Hostname: page-component-cd9895bd7-q99xh Total loading time: 0 Render date: 2024-12-26T07:10:27.913Z Has data issue: false hasContentIssue false

Molecular mechanisms and treatment of bone metastasis

Published online by Cambridge University Press:  06 March 2008

Gregory A. Clines
Affiliation:
Division of Endocrinology and Metabolism, The University of Virginia, Charlottesville, VA 22908-1420, USA.
Theresa A. Guise*
Affiliation:
Division of Endocrinology and Metabolism, The University of Virginia, Charlottesville, VA 22908-1420, USA.
*
*Corresponding author: Theresa A. Guise, Division of Endocrinology and Metabolism, The University of Virginia, PO Box 801419, Charlottesville, VA 22908-1419, USA. Tel: +1 434 243 0305; Fax: +1 434 982 3314; E-mail: [email protected]

Abstract

The metastasis of cancer cells to bone alters bone architecture and mineral homeostasis. As described by the ‘seed and soil’ hypothesis, bone represents a fertile ground for cancer cells to flourish. A ‘vicious cycle’ of reciprocal bone–cancer cellular signals occurs with osteolytic (bone-resorbing) metastases, and a similar mechanism likely modulates osteoblastic (bone-forming) metastatic lesions as well. The development of targeted therapies either to block initial cancer cell chemotaxis, invasion and adhesion or to break the ‘vicious cycle’ is dependent on a more complete understanding of bone metastases. Although bisphosphonates delay progression of skeletal metastases, it is clear that more-effective therapies are needed. Cancer-associated bone morbidity remains a major public health problem, and to improve therapy and prevention it is important to understand the pathophysiology of the effects of cancer on bone. This review details scientific advances in this area.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2008

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Clines, G.A. and Guise, T.A. (2005) Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone. Endocr Relat Cancer 12, 549-583CrossRefGoogle ScholarPubMed
2Galasko, C.S.B. (1981) The Anatomy and Pathways of Skeletal Metastases (Weiss, I. and Gilbert, A.H., series eds), GK Hall, BostonGoogle Scholar
3Guise, T.A. and Mundy, G.R. (1998) Cancer and bone. Endocr Rev 19, 18-54Google ScholarPubMed
4Deyo, R.A. and Diehl, A.K. (1988) Cancer as a cause of back pain: frequency, clinical presentation, and diagnostic strategies. J Gen Intern Med 3, 230-238CrossRefGoogle ScholarPubMed
5Jarvik, J.G. and Deyo, R.A. (2002) Diagnostic evaluation of low back pain with emphasis on imaging. Ann Intern Med 137, 586-597CrossRefGoogle ScholarPubMed
6Du, Y. et al. (2007) Fusion of metabolic function and morphology: sequential [18F]fluorodeoxyglucose positron-emission tomography/computed tomography studies yield new insights into the natural history of bone metastases in breast cancer. J Clin Oncol 25, 3440-3447CrossRefGoogle ScholarPubMed
7Hur, J. et al. (2007) Accuracy of fluorodeoxyglucose-positron emission tomography for diagnosis of single bone metastasis: comparison with bone scintigraphy. J Comput Assist Tomogr 31, 812-819CrossRefGoogle ScholarPubMed
8Costa, L. et al. (2002) Prospective evaluation of the peptide-bound collagen type I cross-links N-telopeptide and C-telopeptide in predicting bone metastases status. J Clin Oncol 20, 850-856CrossRefGoogle ScholarPubMed
9Coleman, R.E. et al. (2005) Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol 23, 4925-4935CrossRefGoogle ScholarPubMed
10Brown, J.E. et al. (2005) Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 97, 59-69CrossRefGoogle ScholarPubMed
11Egeblad, M. and Werb, Z. (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2, 161-174CrossRefGoogle ScholarPubMed
12Bachmeier, B.E. et al. (2001) Matrix metalloproteinases (MMPs) in breast cancer cell lines of different tumorigenicity. Anticancer Res 21, 3821-3828Google ScholarPubMed
13Upadhyay, J. et al. (1999) Membrane type 1-matrix metalloproteinase (MT1-MMP) and MMP-2 immunolocalization in human prostate: change in cellular localization associated with high-grade prostatic intraepithelial neoplasia. Clin Cancer Res 5, 4105-4110Google ScholarPubMed
14Nakopoulou, L. et al. (2003) MMP-2 protein in invasive breast cancer and the impact of MMP-2/TIMP-2 phenotype on overall survival. Breast Cancer Res Treat 77, 145-155CrossRefGoogle ScholarPubMed
15Ranuncolo, S.M. et al. (2003) Plasma MMP-9 (92 kDa-MMP) activity is useful in the follow-up and in the assessment of prognosis in breast cancer patients. Int J Cancer 106, 745-751CrossRefGoogle ScholarPubMed
16Lynch, C.C. et al. (2005) MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell 7, 485-496CrossRefGoogle ScholarPubMed
17Palumbo, J.S. et al. (2005) Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood 105, 178-185CrossRefGoogle ScholarPubMed
18Boucharaba, A. et al. (2004) Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer. J Clin Invest 114, 1714-1725CrossRefGoogle ScholarPubMed
19Muller, A. et al. (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50-56CrossRefGoogle ScholarPubMed
20Sun, Y.X. et al. (2005) Skeletal localization and neutralization of the SDF-1(CXCL12)/CXCR4 axis blocks prostate cancer metastasis and growth in osseous sites in vivo. J Bone Miner Res 20, 318-329CrossRefGoogle ScholarPubMed
21Wang, J., Loberg, R. and Taichman, R.S. (2006) The pivotal role of CXCL12 (SDF-1)/CXCR4 axis in bone metastasis. Cancer Metastasis Rev 25, 573-587CrossRefGoogle ScholarPubMed
22Kang, Y. et al. (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537-549CrossRefGoogle ScholarPubMed
23Taichman, R.S. et al. (2002) Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res 62, 1832-1837Google ScholarPubMed
24Sung, V. et al. (1998) Bone sialoprotein supports breast cancer cell adhesion proliferation and migration through differential usage of the alpha(v)beta3 and alpha(v)beta5 integrins. J Cell Physiol 176, 482-4943.0.CO;2-K>CrossRefGoogle ScholarPubMed
25Felding-Habermann, B. et al. (2001) Integrin activation controls metastasis in human breast cancer. Proc Natl Acad Sci U S A 98, 1853-1858CrossRefGoogle ScholarPubMed
26Zhao, Y. et al. (2007) Tumor alphavbeta3 integrin is a therapeutic target for breast cancer bone metastases. Cancer Res 67, 5821-5830CrossRefGoogle ScholarPubMed
27Guise, T.A. et al. (1996) Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Invest 98, 1544-1549CrossRefGoogle ScholarPubMed
28Thomas, R.J. et al. (1999) Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology 140, 4451-4458CrossRefGoogle ScholarPubMed
30Javelaud, D. et al. (2007) Stable overexpression of Smad7 in human melanoma cells impairs bone metastasis. Cancer Res 67, 2317-2324CrossRefGoogle ScholarPubMed
31Javed, A. et al. (2005) Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo. Proc Natl Acad Sci U S A 102, 1454-1459CrossRefGoogle ScholarPubMed
32Sterling, J.A. et al. (2006) The hedgehog signaling molecule Gli2 induces parathyroid hormone-related peptide expression and osteolysis in metastatic human breast cancer cells. Cancer Res 66, 7548-7553CrossRefGoogle ScholarPubMed
33Kakonen, S.M. et al. (2002) Breast cancer cell lines selected from bone metastases have greater metastatic capacity and express increased vascular endothelial growth factor (VEGF), interleukin-11 (IL-11), and parathyroid hormone-related protein (PTHrP). J Bone Miner Metab 17, M060, http://www.abstractsonline.com/viewer/viewAbstractPrintFriendly.asp&CKey&={12303D77-5768-4955-AF16-11ED38413479}&SKey&={C32FC098-4831-49E9-9C80-59E6409CCC51}&MKey&={F20CE5E7-B833-4CD0-95D1-A10258D95F7F}&AKey&={D0C01D4F-E23B-45E2-ACD4-0AF8AC866B8B}Google Scholar
34de la Mata, J. et al. (1995) Interleukin-6 enhances hypercalcemia and bone resorption mediated by parathyroid hormone-related protein in vivo. J Clin Invest 95, 2846-2852CrossRefGoogle ScholarPubMed
35Bendre, M.S. et al. (2002) Expression of interleukin 8 and not parathyroid hormone-related protein by human breast cancer cells correlates with bone metastasis in vivo. Cancer Res 62, 5571-5579Google Scholar
36Sachdev, D. and Yee, D. (2001) The IGF system and breast cancer. Endocrine-Related Cancer 8, 197-209CrossRefGoogle ScholarPubMed
37Yoneda, T. et al. (2001) A bone-seeking clone exhibits different biological properties from the MDA-MB-231 parental human breast cancer cells and a brain-seeking clone in vivo and in vitro. J Bone Miner Res 16, 1486-1495CrossRefGoogle Scholar
38Hauschka, P.V. et al. (1986) Growth factors in bone matrix. Isolation of multiple types by affinity chromatography on heparin-Sepharose. J Biol Chem 261, 12665-12674CrossRefGoogle ScholarPubMed
39Yamaguchi, T., Chattopadhyay, N. and Brown, E.M. (2000) G protein-coupled extracellular Ca2+ (Ca2+o)-sensing receptor (CaR): roles in cell signaling and control of diverse cellular functions. Adv Pharmacol 47, 209-253CrossRefGoogle ScholarPubMed
40Buchs, N. et al. (2000) Calcium stimulates parathyroid hormone-related protein production in Leydig tumor cells through a putative cation-sensing mechanism. Eur J Endocrinol 142, 500-505CrossRefGoogle ScholarPubMed
41Sanders, J.L. et al. (2000) Extracellular calcium-sensing receptor expression and its potential role in regulating parathyroid hormone-related peptide secretion in human breast cancer cell lines. Endocrinology 141, 4357-4364CrossRefGoogle ScholarPubMed
42Yin, J.J. et al. (2003) A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases. Proc Natl Acad Sci U S A 100, 10954-10959CrossRefGoogle ScholarPubMed
43Clines, G.A. et al. (2007) Dickkopf homolog 1 mediates endothelin-1-stimulated new bone formation. Mol Endocrinol 22, 486-498CrossRefGoogle Scholar
44Hall, C.L. et al. (2005) Prostate cancer cells promote osteoblastic bone metastases through Wnts. Cancer Res 65, 7554-7560CrossRefGoogle ScholarPubMed
45Mundy, G.R. (2002) Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2, 584-593CrossRefGoogle ScholarPubMed
46Roodman, G.D. (2004) Mechanisms of bone metastasis. N Engl J Med 350, 1655-1664CrossRefGoogle ScholarPubMed
47Cramer, S.D., Chen, Z. and Peehl, D.M. (1996) 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, 526-531CrossRefGoogle ScholarPubMed
48Schluter, K.D., Katzer, C. and Piper, H.M. (2001) A N-terminal PTHrP peptide fragment void of a PTH/PTHrP-receptor binding domain activates cardiac ET(A) receptors. Br J Pharmacol 132, 427-432CrossRefGoogle ScholarPubMed
50Fielder, P.J. et al. (1994) Biochemical analysis of prostate specific antigen-proteolyzed insulin-like growth factor binding protein-3. Growth Regul 4, 164-172Google ScholarPubMed
51Killian, C.S. et al. (1993) Mitogenic response of osteoblast cells to prostate-specific antigen suggests an activation of latent TGF-beta and a proteolytic modulation of cell adhesion receptors. Biochem Biophys Res Commun 192, 940-947CrossRefGoogle Scholar
52Cohen, P. et al. (1994) Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease. J Endocrinol 142, 407-415CrossRefGoogle ScholarPubMed
53Williams, S.A. et al. (2007) Does PSA play a role as a promoting agent during the initiation and/or progression of prostate cancer? Prostate 67, 312-329CrossRefGoogle ScholarPubMed
54Buijs, J.T. et al. (2007) BMP7, a putative regulator of epithelial homeostasis in the human prostate, is a potent inhibitor of prostate cancer bone metastasis in vivo. Am J Pathol 171, 1047-1057CrossRefGoogle ScholarPubMed
55Yi, B. et al. (2002) Tumor-derived platelet-derived growth factor-BB plays a critical role in osteosclerotic bone metastasis in an animal model of human breast cancer. Cancer Res 62, 917-923Google Scholar
56Goblirsch, M.J., Zwolak, P.P. and Clohisy, D.R. (2006) Biology of bone cancer pain. Clin Cancer Res 12, 6231s-6235sCrossRefGoogle ScholarPubMed
57Peters, C.M. et al. (2004) Endothelin and the tumorigenic component of bone cancer pain. Neuroscience 126, 1043-1052CrossRefGoogle ScholarPubMed
58Sevcik, M.A. et al. (2005) Anti-NGF therapy profoundly reduces bone cancer pain and the accompanying increase in markers of peripheral and central sensitization. Pain 115, 128-141CrossRefGoogle ScholarPubMed
59 [No authors listed] (1988) Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomized trials among 28,896 women. Early Breast Cancer Trialists' Collaborative Group. N Engl J Med 319, 1681-1692CrossRefGoogle Scholar
60Fisher, B. et al. (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90, 1371-1388CrossRefGoogle ScholarPubMed
61Pyrhonen, S. et al. (1999) Meta-analysis of trials comparing toremifene with tamoxifen and factors predicting outcome of antiestrogen therapy in postmenopausal women with breast cancer. Breast Cancer Res Treat 56, 133-143CrossRefGoogle ScholarPubMed
62Cauley, J.A. et al. (2001) Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation. Breast Cancer Res Treat 65, 125-134CrossRefGoogle ScholarPubMed
63Bonneterre, J. et al. (2000) Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 18, 3748-3757CrossRefGoogle ScholarPubMed
64Buzdar, A. et al. (2001) Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol 19, 3357-3366CrossRefGoogle ScholarPubMed
65Mouridsen, H. et al. (2003) Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 21, 2101-2109CrossRefGoogle Scholar
66Nabholtz, J.M. et al. (2003) Anastrozole (Arimidex) versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: survival analysis and updated safety results. Eur J Cancer 39, 1684-1689CrossRefGoogle ScholarPubMed
67Heshmati, H.M. et al. (2002) Role of low levels of endogenous estrogen in regulation of bone resorption in late postmenopausal women. J Bone Miner Res 17, 172-178CrossRefGoogle ScholarPubMed
68Howell, A. et al. (2005) Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365, 60-62Google ScholarPubMed
69Seidenfeld, J. et al. (2000) Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med 132, 566-577CrossRefGoogle ScholarPubMed
70Hartsell, W.F. et al. (2005) Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 97, 798-804CrossRefGoogle ScholarPubMed
71Quilty, P.M. et al. (1994) A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol 31, 33-40CrossRefGoogle ScholarPubMed
72Serafini, A.N. (2000) Samarium Sm-153 lexidronam for the palliation of bone pain associated with metastases. Cancer 88, 2934-29393.0.CO;2-S>CrossRefGoogle ScholarPubMed
73Higenbotham, N.L. and Marcove, R.C. (1965) The management of pathological fractures. J Trauma 5, 792-798CrossRefGoogle Scholar
74Harrington, K.D. (1997) Orthopedic surgical management of skeletal complications of malignancy. Cancer 80, 1614-16273.0.CO;2-2>CrossRefGoogle ScholarPubMed
75Masala, S. et al. (2004) Vertebroplasty and kyphoplasty in the treatment of malignant vertebral fractures. J Chemother 16 (Suppl 5), 30-33CrossRefGoogle ScholarPubMed
76Roelofs, A.J. et al. (2006) Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res 12, 6222s-6230sCrossRefGoogle ScholarPubMed
77Lipton, A. et al. (2000) Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer 88, 1082-10903.0.CO;2-Z>CrossRefGoogle ScholarPubMed
78Berenson, J.R. et al. (2001) Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer 91, 1191-12003.0.CO;2-0>CrossRefGoogle ScholarPubMed
79Rosen, L.S. et al. (2001) Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 7, 377-387Google ScholarPubMed
80Powles, T. et al. (2002) Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 20, 3219-3224CrossRefGoogle ScholarPubMed
81Powles, T. et al. (2006) Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res 8, R13CrossRefGoogle ScholarPubMed
82Dearnaley, D.P. et al. (2003) A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst 95, 1300-1311CrossRefGoogle ScholarPubMed
83Saad, F. et al. (2002) A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94, 1458-1468CrossRefGoogle ScholarPubMed
84Smith, M.R. et al. (2003) Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 169, 2008-2012CrossRefGoogle ScholarPubMed
85Rosen, L.S. et al. (2004) Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial. Cancer 100, 2613-2621CrossRefGoogle ScholarPubMed
86Khosla, S. et al. (2007) Bisphosphonate-associated osteonecrosis of the jaw: Report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 22, 1479-1491CrossRefGoogle ScholarPubMed
87Woo, S.B., Hellstein, J.W. and Kalmar, J.R. (2006) Narrative review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 144, 753-761CrossRefGoogle ScholarPubMed
89Carducci, M.A. et al. (2003) 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, 679-689CrossRefGoogle ScholarPubMed
90Nelson, J.B. et al. (2003) Suppression of prostate cancer induced bone remodeling by the endothelin receptor A antagonist atrasentan. J Urol 169, 1143-1149CrossRefGoogle ScholarPubMed
91Carducci, M.A. et al. (2007) A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer 110, 1959-1966CrossRefGoogle ScholarPubMed
92Nelson, J.B. (2005) Endothelin receptor antagonists. World J Urol 23, 19-27CrossRefGoogle ScholarPubMed
93Le Gall, C. et al. (2007) A cathepsin K inhibitor reduces breast cancer induced osteolysis and skeletal tumor burden. Cancer Res 67, 9894-9902CrossRefGoogle ScholarPubMed
94James, N.D. et al. (2007) ZD4054, a potent, specific endothelin A receptor antagonist, improves overall survival in pain-free or mildly symptomatic patients with hormone-resistant prostate cancer (HRPC) and bone metastases. Presented at ECCO 14 - the European Cancer Conference (23–27 September 2007; Barcelona, Spain), http://80.247.210.88/ciw-07ecco/index.cfm?fuseaction=CIS2002&hoofdnav=Abstracts&content=abs.details&what=FREE%20TEXT&searchtext=zd4054&topicselected=*&selection=ABSTRACT&qryStartRowDetail=1Google Scholar
95Braun, S. et al. (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353, 793-802CrossRefGoogle ScholarPubMed
96Janni, W. et al. (2005) The persistence of isolated tumor cells in bone marrow from patients with breast carcinoma predicts an increased risk for recurrence. Cancer 103, 884-891CrossRefGoogle ScholarPubMed
97Pfitzenmaier, J. et al. (2007) The detection and isolation of viable prostate-specific antigen positive epithelial cells by enrichment: a comparison to standard prostate-specific antigen reverse transcriptase polymerase chain reaction and its clinical relevance in prostate cancer. Urol Oncol 25, 214-220CrossRefGoogle ScholarPubMed
98Nakagawa, T. et al. (2006) Proteomic profiling of primary breast cancer predicts axillary lymph node metastasis. Cancer Res 66, 11825-11830CrossRefGoogle ScholarPubMed
99Chandran, U.R. et al. (2007) Gene expression profiles of prostate cancer reveal involvement of multiple molecular pathways in the metastatic process. BMC Cancer 7, 64CrossRefGoogle ScholarPubMed
100Smid, M. et al. (2006) Genes associated with breast cancer metastatic to bone. [see comment]. J Clin Oncol 24, 2261-2267CrossRefGoogle ScholarPubMed
101Tsuchiya, N. et al. (2006) Impact of IGF-I and CYP19 gene polymorphisms on the survival of patients with metastatic prostate cancer. [see comment]. J Clin Oncol 24, 1982-1989CrossRefGoogle ScholarPubMed

Further reading, resources and contacts

The Paget Foundation website is a resource for patients, physicians and researchers that provides information on bone metastasis:

Layfield, R. (2007) The molecular pathogenesis of Paget disease of bone. Expert Rev Mol Med 9, 1-13, doi:10.1017/S1462399407000464CrossRefGoogle ScholarPubMed