Skip to main content

Bone microenvironment signaling of cancer stem cells as a therapeutic target in metastatic prostate cancer

Cell Biology and Toxicology volume 36, pages 115–130 (2020)Cite this article

Abstract

Prostate cancer (PCa) is one of the most prevalent cancers and the second leading cause of cancer death among US males. When diagnosed in an early disease stage, primary tumors of PCa may be treated with surgical resection or radiation, sometimes combined with androgen deprivation therapy, with favorable outcomes. Unfortunately, the treatment efficacy of each approach decreases significantly in later stages of PCa that involve metastasis to soft tissues and bone. Metastatic PCa is a heterogeneous disease containing host cells, mature cancer cells, and subpopulation of cancer stem cells (CSC). CSCs are highly tumorigenic due to their self-renewing and differentiating potential, clinically resulting in recurrence and resistance to standard therapies. Therefore, there is a large unmet clinical need to develop therapies, which target CSC activity. In this review, we summarize the main signaling pathways that are implicated in the current pre-clinical and clinical studies of recurrent metastatic PCa within the bone microenvironment targeting CSCs and discuss the trajectory of therapeutics moving forward.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  • Andersen P, Uosaki H, Shenje LT, Kwon C. Non-canonical Notch signaling: emerging role and mechanism. Trends Cell Biol. 2012;22:257–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bansal N, Mishra PJ, Stein M, DiPaola RS, Bertino JR. Axl receptor tyrosine kinase is up-regulated in metformin resistant prostate cancer cells. Oncotarget. 2015;6:15321–31.

    PubMed  PubMed Central  Google Scholar 

  • Bedard G, Chow E. The failures and challenges of bone metastases research in radiation oncology. J Bone Oncol. 2013;2:84–8.

    Article  PubMed  PubMed Central  Google Scholar 

  • Bisson I, Prowse DM. WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics. Cell Res. 2009;19:683–97.

    Article  CAS  PubMed  Google Scholar 

  • Bluemn EG, Coleman IM, Lucas JM, Coleman RT, Hernandez-Lopez S, Tharakan R, et al. Androgen receptor pathway-independent prostate cancer is sustained through FGF signaling. Cancer Cell. 2017;32:474–89 e476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bousquet G, Alexandre J, Le Tourneau C, Goldwasser F, Faivre S, de Mont-Serrat H, et al. Phase I study of BIBF 1120 with docetaxel and prednisone in metastatic chemo-naive hormone-refractory prostate cancer patients. Br J Cancer. 2011;105:1640–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cackowski FC, Eber MR, Rhee J, Decker AM, Yumoto K, Berry JE, et al. Mer tyrosine kinase regulates disseminated prostate cancer cellular dormancy. J Cell Biochem. 2017;118:891–902.

    Article  CAS  PubMed  Google Scholar 

  • Cashen A, Lopez S, Gao F, Calandra G, MacFarland R, Badel K, et al. A phase II study of plerixafor (AMD3100) plus G-CSF for autologous hematopoietic progenitor cell mobilization in patients with Hodgkin lymphoma. Biol Blood Marrow Transplant. 2008;14:1253–61.

    Article  CAS  PubMed  Google Scholar 

  • Casimiro S, Guise TA, Chirgwin J. The critical role of the bone microenvironment in cancer metastases. Mol Cell Endocrinol. 2009;310:71–81.

    Article  CAS  PubMed  Google Scholar 

  • Chang HH, Chen BY, Wu CY, Tsao ZJ, Chen YY, Chang CP, et al. Hedgehog overexpression leads to the formation of prostate cancer stem cells with metastatic property irrespective of androgen receptor expression in the mouse model. J Biomed Sci. 2011;18:6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Q, Cai Z-k, Chen Y-b, Gu M, Zheng D-c, Zhou J, et al. Poly r (C) binding protein-1 is central to maintenance of cancer stem cells in prostate cancer cells. Cell Physiol Biochem. 2015;35:1052–61.

    Article  CAS  PubMed  Google Scholar 

  • Choi YJ, Kim HS, Park SH, Kim BS, Kim KH, Lee HJ, et al. Phase II study of dovitinib in patients with castration-resistant prostate cancer (KCSG-GU11-05). Cancer Res Treat. 2018;50:1252–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choudhury AD, Gray KP, Supko JG, Harshman LC, Taplin ME, Pace AF, et al. A dose finding clinical trial of cabozantinib (XL184) administered in combination with abiraterone acetate in metastatic castration-resistant prostate cancer. Prostate. 2018;78:1053–62.

    Article  CAS  Google Scholar 

  • Choueiri TK, Vaishampayan U, Rosenberg JE, Logan TF, Harzstark AL, Bukowski RM, et al. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J Clin Oncol. 2013;31:181–6.

    Article  CAS  PubMed  Google Scholar 

  • Cojoc M, Peitzsch C, Trautmann F, Polishchuk L, Telegeev GD, Dubrovska A. Emerging targets in cancer management: role of the CXCL12/CXCR4 axis. Onco Targets Ther. 2013;6:1347–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Coleman R. Bone targeted treatments in cancer - the story so far. J Bone Oncol. 2016;5:90–2.

    Article  PubMed  PubMed Central  Google Scholar 

  • Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005;65:10946–51.

    Article  CAS  PubMed  Google Scholar 

  • Conley-LaComb MK, Semaan L, Singareddy R, Li Y, Heath EI, Kim S, et al. Pharmacological targeting of CXCL12/CXCR4 signaling in prostate cancer bone metastasis. Mol Cancer. 2016;15:68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Corn PG, Wang F, McKeehan WL, Navone N. Targeting fibroblast growth factor pathways in prostate cancer. Clin Cancer Res. 2013;19:5856–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Corno C, Gatti L, Lanzi C, Zaffaroni N, Colombo D, Perego P. Role of the receptor tyrosine kinase Axl and its targeting in cancer cells. Curr Med Chem. 2016;23:1496–512.

    Article  CAS  PubMed  Google Scholar 

  • Cui D, Dai J, Keller JM, Mizokami A, Xia S, Keller ET. Notch pathway inhibition using PF-03084014, a gamma-secretase inhibitor (GSI), enhances the antitumor effect of docetaxel in prostate cancer. Clin Cancer Res. 2015;21:4619–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • da Silva RF, Dhar D, Raina K, Kumar D, Kant R, Cagnon VHA, et al. Nintedanib inhibits growth of human prostate carcinoma cells by modulating both cell cycle and angiogenesis regulators. Sci Rep. 2018;8:9540.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • da Silva RF, Nogueira-Pangrazi E, Kido LA, Montico F, Arana S, Kumar D, et al. Nintedanib antiangiogenic inhibitor effectiveness in delaying adenocarcinoma progression in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP). J Biomed Sci. 2017;24:31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dai J, Zhang H, Karatsinides A, Keller JM, Kozloff KM, Aftab DT, et al. Cabozantinib inhibits prostate cancer growth and prevents tumor-induced bone lesions. Clin Cancer Res. 2014;20:617–30.

    Article  CAS  PubMed  Google Scholar 

  • Das S, Harris LG, Metge BJ, Liu S, Riker AI, Samant RS, et al. The hedgehog pathway transcription factor GLI1 promotes malignant behavior of cancer cells by up-regulating osteopontin. J Biol Chem. 2009;284:22888–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Decker AM, Cackowski FC, Jung Y, Taichman RS. Biochemical changes in the niche following tumor cell invasion. J Cell Biochem. 2017;118:1956–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Delury C, Hart C, Brown M, Clarke N, Parkin E. Stroma-induced Jagged1 expression drives PC3 prostate cancer cell migration; disparate effects of RIP-generated proteolytic fragments on cell behaviour and Notch signaling. Biochem Biophys Res Commun. 2016;472:255–61.

    Article  CAS  PubMed  Google Scholar 

  • Denmeade SR, Isaacs JT. A history of prostate cancer treatment. Nat Rev Cancer. 2002;2:389–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • DiPersio JF, Micallef IN, Stiff PJ, Bolwell BJ, Maziarz RT, Jacobsen E, et al. Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin’s lymphoma. J Clin Oncol. 2009;27:4767–73.

    Article  CAS  PubMed  Google Scholar 

  • Doré JJ, Edens M, Garamszegi N, Leof EB. Heteromeric and homomeric transforming growth factor-β receptors show distinct signaling and endocytic responses in epithelial cells. J Biol Chem. 1998;273:31770–7.

    Article  PubMed  Google Scholar 

  • Droz J-P, Medioni J, Chevreau C, De Mont-Serrat H, Merger M, Stopfer P, et al. Randomized phase II study of nintedanib in metastatic castration-resistant prostate cancer postdocetaxel. Anti-Cancer Drugs. 2014;25:1081–8.

    Article  CAS  PubMed  Google Scholar 

  • Dubrovska A, Elliott J, Salamone RJ, Kim S, Aimone LJ, Walker JR, et al. Combination therapy targeting both tumor-initiating and differentiated cell populations in prostate carcinoma. Clin Cancer Res. 2010;16:5692–702.

    Article  CAS  PubMed  Google Scholar 

  • Dubrovska A, Elliott J, Salamone RJ, Telegeev GD, Stakhovsky AE, Schepotin IB, et al. CXCR4 expression in prostate cancer progenitor cells 9. PLoS One. 2012;7:e31226.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dubrovska A, Kim S, Salamone RJ, Walker JR, Maira SM, Garcia-Echeverria C, et al. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci U S A. 2009;106:268–73.

    Article  CAS  PubMed  Google Scholar 

  • Eccles SA, Aboagye EO, Ali S, Anderson AS, Armes J, Berditchevski F, et al. Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer. Breast Cancer Res. 2013;15:R92.

    Article  PubMed  PubMed Central  Google Scholar 

  • Feng S, Shao L, Yu W, Gavine P, Ittmann M. Targeting fibroblast growth factor receptor signaling inhibits prostate cancer progression. Clin Cancer Res. 2012;18:3880–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Festuccia C, Angelucci A, Gravina GL, Villanova I, Teti A, Abini A, et al. Osteoblast-derived TGF-β1 modulates matrix degrading protease expression and activity in prostate cancer cells. Int J Cancer. 2000;85:407–15.

    Article  CAS  PubMed  Google Scholar 

  • Germann M, Wetterwald A, Guzmán-Ramirez N, van der Pluijm G, Culig Z, Cecchini MG, et al. Stem-like cells with luminal progenitor phenotype survive castration in human prostate cancer. Stem Cells. 2012;30:1076–86.

    Article  CAS  PubMed  Google Scholar 

  • Goruppi S, Ruaro E, Varnum B, Schneider C. Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras. Oncogene. 1999;18:4224–36.

    Article  CAS  PubMed  Google Scholar 

  • Graham TJ, Box G, Tunariu N, Crespo M, Spinks TJ, Miranda S, et al. Preclinical evaluation of imaging biomarkers for prostate cancer bone metastasis and response to cabozantinib. J Natl Cancer Inst. 2014;106:dju033.

    Article  CAS  PubMed  Google Scholar 

  • Gravina GL, Mancini A, Muzi P, Ventura L, Biordi L, Ricevuto E, et al. CXCR4 pharmacogical inhibition reduces bone and soft tissue metastatic burden by affecting tumor growth and tumorigenic potential in prostate cancer preclinical models. Prostate. 2015;75:1227–46.

    Article  CAS  PubMed  Google Scholar 

  • Grönberg H. Prostate cancer epidemiology. Lancet. 2003;361:859–64.

    Article  PubMed  Google Scholar 

  • Gu J-W, Rizzo P, Pannuti A, Golde T, Osborne B, Miele L. Notch signals in the endothelium and cancer “stem-like” cells: opportunities for cancer therapy. Vascular Cell. 2012;4:7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138:645–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hadjimichael C, Chanoumidou K, Papadopoulou N, Arampatzi P, Papamatheakis J, Kretsovali A. Common stemness regulators of embryonic and cancer stem cells. World J Stem Cells. 2015;7:1150–84.

    PubMed  PubMed Central  Google Scholar 

  • Haider M-T, Hunter KD, Robinson SP, Graham TJ, Corey E, Dear TN, et al. Rapid modification of the bone microenvironment following short-term treatment with cabozantinib in vivo. Bone. 2015;81:581–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hall CL, Daignault SD, Shah RB, Pienta KJ, Keller ET. Dickkopf-1 expression increases early in prostate cancer development and decreases during progression from primary tumor to metastasis. Prostate. 2008;68:1396–404.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hall CL, Kang S, MacDougald OA, Keller ET. Role of Wnts in prostate cancer bone metastases. J Cell Biochem. 2006;97:661–72.

    Article  CAS  PubMed  Google Scholar 

  • Han L, Shi S, Gong T, Zhang Z, Sun X. Cancer stem cells: therapeutic implications and perspectives in cancer therapy. Acta Pharm Sin B. 2013;3:65–75.

    Article  Google Scholar 

  • Holen I. The bone microenvironment - multiple players involved in cancer progression. J Bone Oncol. 2016;5:87–9.

    Article  PubMed  PubMed Central  Google Scholar 

  • Horner A, Kemp P, Summers C, Bord S, Bishop N, Kelsall A, et al. Expression and distribution of transforming growth factor-β isoforms and their signaling receptors in growing human bone. Bone. 1998;23:95–102.

    Article  CAS  PubMed  Google Scholar 

  • Hsieh I-S, Chang K-C, Tsai Y-T, Ke J-Y, Lu P-J, Lee K-H, et al. MicroRNA-320 suppresses the stem cell-like characteristics of prostate cancer cells by downregulating the Wnt/beta-catenin signaling pathway. Carcinogenesis. 2012;34:530–8.

    Article  PubMed  CAS  Google Scholar 

  • Hurt EM, Kawasaki BT, Klarmann GJ, Thomas SB, Farrar WL. CD44+ CD24(−) prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis. Br J Cancer. 2008;98:756–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishino R, Minami K, Tanaka S, Nagai M, Matsui K, Hasegawa N, et al. FGF7 supports hematopoietic stem and progenitor cells and niche-dependent myeloblastoma cells via autocrine action on bone marrow stromal cells in vitro. Biochem Biophys Res Commun. 2013;440:125–31.

    Article  CAS  PubMed  Google Scholar 

  • Itkin T, Kaufmann KB, Gur-Cohen S, Ludin A, Lapidot T. Fibroblast growth factor signaling promotes physiological bone remodeling and stem cell self-renewal. Curr Opin Hematol. 2013;20:237–44.

    CAS  PubMed  Google Scholar 

  • Izumi K, Mizokami A, Li YQ, Narimoto K, Sugimoto K, Kadono Y, et al. Tranilast inhibits hormone refractory prostate cancer cell proliferation and suppresses transforming growth factor β1-associated osteoblastic changes. Prostate. 2009;69:1222–34.

    Article  CAS  PubMed  Google Scholar 

  • Jaworska D, Król W, Szliszka E. Prostate cancer stem cells: research advances. Int J Mol Sci. 2015;16:27433–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jeter CR, Liu B, Liu X, Chen X, Liu C, Calhoun-Davis T, et al. NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation. Oncogene. 2011;30:3833–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang Y, Dai J, Zhang H, Sottnik JL, Keller JM, Escott KJ, et al. Activation of the Wnt pathway through AR79, a GSK3beta inhibitor, promotes prostate cancer growth in soft tissue and bone. Mol Cancer Res. 2013;11:1597–610.

    Article  CAS  PubMed  Google Scholar 

  • Jimeno A, Gordon M, Chugh R, Messersmith W, Mendelson D, Dupont J, et al. A first-in-human phase I study of the anticancer stem cell agent ipafricept (OMP-54F28), a decoy receptor for Wnt ligands, in patients with advanced solid tumors. Clin Cancer Res. 2017;23:7490–7.

    Article  CAS  PubMed  Google Scholar 

  • Jung Y, Cackowski FC, Yumoto K, Decker AM, Wang J, Kim JK, et al. CXCL12g promotes metastatic castration-resistant prostate cancer by inducing cancer stem cell and neuroendocrine phenotypes. Cancer Res. 2018;78:2026–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jung Y, Decker AM, Wang J, Lee E, Kana LA, Yumoto K, et al. Endogenous GAS6 and Mer receptor signaling regulate prostate cancer stem cells in bone marrow. Oncotarget. 2016;7:25698–711.

    PubMed  PubMed Central  Google Scholar 

  • Jung Y, Wang J, Lee E, McGee S, Berry JE, Yumoto K, et al. Annexin 2-CXCL12 interactions regulate metastatic cell targeting and growth in the bone marrow. Mol Cancer Res. 2015;13:197–207.

    Article  CAS  PubMed  Google Scholar 

  • Kesper DA, Didt-Koziel L, Vortkamp A. Gli2 activator function in preosteoblasts is sufficient to mediate ihh-dependent osteoblast differentiation, whereas the repressor function of Gli2 is dispensable for endochondral ossification. Dev Dyn. 2010;239:1818–26.

    Article  CAS  PubMed  Google Scholar 

  • Klarmann GJ, Hurt EM, Mathews LA, Zhang X, Duhagon MA, Mistree T, et al. Invasive prostate cancer cells are tumor initiating cells that have a stem cell-like genomic signature. Clin Exp Metastasis. 2009;26:433–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kobayashi A, Okuda H, Xing F, Pandey PR, Watabe M, Hirota S, et al. Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp Med. 2011;208:2641–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kobayashi Y, Maeda K, Takahashi N. Roles of Wnt signaling in bone formation and resorption. Japanese Dental Science Review. 2008;44:76–82.

    Article  Google Scholar 

  • Koeneman KS, Yeung F, Chung LW. Osteomimetic properties of prostate cancer cells: a hypothesis supporting the predilection of prostate cancer metastasis and growth in the bone environment. Prostate. 1999;39:246–61.

    Article  CAS  PubMed  Google Scholar 

  • Kong D, Banerjee S, Ahmad A, Li Y, Wang Z, Sethi S, et al. Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS One. 2010;5:e12445.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kwabi-Addo B, Ozen M, Ittmann M. The role of fibroblast growth factors and their receptors in prostate cancer. Endocr Relat Cancer. 2004;11:709–24.

    Article  CAS  PubMed  Google Scholar 

  • Lataillade JJ, Domenech J, Le Bousse-Kerdiles MC. Stromal cell-derived factor-1 (SDF-1)\CXCR4 couple plays multiple roles on haematopoietic progenitors at the border between the old cytokine and new chemokine worlds: survival, cell cycling and trafficking. Eur Cytokine Netw. 2004;15:177–88.

    CAS  PubMed  Google Scholar 

  • Lauth M, Bergström Å, Shimokawa T, Toftgård R. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci. 2007;104:8455–60.

    Article  CAS  PubMed  Google Scholar 

  • Lebrun, J.J. 2012. The dual role of TGFbeta in human cancer: from tumor suppression to cancer metastasis. ISRN Mol Biol 2012:381428.

  • Lee GT, Hong JH, Mueller TJ, Watson JA, Kwak C, Sheen YY, et al. Effect of IN-1130, a small molecule inhibitor of transforming growth factor-β type I receptor/activin receptor-like kinase-5, on prostate cancer cells. J Urol. 2008;180:2660–7.

    Article  CAS  PubMed  Google Scholar 

  • Lee M, Hong H, Kim W, Zhang L, Friedlander TW, Fong L, et al. Itraconazole as a noncastrating treatment for biochemically recurrent prostate cancer: a phase 2 study. Clin Genitourin Cancer. 2019;17:e92–6.

    Article  PubMed  Google Scholar 

  • Leibowitz-Amit R, Pintilie M, Khoja L, Azad AA, Berger R, Laird AD, et al. Changes in plasma biomarkers following treatment with cabozantinib in metastatic castration-resistant prostate cancer: a post hoc analysis of an extension cohort of a phase II trial. J Transl Med. 2016;14:12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lescarbeau RM, Seib FP, Prewitz M, Werner C, Kaplan DL. In vitro model of metastasis to bone marrow mediates prostate cancer castration resistant growth through paracrine and extracellular matrix factors. PLoS One. 2012;7:e40372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Q, Ye L, Guo W, Wang M, Huang S, Peng X. PHF21B overexpression promotes cancer stem cell-like traits in prostate cancer cells by activating the Wnt/β-catenin signaling pathway. J Exp Clin Cancer Res. 2017;36:85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Li Y, Cozzi P, Graham P, Bucci J, Kearsley J. Cancer stem cells “the root of radioresistance” in prostate cancer radiotherapy. World J Cancer Res. 2013;1:85–8.

    Article  CAS  Google Scholar 

  • Li ZG, Mathew P, Yang J, Starbuck MW, Zurita AJ, Liu J, et al. Androgen receptor-negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms. J Clin Invest. 2008;118:2697–710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin JZ, Wang ZJ, De W, Zheng M, Xu WZ, Wu HF, et al. Targeting AXL overcomes resistance to docetaxel therapy in advanced prostate cancer. Oncotarget. 2017;8:41064–77.

    PubMed  PubMed Central  Google Scholar 

  • Logothetis CJ, Lin SH. Osteoblasts in prostate cancer metastasis to bone. Nat Rev Cancer. 2005;5:21–8.

    Article  CAS  PubMed  Google Scholar 

  • Ma F, Ye H, He HH, Gerrin SJ, Chen S, Tanenbaum BA, et al. SOX9 drives WNT pathway activation in prostate cancer. J Clin Invest. 2016;126:1745–58.

    Article  PubMed  PubMed Central  Google Scholar 

  • Maier GS, Eberhardt C, Kurth AA. Ibandronate: the loading dose concept in the treatment of metastatic bone pain. J Bone Oncol. 2016;5:1–4.

    Article  PubMed  Google Scholar 

  • Massague J. TGFbeta signalling in context. Nat Rev Mol Cell Biol. 2012;13:616–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maughan BL, Suzman DL, Luber B, Wang H, Glavaris S, Hughes R, et al. Pharmacodynamic study of the oral hedgehog pathway inhibitor, vismodegib, in patients with metastatic castration-resistant prostate cancer. Cancer Chemother Pharmacol. 2016;78:1297–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meng X, Vander Ark A, Daft P, Woodford E, Wang J, Madaj Z, et al. Loss of TGF-β signaling in osteoblasts increases basic-FGF and promotes prostate cancer bone metastasis. Cancer Lett. 2018;418:109–18.

    Article  CAS  PubMed  Google Scholar 

  • Miles FL, Tung NS, Aguiar AA, Kurtoglu S, Sikes RA. Increased TGF-β1-mediated suppression of growth and motility in castrate-resistant prostate cancer cells is consistent with Smad2/3 signaling. Prostate. 2012;72:1339–50.

    Article  CAS  PubMed  Google Scholar 

  • Moltzahn F, Thalmann GN. Cancer stem cells in prostate cancer. Transl Androl Urol. 2013;2:242.

    PubMed  PubMed Central  Google Scholar 

  • Nanta R, Kumar D, Meeker D, Rodova M, Van Veldhuizen P, Shankar S, et al. NVP-LDE-225 (Erismodegib) inhibits epithelial–mesenchymal transition and human prostate cancer stem cell growth in NOD/SCID IL2Rγ null mice by regulating Bmi-1 and microRNA-128. Oncogenesis. 2013;2:e42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ogawa K, Yoshioka Y, Isohashi F, Seo Y, Yoshida K, Yamazaki H. Radiotherapy targeting cancer stem cells: current views and future perspectives. Anticancer Res. 2013;33:747–54.

    CAS  PubMed  Google Scholar 

  • Ojo D, Lin X, Wong N, Gu Y, Tang D. Prostate cancer stem-like cells contribute to the development of castration-resistant prostate cancer. Cancers. 2015;7:2290–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pai VC, Hsu CC, Chan TS, Liao WY, Chuu CP, Chen WY, et al. Correction: ASPM promotes prostate cancer stemness and progression by augmenting Wnt-Dvl-3-β-catenin signaling. Oncogene. 2019;38:1354–4.

  • Paller C, Pu H, Begemann DE, Wade CA, Hensley PJ, Kyprianou N. TGF-β receptor I inhibitor enhances response to enzalutamide in a pre-clinical model of advanced prostate cancer. Prostate. 2018.

  • Patrawala L, Calhoun-Davis T, Schneider-Broussard R, Tang DG. Hierarchical organization of prostate cancer cells in xenograft tumors: the CD44+ α2β1+ cell population is enriched in tumor-initiating cells. Cancer Res. 2007;67:6796–805.

    Article  CAS  PubMed  Google Scholar 

  • Pedersen EA, Shiozawa Y, Mishra A, Taichman RS. Structure and function of the solid tumor niche. In: Frontiers in bioscience (Scholar edition, vol. 4; 2012. p. 1–15.

    Google Scholar 

  • Qin J, Liu X, Laffin B, Chen X, Choy G, Jeter CR, et al. The PSA(−/lo) prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration. Cell Stem Cell. 2012;10:556–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qiu S, Deng L, Bao Y, Jin K, Tu X, Li J, et al. Reversal of docetaxel resistance in prostate cancer by Notch signaling inhibition. Anti-Cancer Drugs. 2018;29:871–9.

    Article  CAS  PubMed  Google Scholar 

  • Rimkus T, Carpenter R, Qasem S, Chan M, Lo H-W. Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancers. 2016;8:22.

    Article  PubMed Central  CAS  Google Scholar 

  • Ross AE, Hughes RM, Glavaris S, Ghabili K, He P, Anders NM, et al. Pharmacodynamic and pharmacokinetic neoadjuvant study of hedgehog pathway inhibitor Sonidegib (LDE-225) in men with high-risk localized prostate cancer undergoing prostatectomy. Oncotarget. 2017;8:104182–92.

    PubMed  PubMed Central  Google Scholar 

  • Rossi D, Zlotnik A. The biology of chemokines and their receptors. Annu Rev Immunol. 2000;18:217–42.

    Article  CAS  PubMed  Google Scholar 

  • Ruppender N, Larson S, Lakely B, Kollath L, Brown L, Coleman I, et al. Cellular adhesion promotes prostate cancer cells escape from dormancy. PLoS One. 2015;10:e0130565.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sethi S, Macoska J, Chen W, Sarkar FH. Molecular signature of epithelial-mesenchymal transition (EMT) in human prostate cancer bone metastasis. Am J Transl Res. 2010;3:90–9.

    PubMed  PubMed Central  Google Scholar 

  • Shariat SF, Shalev M, Menesses-Diaz A, Kim IY, Kattan MW, Wheeler TM, 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. 2001;19:2856–64.

    Article  CAS  PubMed  Google Scholar 

  • Sharpe B, Beresford M, Bowen R, Mitchard J, Chalmers AD. Searching for prostate cancer stem cells: markers and methods. Stem Cell Rev Rep. 2013;9:721–30.

    Article  CAS  PubMed  Google Scholar 

  • Shiozawa Y, Berry JE, Eber MR, Jung Y, Yumoto K, Cackowski FC, et al. The marrow niche controls the cancer stem cell phenotype of disseminated prostate cancer. Oncotarget. 2016;7:41217–32.

    Article  PubMed  PubMed Central  Google Scholar 

  • Shiozawa Y, Pedersen EA, Havens AM, Jung Y, Mishra A, Joseph J, et al. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest. 2011;121:1298–312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shiozawa Y, Pedersen EA, Patel LR, Ziegler AM, Havens AM, Jung Y, et al. GAS6/AXL axis regulates prostate cancer invasion, proliferation, and survival in the bone marrow niche. Neoplasia. 2010;12:116–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith DC, Smith MR, Sweeney C, Elfiky AA, Logothetis C, Corn PG, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013;31:412–9.

    Article  CAS  PubMed  Google Scholar 

  • Smith M, De Bono J, Sternberg C, Le Moulec S, Oudard S, De Giorgi U, et al. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. 2016;34:3005–13.

    Article  CAS  PubMed  Google Scholar 

  • Smith MR, Sweeney CJ, Corn PG, Rathkopf DE, Smith DC, Hussain M, et al. Cabozantinib in chemotherapy-pretreated metastatic castration-resistant prostate cancer: results of a phase II nonrandomized expansion study. J Clin Oncol. 2014;32:3391–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stern PH, Alvares K. Antitumor agent cabozantinib decreases RANKL expression in osteoblastic cells and inhibits osteoclastogenesis and PTHrP-stimulated bone resorption. J Cell Biochem. 2014;115:2033–8.

    CAS  PubMed  Google Scholar 

  • Stoyanova T, Riedinger M, Lin S, Faltermeier CM, Smith BA, Zhang KX, et al. Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer. Proc Natl Acad Sci. 2016;113:E6457–66.

    Article  CAS  PubMed  Google Scholar 

  • Taichman RS, Patel LR, Bedenis R, Wang J, Weidner S, Schumann T, et al. GAS6 receptor status is associated with dormancy and bone metastatic tumor formation. PLoS One. 2013;8:e61873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takebe N, Miele L, Harris PJ, Jeong W, Bando H, Kahn M, et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol. 2015;12:445–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takeishi S, Nakayama KI. To wake up cancer stem cells, or to let them sleep, that is the question. Cancer Sci. 2016;107:875–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trautmann F, Cojoc M, Kurth I, Melin N, Bouchez LC, Dubrovska A, et al. CXCR4 as biomarker for radioresistant cancer stem cells. Int J Radiat Biol. 2014;90:687–99.

    Article  CAS  PubMed  Google Scholar 

  • Tsujimura A, Koikawa Y, Salm S, Takao T, Coetzee S, Moscatelli D, et al. Proximal location of mouse prostate epithelial stem cells: a model of prostatic homeostasis. J Cell Biol. 2002;157:1257–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valta MP, Tuomela J, Bjartell A, Valve E, Väänänen HK, Härkönen P. FGF-8 is involved in bone metastasis of prostate cancer. Int J Cancer. 2008;123:22–31.

    Article  CAS  PubMed  Google Scholar 

  • Varkaris A, Corn PG, Gaur S, Dayyani F, Logothetis CJ, Gallick GE. The role of HGF/c-Met signaling in prostate cancer progression and c-Met inhibitors in clinical trials. Expert Opin Investig Drugs. 2011;20:1677–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wan X, Corn PG, Yang J, Palanisamy N, Starbuck MW, Efstathiou E, et al. Prostate cancer cell–stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases. Sci Transl Med. 2014;6:252ra122–2.

  • Wan X, Li Z-G, Yingling JM, Yang J, Starbuck MW, Ravoori MK, et al. Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth. Bone. 2012;50:695–703.

    Article  CAS  PubMed  Google Scholar 

  • Wang N, Docherty F, Brown HK, Reeves K, Fowles A, Lawson M, et al. Mitotic quiescence, but not unique “stemness,” marks the phenotype of bone metastasis-initiating cells in prostate cancer. FASEB J. 2015a;29:3141–50.

    Article  CAS  PubMed  Google Scholar 

  • Wang N, Docherty F, Brown HK, Reeves K, Fowles A, Lawson M, et al. Mitotic quiescence, but not unique “stemness,” marks the phenotype of bone metastasis-initiating cells in prostate cancer. FASEB J. 2015b;29:3141–50.

    Article  CAS  PubMed  Google Scholar 

  • West AF, O'Donnell M, Charlton RG, Neal DE, Leung HY. Correlation of vascular endothelial growth factor expression with fibroblast growth factor-8 expression and clinico-pathologic parameters in human prostate cancer. Br J Cancer. 2001;85:576–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yadav SS, Li J, Stockert JA, Herzog B, O'Connor J, Garzon-Manco L, et al. Induction of neuroendocrine differentiation in prostate cancer cells by dovitinib (TKI-258) and its therapeutic implications. Transl Oncol. 2017;10:357–66.

    Article  PubMed  PubMed Central  Google Scholar 

  • Yardy GW, Brewster SF. Wnt signalling and prostate cancer. Prostate Cancer Prostatic Dis. 2005;8:119–26.

    Article  CAS  PubMed  Google Scholar 

  • Zhang K, Guo Y, Wang X, Zhao H, Ji Z, Cheng C, et al. WNT/β-catenin directs self-renewal symmetric cell division of hTERThigh prostate cancer stem cells. Cancer Res. 2017a;77:2534–47.

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Sha J, Yang G, Huang X, Bo J, Huang Y. Activation of Notch pathway is linked with epithelial-mesenchymal transition in prostate cancer cells. Cell Cycle. 2017b;16:999–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Z, Cheng L, Li J, Farah E, Atallah NM, Pascuzzi PE, et al. Inhibition of the Wnt/beta-catenin pathway overcomes resistance to enzalutamide in castration-resistant prostate cancer. Cancer Res. 2018;78:3147–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Z, Pu F, Shao Z. The skeletal-related events of denosumab versus zoledronic acid in patients with bone metastases: a meta-analysis of randomized controlled trials. J Bone Oncol. 2017c;9:21–4.

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhao M, Qiao M, Harris SE, Chen D, Oyajobi BO, Mundy GR. The zinc finger transcription factor Gli2 mediates bone morphogenetic protein 2 expression in osteoblasts in response to hedgehog signaling. Mol Cell Biol. 2006;26:6197–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou G, Yin L-C, Wang D-W, Li L, Pei S, Gentle IR, et al. Fibrous hybrid of graphene and sulfur nanocrystals for high-performance lithium–sulfur batteries. ACS Nano. 2013;7:5367–75.

    Article  CAS  PubMed  Google Scholar 

  • Zou J, Hong Y, Tong Y, Wei J, Qin Y, Shao S, et al. Sonic hedgehog produced by bone marrow-derived mesenchymal stromal cells supports cell survival in myelodysplastic syndrome. Stem Cells Int. 2015;2015:957502.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgments

Dr. Younghun Jung gave valuable critique on the signaling pathway of cancer stem cells. R.T. receives support as the Major McKinley Ash Collegiate Professor.

Funding

This work is financially supported by the National Cancer Institute (R.S. Taichman (CA093900 and CA163124)), the Department of Defense (R.S. Taichman (W81XW-15-1-0413 and W81XWH-14-1-0403)) and the Prostate Cancer Foundation Challenge Award R.S. Taichman (16CHAL05), Prostate Cancer Foundation Challenge Award (F.C. Cackowski (16CHAL05), a Career Enhancement Award, Sub-Award (F.C. Cackowski ((F048931)) of NIH/NCI Prostate Cancer Specialized Program in Research Excellence (SPORE) to Arul Chinnaiyan at the University of Michigan (F036250), and Prostate Cancer Foundation Young Investigator Award (F.C. Cackowski (18YOUN04).

Author information

Author notes

  1. Russell S. Taichman

    Present address: Department of Periodontology, University of Alabama Birmingham School of Dentistry, Birmingham, Alabama, USA

Authors and Affiliations

  1. Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, 48109, USA

    Clara H. Lee, Ann M. Decker, Frank C. Cackowski & Russell S. Taichman

  2. Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA

    Frank C. Cackowski

Authors
  1. Clara H. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ann M. Decker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frank C. Cackowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Russell S. Taichman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Russell S. Taichman.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lee, C.H., Decker, A.M., Cackowski, F.C. et al. Bone microenvironment signaling of cancer stem cells as a therapeutic target in metastatic prostate cancer. Cell Biol Toxicol 36, 115–130 (2020). https://doi.org/10.1007/s10565-019-09483-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10565-019-09483-7

Keywords

  • Prostate cancer
  • Metastasis
  • Cancer stem cells
  • Bone microenvironment
  • Signaling pathway
  • Therapy