Key Points
-
Patients with advanced prostate cancer frequently develop bone metastases.
-
The tropism of prostate cancer cells for bone and their tendency to induce the osteoblastic phenotype is a result of interactions between prostate cancer cells and osteoblasts. Prostate cancer cells might depend on an osteoblast-derived factor for their growth.
-
Prostate cancer cells produce factors that perturb the bone microenvironment in ways that affect the normal functional balance between osteoblast and osteoclast activities, resulting in osteoblastic metastases.
-
Osteoblasts also secrete factors that facilitate progression of prostate cancer in bone.
-
Therapeutics designed to target the interaction between prostate cancer and osteoblasts might prevent or treat prostate cancer bone metastases.
Abstract
Metastasis to bone is common in lung, kidney, breast and prostate cancers. However, prostate cancer is unique in that bone is often the only clinically detectable site of metastasis, and the resulting tumours tend to be osteoblastic (bone forming) rather than osteolytic (bone lysing). The interaction between host cells and metastatic cancer cells is an important component of organ-specific cancer progression. How can this knowledge lead to the development of more effective therapies?
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Jacobs, S. C. Spread of prostatic cancer to bone. Urology 21, 337–344 (1983).
Jung, K. et al. Comparison of 10 serum bone turnover markers in prostate carcinoma patients with bone metastatic spread: diagnostic and prognostic implications. Int. J. Cancer. 111, 783–791 (2004).
Quilty, P. M. et al. A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother. Oncol. 31, 33–40 (1994).
Sartor, O. et al. Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology 63, 940–945 (2004).
Han, S. H. et al. The PLACORHEN study: a double-blind, placebo-controlled, randomized radionuclide study with (186)Re-etidronate in hormone-resistant prostate cancer patients with painful bone metastases. Placebo Controlled Rhenium Study. J. Nucl. Med. 43, 1150–1156 (2002).
Tu, S. -M. et al. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomized phase II trial. Lancet 357, 336–341 (2001). First clinical trial showing that bone-targeting therapy (with strontium-89) can increase survival in patients with advanced androgen-independent carcinoma of the prostate.
Saad, F. et al. A randomized, placebo-controlled trial of Zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J. Natl Cancer Inst. 94, 1458–1468 (2002).
Nelson, J. B. et al. Suppression of prostate cancer induced bone remodeling by the endothelin receptor A antagonist atrasentan. J. Urol. 169, 1143–1149 (2003).
Nelson, J. B. et al. Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nature Med. 1, 944–949 (1995).
Takuwa, Y., Masaki, T. & Yamashita, K. The effects of the endothelin family peptides on cultured osteoblastic cells from rat calvariae. Biochem. Biophys. Res. Commun. 170, 998–1005 (1990).
Carducci, M. A. et al. Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial. J. Clin. Oncol. 21, 679–689 (2003). First clinical trial that blocks a specific pathway, such as ET1 signalling, implicated in the progression of prostate cancer in bone.
Mundy, G. R. et al. Growth regulatory factors and bone. Rev. Endocr. Metab. Disord. 2, 105–115 (2001).
Ducy, P., Zhang, R., Geoffroy, V., Ridall, A. L. & Karsenty, G. Osf2/Cbfa1: A transcriptional activator of osteoblast differentiation. Cell 89, 747–754 (1997).
Komori, T. et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89, 755–764 (1997).
Otto, F. et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89, 765–771 (1997).
Nakashima, K. et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108, 17–29 (2002).
Lee, K. S. et al. Runx2 is a common target of transforming growth factor β1 and bone morphogenetic protein 2, and cooperation between Runx2 and Smad5 induces osteoblast-specific gene expression in the pluripotent mesenchymal precursor cell line C2C12. Mol. Cell. Biol. 20, 8783–8792 (2000).
Kim, H. J. et al. The protein kinase C pathway plays a central role in the fibroblast growth factor-stimulated expression and transactivation activity of Runx2. J. Biol. Chem. 278, 319–326 (2003).
Boyden, L. M. et al. High bone density due to a mutation in LDL-receptor-related protein 5. N. Engl. J. Med. 346, 1513–1521 (2002).
Little, R. D. et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am. J. Hum. Genet. 70, 11–19 (2002).
Kato, M. et al. Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J. Cell Biol. 157, 303–314 (2002).
Mao, J. et al. Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol. Cell 7, 801–809 (2001).
Orford, K., Crockett, C., Jensen, J. P., Weissman, A. M. & Byers, S. W. Serine phosphorylation-regulated ubiquitination and degradation of β-catenin. J. Biol. Chem. 272, 24735–24738 (1997).
Ikeda, S. et al. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3β catenin and promotes GSK-3β-dependent phosphorylation of β-catenin. EMBO J. 17, 1371–1384 (1998).
Behrens, J. et al. Functional interaction of β-catenin with the transcription factor LEF-1. Nature 382, 638–642 (1996).
van de Wetering, M. et al. Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF. Cell 88, 789–799 (1997).
Autzen, P. et al. Bone morphogenetic protein 6 in skeletal metastases from prostate cancer and other common human malignancies. Br. J. Cancer 78, 1219–1223 (1998).
Harris, S. E. et al. Expression of bone morphogenetic protein messenger RNAs by normal rat and human prostate and prostate cancer cells. Prostate 24, 204–211 (1994).
Marquardt, H., Lioubin, M. N. & Ikeda, T. Complete amino acid sequence of human transforming growth factor type b2. J. Biol. Chem. 262, 12127–12131 (1987).
Shariat, S. F. et al. Preoperative plasma levels of transforming growth factor β1 (TGF-β1) strongly predict progression in patients undergoing radical prostatectomy. J. Clin. Oncol. 19, 2856–2864 (2001).
Chan, J. M. et al. Plasma insulin-like growth factor-1 and prostate cancer risk: a prospective study. Science 279, 563–566 (1998).
Baserga, R. The insulin-like growth factor 1 receptor: a key to tumor growth? Cancer Res. 55, 249–252 (1995).
Baserga, R., Hongo, A., Rubini, M., Prisco, M. & Valentinis, B. The IGF-I receptor in cell growth, transformation and apoptosis. Biochem. Biophys. Acta 1332, F105–F126 (1997).
Jones, J. I. & Clemmons, D. R. Insulin-like growth factors and their binding proteins: biological actions. Endocr. Rev. 16, 3–34 (1995).
Li, L., Yu, H., Schumacher, F., Casey, G. & Witte, J. S. Relation of serum insulin-like growth factor-I (IGF-I) and IGF binding protein-3 to risk of prostate cancer (United States). Cancer Causes Control 14, 721–726 (2003).
Ali, O., Cohen, P. & Lee, K. W. Epidemiology and biology of insulin-like growth factor binding protein-3 (IGFBP-3) as an anti-cancer molecule. Horm. Metab. Res. 35, 726–733 (2003).
Funa, K., Nordgren, H. & Nilsson, S. In situ expression of mRNA for proto-oncogenes in benign prostatic hyperplasia and in prostatic carcinoma. Scand. J. Urol. Nephrol. 25, 95–100 (1991).
Fudge, K., Wang, C. Y. & Stearns, M. E. Immunohistochemistry analysis of platelet-derived growth factor A and B chains and platelet-derived growth factor α and β receptor expression in benign prostatic hyperplasias and Gleason-graded human prostate adenocarcinomas. Modern Path. 7, 549–554 (1994).
Matuo, Y. et al. Heparin binding affinity of rat prostatic growth factor in normal and cancerous prostates: partial purification and characterization of rat prostatic growth factor in the Dunning tumor. Cancer Res. 47, 188–192 (1987).
Ferrer, F. A. et al. Vascular endothelial growth factor (VEGF) expression in human prostate cancer: in situ and in vitro expression of VEGF by human prostate cancer cells. J. Urol. 157, 2329–2333 (1997).
Dai, J. et al. Vascular endothelial growth factor contributes to the prostate cancer-induced osteoblast differentiation mediated by bone morphogenetic protein. Cancer Res. 64, 994–999 (2004).
Gerber, H. P. et al. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nature Med. 5, 623–628 (1999).
Street, J. et al. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc. Natl Acad. Sci. USA 99, 9656–9661 (2002).
Midy, V. & Plouet, J. Vasculotropin/vascular endothelial growth factor induces differentiation in cultured osteoblasts. Biochem. Biophys. Res. Commun. 199, 380–386 (1994).
Chen, G. et al. Up-regulation of Wnt-1 and β-catenin production in patients with advanced metastatic prostate carcinoma. Cancer 101, 1345–1356 (2004).
Tian, E. et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N. Engl. J. Med. 349, 2483–2494 (2003).
Yanagisawa, M. et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332, 411–415 (1988).
Rabbani, S. A. et al. An amino-terminal fragment of urokinase isolated from a prostate cancer cell line (PC-3) is mitogenic for osteoblast-like cells. Biochem. Biophys. Res. Commun. 173, 1058–1064 (1990).
Koutsilieris, M. Osteoblastic metastasis in advanced prostate cancer. Anticancer Res. 13, 443–450 (1993).
Cramer, S. D., Chen, Z. & Peehl, D. M. Prostate specific antigen cleaves parathyroid hormone-related protein in the PTH-like domain: inactivation of PTHrP-stimulated cAMP accumulation in mouse osteoblasts. J. Urol. 156, 526–531 (1996).
Iwamura, M., Hellman, J., Cockett, A. T. K., Lilja, H. & Gershagen, S. Alteration of the hormonal bioactivity of parathyroid hormone-related protein (PTHrP) as a result of limited proteolysis by prostate-specific antigen. Urology 48, 317–325 (1996).
Cohen, P., Peehl, D. M., Graves, H. & Rosenfeld, R. G. Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease. J. Endocrinol. 142, 407–415 (1994).
Vakar-Lopez, F. et al. Up-regulation of MDA-BF-1, a secreted isoform of ErbB3, in metastatic prostate cancer cells and activated osteoblasts in bone marrow. J. Path. 203, 688–695 (2004). First isolation of a bone metastasis-related factor from bone-marrow supernatant of patients with metastatic prostate cancer.
Yang, J. et al. Prostate cancer cells induce osteoblast differentiation through a cbfa1-dependent pathway. Cancer Res. 61, 5652–5659 (2001).>First report of prostate cancer cell lines that produce osteoblastic tumour.
Gleave, M. E., Hsieh, J. T., Gao, C., von Eschenbach, A. C. & Chung, L. W. K. Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts. Cancer Res. 51, 3753–3761 (1991). First demonstration that bone-derived factors can accelerate human prostate tumour growth.
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).
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).
Chackal-Roy, M., Niemeyer, C., Moore, M. & Zetter, B. R. Stimulation of human prostatic carcinoma cell growth by factors present in human bone marrow. J. Clin. Invest. 84, 43–50 (1989).
Lang, S. H., Miller, W. R. & Habib, F. K. Stimulation of human prostate cancer cell lines by factors present in human osteoblast-like cells but not in bone marrow. Prostate 27, 287–293 (1995).
Udagawa, N. et al. Osteoprotegerin produced by osteoblasts is an important regulator in osteoclast development and function. Endocrinology 141, 3478–3484 (2000).
Boyle, W. J., Simonet, W. S. & Lacey, D. L. Osteoclast differentiation and activation. Nature 423, 337–342 (2003).
Brown, J. M. et al. Serum osteoprotegerin levels are increased in patients with advanced prostate cancer. Clin. Cancer Res. 7, 2977–2983 (2001).
Corral, D. A. et al. Dissociation between bone resorption and bone formation in osteopenic transgenic mice. Proc. Natl Acad. Sci. USA 95, 13835–13840 (1998).
Cohen, P. et al. Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. J. Clin. Endocrinol. Metab. 75, 1046–1053 (1992).
Kaighn, M. E., Narayan, K. S., Ohnuki, Y., Lechner, J. F. & Jones, L. W. Establishment and characterization of a human prostatic carcinoma cell line (PC-3). Invest. Urol. 17, 16–23 (1979).
Navone, N. M. et al. Establishment of two human prostate cancer cell lines derived from a single bone metastasis. Clin. Cancer Res. 3, 2493–2500 (1997).
Craft, N. et al. Evidence for clonal outgrowth of androgen-independent prostate cancer cells from androgen-dependent tumors through a two-step process. Cancer Res. 59, 5030–5036 (1999).
Lee, Y. P. et al. Use of zoledronate to treat osteoblastic versus osteolytic lesions in a severe-combined-immunodeficient mouse model. Cancer Res. 62, 5564–5570 (2002).
Korenchuk, S. et al. VCaP, a cell-based model system of human prostate cancer. In Vivo 15, 163–168 (2001).
Horoszewicz, J. S. et al. LNCaP model of human prostatic carcinoma. Cancer Res. 43, 1809–1818 (1983).
Thalmann, G. N. et al. Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Res. 54, 2577–2581 (1994).
Thalmann, G. N. et al. LNCaP progression model of human prostate cancer: androgen-independence and osseous metastasis. Prostate 44, 91–103 (2000).
Ellis, W. J. et al. Characterization of a novel androgen-sensitive, prostate-specific antigen-producing prostatic carcinoma xenograft: LuCaP 23. Clin. Cancer Res. 2, 1039–1048 (1996).
Corey, E. et al. Establishment and characterization of osseous prostate cancer models: intra-tibial injection of human prostate cancer cells. Prostate 52, 20–33 (2002).
Corey, E. et al. LuCaP 35: a new model of prostate cancer progression to androgen independence. Prostate 55, 239–246 (2003).
True, L. D. et al. A neuroendocrine/small cell prostate carcinoma xenograft-LuCaP 49. Am. J. Pathol. 161, 705–715 (2002).
Klein, K. A. et al. Progression of metastatic human prostate cancer to androgen independence in immunodeficient SCID mice. Nature Med. 3, 402–408 (1997).
Pinthus, J. H. et al. WISH-PC2: a unique xenograft model of human prostatic small cell carcinoma. Cancer Res. 60, 6563–6567 (2000).
Wainstein, M. A. et al. CWR22: androgen-dependent xenograft model derived from a primary human prostatic carcinoma. Cancer Res. 54, 6049–6052 (1994).
Stone, K. R., Mickey, D. D., Wunderli, H., Mickey, G. H. & Paulson, D. F. Isolation of a human prostate carcinoma cell line (DU145). Int. J. Cancer 21, 274–281 (1978).
Lee, Y. G. et al. Establishment and characterization of a new human prostatic cancer cell line: DuCaP. In Vivo 15, 157–162 (2001).
Nemeth, J. A. et al. Severe combined immunodeficient-hu model of human prostate cancer metastasis to human bone. Cancer Res. 59, 1987–1993 (1999).
Wu, T. T. et al. Establishing human prostate cancer cell xenografts in bone: induction of osteoblastic reaction by prostate-specific antigen-producing tumors in athymic and SCID/bg mice using LNCaP and lineage-derived metastatic sublines. Int. J. Cancer 77, 887–894 (1998).
Acknowledgements
We thank L.-Y. Yu-Lee, J. Kim and S.-M. Tu for helpful comments.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Related links
DATABASES
Entrez Gene
National Cancer Institute
FURTHER INFORMATION
Advances in the treatment of metastatic prostate cancer
Bone tumour information source
eMedicine article on prostate cancer
Glossary
- HEMIPARESIS
-
Complete loss of muscle strength involving one side of the body.
- PARESIS
-
Complete loss of muscle strength on both sides of the body.
- BISPHOSPHONATES
-
A class of drugs used to strengthen bone by inhibiting osteoclast bone resorption.
Rights and permissions
About this article
Cite this article
Logothetis, C., Lin, SH. Osteoblasts in prostate cancer metastasis to bone. Nat Rev Cancer 5, 21–28 (2005). https://doi.org/10.1038/nrc1528
Issue Date:
DOI: https://doi.org/10.1038/nrc1528
This article is cited by
-
Procoxacin bidirectionally inhibits osteoblastic and osteoclastic activity in bone and suppresses bone metastasis of prostate cancer
Journal of Experimental & Clinical Cancer Research (2023)
-
Breast Cancer Exosomal microRNAs Facilitate Pre-Metastatic Niche Formation in the Bone: A Mathematical Model
Bulletin of Mathematical Biology (2023)
-
The LINC00852/miR-29a-3p/JARID2 axis regulates the proliferation and invasion of prostate cancer cell
BMC Cancer (2022)
-
Prostate tumor-induced stromal reprogramming generates Tenascin C that promotes prostate cancer metastasis through YAP/TAZ inhibition
Oncogene (2022)
-
Risk assessment of femoral pathological fracture in prostate cancer patients by computed tomography analysis
Journal of Bone and Mineral Metabolism (2022)