone metastatic tissues. We recapitulated the human situation with a conditional stromal Tgfbr2 knockout (Tgfbr2-KO) mouse model. Conditioned media from primary cultured Tgfbr2-KO or control Tgfbr2-flox prostatic fibroblasts (koPFCM or wtPFCM, respectively) were applied to C4-2B prostate cancer cells before grafting the cells tibially. We found that koPFCM promoted prostate cancer cell growth in the bone and development of early mixed osteoblastic/osteolytic bone lesions. Furthermore, the koPFCM promoted greater C4-2B adhesion to type-I collagen, the major component of bone matrix, compared to wtPFCM-treated C4-2B. Cytokine antibody array analysis revealed that koPFCM had more than two-fold elevation in granulocyte colony-stimulating factor and CXCL1, CXCL16, and CXCL5 expression relative to wtPFCM. Interestingly, neutralizing antibodies of CXCL16 or CXCL1 were able to reduce koPFCM-associated C4-2B type-I collagen adhesion to that comparable with wtPFCM-mediated adhesion. Collectively, our data indicate that loss of TGF-β responsiveness in prostatic fibroblasts results in upregulation of CXCL16 and CXCL1 and that these paracrine signals increase prostate cancer cell adhesion in the bone matrix. These microenvironment changes at the primary tumor site can mediate early establishment of prostate cancer cells in the bone and support subsequent tumor development at the metastatic site. Mol Cancer Res; 10(4); 494–503. ©2012 AACR.

This article is featured in Highlights of This Issue, p. 483

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Received October 19, 2011.
  • Revision received January 26, 2012.
  • Accepted January 26, 2012.
  • ©2012 American Association for Cancer Research.
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Molecular Cancer Research: 10 (4)
April 2012
Volume 10, Issue 4
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Loss of TGF-β Responsiveness in Prostate Stromal Cells Alters Chemokine Levels and Facilitates the Development of Mixed Osteoblastic/Osteolytic Bone Lesions
Xiaohong Li, Julie A. Sterling, Kang-Hsien Fan, Robert L. Vessella, Yu Shyr, Simon W. Hayward, Lynn M. Matrisian and Neil A. Bhowmick
Mol Cancer Res April 1 2012 (10) (4) 494-503; DOI: 10.1158/1541-7786.MCR-11-0506

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Loss of TGF-β Responsiveness in Prostate Stromal Cells Alters Chemokine Levels and Facilitates the Development of Mixed Osteoblastic/Osteolytic Bone Lesions
Xiaohong Li, Julie A. Sterling, Kang-Hsien Fan, Robert L. Vessella, Yu Shyr, Simon W. Hayward, Lynn M. Matrisian and Neil A. Bhowmick
Mol Cancer Res April 1 2012 (10) (4) 494-503; DOI: 10.1158/1541-7786.MCR-11-0506
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Molecular Cancer Research
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