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Renal cell carcinoma bone metastasis—elucidating the molecular targets

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Abstract

The development of bone metastasis from renal cell carcinoma (RCC) signals a transition to a terminal state for the patient with previously isolated disease. These patients may suffer the morbidity of severe, persistent pain, pathologic fractures, and spinal compression from vertebral metastasis before they succumb to their cancer. Although recent advancements have been made in the understanding of breast and prostate bone metastasis, there has been less knowledge in the area of metastatic RCC to the skeleton. This particular cancer in bone remains relatively resistant to standard forms of treatment such as radiation and chemotherapy. A better understanding of the biology of RCC bone metastasis is critically needed in order to improve treatment. Bone-derived cell lines and an experimental animal model have been developed in order to explore the relevant mechanisms of how RCC cells survive within and destroy the bone. This review will focus on the growth factor signaling pathways most important for the RCC-stimulated osteoclast-mediated bone destruction, namely the epidermal growth factor receptor (EGF-R) and transforming growth factor-β receptor (TGF-βR) pathways. By inhibiting these receptors, growth of RCC within the bone is decreased which, directly or indirectly, decreases bone destruction.

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References

  1. Jemal, A., Tiwari, R. C., Murray, T., Ghafoor, A., Samuels, A., Ward, E., et al. (2004). Cancer statistics, 2004. CA: A Cancer Journal for Clinicians, 54, 8–9

    Article  Google Scholar 

  2. Weber, K. L., Lewis, V. O., Randall, R. L., Lee, A. K., & Springfield, D. (2004). An approach to the management of the patient with metastatic bone disease. Instructional Course Lectures, 53, 663–76.

    PubMed  Google Scholar 

  3. Berenson, J. R. (2005). Recommendations for zoledronic acid treatment of patients with bone metastases. Oncologist, 10, 52–2.

    Article  PubMed  CAS  Google Scholar 

  4. Kedar, I., Mermershtain, W., & Ivgi, H. (2004). Thalidomide reduces serum C-reactive protein and interleukin-6 and induces response to IL-2 in a fraction of metastatic renal cell cancer patients who failed IL-2-based therapy. International Journal of Cancer, 110, 260–65.

    Article  CAS  Google Scholar 

  5. Porta, C., Zimatore, M., Imarisio, I., Natalizi, A., Sartore-Bianchi, A., Danova, M., et al. (2004). Gemcitabine and oxaliplatin in the treatment of patients with immunotherapy-resistant advanced renal cell carcinoma: Final results of a single-institution Phase II study. Cancer, 100, 2132–138.

    Article  PubMed  CAS  Google Scholar 

  6. Russo, P. (2000). Renal cell carcinoma: Presentation, staging, and surgical treatment. Seminars in Oncology, 27, 160–76.

    PubMed  CAS  Google Scholar 

  7. Durr, H. R., Maier, M., Pfahler, M., Baur, A., & Refior, H. J. (1999). Surgical treatment of osseous metastases in patients with renal cell carcinoma. Clinical Orthopaedics and Related Research, 283–90.

  8. O’Connor, M., & Weber, K. (2003). Indications and operative treatment for long bone metastasis with a focus on the femur. Clinical Orthopaedics and Related Research, 415S, 276–78.

    Google Scholar 

  9. Weber, K. L. (2004). What’s new in musculoskeletal oncology. Journal of Bone and Joint Surgery. American Volume, 86-A, 1104–109.

    Google Scholar 

  10. 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, 670–76.

    Article  PubMed  CAS  Google Scholar 

  11. Kakonen, S. M., Selander, K. S., Chirgwin, J. M., Yin, J. J., Burns, S., Rankin, W. A., et al. (2002). Transforming growth factor-beta stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways. Journal of Biological Chemistry 277, 24571–4578.

    Article  PubMed  CAS  Google Scholar 

  12. Chirgwin, J. M., Mohammad, K. S., & Guise, T. A. (2004). Tumor’bone cellular interactions in skeletal metastases. Journal of Musculoskeletal Neuronal Interactions, 4, 308–18.

    PubMed  CAS  Google Scholar 

  13. Guise, T. A., Yin, J. J., & Mohammad, K. S. (2003). Role of endothelin-1 in osteoblastic bone metastases. Cancer, 97, 779–84.

    Article  PubMed  Google Scholar 

  14. Yin, J. J., Mohammad, K. S., Kakonen, S. M., Harris, S., Wu-Wong, J. R., Wessale, J. L., et al. (2003) A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases. Proceedings of the National Academy of Sciences of the United States of America, 100, 10954–0959.

    Article  PubMed  CAS  Google Scholar 

  15. Weber, K. L., Pathak, S., Multani, A. S., & Price, J. E. (2002). Characterization of a renal cell carcinoma cell line derived from a human bone metastasis and establishment of an experimental nude mouse model. Journal of Urology, 168, 774–79.

    Article  PubMed  Google Scholar 

  16. Mydlo, J. H., Michaeli, J., Cordon-Cardo, C., Goldenberg, A. S., Heston, W. D., & Fair, W. R. (1989). Expression of transforming growth factor alpha and epidermal growth factor receptor messenger RNA in neoplastic and nonneoplastic human kidney tissue. Cancer Research, 49, 3407–411.

    PubMed  CAS  Google Scholar 

  17. Sargent, E. R., Gomella, L. G., Belldegrun, A., Linehan, W. M., & Kasid, A. (1989). Epidermal growth factor receptor gene expression in normal human kidney and renal cell carcinoma. Journal of Urology, 142, 1364–368.

    PubMed  CAS  Google Scholar 

  18. Stumm, G., Eberwein, S., Rostock-Wolf, S., Stein, H., Pomer, S., Schlegel, J., et al. (1996). Concomitant overexpression of the EGFR and erbB-2 genes in renal cell carcinoma (RCC) is correlated with dedifferentiation and metastasis. International Journal of Cancer, 69, 17–2.

    Article  CAS  Google Scholar 

  19. Moch, H., Sauter, G., Buchholz, N., Gasser, T. C., Bubendorf, L., Waldman, F. M., et al. (1997). Epidermal growth factor receptor expression is associated with rapid tumor cell proliferation in renal cell carcinoma. Human Pathology, 28, 1255–259.

    Article  PubMed  CAS  Google Scholar 

  20. Atlas, I., Mendelsohn, J., Baselga, J., Fair, W. R., Masui, H., & Kumar, R. (1992). Growth regulation of human renal carcinoma cells: Role of transforming growth factor alpha. Cancer Research, 52, 3335–339.

    PubMed  CAS  Google Scholar 

  21. Bruns CJ, Solorzano CC, Harbison MT, Ozawa S, Tsan R, Fan D, et al. (2000). Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer Research, 60, 2926–935.

    PubMed  CAS  Google Scholar 

  22. Mendelsohn, J. (1997). Epidermal growth factor receptor inhibition by a monoclonal antibody as anticancer therapy. Clinical Cancer Research, 3, 2703–707.

    PubMed  CAS  Google Scholar 

  23. Prewett, M., Rothman, M., Waksal, H., Feldman, M., Bander, N. H., & Hicklin, D. J. (1998). Mouse’human chimeric anti-epidermal growth factor receptor antibody C225 inhibits the growth of human renal cell carcinoma xenografts in nude mice. Clinical Cancer Research, 4, 2957–966.

    PubMed  CAS  Google Scholar 

  24. Weber, K. (2003). Epidermal growth factor receptor signaling in renal cell carcinoma bone metastasis. In Molecular biology in orthopaedics (pp. 163–71), AAOS/NIH Textbook.

  25. Weber, K. L., Doucet, M., & Price, J. E. (2003). Renal cell carcinoma bone metastasis: Epidermal growth factor receptor targeting. Clinical Orthopaedics and Related Research, S86’S94.

  26. Weber, K. L., Doucet, M., Price, J. E., Baker, C., Kim, S. J., & Fidler, I. J. (2003). Blockade of epidermal growth factor receptor signaling leads to inhibition of renal cell carcinoma growth in the bone of nude mice. Cancer Research, 63, 2940–947.

    PubMed  CAS  Google Scholar 

  27. Baker, C. H., Solorzano, C. C., & Fidler, I. J. (2002). Blockade of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling for therapy of metastatic human pancreatic cancer. Cancer Research, 62, 1996–003.

    PubMed  CAS  Google Scholar 

  28. Shiurba, R. A., Eng, L. F., Vogel, H., Lee, Y. L., Horoupian, D. S., & Urich, H. (1988). Epidermal growth factor receptor in meningiomas is expressed predominantly on endothelial cells. Cancer, 62, 2139–144.

    Article  PubMed  CAS  Google Scholar 

  29. Langley, R. R., Ramirez, K. M., Tsan, R. Z., Van Arsdall, M., Nilsson, M. B., & Fidler, I. J. (2003). Tissue-specific microvascular endothelial cell lines from H-2K(b)-tsA58 mice for studies of angiogenesis and metastasis. Cancer Research, 63, 2971–976.

    PubMed  CAS  Google Scholar 

  30. Traxler, P. B. E., Furet, P., et al. (1999). Preclinical profile of PKI166: A novel and potent EGF-R tyrosine kinase inhibitor for clinical development. Clinical Cancer Research, 5, 3750.

    Google Scholar 

  31. Yokoi, K., Thaker, P. H., Yazici, S., Rebhun, R. R., Nam, D. H., He, J., et al. (2005). Dual inhibition of epidermal growth factor receptor and vascular endothelial growth factor receptor phosphorylation by AEE788 reduces growth and metastasis of human colon carcinoma in an orthotopic nude mouse model. Cancer Research, 65, 3716–725.

    Article  PubMed  CAS  Google Scholar 

  32. Younes, M. N., Yigitbasi, O. G., Park, Y. W., Kim, S. J., Jasser, S. A., Hawthorne, V. S., et al. (2005). Antivascular therapy of human follicular thyroid cancer experimental bone metastasis by blockade of epidermal growth factor receptor and vascular growth factor receptor phosphorylation. Cancer Research, 65, 4716–727.

    Article  PubMed  CAS  Google Scholar 

  33. Baker, C. H., Kedar, D., McCarty, M. F., Tsan, R., Weber, K. L., Bucana, C. D., et al. (2002). Blockade of epidermal growth factor receptor signaling on tumor cells and tumor-associated endothelial cells for therapy of human carcinomas. American Journal of Pathology, 161, 929–38.

    PubMed  CAS  Google Scholar 

  34. Senaratne, S. G., Mansi, J. L., & Colston, K. W. (2002). The bisphosphonate zoledronic acid impairs Ras membrane [correction of impairs membrane] localisation and induces cytochrome c release in breast cancer cells. British Journal of Cancer, 86, 1479–486.

    Article  PubMed  CAS  Google Scholar 

  35. Dumont, N., & Arteaga, C. L. (2003). Targeting the TGF beta signaling network in human neoplasia. Cancer Cell, 3, 531–36.

    Article  PubMed  CAS  Google Scholar 

  36. Derynck, R., Akhurst, R. J., & Balmain, A. (2001). TGF-beta signaling in tumor suppression and cancer progression. Nature Genetics, 29, 117–29.

    Article  PubMed  CAS  Google Scholar 

  37. Massague, J., Blain, S. W., & Lo, R. S. (2000). TGFbeta signaling in growth control, cancer, and heritable disorders. Cell, 103, 295–09.

    Article  PubMed  CAS  Google Scholar 

  38. Siegel, P. M., & Massague, J. (2003). Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nature Reviews. Cancer, 3, 807–21.

    Article  PubMed  CAS  Google Scholar 

  39. Wakefield, L. M., & Roberts, A. B. (2002). TGF-beta signaling: Positive and negative effects on tumorigenesis. Current Opinion in Genetics & Development, 12, 22–9.

    Article  CAS  Google Scholar 

  40. Mundy, G. R. (2002). Metastasis to bone: Causes, consequences and therapeutic opportunities. Nature Reviews. Cancer, 2, 584–93.

    Article  PubMed  CAS  Google Scholar 

  41. Roodman, G. D. (1993). Role of cytokines in the regulation of bone resorption. Calcified Tissue International, 53(Suppl 1):S94’S98.

    Article  PubMed  CAS  Google Scholar 

  42. Kominsky, S., Doucet, M., Brady, K., & Weber, K. L. (2007). TGF-β influences the development of renal cell carcinoma bone metastasis. Journal of Bone and Mineral Research, 22, 37–4.

    Article  PubMed  CAS  Google Scholar 

  43. Yingling, J. M., Blanchard, K. L., & Sawyer, J. S. (2004). Development of TGF-beta signalling inhibitors for cancer therapy. Nature Reviews Drug Discovery, 3, 1011–022.

    Article  PubMed  CAS  Google Scholar 

  44. Paule, B., Clerc, D., Rudant, C., Coulombel, C., Bonhomme-Faivre, L., Quillard, J., et al. (1998). Enhanced expression of interleukin-6 in bone and serum of metastatic renal cell carcinoma. Human Pathology, 29, 421–24.

    Article  PubMed  CAS  Google Scholar 

  45. Kwan Tat, S., Padrines, M., Théoleyre, S., Heymann, D., Fortun, Y. (2004). I:-6, RANKL, TNF-alpha/IL-1: Interrelations in bone resorption pathophysiology. Cytokine & Growth Factor Reviews, 15, 49–0.

    Article  CAS  Google Scholar 

  46. Negrier, S., Perol, D., Menetrier-Caux, C., Escudier, B., Pallardy, M., Ravaud, A., et al. (2004). Interleukin-6, interleukin-10, and vascular endothelial growth factor in metastatic renal cell carcinoma: Prognostic value of interleukin-6-from the Groupe Francais d’Immunotherapie. Journal of Clinical Oncology, 22, 2371–378.

    Article  PubMed  CAS  Google Scholar 

  47. Miki, S., Iwano, M., Miki, Y., Yamamoto, M., Tang, B., Yokokawa, K., et al. (1989). Interleukin-6 (IL-6) functions as an in vitro autocrine growth factor in renal cell carcinomas. FEBS Letters, 250, 607–10.

    Article  PubMed  CAS  Google Scholar 

  48. O’Brien, C. A., Gubrij, I., Lin, S. C., Saylors, R. L., & Manolagas, S. C. (1999). STAT3 activation in stromal/osteoblastic cells is required for induction of the receptor activator of NF-kappaB ligand and stimulation of osteoclastogenesis by gp130-utilizing cytokines or interleukin-1 but not 1,25-dihydroxyvitamin D3 or parathyroid hormone. Journal of Biological Chemistry, 274, 19301–9308.

    Article  PubMed  Google Scholar 

  49. Park, J. I., Lee, M. G., Cho, K., Park, B. J., Chae, K. S., Byun, D. S., et al. (2003). Transforming growth factor-beta1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK, and Ras signaling pathways. Oncogene, 22, 4314–332.

    Article  PubMed  CAS  Google Scholar 

  50. Egeblad, M., & Werb, Z. (2002). New functions for the matrix metalloproteinases in cancer progression. Nature Reviews. Cancer, 2, 161–74.

    Article  PubMed  CAS  Google Scholar 

  51. Sternlicht, M. D., & Werb, Z. (2001). How matrix metalloproteinases regulate cell behavior. Annual Review of Cell and Developmental Biology, 17, 463–16.

    Article  PubMed  CAS  Google Scholar 

  52. Kusano, K., Miyaura, C., Inada, M., Tamura, T., Ito, A., Nagase, H., et al. (1998). Regulation of matrix metalloproteinases (MMP-2, -3, -9, and -13) by interleukin-1 and interleukin-6 in mouse calvaria: Association of MMP induction with bone resorption. Endocrinology, 139, 1338–345.

    Article  PubMed  CAS  Google Scholar 

  53. Selvamurugan, N., Kwok, S., Alliston, T., Reiss, M., & Partridge, N. C. (2004). Transforming growth factor-beta 1 regulation of collagenase-3 expression in osteoblastic cells by cross-talk between the Smad and MAPK signaling pathways and their components, Smad2 and Runx2. Journal of Biological Chemistry, 279, 19327–9334.

    Article  PubMed  CAS  Google Scholar 

  54. Ueda, M., Fujii, H., Yoshizawa, K., Terai, Y., Kumagai, K., Ueki, K., et al. (1998). Effects of EGF and TGF-alpha on invasion and proteinase expression of uterine cervical adenocarcinoma OMC-4 cells. Invasion Metastasis, 18, 176–83.

    Article  PubMed  CAS  Google Scholar 

  55. Fuller, K., & Chambers, T. J. (1995). Localisation of mRNA for collagenase in osteocytic, bone surface and chondrocytic cells but not osteoclasts. Journal of Cell Science, 108(Pt 6), 2221–230.

    PubMed  CAS  Google Scholar 

  56. Holliday, L. S., Welgus, H. G., Fliszar, C. J., Veith, G. M., Jeffrey, J. J., & Gluck, S. L. (1997). Initiation of osteoclast bone resorption by interstitial collagenase. Journal of Biological Chemistry, 272, 22053–2058.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Departments of Orthopaedic Surgery and Oncology, 601 N. Caroline St., JHOC #5251, Baltimore, MD, 21287, USA

    Kristy Weber

  2. Department of Orthopaedic Surgery, 720 Rutland Ave, Ross #209, Baltimore, MD, 21205, USA

    Michele Doucet & Scott Kominsky

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  1. Kristy Weber
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  2. Michele Doucet
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Correspondence to Kristy Weber.

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Weber, K., Doucet, M. & Kominsky, S. Renal cell carcinoma bone metastasis—elucidating the molecular targets. Cancer Metastasis Rev 26, 691–704 (2007). https://doi.org/10.1007/s10555-007-9090-y

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