Skip to main content

Advertisement

SpringerLink
Log in

Skeletal metastasis: Established and emerging roles of parathyroid hormone related protein (PTHrP)

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Parathyroid hormone related protein (PTHrP) is a well characterized tumor derived product that also has integral functions in normal development and homeostasis. PTHrP is produced by virtually all tumor types that metastasize to bone and numerous studies have demonstrated a correlation between PTHrP expression and skeletal localization of tumors. PTHrP has prominent effects in bone via its interaction with the PTH-1 receptor on osteoblastic cells. Through indirect means, PTHrP supports osteoclastogenesis by upregulating the receptor activator of NFκB ligand (RANKL) in osteoblasts. PTHrP also regulates osteoblast proliferation and differentiation in manners that are temporal and dose dependent. Bone turnover has been implicated in the localization of tumors to bone and PTHrP increases bone turnover. Bone turnover results in the release of growth factors such as TGFβ and minerals such as calcium, both of which impact tumor cell growth and contribute to continued PTHrP production. PTHrP also has anabolic properties and could be in part responsible for osteoblastic type reactions in prostate cancer. Finally, emerging roles of PTH and PTHrP in the support of hematopoietic stem cell development in the bone marrow microenvironment suggest that an interaction between hematopoietic cells and tumor cells warrants further investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Coleman, R. E. (1997). Skeletal complications of malignancy. Cancer, 80(8 suppl), 1588–1594.

    PubMed  CAS  Google Scholar 

  2. Suva, L. J., Winslow, G. A., Wettenhall, R. E., Hammonds, R. G., Moseley, J. M., Diefenbach-Jagger, H., et al. (1987). A parathyroid hormone-related protein implicated in malignant hypercalcemia: Cloning and expression. Science, 237, 893–896.

    PubMed  CAS  Google Scholar 

  3. Moseley, J. M., Kubota, M., Diefenbach-Jagger, H., Wettenhall, R. E., Kemp, B. E., Suva, L. J., et al. (1987). Parathyroid hormone-related protein purified from a human lung cancer cell line. Proceedings of the National Academy of Sciences of the United States of America, 84, 5048–5052.

    PubMed  CAS  Google Scholar 

  4. Southby, J., O’Keeffe, L. M., Martin, T. J., & Gillespie, M. T. (1995). Alternative promoter usage and mRNA splicing pathways for parathyroid hormone-related protein in normal tissues and tumours. British Journal of Cancer, 72, 702–707.

    PubMed  CAS  Google Scholar 

  5. Burtis, W. J. (1992). Parathyroid hormone-related protein: Structure, function, and measurement. Clinical Chemistry, 38, 2171–2183.

    PubMed  CAS  Google Scholar 

  6. Sellers, R. S., Luchin, A. I., Richard, V., Brena, R. M., Lima, D., & Rosol, T. J. (2004). Alternative splicing of parathyroid hormone-related protein mRNA: Expression and stability. Journal of Molecular Endocrinology, 33, 227–241.

    PubMed  CAS  Google Scholar 

  7. Wysolmerski, J. J., Stewart, A. F., & Martin, T. J. (2002). Physiological actions of parathyroid hormone (PTH) and PTH-related protein (chapter 29). In J. P. Bilezikian, L. G. Raisz, & G. A. Rodan (Eds.), Principles of bone biology (pp. 515–530). San Diego, CA: Academic.

    Google Scholar 

  8. Philbrick, W. M., Dreyer, B. E., Nakchbandi, I. A., & Karaplis, A. C. (1998). Parathyroid hormone-related protein is required for tooth eruption. Proceedings of the National Academy of Sciences of the United States of America, 95, 11846–11851.

    PubMed  CAS  Google Scholar 

  9. Weir, E. C., Philbrick, W. M., Amling, M., Neff, L. A., Baron, R., & Broadus, A. E. (1996). Targeted overexpression of parathyroid hormone-related peptide in chondrocytes causes chondrodysplasia and delayed endochondral bone formation. Proceedings of the National Academy of Sciences of the United States of America, 93, 10240–10245.

    PubMed  CAS  Google Scholar 

  10. Foley, J., Dann, P., Hong, J., Cosgrove, J., Dreyer, B., Rimm, D., et al. (2001). Parathyroid hormone-related protein maintains mammary epithelial fate and triggers nipple skin differentiation during embryonic breast development. Development, 128, 513–525.

    PubMed  CAS  Google Scholar 

  11. Ardeshirpour, L., Dann, P., Pollak, M., Wysolmerski, J., & VanHouten, J. (2006). The calcium-sensing receptor regulates PTHrP production and calcium transport in the lactating mammary gland. Bone, 38, 787–793.

    PubMed  CAS  Google Scholar 

  12. Budayr, A. A., Halloran, B. P., King, J. C., Diep, D., Nissenson, R. A., & Strewler, G. J. (1989). High levels of a parathyroid hormone-like protein in milk. Proceedings of the National Academy of Sciences of the United States of America, 86, 7183–7185.

    PubMed  CAS  Google Scholar 

  13. Henderson, J. E., Amizuka, N., Warshawsky, H., Biasotto, D., Lanske, B. M., Goltzman, D., et al. (1995). Nucleolar localization of parathyroid hormone-related peptide enhances survival of chondrocytes under conditions that promote apoptotic cell death. Molecular and Cellular Biology, 15, 4064–4075.

    PubMed  CAS  Google Scholar 

  14. Dougherty, K. M., Blomme, E. A., Koh, A. J., Henderson, J. E., Pienta, K. J., Rosol, T. J., et al. (1999). Parathyroid hormone-related protein as a growth regulator of prostate carcinoma. Cancer Research, 59, 6015–6022.

    PubMed  CAS  Google Scholar 

  15. Lam, M. H., Thomas, R. J., Martin, T. J., Gillespie, M. T., & Jans, D. A. (2000). Nuclear and nucleolar localization of parathyroid hormone-related protein. Immunology and Cell Biology, 78, 395–402.

    PubMed  CAS  Google Scholar 

  16. Lam, M. H., Briggs, L. J., Hu, W., Martin, T. J., Gillespie, M. T., & Jans, D. A. (1999). Importin beta recognizes parathyroid hormone-related protein with high affinity and mediates its nuclear import in the absence of importin alpha. Journal of Biological Chemistry, 274, 7391–7398.

    PubMed  CAS  Google Scholar 

  17. Abdallah, Y., Ross, G., Dolf, A., Heinemann, M. P., & Schluter, K. D. (2006). N-terminal parathyroid hormone-related peptide hyperpolarizes endothelial cells and causes a reduction of the coronary resistance of the rat heart via endothelial hyperpolarization. Peptides, 27(11), 2927–2934.

    PubMed  CAS  Google Scholar 

  18. Bakre, M. M., Zhu, Y., Yin, H., Burton, D. W., Terkeltaub, R., Deftos, L. J., et al. (2002). Parathyroid hormone-related peptide is a naturally occurring, protein kinase A-dependent angiogenesis inhibitor. Natural Medicines, 8, 995–1003.

    CAS  Google Scholar 

  19. Diamond, A. G., Gonterman, R. M., Anderson, A. L., Menon, K., Offutt, C. D., Weaver, C. H., et al. (2006). Parathyroid hormone hormone-related protein and the PTH receptor regulate angiogenesis of the skin. Journal of Investigative Dermatology, 126, 2127–2134.

    PubMed  CAS  Google Scholar 

  20. Akino, K., Ohtsuru, A., Kanda, K., Yasuda, A., Yamamoto, T., Akino, Y., et al. (2000). Parathyroid hormone-related peptide is a potent tumor angiogenic factor. Endocrinology, 141, 4313–4316.

    PubMed  CAS  Google Scholar 

  21. Rian, E., Jemtland, R., Olstad, O. K., Endresen, M. J., Grasser, W. A., Thiede, M. A., et al. (1994). Parathyroid hormone-related protein is produced by cultured endothelial cells: A possible role in angiogenesis. Biochemical and Biophysical Research Communications, 198, 740–747.

    PubMed  CAS  Google Scholar 

  22. Koh, A. J., Beecher, C. A., Rosol, T. J., & McCauley, L. K. (1999). 3′,5′-Cyclic adenosine monophosphate activation in osteoblastic cells: Effects on parathyroid hormone-1 receptors and osteoblastic differentiation in vitro. Endocrinology, 140, 3154–3162.

    PubMed  CAS  Google Scholar 

  23. Gopalakrishnan, R., Ouyang, H., Somerman, M. J., McCauley, L. K., & Franceschi, R. T. (2001). Matrix gamma-carboxyglutamic acid protein is a key regulator of PTH-mediated inhibition of mineralization in MC3T3-E1 osteoblast-like cells. Endocrinology, 142, 4379–4388.

    PubMed  CAS  Google Scholar 

  24. Bellows, C. G., Ishida, H., Aubin, J. E., & Heersche, J. N. (1990). Parathyroid hormone reversibly suppresses the differentiation of osteoprogenitor cells into functional osteoblasts. Endocrinology, 127, 3111–3116.

    PubMed  CAS  Google Scholar 

  25. Schiller, P. C., D’Ippolito, G., Roos, B. A., & Howard, G. A. (1999). Anabolic or catabolic responses of MC3T3-E1 osteoblastic cells to parathyroid hormone depend on time and duration of treatment. Journal of Bone and Mineral Research, 14, 1504–1512.

    PubMed  CAS  Google Scholar 

  26. Kronenberg, H. M. (2006). PTHrP and skeletal development. Annals of the New York Academy of Sciences, 1068, 1–13.

    PubMed  CAS  Google Scholar 

  27. Datta, N. S., Chen, C., Berry, J. E., & McCauley, L. K. (2005). PTHrP signaling targets cyclin D1 and induces osteoblastic cell growth arrest. Journal of Bone and Mineral Research, 20, 1051–1064.

    PubMed  CAS  Google Scholar 

  28. Datta, N. S., Pettway, G. J., Chen, C., Koh, A. J., McCauley, L. K. (2006). Cyclin D1 as a target for the proliferative effect of PTH and PTHrP in early osteoblastic cells. Journal of Bone and Mineral Research, 21(Suppl.), F178.

    Google Scholar 

  29. Mannstadt, M., Juppner, H., & Gardella, T. J. (1999). Receptors for PTH and PTHrP: Their biological importance and functional properties. American Journal of Physiology, 277, F665–F675.

    PubMed  CAS  Google Scholar 

  30. Weinman, E. J., Hall, R. A., Friedman, P. A., Liu-Chen, L. Y., & Shenolikar, S. (2006). The association of NHERF adaptor proteins with g protein-coupled receptors and receptor tyrosine kinases. Annual Review of Physiology, 68, 491–505.

    PubMed  CAS  Google Scholar 

  31. Sneddon, W. B., Magyar, C. E., Willick, G. E., Syme, C. A., Galbiati, F., Bisello, A., et al. (2004). Ligand-selective dissociation of activation and internalization of the parathyroid hormone (PTH) receptor: Conditional efficacy of PTH peptide fragments. Endocrinology, 145, 2815–2823.

    PubMed  CAS  Google Scholar 

  32. Mahon, M. J., Donowitz, M., Yun, C. C., & Segre, G. V. (2002). Na(+)/H(+) exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling. Nature, 417, 858–861.

    PubMed  CAS  Google Scholar 

  33. Sneddon, W. B., Syme, C. A., Bisello, A., Magyar, C. E., Rochdi, M. D., Parent, J. L., et al. (2003). Activation-independent parathyroid hormone receptor internalization is regulated by NHERF1 (EBP50). Journal of Biological Chemistry, 278, 43787–43796.

    PubMed  CAS  Google Scholar 

  34. Demiralp, B., Chen, H. L., Koh, A. J., Keller, E. T., & McCauley, L. K. (2002). Anabolic actions of parathyroid hormone during bone growth are dependent on c-fos. Endocrinology, 143, 4038–4047.

    PubMed  CAS  Google Scholar 

  35. Koh, A. J., Demiralp, B., Neiva, K. G., Hooten, J., Nohutcu, R. M., Shim, H., et al. (2005) Cells of the osteoclast lineage as mediators of the anabolic actions of parathyroid hormone in bone. Endocrinology, 146, 4584–4596.

    PubMed  CAS  Google Scholar 

  36. Berry, J. E., Ealba, E. L., Pettway, G. J., Datta, N. S., Swanson, E. C., Somerman, M. J., et al. (2006). JunB as a downstream mediator of PTHrP actions in cementoblasts. Journal of Bone and Mineral Research, 21, 246–257.

    PubMed  CAS  Google Scholar 

  37. Yamashita, J., & McCauley, L. K. (2006). The activating protein-1 transcriptional complex: Essential and multifaceted roles in bone. Clinical Reviews in Bone and Mineral Metabolism, 4, 107–122.

    CAS  Google Scholar 

  38. Southby, J., Kissin, M. W., Danks, J. A., Hayman, J. A., Moseley, J. M., Henderson, M. A., et al. (1990). Immunohistochemical localization of parathyroid hormone-related protein in human breast cancer. Cancer Research, 50, 7710–7716.

    PubMed  CAS  Google Scholar 

  39. Powell, G. J., Southby, J., Danks, J. A., Stillwell, R. G., Hayman, J. A., Henderson, M. A., et al. (1991). Localization of parathyroid hormone-related protein in breast cancer metastases: Increased incidence in bone compared with other sites. Cancer Research, 51, 3059–3061.

    PubMed  CAS  Google Scholar 

  40. Kohno, N., Kitazawa, S., Fukase, M., Sakoda, Y., Kanbara, Y., Furuya, Y., et al. (1994). The expression of parathyroid hormone-related protein in human breast cancer with skeletal metastases. Surgery Today, 24, 215–220.

    PubMed  CAS  Google Scholar 

  41. Linforth, R., Anderson, N., Hoey, R., Nolan, T., Downey, S., Brady, G., et al. (2002). Coexpression of parathyroid hormone related protein and its receptor in early breast cancer predicts poor patient survival. Clinical Cancer Research, 8, 3172–3177.

    PubMed  CAS  Google Scholar 

  42. Bouizar, Z., Spyratos, F., & De vernejoul, M. C. (1999). The parathyroid hormone-related protein (PTHrP) gene: Use of downstream TATA promotor and PTHrP 1–139 coding pathways in primary breast cancers vary with the occurrence of bone metastasis. Journal of Bone and Mineral Research, 14, 406–414.

    PubMed  CAS  Google Scholar 

  43. Grill, V., Ho, P., Body, J. J., Johanson, N., Lee, S. C., Kukreja, S. C., et al. (1991). Parathyroid hormone-related protein: Elevated levels in both humoral hypercalcemia of malignancy and hypercalcemia complicating metastatic breast cancer. Journal of Clinical Endocrinology and Metabolism, 73, 1309–1315.

    PubMed  CAS  Google Scholar 

  44. Liapis, H., Crouch, E. C., Grosso, L. E., Kitazawa, S., & Wick, M. R. (1993). Expression of parathyroidlike protein in normal, proliferative, and neoplastic human breast tissues. American Journal of Pathology, 143, 1169–1178.

    PubMed  CAS  Google Scholar 

  45. Yoshida, A., Nakamura, Y., Shimizu, A., Harada, M., Kameda, Y., Nagano, A., et al. (2000). Significance of the parathyroid hormone-related protein expression in breast carcinoma. Breast Cancer, 7, 215–220.

    Article  PubMed  CAS  Google Scholar 

  46. Bundred, N. J., Walker, R. A., Ratcliffe, W. A., Warwick, J., Morrison, J. M., & Ratcliffe, J. G. (1992). Parathyroid hormone related protein and skeletal morbidity in breast cancer. European Journal of Cancer, 28, 690–692.

    PubMed  CAS  Google Scholar 

  47. Henderson, M. A., Danks, J. A., Slavin, J. L., Byrnes, G. B., Choong, P. F., Spillane, J. B., et al. (2006). Parathyroid hormone-related protein localization in breast cancers predict improved prognosis. Cancer Research, 66, 2250–2256.

    PubMed  CAS  Google Scholar 

  48. Fenton, A. J., Kemp, B. E., Kent, G. N., Moseley, J. M., Zheng, M. H., Rowe, D. J., et al. (1991). A carboxyl-terminal peptide from the parathyroid hormone-related protein inhibits bone resorption by osteoclasts. Endocrinology, 129, 1762–1768.

    Article  PubMed  CAS  Google Scholar 

  49. Iwamura, M., Wu, G., Abrahamsson, P. A., di Sant’Agnese, P. A., Cockett, A. T., & Deftos, L. J. (1994). Parathyroid hormone-related protein is expressed by prostatic neuroendocrine cells. Urology, 43, 667–674.

    PubMed  CAS  Google Scholar 

  50. Iwamura, M., Abrahamsson, P. A., Schoen, S., Cockett, A. T., & Deftos, L. J. (1994). Immunoreactive parathyroid hormone-related protein is present in human seminal plasma and is of prostate origin. Journal of Andrology, 15, 410–414.

    PubMed  CAS  Google Scholar 

  51. Rubin, M. A., Putzi, M., Mucci, N., Smith, D. C., Wojno, K., Korenchuk, S., et al. (2000). Rapid (“warm”) autopsy study for procurement of metastatic prostate cancer. Clinical Cancer Research, 6, 1038–1045.

    PubMed  CAS  Google Scholar 

  52. Iwamura, M., di Sant’Agnese, P. A., Wu, G., Benning, C. M., Cockett, A. T., Deftos, L. J., et al. (1993). Immunohistochemical localization of parathyroid hormone-related protein in human prostate cancer. Cancer Research, 53, 1724–1726.

    PubMed  CAS  Google Scholar 

  53. Asadi, F., Farraj, M., Sharifi, R., Malakouti, S., Antar, S., & Kukreja, S. (1996). Enhanced expression of parathyroid hormone-related protein in prostate cancer as compared with benign prostatic hyperplasia. Human Pathology, 27, 1319–1323.

    PubMed  CAS  Google Scholar 

  54. Bryden, A. A., Hoyland, J. A., Freemont, A. J., Clarke, N. W., & George, N. J. (2002). Parathyroid hormone related peptide and receptor expression in paired primary prostate cancer and bone metastases. British Journal of Cancer, 86, 322–325.

    PubMed  CAS  Google Scholar 

  55. Brandt, D. W., Burton, D. W., Gazdar, A. F., Oie, H. E., & Deftos, L. J. (1991). All major lung cancer cell types produce parathyroid hormone-like protein: Heterogeneity assessed by high performance liquid chromatography. Endocrinology, 129, 2466–2470.

    PubMed  CAS  Google Scholar 

  56. Kitazawa, S., Fukase, M., Kitazawa, R., Takenaka, A., Gotoh, A., Fujita, T., et al. (1991). Immunohistologic evaluation of parathyroid hormone-related protein in human lung cancer and normal tissue with newly developed monoclonal antibody. Cancer, 67, 984–989.

    PubMed  CAS  Google Scholar 

  57. Davidson, L. A., Black, M., Carey, F. A., Logue, F., & McNicol, A. M. (1996). Lung tumours immunoreactive for parathyroid hormone related peptide: Analysis of serum calcium levels and tumour type. Journal of Pathology, 178(4), 398–401.

    PubMed  CAS  Google Scholar 

  58. Nishigaki, Y., Ohsaki, Y., Toyoshima, E., & Kikuchi, K. (1999). Increased serum and urinary levels of a parathyroid hormone-related protein COOH terminus in non-small cell lung cancer patients. Clinical Cancer Research, 5, 1473–1481.

    PubMed  CAS  Google Scholar 

  59. Hidaka, N., Nishimura M., & Nagao, K. (1998). Establishment of two human small cell lung cancer cell lines: The evidence of accelerated production of parathyroid hormone-related protein with tumor progression. Cancer Letters, 125, 149–155.

    PubMed  CAS  Google Scholar 

  60. Ganderton, R. H., & Briggs, R. S. (2000). Increased upstream methylation has no influence on the overexpression of the parathyroid hormone-related protein gene in squamous cell carcinoma of the lung. European Journal of Cancer, 36, 2128–2136.

    PubMed  CAS  Google Scholar 

  61. Sourbier, C., & Massfelder, T. (2006). Parathyroid hormone-related protein in human renal cell carcinoma. Cancer Letters, 240, 170–182.

    PubMed  CAS  Google Scholar 

  62. Iwamura, M., Wu, W., Muramoto, M., Ohori, M., Egawa, S., Uchida, T., et al. (1999). Parathyroid hormone-related protein is an independent prognostic factor for renal cell carcinoma. Cancer, 86, 1028–1034.

    PubMed  CAS  Google Scholar 

  63. Gotoh, A., Kitazawa, S., Mizuno, Y., Takenaka, A., Arakawa, S., Matsumoto, O., et al. (1993). Common expression of parathyroid hormone-related protein and no correlation of calcium level in renal cell carcinomas. Cancer, 71, 2803–2806.

    PubMed  CAS  Google Scholar 

  64. Papworth, K., Grankvist, K., Ljungberg, B., & Rasmuson, T. (2005). Parathyroid hormone-related protein and serum calcium in patients with renal cell carcinoma. Tumour Biology, 26, 201–206.

    PubMed  CAS  Google Scholar 

  65. Kamai, T., Arai, K., Koga, F., Abe, H., Nakanishi, K., Kambara, T., et al. (2001). Higher expression of K-ras is associated with parathyroid hormone-related protein-induced hypercalcaemia in renal cell carcinoma. BJU International, 88, 960–966.

    PubMed  CAS  Google Scholar 

  66. Links, M., Ho, H., Clingan, P., & Diamond, T. (1994). Hypercalcaemia in a patient with fatal adenosquamous carcinoma of the colon. Medical Journal of Australia, 160, 286–287.

    PubMed  CAS  Google Scholar 

  67. Malakouti, S., Asadi, F. K., Kukreja, S. C., Abcarian, H. A., & Cintron, J. R. (1996). Parathyroid hormone-related protein expression in the human colon: Immunohistochemical evaluation. American Surgery, 62, 540–544; discussion 544–545.

    CAS  Google Scholar 

  68. Sidler, B., Alpert, L., Henderson, J. E., Deckelbaum, R., Amizuka, N., Silva, J. E., et al. (1996). Amplification of the parathyroid hormone-related peptide gene in a colonic carcinoma. Journal of Clinical Endocrinology and Metabolism, 81, 2841–2847.

    PubMed  CAS  Google Scholar 

  69. Iguchi, H., Tanaka, S., Ozawa, Y., Kashiwakuma, T., Kimura, T., Hiraga, T., et al. (1996). An experimental model of bone metastasis by human lung cancer cells: The role of parathyroid hormone-related protein in bone metastasis. Cancer Research, 56, 4040–4043.

    PubMed  CAS  Google Scholar 

  70. Guise, T. A., Yin, J. J., Taylor, S. D., Kumagai, Y., Dallas, M., Boyce, B. F., et al. (1993). Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. Journal of Clinical Investigation, 98, 1544–1549.

    Article  Google Scholar 

  71. Guise, T. A., Yin, J. J., Thomas, R. J., Dallas, M., Cui, Y., & Gillespie, M. T. (2002). Parathyroid hormone-related protein (PTHrP)-(1–139) isoform is efficiently secreted in vitro and enhances breast cancer metastasis to bone in vivo. Bone, 30, 670–676.

    PubMed  CAS  Google Scholar 

  72. Deftos, L. J., Barken, I., Burton, D. W., Hoffman, R. M., & Geller J. (2005). Direct evidence that PTHrP expression promotes prostate cancer progression in bone. Biochemical and Biophysical Research Communications, 327, 468–472.

    PubMed  CAS  Google Scholar 

  73. Downey, S. E., Hoyland, J., Freemont, A. J., Knox, F., Walls, J., & Bundred, N. J. (1997). Expression of the receptor for parathyroid hormone-related protein in normal and malignant breast tissue. Journal of Pathology, 183, 212–217.

    PubMed  CAS  Google Scholar 

  74. Beier, F., Ali, Z., Mok, D., Taylor, A. C., Leask, T., Albanese, C., et al. (2001). TGFbeta and PTHrP control chondrocyte proliferation by activating cyclin D1 expression. Molecular Biology of the Cell, 12, 3852–3863.

    PubMed  CAS  Google Scholar 

  75. Hoey, R. P., Sanderson, C., Iddon, J., Brady, G., Bundred, N. J., & Anderson, N. G. (2003). The parathyroid hormone-related protein receptor is expressed in breast cancer bone metastases and promotes autocrine proliferation in breast carcinoma cells. British Journal of Cancer, 88, 567–573.

    PubMed  CAS  Google Scholar 

  76. Cataisson, C., Lieberherr, M., Cros, M., Gauville, C., Graulet, A. M., Cotton, J., et al. (2000). Parathyroid hormone-related peptide stimulates proliferation of highly tumorigenic human SV40-immortalized breast epithelial cells. Journal of Bone and Mineral Research, 15, 2129–2139.

    PubMed  CAS  Google Scholar 

  77. Massfelder, T., Lang, H., Schordan, E., Lindner, V., Rothhut, S., Welsch, S., et al. (2004). Parathyroid hormone-related protein is an essential growth factor for human clear cell renal carcinoma and a target for the von Hippel–Lindau tumor suppressor gene. Cancer Research, 64, 180–188.

    PubMed  CAS  Google Scholar 

  78. Shen, X., & Falzon, M. (2005). PTH-related protein enhances LoVo colon cancer cell proliferation, adhesion, and integrin expression. Regulatory Peptides, 125, 17–27.

    PubMed  CAS  Google Scholar 

  79. Shen, X., & Falzon, M. (2003). PTH-related protein modulates PC-3 prostate cancer cell adhesion and integrin subunit profile. Molecular and Cellular Endocrinology, 199, 165–177.

    PubMed  CAS  Google Scholar 

  80. Hastings, R. H., Araiza, F., Burton, D. W., Zhang, L., Bedley, M., & Deftos, L. J. (2003). Parathyroid hormone-related protein ameliorates death receptor-mediated apoptosis in lung cancer cells. American Journal of Physiology, Cell Physiology, 285, C1429–C1436.

    CAS  Google Scholar 

  81. Tovar Sepulveda, V. A., Shen, X., & Falzon, M. (2002). Intracrine PTHrP protects against serum starvation-induced apoptosis and regulates the cell cycle in MCF-7 breast cancer cells. Endocrinology, 143, 596–606.

    PubMed  CAS  Google Scholar 

  82. Liao, J., Schneider, A., Datta, N. S., & McCauley, L. K. (2006). Extracellular calcium as a candidate mediator of prostate cancer skeletal metastasis. Cancer Research, 66(18), 9065-9073.

    PubMed  CAS  Google Scholar 

  83. Sanders, J. L., Chattopadhyay, N., Kifor, O., Yamaguchi, T., & Brown, E. M. (2001). Ca(2+)-sensing receptor expression and PTHrP secretion in PC-3 human prostate cancer cells. American Journal of Physiology: Endocrinology and Metabolism, 281, E1267–E1274.

    PubMed  CAS  Google Scholar 

  84. Schneider, A., Kalikin, L. M., Mattos, A. C., Keller, E. T., Allen, M. J., Pienta, K. J., et al. (2005). Bone turnover mediates preferential localization of prostate cancer in the skeleton. Endocrinology, 146, 1727–1736.

    PubMed  CAS  Google Scholar 

  85. Miwa, S., Mizokami, A., Keller, E. T., Taichman, R., Zhang, J., & Namiki, M. (2005). The bisphosphonate YM529 inhibits osteolytic and osteoblastic changes and CXCR-4-induced invasion in prostate cancer. Cancer Research, 65, 8818–8825.

    PubMed  CAS  Google Scholar 

  86. Clezardin, P., Ebetino, F. H., & Fournier, P. G. (2005). Bisphosphonates and cancer-induced bone disease: Beyond their antiresorptive activity. Cancer Research, 65, 4971–4974.

    PubMed  CAS  Google Scholar 

  87. Smith, M. R. (2005). Zoledronic acid to prevent skeletal complications in cancer: Corroborating the evidence. Cancer Treatment Reviews, 31(Suppl 3), 19–25.

    PubMed  Google Scholar 

  88. Michaelson, M. D., & Smith, M. R. (2005). Bisphosphonates for treatment and prevention of bone metastases. Journal of Clinical Oncology, 23, 8219–8224.

    PubMed  CAS  Google Scholar 

  89. Kiriyama, T., Gillespie, M. T., Glatz, J. A., Fukumoto, S., Moseley, J. M., & Martin, T. J. (1993). Transforming growth factor beta stimulation of parathyroid hormone-related protein (PTHrP): A paracrine regulator? Molecular and Cellular Endocrinology, 92, 55–62.

    PubMed  CAS  Google Scholar 

  90. Roodman, G. D. (2004). Mechanisms of bone metastasis. New England Journal of Medicine, 350, 1655–1664.

    PubMed  CAS  Google Scholar 

  91. Pettway, G. J., Schneider, A., Koh, A. J., Widjaja, E., Morris, M. D., Meganck, J. A., et al. (2005). Anabolic actions of PTH (1–34): Use of a novel tissue engineering model to investigate temporal effects on bone. Bone, 36, 959–970.

    PubMed  CAS  Google Scholar 

  92. Miao, D., He, B., Jiang, Y., Kobayashi, T., Soroceanu, M. A., Zhao, J., et al. (2005). Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1–34. Journal of Clinical Investigation, 115, 2402–2411.

    PubMed  CAS  Google Scholar 

  93. Cramer, S. D., Chen, Z., & 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. Journal of Urology, 156, 526–531.

    PubMed  CAS  Google Scholar 

  94. Hiraki, A., Ueoka, H., Bessho, A., Segawa, Y., Takigawa, N., Kiura, K., et al. (2002). Parathyroid hormone-related protein measured at the time of first visit is an indicator of bone metastases and survival in lung carcinoma patients with hypercalcemia. Cancer, 95, 1706–1713.

    PubMed  CAS  Google Scholar 

  95. Truong, N. U., deB Edwardes, M. D., Papavasiliou, V., Goltzman, D., & Kremer, R. (2003). Parathyroid hormone-related peptide and survival of patients with cancer and hypercalcemia. American Journal of Medicine, 115, 115–121.

    PubMed  CAS  Google Scholar 

  96. Kao, P. C., Klee, G. G., Taylor, R. L., & Heath, H., 3rd (1990). Parathyroid hormone-related peptide in plasma of patients with hypercalcemia and malignant lesions. Mayo Clinic Proceedings, 65, 1399–1407.

    PubMed  CAS  Google Scholar 

  97. Kageshita, T., Matsui, T., Hirai, S., Fukuda, Y., & Ono, T. (1999). Hypercalcaemia in melanoma patients associated with increased levels of parathyroid hormone-related protein. Melanoma Research, 9, 69–73.

    PubMed  CAS  Google Scholar 

  98. Oda, N., Nakai, A., Hayashi, R., Hayakawa, N., Hamada, M., Kojima, K., et al. (1998). Utility of measuring serum parathyroid hormone-related protein concentration in leukemic patients with hypercalcemia for assessing disease status. European Journal of Endocrinology, 139, 323–329.

    PubMed  CAS  Google Scholar 

  99. Bouvet, M., Nardin, S. R., Burton, D. W., Lee, N. C., Yang, M., Wang, X., et al. (2002). Parathyroid hormone-related protein as a novel tumor marker in pancreatic adenocarcinoma. Pancreas, 24, 284–290.

    PubMed  Google Scholar 

  100. van der Pluijm, G., Sijmons, B., Vloedgraven, H., Deckers, M., Papapoulos, S., & Lowik, C. (2001). Monitoring metastatic behavior of human tumor cells in mice with species-specific polymerase chain reaction: Elevated expression of angiogenesis and bone resorption stimulators by breast cancer in bone metastases. Journal of Bone and Mineral Research, 16, 1077–1091.

    PubMed  Google Scholar 

  101. Onuma, E., Azuma, Y., Saito, H., Tsunenari, T., Watanabe, T., Hirabayashi, M., et al. (2005). Increased renal calcium reabsorption by parathyroid hormone-related protein is a causative factor in the development of humoral hypercalcemia of malignancy refractory to osteoclastic bone resorption inhibitors. Clinical Cancer Research, 11, 4198–4203.

    PubMed  CAS  Google Scholar 

  102. Sato, K., Onuma, E., Yocum, R. C., & Ogata, E. (2003). Treatment of malignancy-associated hypercalcemia and cachexia with humanized anti-parathyroid hormone-related protein antibody. Seminars in Oncology, 30, 167–173.

    PubMed  CAS  Google Scholar 

  103. Saito, H., Tsunenari, T., Onuma, E., Sato, K., Ogata, E., & Yamada-Okabe, H. (2005). Humanized monoclonal antibody against parathyroid hormone-related protein suppresses osteolytic bone metastasis of human breast cancer cells derived from MDA-MB-231. Anticancer Research, 25, 3817–3823.

    PubMed  CAS  Google Scholar 

  104. Gallwitz, W. E., Guise, T. A., & Mundy, G. R. (2002). Guanosine nucleotides inhibit different syndromes of PTHrP excess caused by human cancers in vivo. Journal of Clinical Investigation, 110, 1559–1572.

    PubMed  CAS  Google Scholar 

  105. Nakagawa, K., Sasaki, Y., Kato, S., Kubodera, N., & Okano, T. (2005). 22-Oxa-1alpha,25-dihydroxyvitamin D3 inhibits metastasis and angiogenesis in lung cancer. Carcinogenesis, 26, 1044–1054.

    PubMed  CAS  Google Scholar 

  106. Arima, Y., Matsueda, S., Yano, H., Harada, M., & Itoh, K. (2005). Parathyroid hormone-related protein as a common target molecule in specific immunotherapy for a wide variety of tumor types. International Journal of Oncology, 27, 981–988.

    PubMed  CAS  Google Scholar 

  107. Taichman, R. S. (2005). Blood and bone: Two tissues whose fates are intertwined to create the hematopoietic stem-cell niche. Blood, 105, 2631–2639.

    PubMed  CAS  Google Scholar 

  108. Calvi, L. M., Adams, G. B., Weibrecht, K. W., Weber, J. M., Olson, D. P., Knight, M. C., et al. (2003). Osteoblastic cells regulate the haematopoietic stem cell niche. Nature, 425, 841–846.

    PubMed  CAS  Google Scholar 

  109. Li, X., Qin, L., & Partridge, N.C. (2005). Parathyroid hormone stimulates osteoblastic expression of monocyte chemotactic protein-1 to recruit pre/osteoclasts [Abstract]. ASBMR 27th Annual Meeting.

  110. Berry, J. E., Datta, N., Pettway, G. J., & McCauley, L. (2006). PTHrP actions via JunB: New gene targets in cementoblasts [Abstract]. Journal of Dental Research. International Association for Dental Research. Presented in Brisbane, Australia.

Download references

Author information

Authors and Affiliations

  1. Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, 48109-1078, USA

    Jinhui Liao & Laurie K. McCauley

  2. Department of Pathology, Medical School, University of Michigan, Ann Arbor, MI, 48109-1078, USA

    Laurie K. McCauley

Authors
  1. Jinhui Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laurie K. McCauley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Laurie K. McCauley.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liao, J., McCauley, L.K. Skeletal metastasis: Established and emerging roles of parathyroid hormone related protein (PTHrP). Cancer Metastasis Rev 25, 559–571 (2006). https://doi.org/10.1007/s10555-006-9033-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-006-9033-z

Keywords

Search

Navigation