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Therapeutic targeting of the prostate cancer microenvironment

Nature Reviews Urology volume 7, pages 494–509 (2010)Cite this article

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Abstract

Solid tumors can be thought of as multicellular 'organs' that consist of a variety of cells as well as a scaffold of noncellular matrix. Stromal–epithelial crosstalk is integral to prostate cancer progression and metastasis, and androgen signaling is an important component of this crosstalk at both the primary and metastatic sites. Intratumoral production of androgen is an important mechanism of castration resistance and has been the focus of novel therapeutic approaches with promising results. Various other pathways are important for stromal–epithelial crosstalk and represent attractive candidate therapeutic targets. Hedgehog signaling has been associated with tumor progression, growth and survival, while Src family kinases have been implicated in tumor progression and in regulation of cancer cell migration. Fibroblast growth factors and transforming growth factor β signaling regulate cell proliferation, apoptosis and angiogenesis in the prostate cancer microenvironment. Integrins mediate communication between the cell and the extracellular matrix, enhancing growth, migration, invasion and metastasis of cancer cells. The contribution of stromal–epithelial crosstalk to prostate cancer initiation and progression provides the impetus for combinatorial microenvironment-targeting strategies.

Key Points

  • Stromal–epithelial interactions are integral to prostate carcinogenesis and metastasis formation, representing promising therapeutic targets as part of a combinatorial approach in anticancer therapy

  • A concomitant evolution of the tumor stroma with the progression of prostatic carcinoma mediates development of the disease from stroma-restrained to stroma-dependent to eventually stroma-independent or epitheliocentric

  • Current efforts focus on inhibition of intratumoral androgen production and efficient blocking of the androgen receptor as effective strategies to overcome castration resistance, using molecules such as the CYP17 inhibitor abiraterone acetate and the antiandrogen MDV3100, respectively

  • Several pathways contribute to prostate cancer initiation and progression, including, but not limited to, the Hedgehog and Src signaling pathways, for which small molecule inhibitors are in clinical trials

  • Integrins are integral to the metastatic process and represent promising therapeutic targets for patients with advanced-stage disease

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Figure 1: Signaling between a tumor cell and a cancer-associated stromal cell.
Figure 2: Stromal–epithelial signaling pathways.
Figure 3: Stromal–epithelial signaling pathways.

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References

  1. Mueller, M. M. & Fusenig, N. E. Friend or foes—bipolar effects of the tumour stroma in cancer. Nat. Rev. Cancer 4, 839–849 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Witz, I. P. & Levy-Nissenbaum, O. The tumor microenvironment in the post-PAGET era. Cancer Lett. 242, 1–10 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Paget, S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 8, 98–101 (1989).

    CAS  PubMed  Google Scholar 

  4. Cunha, G. R., Hayward, S. W., Dahiya, R. & Foster, B. A. Smooth muscle-epithelial interactions in normal and neoplastic prostatic development. Acta Anat. (Basel) 155, 63–72 (1996).

    Article  CAS  Google Scholar 

  5. Efstathiou, E. & Logothetis, C. J. L. A new therapy paradigm for prostate cancer founded on clinical observations. Clin. Cancer Res. 16, 1100–1107 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hayward, S. W. et al. Interactions between adult human prostatic epithelium and rat urogenital sinus mesenchyme in a tissue recombination model. Differentiation 63, 131–140 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. You, X. et al. Regulation of migration of primary prostate epithelial cells by secreted factors from prostate stromal cells. Exp. Cell Res. 288, 246–256 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. De Wever, O., Demetter, P., Mareel, M. & Bracke, M. Stromal myofibroblasts are drivers of invasive cancer growth. Int. J. Cancer 123, 2229–2238 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Desmoulière, A., Guyot, C. & Gabbiani, G. The stroma reaction myofibroblast: a key player in the control of tumor cell behavior. Int. J. Dev. Biol. 48, 509–517 (2004).

    Article  PubMed  Google Scholar 

  10. Wu, X., Jin, C., Wang, F., Yu, C. & McKeehan, W. L. Stromal cell heterogeneity in fibroblast growth factor-mediated stromal-epithelial cell cross-talk in premalignant prostate tumors. Cancer Res. 63, 4936–4944 (2003).

    CAS  PubMed  Google Scholar 

  11. Chauhan, H. et al. There is more than one kind of myofibroblast: analysis of CD34 expression in benign, in situ, and invasive breast lesions. J. Clin. Pathol. 56, 271–276 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhao, H. & Peehl, D. M. Tumor-promoting phenotype of CD90hi prostate cancer-associated fibroblasts. Prostate 69, 991–1000 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Darke, M. J., Fry, C. H. & Eyden, B. Structural characterization of myofibroblasts in the bladder. BJU Int. 97, 29–32 (2006).

    Article  Google Scholar 

  14. Olumi, A. F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).

    CAS  PubMed  Google Scholar 

  15. Barclay, W. W., Woodruff, R. D., Hall, M. C. & Cramer, S. D. A system for studying epithelial-stromal interactions reveals distinct inductive abilities of stromal cells from benign prostatic hyperplasia and prostate cancer. Endocrinology 146, 13–18 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Tuxhorn, J. A. et al. Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling. Clin. Cancer Res. 8, 2912–2923 (2002).

    CAS  PubMed  Google Scholar 

  17. Thalmann, G. N. et al. Human prostate fibroblasts induce growth and confer castration resistance and metastatic potential in LNCaP cells. Eur. Urol. 58, 162–172 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Yan, G., Fukabori, Y., McBride, G., Nikolaropolous, S. & McKeehan, W. L. Exon switching and activation of stromal and embryonic fibroblast growth factor (FGF)-FGF receptor genes in prostate epithelial cells accompany stromal independence and malignancy. Mol. Cell. Biol. 13, 4513–4522 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ayala, G. et al. Reactive stroma as a predictor of biochemical-free recurrence in prostate cancer. Clin. Cancer Res. 9, 4792–4801 (2003).

    CAS  PubMed  Google Scholar 

  20. Yanagisawa, N. et al. Stromogenic prostatic carcinoma pattern (carcinomas with reactive stromal grade 3) in needle biopsies predicts biochemical recurrence-free survival in patients after radical prostatectomy. Hum. Pathol. 38, 1611–1620 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Ishii, K. et al. Evidence that androgen-independent stromal growth factor signals promote androgen-insensitive prostate cancer cell growth in vivo. Endocr. Relat. Cancer 16, 415–428 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Tannock, I. F. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N. Engl. J. Med. 351, 1502–1512 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Shepard, D. R. et al. Phase II trial of neoadjuvant nab-paclitaxel in high risk patients with prostate cancer undergoing radical prostatectomy. J. Urol. 181, 1672–1677 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Morrissey, C. & Vessella, R. L. The role of tumor microenvironment in prostate cancer bone metastasis. J. Cell Biochem. 101, 873–886 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Logothetis, C. J. & Lin, S. H. Osteoblasts in prostate cancer metastasis to bone. Nat. Rev. Cancer 5, 21–28 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Sung, S. Y. et al. Coevolution of prostate cancer and bone stroma in three-dimensional coculture: implications for cancer growth and metastasis. Cancer Res. 68, 9996–10003 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Fizazi, K. et al. Prostate cancer cells-osteoblast interaction shifts expression of growth/survival-related genes in prostate cancer and reduces expression of osteoprotegerin in osteoblasts. Clin. Cancer Res. 9, 2587–2597 (2003).

    CAS  PubMed  Google Scholar 

  28. Lu, Y. et al. Osteoblasts induce prostate cancer proliferation and PSA expression through interleukin-6-mediated activation of the androgen receptor. Clin. Exp. Metastasis 21, 399–408 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Liu, X. H. et al. Androgen-induced Wnt signaling in preosteoblasts promotes the growth of MDA-PCa-2b human prostate cancer cells. Cancer Res. 67, 5747–5753 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Gleave, M., Hsieh, J. T., Gao, C. A., von Eschenbach, A. C. & Chung, L. W. Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts. Cancer Res. 51, 3753–3761 (1991).

    CAS  PubMed  Google Scholar 

  31. Festuccia, C. et al. Osteoblasts modulate secretion of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9) in human prostate cancer cells promoting migration and matrigel invasion. Oncol. Res. 11, 17–31 (1999).

    CAS  PubMed  Google Scholar 

  32. Huggins, C. Effect of orchiectomy and irradiation on cancer of the prostate. Ann. Surg. 115, 1192–1200 (1942).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Petrylak, D. P. et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N. Engl. J. Med. 351, 1513–1520 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. De Bono, J. S. et al. Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: final results of a multinational phase III trial (TROPIC). J. Clin. Oncol. 28, 15s (2010).

    Article  Google Scholar 

  35. Millikan, R. E. et al. Phase III trial of androgen ablation with or without three cycles of systemic chemotherapy for advanced prostate cancer. J. Clin. Oncol. 26, 5936–5942 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Takeda, H., Mizuno, T. & Lasnitzki, I. Autoradiographic studies of androgen-binding sites in the rat urogenital sinus and postnatal prostate. J. Endocrinol. 104, 87–92 (1985).

    Article  CAS  PubMed  Google Scholar 

  37. Gerdes, M. J. et al. Regulation of rat prostate stromal cell myodifferentiation by androgen and TGF-beta1. Prostate 58, 299–307 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. King, K. J., Nicholson, H. D. & Assinder, S. J. Effect of increasing ratio of estrogen: androgen on proliferation of normal human prostate stromal and epithelial cells, and the malignant cell line LNCaP. Prostate 66, 105–114 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Kurita, T. et al. Paracrine regulation of apoptosis by steroid hormones in the male and female reproductive system. Cell Death Differ. 8, 192–200 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Gao, J., Arnold, J. T. & Isaacs, J. T. Conversion from a paracrine to an autocrine mechanism of androgen-stimulated growth during malignant transformation of prostatic epithelial cells. Cancer Res. 61, 5038–5044 (2001).

    CAS  PubMed  Google Scholar 

  41. Olapade-Olaopa, E. O. et al. Malignant transformation of human prostatic epithelium is associated with the loss of androgen receptor immunoreactivity in the surrounding stroma. Clin. Cancer Res. 5, 569–576 (1999).

    CAS  PubMed  Google Scholar 

  42. Cano, P., Godoy, A., Escamilla, R., Dhir, R. & Onate, S. A. Stromal-epithelial cell interactions and androgen receptor-coregulator recruitment is altered in the tissue microenvironment of prostate cancer. Cancer Res. 67, 511–519 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Henshall, S. M. et al. Altered expression of androgen receptor in the malignant epithelium and adjacent stroma is associated with early relapse in prostate cancer. Cancer Res. 61, 423–427 (2001).

    CAS  PubMed  Google Scholar 

  44. Ricciardelli, C. et al. Androgen receptor levels in prostate cancer epithelial and peritumoral stromal cells identify non-organ confined disease. Prostate 63, 19–28 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Minamiguchi, K., Kawada, M., Someno, T. & Ishizuka, M. Androgen-independent prostate cancer DU145 cells suppress androgen-dependent growth of prostate stromal cells through production of inhibitory factors for androgen responsiveness. Biochem. Biophys. Res. Commun. 306, 629–636 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Planz, B., Wang, Q., Kirley, S. D., Lin, C. W. & McDougal, W. S. Androgen responsiveness of stromal cells of the human prostate: regulation of cell proliferation and keratinocyte growth factor by androgen. J. Urol. 160, 1850–1855 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Nakano, K. et al. Androgen-stimulated human prostate epithelial growth mediated by stromal-derived fibroblast growth factor-10. Endocr. J. 46, 405–413 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Le, H., Arnold, J. T., McFann, K. K. & Blackman, M. R. DHT and testosterone, but not DHEA or E2, differentially modulate IGF-I, IGFBP-2, and IGFBP-3 in human prostatic stromal cells. Am. J. Physiol. Endocrinol. Metab. 290, E952–E960 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Levine, A. C. et al. Androgens induce the expression of vascular endothelial growth factor in human fetal prostatic fibroblasts. Endocrinology 139, 4672–4678 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Niu, Y. et al. Targeting the stromal androgen receptor in primary prostate tumors at earlier stages. Proc. Natl Acad. Sci. USA 105, 12188–12193 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Shigemura, K. et al. Soluble factors derived from stroma activated androgen receptor phosphorylation in human prostate LNCaP cells: roles of ERK/MAP kinase. Prostate 69, 949–955 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Arnold, J. T. et al. Human prostate stromal cells stimulate increased PSA production in DHEA-treated prostate cancer epithelial cells. J. Steroid Biochem. Mol. Biol. 111, 240–246 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. El-Alfy, M. et al. Localization of type 5 17beta-hydroxysteroid dehydrogenase, 3beta-hydroxysteroid dehydrogenase, and androgen receptor in the human prostate by in situ hybridization and immunocytochemistry. Endocrinology 140, 1481–1491 (1999).

    Article  CAS  PubMed  Google Scholar 

  54. Mizokami, A. et al. Prostate cancer stromal cells and LNCaP cells coordinately activate the androgen receptor through synthesis of T and DHT from DHEA. Endocr. Relat. Cancer 16, 1139–1155 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Hofbauer, L. C. & Khosla, S. Androgen effects on bone metabolism: recent progress and controversies. Eur. J. Endocrinol. 140, 271–286 (1999).

    Article  CAS  PubMed  Google Scholar 

  56. Attard, G. et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J. Clin. Oncol. 26, 4563–4571 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Tran, C. et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324, 787–790 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Scher, H. I. et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet 375, 1437–1446 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lamm, M. L. et al. Sonic hedgehog activates mesenchymal Gli1 expression during prostate ductal bud formation. Dev. Biol. 249, 349–366 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Karhadkar, S. S. et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431, 707–712 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Shaw, A., Gipp, J. & Bushman, W. The Sonic Hedgehog pathway stimulates prostate tumor growth by paracrine signaling and recapitulates embryonic gene expression in tumor myofibroblasts. Oncogene 28, 4480–4490 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sheng, T. et al. Activation of the hedgehog pathway in advanced prostate cancer. Mol. Cancer 3, 29 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sanchez, P. et al. Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proc. Natl Acad. Sci. USA 101, 12561–12566 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Fan, L. et al. Hedgehog signaling promotes prostate xenograft tumor growth. Endocrinology 145, 3961–3970 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Louro, I. D. et al. Comparative gene expression profile analysis of GLI and c-MYC in an epithelial model of malignant transformation. Cancer Res. 62, 5867–5873 (2002).

    CAS  PubMed  Google Scholar 

  66. Edwards, P. C. et al. Sonic hedgehog gene-enhanced tissue engineering for bone regeneration. Gene Ther. 12, 75–86 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Karp, S. J. et al. Indian hedgehog coordinates endochondral bone growth and morphogenesis via parathyroid hormone related-protein-dependent and -independent pathways. Development 127, 543–548 (2000).

    CAS  PubMed  Google Scholar 

  68. Athar, M. et al. Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis. Cancer Res. 64, 7545–7552 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Feldmann, G. et al. An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer. Mol. Cancer Ther. 7, 2725–2735 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Efstathiou, E. et al. Initial modulation of the tumor microenvironment accounts for thalidomide activity in prostate cancer. Clin. Cancer Res. 13, 1224–1231 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Romer, J. T. et al. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(±)p53(−/−) mice. Cancer Cell 6, 229–240 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Yauch, R. L. et al. A paracrine requirement for hedgehog signalling in cancer. Nature 455, 406–410 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Von Hoff, D. D. et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N. Engl. J. Med. 361, 1164–1172 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Lauth, M., Bergström, A., Shimokawa, T. & Toftgård, R. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc. Natl Acad. Sci. USA 104, 8455–8460 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hosoya, T., Arai, M. A., Koyano, T., Kowithayakorn, T. & Ishibashim, M. Naturally occurring small-molecule inhibitors of hedgehog/GLI-mediated transcription. Chembiochem 9, 1082–1092 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. Kwabi-Addo, B., Ozen, M. & Ittmann, M. The role of fibroblast growth factors and their receptors in prostate cancer. Endocr. Relat. Cancer 11, 709–724 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Cronauer, M. V., Schulz, W. A., Seifert, H. H., Ackermann, R. & Burchardt, M. Fibroblast growth factors and their receptors in urological cancers: basic research and clinical implications. Eur. Urol. 43, 309–319 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Yang, F., Strand, D. W. & Rowley, D. R. Fibroblast growth factor-2 mediates transforming growth factor-beta action in prostate cancer reactive stroma. Oncogene 27, 450–459 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Huang, Y. W. et al. Effect of keratinocyte growth factor on cell viability in primary cultured human prostate cancer stromal cells. J. Steroid Biochem. Mol. Biol. 100, 24–33 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Ropiquet, F., Giri, D., Kwabi-Addo, B., Mansukhani, A. & Ittmann, M. Increased expression of fibroblast growth factor 6 in human prostatic intraepithelial neoplasia and prostate cancer. Cancer Res. 60, 4245–4250 (2000).

    CAS  PubMed  Google Scholar 

  81. Dorkin, T. J. et al. FGF8 over-expression in prostate cancer is associated with decreased patient survival and persists in androgen independent disease. Oncogene 18, 2755–2761 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. Li, Z. G. et al. Androgen receptor-negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms. J. Clin. Invest. 118, 2697–2710 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Friesel, R., Burgess, W. H., Mehlman, T. & Maciag, T. The characterization of the receptor for endothelial cell growth factor by covalent ligand attachment. J. Biol. Chem. 261, 7581–7584 (1986).

    CAS  PubMed  Google Scholar 

  84. Olwin, B. B. & Hauschka, S. D. Identification of the fibroblast growth factor receptor of Swiss 3T3 cells and mouse skeletal muscle myoblasts. Biochemistry 25, 3487–3492 (1986).

    Article  CAS  PubMed  Google Scholar 

  85. Feng, S., Wang, F., Matsubara, A., Kan, M. & McKeehan, W. L. Fibroblast growth factor receptor 2 limits and receptor 1 accelerates tumorigenicity of prostate epithelial cells. Cancer Res. 57, 5369–5378 (1997).

    CAS  PubMed  Google Scholar 

  86. Udayakumar, T. S., Bair, E. L., Nagle, R. B. & Bowden, G. T. Pharmacological inhibition of FGF receptor signaling inhibits LNCaP prostate tumor growth, promatrilysin, and PSA expression. Mol. Carcinog. 38, 70–77 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Maruyama-Takahashi, K. et al. Neutralizing anti-fibroblast growth factor (FGF) 8 monoclonal antibody shows anti-tumor activity against FGF8b-expressing LNCaP xenografts in androgen-dependent and -independent conditions. Prostate 68, 640–650 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Unni, E. et al. Changes in androgen receptor nongenotropic signaling correlate with transition of LNCaP cells to androgen independence. Cancer Res. 64, 7156–7168 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Park, S. I., Shah, A. N., Zhang, J. & Gallick, G. E. Regulation of angiogenesis and vascular permeability by Src family kinases: opportunities for therapeutic treatment of solid tumors. Expert Opin. Ther. Targets 11, 1207–1217 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Lee, S. E. et al. Tumor necrosis factor-alpha supports the survival of osteoclasts through the activation of Akt and ERK. J. Biol. Chem. 276, 49343–49349 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Lee, L. F., Guan, J., Qiu, Y. & Kung, H. J. Neuropeptide-induced androgen independence in prostate cancer cells: roles of nonreceptor tyrosine kinases Etk/Bmx, Src, and focal adhesion kinase. Mol. Cell Biol. 21, 8385–8397 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Violette, S. M. et al. Bone-targeted Src SH2 inhibitors block Src cellular activity and osteoclast-mediated resorption. Bone 28, 54–64 (2001).

    Article  CAS  PubMed  Google Scholar 

  93. Shakespeare, W. et al. Structure-based design of an osteoclast-selective, nonpeptide src homology 2 inhibitor with in vivo antiresorptive activity. Proc. Natl Acad. Sci. USA 97, 9373–9378 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Recchia, I. et al. Reduction of c-Src activity by substituted 5,7-diphenyl-pyrrolo[2,3-d]-pyrimidines induces osteoclast apoptosis in vivo and in vitro. Involvement of ERK1/2 pathway. Bone 34, 65–79 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Lee, L. F. et al. Interleukin-8 confers androgen-independent growth and migration of LNCaP: differential effects of tyrosine kinases Src and FAK. Oncogene 23, 2197–2205 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Marzia, M. et al. Decreased c-Src expression enhances osteoblast differentiation and bone formation. J. Cell. Biol. 151, 311–320 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Nautiyal, J., Majumder, P., Patel, B. B., Lee, F. Y. & Majumdar, A. P. Src inhibitor dasatinib inhibits growth of breast cancer cells by modulating EGFR signaling. Cancer Lett. 283, 143–151 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. Luo, F. R. et al. Identification and validation of phospho-SRC, a novel and potential pharmacodynamic biomarker for dasatinib (SPRYCEL), a multi-targeted kinase inhibitor. Cancer Chemother. Pharmacol. 62, 1065–1074 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Araujo, J. C. et al. Dasatinib inhibits both osteoclast activation and prostate cancer PC-3 cell-induced osteoclast formation. Cancer Biol. Ther. 8, 2153–2159 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Saad, F. Src as a therapeutic target in men with prostate cancer and bone metastases. BJU Int. 103, 434–440 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Chang, Y. M. et al. Src family kinase oncogenic potential and pathways in prostate cancer as revealed by AZD0530. Oncogene 27, 6365–6375 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Evans, C. P., Lara, P. N. Jr, Kung, H. & Yang, J. C. Activity of the Src-kinase inhibitor AZD0530 in androgen-independent prostate cancer (AIPC): Pre-clinical rationale for a phase II trial. J. Clin. Oncol. 24, 18S (2006).

    Article  Google Scholar 

  103. Lockton, J. A. et al. Phase I ascending single and multiple dose studies to assess the safety, tolerability and pharmacokinetics of AZD0530, a highly selective, dual-specific Src-Abl inhibitor. J. Clin. Oncol. 23, 16S (2005).

    Article  Google Scholar 

  104. Golas, J. M. et al. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res. 63, 375–381 (2003).

    CAS  PubMed  Google Scholar 

  105. Araujo, J. et al. Dasatinib and docetaxel combination treatment for patients with castration-resistant progressive prostate cancer: a phase I/II study (CA180086) [abstract 5061]. J. Clin. Oncol. 27, 249S (2009).

    Google Scholar 

  106. Tang, B. et al. Loss of responsiveness to transforming growth factor beta induces malignant transformation of nontumorigenic rat prostate epithelial cells. Cancer Res. 59, 4834–4842 (1999).

    CAS  PubMed  Google Scholar 

  107. Li, X. et al. Prostate tumor progression is mediated by a paracrine TGF-beta/Wnt3a signaling axis. Oncogene 27, 7118–7130 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Placencio, V. R. et al. Stromal transforming growth factor-beta signaling mediates prostatic response to androgen ablation by paracrine Wnt activity. Cancer Res. 68, 4709–4718 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. San Francisco, I. F., DeWolf, W. C., Peehl, D. M. & Olumi, A. F. Expression of transforming growth factor-beta 1 and growth in soft agar differentiate prostate carcinoma-associated fibroblasts from normal prostate fibroblasts. Int. J. Cancer 112, 213–218 (2004).

    Article  CAS  PubMed  Google Scholar 

  110. Kim, I. Y. et al. Loss of expression of transforming growth factor-beta receptors is associated with poor prognosis in prostate cancer patients. Clin. Cancer Res. 4, 1625–1630 (1998).

    CAS  PubMed  Google Scholar 

  111. Zhang, Q. et al. Insensitivity to transforming growth factor-beta results from promoter methylation of cognate receptors in human prostate cancer cells (LNCaP). Mol. Endocrinol. 19, 2390–2399 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Ao, M., Williams, K., Bhowmick, N. A. & Hayward, S. W. Transforming growth factor-beta promotes invasion in tumorigenic but not in nontumorigenic human prostatic epithelial cells. Cancer Res. 66, 8007–8016 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Horvath, L. G. et al. Loss of BMP2, Smad8, and Smad4 expression in prostate cancer progression. Prostate 59, 234–242 (2004).

    Article  CAS  PubMed  Google Scholar 

  114. Park, B. J., Park, J. I., Byun, D. S., Park, J. H. & Chi, S. G. Mitogenic conversion of transforming growth factor-beta1 effect by oncogenic Ha-Ras-induced activation of the mitogen-activated protein kinase signaling pathway in human prostate cancer. Cancer Res. 60, 3031–3038 (2000).

    CAS  PubMed  Google Scholar 

  115. Morton, D. M. & Barrack, E. R. Modulation of transforming growth factor beta 1 effects on prostate cancer cell proliferation by growth factors and extracellular matrix. Cancer Res. 55, 2596–2602 (1995).

    CAS  PubMed  Google Scholar 

  116. Steiner, M. S. & Barrack, E. R. Transforming growth factor-beta 1 overproduction in prostate cancer: effects on growth in vivo and in vitro. Mol. Endocrinol. 6, 15–25 (1992).

    CAS  PubMed  Google Scholar 

  117. Verona, E. V. et al. Transforming growth factor-beta signaling in prostate stromal cells supports prostate carcinoma growth by up-regulating stromal genes related to tissue remodeling. Cancer Res. 67, 5737–5746 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. Basanta, D. et al. The role of transforming growth factor-beta-mediated tumor-stroma interactions in prostate cancer progression: an integrative approach. Cancer Res. 69, 7111–7120 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Massagué, J., Blain, S. W. & Lo, R. S. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 103, 295–309 (2000).

    Article  PubMed  Google Scholar 

  120. Jones, E., Pu, H. & Kyprianou, N. Targeting TGF-beta in prostate cancer: therapeutic possibilities during tumor progression. Expert Opin. Ther. Targets 13, 227–234 (2009).

    Article  CAS  PubMed  Google Scholar 

  121. Yang, F. et al. Stromal expression of connective tissue growth factor promotes angiogenesis and prostate cancer tumorigenesis. Cancer Res. 65, 8887–8895 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Gorelik, L. & Flavell, R. A. Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat. Med. 7, 1118–1122 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Anderson, M. J., Shafer-Weaver, K., Greenberg, N. M. & Hurwitz, A. A. Tolerization of tumor-specific T cells despite efficient initial priming in a primary murine model of prostate cancer. J. Immunol. 178, 1268–1276 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Shafer-Weaver, K. A. et al. Cutting edge: tumor-specific CD8+ T cells infiltrating prostatic tumors are induced to become suppressor cells. J. Immunol. 183, 4848–4852 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. Liau, L. M., Fakhrai, H. & Black, K. L. Prolonged survival of rats with intracranial C6 gliomas by treatment with TGF-beta antisense gene. Neurol. Res. 20, 742–747 (1998).

    Article  CAS  PubMed  Google Scholar 

  126. Zhu, M. L., Partin, J. V., Bruckheimer, E. M., Strup, S. E. & Kyprianou, N. TGF-beta signaling and androgen receptor status determine apoptotic cross-talk in human prostate cancer cells. Prostate 68, 287–295 (2008).

    Article  CAS  PubMed  Google Scholar 

  127. Taplin, M. E. & Balk, S. P. Androgen receptor: a key molecule in the progression of prostate cancer to hormone independence. J. Cell. Biochem. 91, 483–490 (2004).

    Article  CAS  PubMed  Google Scholar 

  128. Adler, H. L. et al. Elevated levels of circulating interleukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma. J. Urol. 161, 182–187 (1999).

    Article  CAS  PubMed  Google Scholar 

  129. Shariat, S. F. et al. Preoperative plasma levels of transforming growth factor beta(1) (TGF-beta(1)) strongly predict progression in patients undergoing radical prostatectomy. J. Clin. Oncol. 19, 2856–2864 (2001).

    Article  CAS  PubMed  Google Scholar 

  130. Horner, A. et al. Expression and distribution of transforming growth factor-beta isoforms and their signaling receptors in growing human bone. Bone 23, 95–102 (1998).

    Article  CAS  PubMed  Google Scholar 

  131. Festuccia, C. et al. Osteoblast-derived TGF-beta1 modulates matrix degrading protease expression and activity in prostate cancer cells. Int. J. Cancer 85, 407–415 (2000).

    Article  CAS  PubMed  Google Scholar 

  132. Karsdal, M. A. et al. Matrix metalloproteinase-dependent activation of latent transforming growth factor-beta controls the conversion of osteoblasts into osteocytes by blocking osteoblast apoptosis. J. Biol. Chem. 277, 44061–44067 (2002).

    Article  CAS  PubMed  Google Scholar 

  133. Stabellini, G. et al. In vitro human osteoblast and extracellular matrix changes after transforming growth factor beta 1 treatment. Pathology 37, 347–354 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Festuccia, C. et al. Osteoblast conditioned media contain TGF-beta1 and modulate the migration of prostate tumor cells and their interactions with extracellular matrix components. Int. J. Cancer 81, 395–403 (1999).

    Article  CAS  PubMed  Google Scholar 

  135. Odero-Marah, V. A. et al. Receptor activator of NF-kappaB ligand (RANKL) expression is associated with epithelial to mesenchymal transition in human prostate cancer cells. Cell Res. 18, 858–870 (2008).

    Article  CAS  PubMed  Google Scholar 

  136. Izumi, K. et al. Tranilast inhibits hormone refractory prostate cancer cell proliferation and suppresses transforming growth factor beta1-associated osteoblastic changes. Prostate 69, 1222–1234 (2009).

    Article  CAS  PubMed  Google Scholar 

  137. Biswas, S., Criswell, T. L., Wang, S. E. & Arteaga, C. L. Inhibition of transforming growth factor-beta signaling in human cancer: targeting a tumor suppressor network as a therapeutic strategy. Clin. Cancer Res. 12, 4142–4146 (2006).

    Article  CAS  PubMed  Google Scholar 

  138. Khaw, P. et al. A phase III study of subconjunctival human anti-transforming growth factor beta(2) monoclonal antibody (CAT-152) to prevent scarring after first-time trabeculectomy. Ophthalmology 114, 1822–1830 (2007).

    Article  PubMed  Google Scholar 

  139. Tuxhorn, J. A., McAlhany, S. J., Yang, F., Dang, T. D. & Rowley, D. R. Inhibition of transforming growth factor-beta activity decreases angiogenesis in a human prostate cancer-reactive stroma xenograft model. Cancer Res. 62, 6021–6025 (2002).

    CAS  PubMed  Google Scholar 

  140. Bandyopadhyay, A. et al. Systemic administration of a soluble betaglycan suppresses tumor growth, angiogenesis, and matrix metalloproteinase-9 expression in a human xenograft model of prostate cancer. Prostate 63, 81–90 (2005).

    Article  CAS  PubMed  Google Scholar 

  141. Mol, A. J., Geldof, A. A., Meijer, G. A., van der Poel, H. G. & van Moorselaar, R. J. New experimental markers for early detection of high-risk prostate cancer: role of cell-cell adhesion and cell migration. J. Cancer Res. Clin. Oncol. 133, 687–695 (2007).

    Article  CAS  PubMed  Google Scholar 

  142. Goel, H. L., Li, J., Kogan, S. & Languino, L. R. Integrins in prostate cancer progression. Endocr. Relat. Cancer 15, 657–664 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Davis, T. L., Cress, A. E., Dalkin, B. L. & Nagle, R. B. Unique expression pattern of the alpha6beta4 integrin and laminin-5 in human prostate carcinoma. Prostate 46, 240–248 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Dedhar, S., Saulnier, R., Nagle, R. & Overall, C. M. Specific alterations in the expression of alpha 3 beta 1 and alpha 6 beta 4 integrins in highly invasive and metastatic variants of human prostate carcinoma cells selected by in vitro invasion through reconstituted basement membrane. Clin. Exp. Metastasis 11, 391–400 (1993).

    Article  CAS  PubMed  Google Scholar 

  145. Mitra, S. K. & Schlaepfer, D. D. Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr. Opin. Cell Biol. 18, 516–523 (2006).

    Article  CAS  PubMed  Google Scholar 

  146. Hüser, M. et al. MEK kinase activity is not necessary for Raf-1 function. EMBO J. 20, 1940–1951 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Bisanz, K. et al. Targeting ECM-integrin interaction with liposome-encapsulated small interfering RNAs inhibits the growth of human prostate cancer in a bone xenograft imaging model. Mol. Ther. 12, 634–643 (2005).

    Article  CAS  PubMed  Google Scholar 

  148. McCabe, N. P., De, S., Vasanji, A., Brainard, J. & Byzova, T. V. Prostate cancer specific integrin alphavbeta3 modulates bone metastatic growth and tissue remodeling. Oncogene 26, 6238–6243 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Hynes, R. O. Cell-matrix adhesion in vascular development. J. Thromb. Haemost. 5 (Suppl. 1), 32–40 (2007).

    Article  CAS  PubMed  Google Scholar 

  150. Cai, W., Niu, G. & Chen, X. Imaging of integrins as biomarkers for tumor angiogenesis. Curr. Pharm. Des. 14, 2943–2973 (2008).

    Article  CAS  PubMed  Google Scholar 

  151. Brooks, P. C., Clark, R. A. & Cheresh, D. A. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 264, 569–571 (1994).

    Article  CAS  PubMed  Google Scholar 

  152. Nemeth, J. A. et al. Inhibition of alpha(v)beta3 integrin reduces angiogenesis, bone turnover, and tumor cell proliferation in experimental prostate cancer bone metastases. Clin. Exp. Metastasis 20, 413–420 (2003).

    Article  CAS  PubMed  Google Scholar 

  153. Gennigens, C., Menetrier-Caux, C. & Droz, J. P. Insulin-like growth factor (IGF) family and prostate cancer. Crit. Rev. Oncol. Hematol. 58, 124–145 (2006).

    Article  CAS  PubMed  Google Scholar 

  154. Wu, L. D. et al. In vivo effects of the human type I insulin-like growth factor receptor antibody A12 on androgen-dependent and androgen-independent xenograft human prostate tumors. Clin. Cancer Res. 15, 3065–3074 (2005).

    Article  Google Scholar 

  155. Wu, J. D. et al. Combined in vivo effect of A12, a type 1 insulin-like growth factor receptor antibody, and docetaxel against prostate cancer tumors. Clin. Cancer Res. 12, 6153–6160 (2006).

    Article  CAS  PubMed  Google Scholar 

  156. Villaronga, M. A., Bevan, C. L. & Belandia, B. Notch signaling: a potential therapeutic target in prostate cancer. Curr. Cancer Drug Targets 8, 566–580 (2008).

    Article  CAS  PubMed  Google Scholar 

  157. Orr, B., Grace, O. C., Vanpoucke, G., Ashley, G. R. & Thomson, A. A. A role for notch signaling in stromal survival and differentiation during prostate development. Endocrinology 150, 463–472 (2009).

    Article  CAS  PubMed  Google Scholar 

  158. Leong, K. G. & Gao, W. Q. The Notch pathway in prostate development and cancer. Differentiation 76, 699–716 (2008).

    Article  CAS  PubMed  Google Scholar 

  159. Bin Hafeez, B. et al. Targeted knockdown of Notch1 inhibits invasion of human prostate cancer cells concomitant with inhibition of matrix metalloproteinase-9 and urokinase plasminogen activator. Clin. Cancer Res. 15, 452–459 (2009).

    Article  CAS  PubMed  Google Scholar 

  160. Skvortsova, I. et al. Intracellular signaling pathways regulating radioresistance of human prostate carcinoma cells. Proteomics 8, 4521–4533 (2008).

    Article  CAS  PubMed  Google Scholar 

  161. Torlakovic, E. et al. Differential expression of steroid receptors in prostate tissues before and after radiation therapy for prostatic adenocarcinoma. Int. J. Cancer 117, 381–386 (2005).

    Article  CAS  PubMed  Google Scholar 

  162. Pinthus, J. H. et al. Androgen induces adaptation to oxidative stress in prostate cancer: implications for treatment with radiation therapy. Neoplasia 9, 68–80 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Bolla, M. et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 360, 103–106 (2002).

    Article  CAS  PubMed  Google Scholar 

  164. D'Amico, A. V. et al. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA 292, 821–827 (2004).

    Article  CAS  PubMed  Google Scholar 

  165. Zapatero, A. et al. Long-term versus short-term androgen deprivation combined with high-dose radiotherapy for localized prostate cancer: a Spanish multicenter phase III trial. J. Clin. Oncol. 28, e15036 (2010).

    Article  Google Scholar 

  166. Sandler, H. M. et al. A phase III protocol of androgen suppression (AS) and radiation therapy (RT) versus AS and RT followed by chemotherapy with paclitaxel, estramustine, and etoposide (TEE) for localized, high-risk, prostate cancer, RTOG 9902 [abstract 4632]. J. Clin. Oncol. 28, 15S (2010).

  167. Abdollahi, A. et al. SU5416 and SU6668 attenuate the angiogenic effects of radiation-induced tumor cell growth factor production and amplify the direct anti-endothelial action of radiation in vitro. Cancer Res. 63, 3755–3763 (2003).

    CAS  PubMed  Google Scholar 

  168. Singh-Gupta, V. et al. Radiation-induced HIF-1alpha cell survival pathway is inhibited by soy isoflavones in prostate cancer cells. Int. J. Cancer 124, 1675–1684 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Kim, M. J. et al. c-Src-p38 mitogen-activated protein kinase signaling is required for Akt activation in response to ionizing radiation. Mol. Cancer Res. 6, 1872–1880 (2008).

    Article  CAS  PubMed  Google Scholar 

  170. Purnell, P. R. et al. The Src inhibitor AZD0530 blocks invasion and may act as a radiosensitizer in lung cancer cells. J. Thorac. Oncol. 4, 448–454 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Kuroda, K. et al. Docetaxel down-regulates the expression of androgen receptor and prostate-specific antigen but not prostate-specific membrane antigen in prostate cancer cell lines: implications for PSA surrogacy. Prostate 69, 1579–1585 (2009).

    Article  CAS  PubMed  Google Scholar 

  172. Gan, L. et al. Inhibition of the androgen receptor as a novel mechanism of taxol chemotherapy in prostate cancer. Cancer Res. 69, 8386–8394 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Thomas, F., Holly, J. M., Persad, R., Bahl, A. & Perks, C. M. Fibronectin confers survival against chemotherapeutic agents but not against radiotherapy in DU145 prostate cancer cells: involvement of the insulin like growth factor-1 receptor. Prostate 70, 856–865 (2010).

    CAS  PubMed  Google Scholar 

  174. Mimeault, M., Johansson, S. L., Henichart, J. P., Depreux, P. & Batra, S. K. Cytotoxic effects induced by docetaxel, gefitinib, and cyclopamine on side population and nonside population cell fractions from human invasive prostate cancer cells. Mol. Cancer Ther. 9, 617–630 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Ning, Y. M. et al. Phase II trial of bevacizumab, thalidomide, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer. J. Clin. Oncol. 28, 2070–2076 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Di Lorenzo, G. et al. Combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer: a phase 2 study. Eur. Urol. 54, 1089–1094 (2008).

    Article  CAS  PubMed  Google Scholar 

  177. Minchinton, A. I. & Tannock, I. F. Drug penetration in solid tumours. Nat. Rev. Cancer 6, 583–592 (2006).

    Article  CAS  PubMed  Google Scholar 

  178. Subarsky, P. & Hill, R. P. The hypoxic tumour microenvironment and metastatic progression. Clin. Exp. Metastasis 20, 237–250 (2003).

    Article  CAS  PubMed  Google Scholar 

  179. Harris, A. L. Hypoxia—a key regulatory factor in tumour growth. Nat. Rev. Cancer 2, 38–47 (2002).

    Article  CAS  PubMed  Google Scholar 

  180. Vaupel, P., Kelleher, D. K. & Höckel, M. Oxygen status of malignant tumors: pathogenesis of hypoxia and significance for tumor therapy. Semin. Oncol. 28, 29–35 (2001).

    Article  CAS  PubMed  Google Scholar 

  181. Ljungkvist, A. S. et al. Dynamics of hypoxia, proliferation and apoptosis after irradiation in a murine tumor model. Radiat. Res. 165, 326–336 (2006).

    Article  CAS  PubMed  Google Scholar 

  182. Overgaard, J. Hypoxic radiosensitization: adored and ignored. J. Clin. Oncol. 25, 4066–4074 (2007).

    Article  PubMed  Google Scholar 

  183. Milosevic, M. et al. Androgen withdrawal in patients reduces prostate cancer hypoxia: implications for disease progression and radiation response. Cancer Res. 67, 6022–6025 (2007).

    Article  CAS  PubMed  Google Scholar 

  184. Shaida, N. et al. Expression of BNIP3 correlates with hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha and the androgen receptor in prostate cancer and is regulated directly by hypoxia but not androgens in cell lines. Prostate 68, 336–343 (2008).

    Article  CAS  PubMed  Google Scholar 

  185. Hicks, K. O., Siim, B. G., Pruijn, F. B. & Wilson, W. R. Oxygen dependence of the metabolic activation and cytotoxicity of tirapazamine: implications for extravascular transport and activity in tumors. Radiat. Res. 161, 656–666 (2004).

    Article  CAS  PubMed  Google Scholar 

  186. Raleigh, S. M., Wanogho, E., Burke, M. D., McKeown, S. R. & Patterson, L. H. Involvement of human cytochromes P450 (CYP) in the reductive metabolism of AQ4N, a hypoxia activated anthraquinone di-N-oxide prodrug. Int. J. Radiat. Oncol. Biol. Phys. 42, 763–767 (1998).

    Article  CAS  PubMed  Google Scholar 

  187. Stewart, G. D. et al. The relevance of a hypoxic tumour microenvironment in prostate cancer. BJU Int. 105, 8–13 (2010).

    Article  CAS  PubMed  Google Scholar 

  188. Chan, N., Milosevic, M. & Bristow, R. G. Tumor hypoxia, DNA repair and prostate cancer progression: new targets and new therapies. Future Oncol. 3, 329–341 (2007).

    Article  CAS  PubMed  Google Scholar 

  189. Maffini, M. V., Calabro, J. M., Soto, A. M. & Sonnenschein, C. Stromal regulation of neoplastic development: age-dependent normalization of neoplastic mammary cells by mammary stroma. Am. J. Pathol. 167, 1405–1410 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Carmeliet, P. Angiogenesis in life, disease and medicine. Nature 438, 932–936 (2005).

    Article  CAS  PubMed  Google Scholar 

  191. Ellis, L. M. & Fidler, I. J. Angiogenesis and metastasis. Eur. J. Cancer 32A, 2451–2460 (1996).

    Article  CAS  PubMed  Google Scholar 

  192. Polverini, P. J. How the extracellular matrix and macrophages contribute to angiogenesis-dependent diseases. Eur. J. Cancer 32A, 2430–2437 (1996).

    Article  CAS  PubMed  Google Scholar 

  193. Bono, A. V. et al. Microvessel density in prostate carcinoma. Prostate Cancer Prostatic Dis. 5, 123–127 (2002).

    Article  CAS  PubMed  Google Scholar 

  194. Silberman, M. A., Partin, A. W., Veltri, R. W. & Epstein, J. I. Tumor angiogenesis correlates with progression after radical prostatectomy but not with pathologic stage in Gleason sum 5 to 7 adenocarcinoma of the prostate. Cancer 79, 772–779 (1997).

    Article  CAS  PubMed  Google Scholar 

  195. Fidler, I. J. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat. Rev. Cancer 3, 453–458 (2003).

    Article  CAS  PubMed  Google Scholar 

  196. Ferrara, N. & Kerbel, R. S. Angiogenesis as a therapeutic target. Nature 438, 967–974 (2005).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Kim-Anh T. Vu at the University of Texas, M. D. Anderson Cancer Center for her assistance in preparing the graphic art.

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  1. Department of Genitourinary Medical Oncology, Unit 1374, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M. D. Anderson Cancer Center, P. O. Box 301439, Houston, 77230-1439, TX, USA

    Maria Karlou, Vassiliki Tzelepi & Eleni Efstathiou

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M. Karlou and V. Tzelepi contributed equally to researching data for this article, discussing content, writing and reviewing the manuscript before submission. E. Efstathiou provided substantial contribution to the discussion of content and reviewing the manuscript before submission.

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Karlou, M., Tzelepi, V. & Efstathiou, E. Therapeutic targeting of the prostate cancer microenvironment. Nat Rev Urol 7, 494–509 (2010). https://doi.org/10.1038/nrurol.2010.134

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