Systemic Instigation: A Mouse Model to Study Breast Cancer as a Systemic Disease

Chapter

Abstract

Little is known about the mechanisms that cause indolent tumors – such as micrometastases, occult primary tumors, or minimal residual disease – to erupt into overt, malignant cancers. As a result, predicting which patients are likely to experience disease relapse and treating patients with metastatic disease has been frustratingly limited. We developed an in vivo xenograft model system that provided us with fundamental insights into processes that govern indolent tumor growth and represented a new paradigm for translational cancer research. We learned that systemic endocrine factors and circulating bone marrow-derived cells support the acquisition of malignant traits by otherwise indolent tumors. As a result, we now think of cancer as a systemic disease by which tumors actively perturb as well as respond to the host systemic environment. First, we found that certain human breast carcinoma cell lines (we term “instigators”) facilitate the growth of otherwise-indolent tumor cells (we term “responders”) located at distant anatomical sites within host mice – a process we term “systemic instigation”. Second, systemic instigation is accompanied by incorporation of bone marrow-derived cells into the stroma of the distant once-indolent tumors. Importantly, bone marrow cells (BMCs) of hosts bearing instigating tumors are functionally activated in the marrow prior to their mobilization into the circulation. Third, instigating tumor-derived osteopontin (OPN), a cytokine that is elevated in the plasma of patients with metastatic cancers and is predicitive of poor outcome, is necessary but not sufficient for systemic instigation. Although there may be alternative explanations, this systemic communication between tumors might explain why patients diagnosed with one malignant neoplasm are at an increased risk of presenting with multiple, independent primary cancers or why patients with recurrent disease often present with multiple metastases that appear to arise suddenly and synchronously. In this review, I address the methods by which the systemic instigation model was established, what we’ve learned by using this model, the implications of our studies, and some of the questions that have yet to be answered.

Keywords

Nude Mouse Bone Marrow Cell Minimal Residual Disease Contralateral Breast Cancer Immunocompromised Mouse 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

I thank Dr. Robert A. Weinberg and members of his laboratory for intellectual contributions and critical discussions during the design and implementation of the experiments reviewed herein. Additionally, I thank Ann M. Gifford and Hanna Kuznetsov for technical support and contributions toward unpublished observations mentioned in this review. Finally, I wish to acknowledge Drs. Zafira Castaño Corsino and Moshe Elkabets for helpful discussions.

References

  1. Aguirre-Ghiso, J. A. (2007). Models, mechanisms and clinical evidence for cancer dormancy. Nature Reviews Cancer, 7, 834–846.CrossRefPubMedGoogle Scholar
  2. Almog, N. (2010). Molecular mechanisms underlying tumor dormancy. Cancer Letters, 294, 139–146.CrossRefPubMedGoogle Scholar
  3. Almog, N., Henke, V., Flores, L., Hlatky, L., Kung, A. L., Wright, R. D., et al. (2006). Prolonged dormancy of human liposarcoma is associated with impaired tumor angiogenesis. The FASEB Journal, 20, 947–949.CrossRefPubMedGoogle Scholar
  4. Andreu, P., Johansson, M., Affara, N. I., Pucci, F., Tan, T., Junankar, S., et al. (2010). FcRgamma activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell, 17, 121–134.CrossRefPubMedGoogle Scholar
  5. Ansieau, S., Hinkal, G., Thomas, C., Bastid, J., & Puisieux, A. (2008). Early origin of cancer metastases: Dissemination and evolution of premalignant cells. Cell Cycle, 7, 3659–3663.CrossRefPubMedGoogle Scholar
  6. Badiavas, E. V., Abedi, M., Butmarc, J., Falanga, V., & Quesenberry, P. (2003). Participation of bone marrow derived cells in cutaneous wound healing. Journal of Cellular Physiology, 196, 245–250.CrossRefPubMedGoogle Scholar
  7. Bernards, R., & Weinberg, R. A. (2002). A progression puzzle. Nature, 418, 823.CrossRefPubMedGoogle Scholar
  8. Black, W. C., & Welch, H. G. (1993). Advances in diagnostic imaging and overestimations of disease prevalence and the benefits of therapy. New England Journal of Medicine, 328, 1237–1243.CrossRefPubMedGoogle Scholar
  9. Carmichael, A. R., Bendall, S., Lockerbie, L., Prescott, R., & Bates, T. (2002). The long-term outcome of synchronous bilateral breast cancer is worse than metachronous or unilateral tumours. European Journal of Surgical Oncology, 28, 388–391.CrossRefPubMedGoogle Scholar
  10. Casanovas, O., Hicklin, D. J., Bergers, G., & Hanahan, D. (2005). Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell, 8, 299–309.CrossRefPubMedGoogle Scholar
  11. Chambers, A. F., Naumov, G. N., Vantyghem, S. A., & Tuck, A. B. (2000). Molecular biology of breast cancer metastasis. Clinical implications of experimental studies on metastatic inefficiency. Breast Cancer Research, 2, 400–407.CrossRefPubMedGoogle Scholar
  12. Cho, H. J., & Kim, H. S. (2009). Osteopontin: A multifunctional protein at the crossroads of inflammation, atherosclerosis, and vascular calcification. Current Atherosclerosis Reports, 11, 206–213.CrossRefPubMedGoogle Scholar
  13. Christensen, B., Kazanecki, C. C., Petersen, T. E., Rittling, S. R., Denhardt, D. T., & Sorensen, E. S. (2007). Cell type-specific post-translational modifications of mouse osteopontin are associated with different adhesive properties. Journal of Biological Chemistry, 282, 19463–19472.CrossRefPubMedGoogle Scholar
  14. Cook, A. C., Tuck, A. B., McCarthy, S., Turner, J. G., Irby, R. B., Bloom, G. C., et al. (2005). Osteopontin induces multiple changes in gene expression that reflect the six “hallmarks of cancer” in a model of breast cancer progression. Molecular Carcinogenesis, 43, 225–236.CrossRefPubMedGoogle Scholar
  15. Coussens, L. M., & Werb, Z. (2002). Inflammation and cancer. Nature, 420, 860–867.CrossRefPubMedGoogle Scholar
  16. Crawford, H. C., Matrisian, L. M., & Liaw, L. (1998). Distinct roles of osteopontin in host defense activity and tumor survival during squamous cell carcinoma progression in vivo. Cancer Research, 58, 5206–5215.PubMedGoogle Scholar
  17. de Visser, K. E., Korets, L. V., & Coussens, L. M. (2005). De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell, 7, 411–423.CrossRefPubMedGoogle Scholar
  18. Denhardt, D. T., Noda, M., O’Regan, A. W., Pavlin, D., & Berman, J. S. (2001). Osteopontin as a means to cope with environmental insults: Regulation of inflammation, tissue remodeling, and cell survival. The Journal of Clinical Investigation, 107, 1055–1061.CrossRefPubMedGoogle Scholar
  19. Direkze, N. C., Hodivala-Dilke, K., Jeffery, R., Hunt, T., Poulsom, R., Oukrif, D., et al. (2004). Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Research, 64, 8492–8495.CrossRefPubMedGoogle Scholar
  20. Ebos, J. M., Lee, C. R., & Kerbel, R. S. (2009). Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin Cancer Research, 15, 5020–5025.CrossRefGoogle Scholar
  21. Elenbaas, B., Spirio, L., Koerner, F., Fleming, M. D., Zimonjic, D. B., Donaher, J. L., et al. (2001). Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes & Development, 15, 50–65.CrossRefGoogle Scholar
  22. Engel, J., Eckel, R., Kerr, J., Schmidt, M., Furstenberger, G., Richter, R., et al. (2003). The process of metastasisation for breast cancer. The European Journal of Cancer, 39, 1794–1806.CrossRefGoogle Scholar
  23. Fathke, C., Wilson, L., Hutter, J., Kapoor, V., Smith, A., Hocking, A., et al. (2004). Contribution of bone marrow-derived cells to skin: Collagen deposition and wound repair. Stem Cells, 22, 812–822.CrossRefPubMedGoogle Scholar
  24. Fehm, T., Mueller, V., Marches, R., Klein, G., Gueckel, B., Neubauer, H., et al. (2008). Tumor cell dormancy: Implications for the biology and treatment of breast cancer. APMIS, 116, 742–753.CrossRefPubMedGoogle Scholar
  25. Feng, F., & Rittling, S. R. (2000). Mammary tumor development in MMTV-c-myc/MMTV-v-Ha-ras transgenic mice is unaffected by osteopontin deficiency. Breast Cancer Research and Treatment, 63, 71–79.CrossRefPubMedGoogle Scholar
  26. Fidler, I. J. (2003). The pathogenesis of cancer metastasis: The ‘seed and soil’ hypothesis revisited. Nature Reviews Cancer, 3, 453–458.CrossRefPubMedGoogle Scholar
  27. Fidler, I. J., & Kripke, M. L. (1977). Metastasis results from preexisting variant cells within a malignant tumor. Science, 197, 893–895.CrossRefPubMedGoogle Scholar
  28. Folkman, J., & Kalluri, R. (2004). Cancer without disease. Nature, 427, 787.CrossRefPubMedGoogle Scholar
  29. Franzen, A., & Heinegard, D. (1985). Isolation and characterization of two sialoproteins present only in bone calcified matrix. Biochemical Journal, 232, 715–724.PubMedGoogle Scholar
  30. Furger, K. A., Menon, R. K., Tuck, A. B., Bramwell, V. H., & Chambers, A. F. (2001). The functional and clinical roles of osteopontin in cancer and metastasis. Current Molecular Medicine, 1, 621–632.CrossRefPubMedGoogle Scholar
  31. Gohongi, T., Fukumura, D., Boucher, Y., Yun, C. O., Soff, G. A., Compton, C., et al. (1999). Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth: Involvement of transforming growth factor beta1. Nature Medicine, 5, 1203–1208.CrossRefPubMedGoogle Scholar
  32. Heissig, B., Hattori, K., Dias, S., Friedrich, M., Ferris, B., Hackett, N. R., et al. (2002). Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell, 109, 625–637.CrossRefPubMedGoogle Scholar
  33. Holzer, G., Obermair, A., Koschat, M., Preyer, O., Kotz, R., & Trieb, K. (2001). Concentration of vascular endothelial growth factor (VEGF) in the serum of patients with malignant bone tumors. Medical and Pediatric Oncology, 36, 601–604.CrossRefPubMedGoogle Scholar
  34. Ince, T. A., Richardson, A. L., Bell, G. W., Saitoh, M., Godar, S., Karnoub, A. E., et al. (2007). Transformation of different human breast epithelial cell types leads to distinct tumor phenotypes. Cancer Cell, 12, 160–170.CrossRefPubMedGoogle Scholar
  35. Iwata, M., Awaya, N., Graf, L., Kahl, C., & Torok-Storb, B. (2004). Human marrow stromal cells activate monocytes to secrete osteopontin, which down-regulates Notch1 gene expression in CD34+ cells. Blood, 103, 4496–4502.CrossRefPubMedGoogle Scholar
  36. Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., & Thun, M. J. (2009). Cancer statistics, 2009. CA: A Cancer Journal for Clinicians, 59, 225–249.CrossRefGoogle Scholar
  37. Johnston, N. I., & El-Tanani, M. K. (2008). Osteopontin: A new role for a familiar actor. Breast Cancer Research, 10, 306.CrossRefPubMedGoogle Scholar
  38. Joyce, J. A., & Pollard, J. W. (2009). Microenvironmental regulation of metastasis. Nature Reviews Cancer, 9, 239–252.CrossRefPubMedGoogle Scholar
  39. Kang, S. Y., & Watnick, R. S. (2008). Regulation of tumor dormancy as a function of tumor-mediated paracrine regulation of stromal Tsp-1 and VEGF expression. APMIS, 116, 638–647.CrossRefPubMedGoogle Scholar
  40. Kazanecki, C. C., Kowalski, A. J., Ding, T., Rittling, S. R., & Denhardt, D. T. (2007a). Characterization of anti-osteopontin monoclonal antibodies: Binding sensitivity to post-translational modifications. Journal of Cellular Biochemistry, 102, 925–935.CrossRefPubMedGoogle Scholar
  41. Kazanecki, C. C., Uzwiak, D. J., & Denhardt, D. T. (2007b). Control of osteopontin signaling and function by post-translational phosphorylation and protein folding. Journal of Cellular Biochemistry, 102, 912–924.CrossRefPubMedGoogle Scholar
  42. Klein, C. A. (2009). Parallel progression of primary tumours and metastases. Nature Reviews Cancer, 9, 302–312.CrossRefPubMedGoogle Scholar
  43. Klein, C. A., Blankenstein, T. J., Schmidt-Kittler, O., Petronio, M., Polzer, B., Stoecklein, N. H., et al. (2002). Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. Lancet, 360, 683–689.CrossRefPubMedGoogle Scholar
  44. Kopp, H. G., Ramos, C. A., & Rafii, S. (2006). Contribution of endothelial progenitors and proangiogenic hematopoietic cells to vascularization of tumor and ischemic tissue. Current Opinion in Hematology, 13, 175–181.CrossRefPubMedGoogle Scholar
  45. Likui, W., Hong, W., & Shuwen, Z. (2010). Clinical significance of the upregulated osteopontin mRNA expression in human colorectal cancer, The Journal of Gastrointestinal Surgery, 14, 74–81.CrossRefGoogle Scholar
  46. McAllister, S. S., Gifford, A. M., Greiner, A. L., Kelleher, S. P., Saelzler, M. P., Ince, T. A., et al. (2008). Systemic endocrine instigation of indolent tumor growth requires osteopontin. Cell, 133, 994–1005.CrossRefPubMedGoogle Scholar
  47. McAllister, S. S., & Weinberg, R. A. (2010). Tumor-host interactions: A far-reaching relationship. Journal of Clinical Oncology, 28, 4022–4028.CrossRefPubMedGoogle Scholar
  48. Minn, A. J., Gupta, G. P., Siegel, P. M., Bos, P. D., Shu, W., Giri, D. D., et al. (2005). Genes that mediate breast cancer metastasis to lung. Nature, 436, 518–524.CrossRefPubMedGoogle Scholar
  49. Moore, M. A., Hattori, K., Heissig, B., Shieh, J. H., Dias, S., Crystal, R. G., et al. (2001). Mobilization of endothelial and hematopoietic stem and progenitor cells by adenovector-mediated elevation of serum levels of SDF-1, VEGF, and angiopoietin-1. Annals of the New York Academy of Sciences, 938, 36–45, discussion 45–37.CrossRefPubMedGoogle Scholar
  50. Mullen, C. A., Urban, J. L., Van Waes, C., Rowley, D. A., & Schreiber, H. (1985). Multiple cancers. Tumor burden permits the outgrowth of other cancers. Journal of Experimental Medicine, 162, 1665–1682.CrossRefPubMedGoogle Scholar
  51. Murdoch, C., Muthana, M., Coffelt, S. B., & Lewis, C. E. (2008). The role of myeloid cells in the promotion of tumour angiogenesis. Nature Reviews Cancer, 8, 618–631.CrossRefPubMedGoogle Scholar
  52. Nagrath, S., Sequist, L. V., Maheswaran, S., Bell, D. W., Irimia, D., Ulkus, L., et al. (2007). Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature, 450, 1235–1239.CrossRefPubMedGoogle Scholar
  53. Naumov, G. N., Bender, E., Zurakowski, D., Kang, S. Y., Sampson, D., Flynn, E., et al. (2006). A model of human tumor dormancy: An angiogenic switch from the nonangiogenic phenotype. Journal of the National Cancer Institute, 98, 316–325.CrossRefPubMedGoogle Scholar
  54. Nemir, M., Bhattacharyya, D., Li, X., Singh, K., Mukherjee, A. B., & Mukherjee, B. B. (2000). Targeted inhibition of osteopontin expression in the mammary gland causes abnormal morphogenesis and lactation deficiency. The Journal of Biological Chemistry, 275, 969–976.CrossRefPubMedGoogle Scholar
  55. Nguyen, D. X., Bos, P. D., & Massague, J. (2009). Metastasis: From dissemination to organ-specific colonization. Nature Reviews Cancer, 9, 274–284.CrossRefPubMedGoogle Scholar
  56. Nielsen, M., Thomsen, J. L., Primdahl, S., Dyreborg, U., & Andersen, J. A. (1987). Breast cancer and atypia among young and middle-aged women: A study of 110 medicolegal autopsies. British Journal of Cancer, 56, 814–819.CrossRefPubMedGoogle Scholar
  57. Nilsson, S. K., Johnston, H. M., Whitty, G. A., Williams, B., Webb, R. J., Denhardt, D. T., et al. (2005). Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells. Blood, 106, 1232–1239.CrossRefPubMedGoogle Scholar
  58. O’Reilly, M. S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W. S., et al. (1997). Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell, 88, 277–285.CrossRefPubMedGoogle Scholar
  59. O’Reilly, M. S., Holmgren, L., Shing, Y., Chen, C., Rosenthal, R. A., Moses, M., et al. (1994). Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell, 79, 315–328.CrossRefPubMedGoogle Scholar
  60. Paez-Ribes, M., Allen, E., Hudock, J., Takeda, T., Okuyama, H., Vinals, F., et al. (2009). Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell, 15, 220–231.CrossRefPubMedGoogle Scholar
  61. Paget, S. (1889). The distribution of secondary growths in cancer of the breast. Lancet, 1, 571–573.CrossRefGoogle Scholar
  62. Pantel, K., Cote, R. J., & Fodstad, O. (1999). Detection and clinical importance of micrometastatic disease. Journal of the National Cancer Institute, 91, 1113–1124.CrossRefPubMedGoogle Scholar
  63. Peehl, D. M. (2004). Are primary cultures realistic models of prostate cancer? Journal of Cellular Biochemistry, 91, 185–195.CrossRefPubMedGoogle Scholar
  64. Poon, R. T., Ng, I. O., Lau, C., Zhu, L. X., Yu, W. C., Lo, C. M., et al. (2001). Serum vascular endothelial growth factor predicts venous invasion in hepatocellular carcinoma: A prospective study. Annals of Surgery, 233, 227–235.CrossRefPubMedGoogle Scholar
  65. Pritchard, H., & Micklem, H. S. (1973). Haemopoietic stem cells and progenitors of functional T-lymphocytes in the bone marrow of ‘nude’ mice. Clinical & Experimental Immunology, 14, 597–607.Google Scholar
  66. Rafii, S. (2000). Circulating endothelial precursors: Mystery, reality, and promise. The Journal of Clinical Investigation, 105, 17–19.CrossRefPubMedGoogle Scholar
  67. Ramankulov, A., Lein, M., Kristiansen, G., Meyer, H. A., Loening, S. A., & Jung, K. (2007). Elevated plasma osteopontin as marker for distant metastases and poor survival in patients with renal cell carcinoma. Journal of Cancer Research and Clinical Oncology, 133, 643–652.CrossRefPubMedGoogle Scholar
  68. Ramaswamy, S., Ross, K. N., Lander, E. S., & Golub, T. R. (2003). A molecular signature of metastasis in primary solid tumors. Nature Genetics, 33, 49–54.CrossRefPubMedGoogle Scholar
  69. Richardson, A. L., Wang, Z. C., De Nicolo, A., Lu, X., Brown, M., Miron, A., et al. (2006). X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell, 9, 121–132.CrossRefPubMedGoogle Scholar
  70. Rittling, S. R., Chen, Y., Feng, F., & Wu, Y. (2002). Tumor-derived osteopontin is soluble, not matrix associated. Journal of Biological Chemistry, 277, 9175–9182.CrossRefPubMedGoogle Scholar
  71. Rudland, P. S., Platt-Higgins, A., El-Tanani, M., De Silva Rudland, S., Barraclough, R., Winstanley, J. H., et al. (2002). Prognostic significance of the metastasis-associated protein osteopontin in human breast cancer. Cancer Research, 62, 3417–3427.PubMedGoogle Scholar
  72. Ruiterkamp, J., Ernst, M. F., van de Poll-Franse, L. V., Bosscha, K., Tjan-Heijnen, V. C., & Voogd, A. C. (2009). Surgical resection of the primary tumour is associated with improved survival in patients with distant metastatic breast cancer at diagnosis, European Journal of Surgical Oncology, 35, 1146–1151.CrossRefPubMedGoogle Scholar
  73. Ruiterkamp, J., Voogd, A. C., Bosscha, K., Tjan-Heijnen, V. C., & Ernst, M. F. (2010). Impact of breast surgery on survival in patients with distant metastases at initial presentation: A systematic review of the literature. Breast Cancer Research and Treatment, 120, 9–16.CrossRefPubMedGoogle Scholar
  74. Schaapveld, M., Visser, O., Louwman, W. J., Willemse, P. H., de Vries, E. G., van der Graaf, W. T., et al. (2008b). The impact of adjuvant therapy on contralateral breast cancer risk and the prognostic significance of contralateral breast cancer: A population based study in the Netherlands. Breast Cancer Research and Treatment, 110, 189–197.CrossRefPubMedGoogle Scholar
  75. Schaapveld, M., Visser, O., Louwman, M. J., de Vries, E. G., Willemse, P. H., Otter, R., et al. (2008a). Risk of new primary nonbreast cancers after breast cancer treatment: A Dutch population-based study. Journal of Clinical Oncology, 26, 1239–1246.CrossRefPubMedGoogle Scholar
  76. Schedi, M. P., Goldstein, G., & Boyce, E. A. (1975). Differentiation of T cells in nude mice. Science, 190, 1211–1213.CrossRefPubMedGoogle Scholar
  77. Schmidt-Kittler, O., Ragg, T., Daskalakis, A., Granzow, M., Ahr, A., Blankenstein, T. J., et al. (2003). From latent disseminated cells to overt metastasis: Genetic analysis of systemic breast cancer progression. Proceedings of the National Academy of Sciences of the United States of America, 100, 7737–7742.CrossRefPubMedGoogle Scholar
  78. Schoenberg, B. S. (1977). Multiple primary malignant neoplasms. The connecticut experience, 1935–1964. Recent Results Cancer Research, 58, 1–173.Google Scholar
  79. Senger, D. R., Wirth, D. F., & Hynes, R. O. (1979). Transformed mammalian cells secrete specific proteins and phosphoproteins. Cell, 16, 885–893.CrossRefPubMedGoogle Scholar
  80. Shojaei, F., Wu, X., Malik, A. K., Zhong, C., Baldwin, M. E., Schanz, S., et al. (2007). Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nature Biotechnology, 25, 911–920.CrossRefPubMedGoogle Scholar
  81. Stier, S., Ko, Y., Forkert, R., Lutz, C., Neuhaus, T., Grunewald, E., et al. (2005). Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. The Journal of Experimental Medicine, 201, 1781–1791.CrossRefPubMedGoogle Scholar
  82. Takigawa, M., & Hanaoka, M. (1978). In vivo maturation of B cells in the spleen of nude mice following administration of bacterial lipopolysaccharide. International Archives of Allergy and Applied Immunology, 56, 115–122.CrossRefPubMedGoogle Scholar
  83. Tuck, A. B., Chambers, A. F., & Allan, A. L. (2007). Osteopontin overexpression in breast cancer: Knowledge gained and possible implications for clinical management. Journal of Cellular Biochemistry, 102, 859–868.CrossRefPubMedGoogle Scholar
  84. Ugurel, S., Rappl, G., Tilgen, W., & Reinhold, U. (2001). Increased serum concentration of angiogenic factors in malignant melanoma patients correlates with tumor progression and survival. Journal of Clinical Oncology, 19, 577–583.PubMedGoogle Scholar
  85. van de Vijver, M. J., He, Y. D., van’t Veer, L. J., Dai, H., Hart, A. A., Voskuil, D. W., et al. (2002). A gene-expression signature as a predictor of survival in breast cancer. The New England Journal of Medicine, 347, 1999–2009.CrossRefPubMedGoogle Scholar
  86. van ‘t Veer, L. J., Dai, H., van de Vijver, M. J., He, Y. D., Hart, A. A., Mao, M., et al. (2002). Gene expression profiling predicts clinical outcome of breast cancer. Nature, 415, 530–536.CrossRefPubMedGoogle Scholar
  87. Vecchi, M., Confalonieri, S., Nuciforo, P., Vigano, M. A., Capra, M., Bianchi, M., et al. (2008). Breast cancer metastases are molecularly distinct from their primary tumors. Oncogene, 27, 2148–2158.CrossRefPubMedGoogle Scholar
  88. Visonneau, S., Cesano, A., Torosian, M. H., Miller, E. J., & Santoli, D. (1998). Growth characteristics and metastatic properties of human breast cancer xenografts in immunodeficient mice. The American Journal of Pathology, 152, 1299–1311.PubMedGoogle Scholar
  89. Volpert, O. V., Lawler, J., & Bouck, N. P. (1998). A human fibrosarcoma inhibits systemic angiogenesis and the growth of experimental metastases via thrombospondin-1. Proceedings of the National Academy of Sciences of the United States of America, 95, 6343–6348.CrossRefPubMedGoogle Scholar
  90. Wai, P. Y., Mi, Z., Guo, H., Sarraf-Yazdi, S., Gao, C., Wei, J., et al. (2005). Osteopontin silencing by small interfering RNA suppresses in vitro and in vivo CT26 murine colon adenocarcinoma metastasis. Carcinogenesis, 26, 741–751.CrossRefPubMedGoogle Scholar
  91. Watanabe, S., Kodama, T., Shimosato, Y., Arimoto, H., Sugimura, T., Suemasu, K., et al. (1984). Multiple primary cancers in 5,456 autopsy cases in the National Cancer Center of Japan. Journal of the National Cancer Institute, 72, 1021–1027.PubMedGoogle Scholar
  92. Weiss, L. (1992). Comments on hematogenous metastatic patterns in humans as revealed by autopsy. Clinical and Experimental Metastasis, 10, 191–199.CrossRefPubMedGoogle Scholar
  93. Welsh, R. M., Jr. (1978). Mouse natural killer cells: Induction specificity, and function. The Journal of Immunology, 121, 1631–1635.PubMedGoogle Scholar
  94. Woelfle, U., Cloos, J., Sauter, G., Riethdorf, L., Janicke, F., van Diest, P., et al. (2003). Molecular signature associated with bone marrow micrometastasis in human breast cancer. Cancer Research, 63, 5679–5684.PubMedGoogle Scholar
  95. Worthley, D. L., Ruszkiewicz, A., Davies, R., Moore, S., Nivison-Smith, I., Bik To, L., et al. (2009). Human gastrointestinal neoplasia-associated myofibroblasts can develop from bone marrow-derived cells following allogeneic stem cell transplantation. Stem Cells, 27, 1463–1468.CrossRefPubMedGoogle Scholar
  96. Wortis, H. H. (1971). Immunological responses of ‘nude’ mice. Clinical & Experimental Immunology, 8, 305–317.Google Scholar

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© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  1. 1.Harvard Medical SchoolBostonUSA
  2. 2.HematologyBrigham and Women’s HospitalBostonUSA

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