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Tumor metastasis: mechanistic insights and clinical challenges

Metastatic disease is the primary cause of death for most cancer patients. Complex and redundant pathways involving the tumor cell and the microenvironment mediate tumor invasion at the primary site, survival and arrest in the bloodstream, and progressive outgrowth at a distant site. Understanding these pathways and their dynamic interactions will help identify promising molecular targets for cancer therapy and key obstacles to their clinical development.

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Figure 1: The tumor metastatic process.
Figure 2: Dynamic signaling in invasion.
Figure 3: Tumor cell–microenvironment interactions in osteoclastic bone metastases.
Figure 4: Surveillance Epidemiology and End Result (SEER) program stage distribution of cancer at diagnosis.

References

  1. Paget, S. The distribution of secondary growths in cancer of the breast. Lancet 1, 571–573 (1889).

    Article  Google Scholar 

  2. Welch, D. Technical considerations for studying cancer metastasis in vivo. Clin. Exp. Metastasis 15, 272–306 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Khanna, C. & Hunter, K. Modeling metastasis in vivo. Carcinogenesis 26, 513–523 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Clifford, C.A., Mackin, A.J. & Henry, C.J. Treatment of canine hemangiosarcoma: 2000 and beyond. J. Vet. Intern. Med. 14, 479–485 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Knapp, S. et al. Naturally-occurring canine transitional cell carcinoma of the urinary bladder- A relevant model of human invasive bladder cancer. Urol. Oncol. 5, 47–59 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Guo, W. & Giancotti, F.G. Integrin signalling during tumour progression. Nat. Rev. Mol. Cell Biol. 5, 816–826 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Cavallaro, U. & Christofori, G. Cell adhesion and signalling by cadherins and IG-CAMs in cancer. Nat. Rev. Cancer 4, 118–132 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Friedl, P. & Wolf, K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat. Rev. Cancer 3, 362–374 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Folgueras, A.R., Pendas, A.M., Sanchez, L.M. & Lopez-Otin, C. Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies. Int. J. Dev. Biol. 48, 411–424 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Overall, C.M. & Kleifeld, O. Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat. Rev. Cancer 6, 227–239 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Goswami, S. et al. Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res. 65, 5278–5283 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Balkwill, F. Chemokine biology in cancer. Semin. Immunol. 15, 49–55 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. McLean, G. et al. The role of focal-adhesion kinase in cancer- a new therapeutic opportunity. Nat. Rev. Cancer 5, 505–514 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Mitra, S., Hanson, D. & Schlaepfer, D. Focal adhesion kinase: In command and control of cell motility. Nat. Rev. Mol. Cell Biol. 6, 56–68 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Playford, M. & Schaller, M. The interplay between Src and integrins in normal and tumor biology. Oncogene 23, 7928–7946 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Birchmeier, C., Birchmeier, W., Gherardi, E. & Vande Woude, G.F. Met, metastasis, motility and more. Nat. Rev. Mol. Cell Biol. 4, 915–925 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Gao, C.F. et al. Proliferation and invasion: plasticity in tumor cells. Proc. Natl. Acad. Sci. USA 102, 10528–10533 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhan, M., Zhao, H. & Han, Z.C. Signalling mechanisms of anoikis. Histol. Histopathol. 19, 973–983 (2004).

    CAS  PubMed  Google Scholar 

  19. Weiss, L. et al. Haematogenous metastatic patterns in colonic carcinoma: an analysis of 1541 necropsies. J. Pathol. 150, 195–203 (1986).

    Article  CAS  PubMed  Google Scholar 

  20. Al-Mehdi, A. et al. Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nat. Med. 6, 100–102 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Mannori, G. et al. Inhibition of colon carcinoma cell lung colony formation by a soluble form of E-selectin. Am. J. Pathol. 151, 233–243 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kim, Y.J., Borsig, L., Varki, N.M. & Varki, A. P-selectin deficiency attenuates tumor growth and metastasis. Proc. Natl. Acad. Sci. USA 95, 9325–9330 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Khatib, A.M. et al. Characterization of the host proinflammatory response to tumor cells during the initial stages of liver metastasis. Am. J. Pathol. 167, 749–759 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Trepel, M., Arap, W. & Pasqualini, R. In vivo phage display and vascular heterogeneity: implications for targeted medicine. Curr. Opin. Chem. Biol. 6, 399–404 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Brown, D. & Ruoslahti, E. Metadherin, a cell surface protein in breast tumors that mediates lung metastasis. Cancer Cell 5, 365–374 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Luzzi, K.J. et al. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am. J. Pathol. 153, 865–873 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kaplan, R.N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hicklin, D.J. & Ellis, L.M. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J. Clin. Oncol. 23, 1011–1027 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. de Vos, F.Y., Willemse, P.H., de Vries, E.G. & Gietema, J.A. Endothelial cell effects of cytotoxics: balance between desired and unwanted effects. Cancer Treat. Rev. 30, 495–513 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Raghunand, N., Gatenby, R.A. & Gillies, R.J. Microenvironmental and cellular consequences of altered blood flow in tumours. Br. J. Radiol. 76 Spec No 1, S11–S22 (2003).

    Article  PubMed  Google Scholar 

  31. Rak, J. & Yu, J.L. Oncogenes and tumor angiogenesis: the question of vascular “supply” and vascular “demand”. Semin. Cancer Biol. 14, 93–104 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).

    Article  CAS  PubMed  Google Scholar 

  33. Dameron, K.M., Volpert, O.V., Tainsky, M.A. & Bouck, N. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265, 1582–1584 (1994).

    Article  CAS  PubMed  Google Scholar 

  34. Weinstat-Saslow, D. et al. Transfection of thrombospondin-1 cDNA into a human breast carcinoma cell lne reduces primary tumor growth, metastatic potneial and angiogenesis. Cancer Res. 54, 6504–6511 (1994).

    CAS  PubMed  Google Scholar 

  35. O'Reilly, M.S. et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277–285 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Asahara, T. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275, 964–967 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Maniotis, A. et al. Vascular channel gformation by human melanoma cells in vivo and in vitro: Vasculogenic mimicry. Am. J. Pathol. 155, 739–752 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Senger, D.R. et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219, 983–985 (1983).

    Article  CAS  PubMed  Google Scholar 

  39. Leung, D.W., Cachianes, G., Kuang, W.J., Goeddel, D.V. & Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246, 1306–1309 (1989).

    Article  CAS  PubMed  Google Scholar 

  40. Yang, J.C. et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N. Engl. J. Med. 349, 427–434 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cobleigh, M.A. et al. A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin. Oncol. 30, 117–124 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Motzer, R.J. et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 24, 16–24 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Arao, T. et al. ZD6474 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model. Int. J. Cancer 118, 483–489 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Strumberg, D. Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment. Drugs Today (Barc.) 41, 773–784 (2005).

    Article  CAS  Google Scholar 

  46. Weis, S.M. & Cheresh, D.A. Pathophysiological consequences of VEGF-induced vascular permeability. Nature 437, 497–504 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Criscuoli, M.L., Nguyen, M. & Eliceiri, B.P. Tumor metastasis but not tumor growth is dependent on Src-mediated vascular permeability. Blood 105, 1508–1514 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Price, D.J., Miralem, T., Jiang, S., Steinberg, R. & Avraham, H. Role of vascular endothelial growth factor in the stimulation of cellular invasion and signaling of breast cancer cells. Cell Growth Differ. 12, 129–135 (2001).

    CAS  PubMed  Google Scholar 

  49. Graells, J. et al. Overproduction of VEGF165 concomitantly expressed with its receptors promotes growth and survival of melanoma cells through MAPK and PI3K signaling. J. Invest. Dermatol. 123, 1151–1161 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. So, J., Wang, F.Q., Navari, J., Schreher, J. & Fishman, D.A. LPA-induced epithelial ovarian cancer (EOC) in vitro invasion and migration are mediated by VEGF receptor-2 (VEGF-R2). Gynecol. Oncol. 97, 870–878 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Mundy, G. Metastasis to the bone: Causes, consequences and therapeutic opportunities. Nat. Rev. Cancer 2, 584–593 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Logothetis, C.J. & Lin, S.H. Osteoblasts in prostate cancer metastasis to bone. Nat. Rev. Cancer 5, 21–28 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Roodman, G. Mechanisms of disease. Mechanisms of bone metastasis. N. Engl. J. Med. 350, 1655–1664 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Roodman, G. Role of stromal-derived cytokines and growth factors in bone metastasis. Cancer 97 Suppl.3, 733–738 (2003).

    Article  Google Scholar 

  55. Kozlow, W. & Guise, T.A. Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy. J. Mammary Gland Biol. Neoplasia 10, 169–180 (2005).

    Article  PubMed  Google Scholar 

  56. Morgan, H., Tumber, A. & Hill, P.A. Breast cancer cells induce osteoclast formation by stimulating host IL-11 production and downregulating granulocyte/macrophage colony-stimulating factor. Int. J. Cancer 109, 653–660 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Kang, Y. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Lev, D.C. et al. Inhibition of platelet-derived growth factor receptor signaling restricts the growth of human breast cancer in the bone of nude mice. Clin. Cancer Res. 11, 306–314 (2005).

    CAS  PubMed  Google Scholar 

  59. Winding, B. et al. Synthetic matrix metalloproteinase inhibitor inhibit growth of established breast cancer osteolytic lesions and prolong survival in mice. Clin. Cancer Res. 8, 1932–1939 (2002).

    CAS  PubMed  Google Scholar 

  60. Price, J.T. et al. The heat shock protein 90 inhibitor, 17-allylamino-17-demethoxygeldanamycin, enhances osteoclast formation and potentiates bone metastasis of a human breast cancer cell line. Cancer Res. 65, 4929–4938 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Isaacs, J., Xu, W. & Neckers, L. Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell 3, 213–217 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Guise, T.A. et al. Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J. Clin. Invest. 98, 1544–1549 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Carducci, M.A. et al. Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial. J. Clin. Oncol. 21, 679–689 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Body, J.J. et al. A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin. Cancer Res. 12, 1221–1228 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Dalton, W. The tumor microenvironment as a determinant of drug response and resistance. Drug Resist. Updat. 2, 285–288 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Neville-Webbe, H.L. et al. Osteoprotegerin (OPG) produced by bone marrow stromal cells protects breast cancer cells from TRAIL-induced apoptosis. Breast Cancer Res. Treat. 86, 269–279 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Zvibel, I., Brill, S., Halpern, Z. & Papa, M. Hepatocyte extracellular matrix modulates expression of growth factors and growth factor receptors in human colon cancer cells. Exp. Cell Res. 245, 123–131 (1998).

    Article  CAS  PubMed  Google Scholar 

  68. Nakagawa, H. et al. Role of cancer-associated stromal fibroblasts in metastatic colon cancer to the liver and their expression profiles. Oncogene 23, 7366–7377 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Stessels, F. et al. Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia. Br. J. Cancer 90, 1429–1436 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Vermeulen, P.B. et al. Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia. J. Pathol. 195, 336–342 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Stephan, S. et al. Effect of rapamycin alone and in combination with antiangiogenesis therapy in an orthotopic model of human pancreatic cancer. Clin. Cancer Res. 10, 6993–7000 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Streck, C.J. et al. Longterm recombinant adeno-associated, virus-mediated, liver-generated expression of an angiogenesis inhibitor improves survival in mice with disseminated neuroblastoma. J. Am. Coll. Surg. 199, 78–86 (2004).

    Article  PubMed  Google Scholar 

  73. Bruns, C.J. et al. Effect of the vascular endothelial growth factor receptor-2 antibody DC101 plus gemcitabine on growth, metastasis and angiogenesis of human pancreatic cancer growing orthotopically in nude mice. Int. J. Cancer 102, 101–108 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Solorzano, C.C. et al. Inhibition of growth and metastasis of human pancreatic cancer growing in nude mice by PTK 787/ZK222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases. Cancer Biother. Radiopharm. 16, 359–370 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Kabbinavar, F.F. et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J. Clin. Oncol. 23, 3697–3705 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Takeda, A. et al. Role of angiogenesis in the development and growth of liver metastasis. Ann. Surg. Oncol. 9, 610–616 (2002).

    Article  PubMed  Google Scholar 

  77. Saha, S. et al. A phosphatase associated with metastasis of colorectal cancer. Science 294, 1343–1346 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Zeng, Q. et al. PRL-3 and PRL-1 promote cell migration, invasion, and metastasis. Cancer Res. 63, 2716–2722 (2003).

    CAS  PubMed  Google Scholar 

  79. Kato, H. et al. High expression of PRL-3 promotes cancer cell motility and liver metastasis in human colorectal cancer: a predictive molecular marker of metachronous liver and lung metastases. Clin. Cancer Res. 10, 7318–7328 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Herlevsen, M., Schmidt, D.S., Miyazaki, K. & Zoller, M. The association of the tetraspanin D6.1A with the alpha6beta4 integrin supports cell motility and liver metastasis formation. J. Cell Sci. 116, 4373–4390 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. Yezhelyev, M.V. et al. Inhibition of SRC tyrosine kinase as treatment for human pancreatic cancer growing orthotopically in nude mice. Clin. Cancer Res. 10, 8028–8036 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Miyamoto, S. et al. Blockade of paracrine supply of insulin-like growth factors using neutralizing antibodies suppresses the liver metastasis of human colorectal cancers. Clin. Cancer Res. 11, 3494–3502 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Lassman, A. & DeAngelis, L. Brain Metastases. Neurol. Clin. 21, 1–23, vii (2003).

    Article  PubMed  Google Scholar 

  84. Bendell, J. et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 97, 2972–2977 (2003).

    Article  PubMed  Google Scholar 

  85. Clayton, A. et al. Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br. J. Cancer 91, 639–643 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Omuro, A.M. et al. High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer 103, 2344–2348 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Entschladen, F. & Drell, T.L.t., Lang, K., Joseph, J. & Zaenker, K.S. Neurotransmitters and chemokines regulate tumor cell migration: potential for a new pharmacological approach to inhibit invasion and metastasis development. Curr. Pharm. Des. 11, 403–411 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Xie, T.X. et al. Activation of stat3 in human melanoma promotes brain metastasis. Cancer Res. 66, 3188–3196 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Kim, L., Huang, S., Lu, W., Lev, D.C. & Price, J. Vascular endothelial growth factor expression promotes the growth of breast cancer brain metastases in nude mice. Clin. Exp. Metastasis 21, 107–118 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Yano, S. et al. Expression of vascular endothelial growt h factor is necessary but not sufficient for production and growth of brain metastasis. Cancer Res. 60, 4959–4967 (2000).

    CAS  PubMed  Google Scholar 

  91. Minn, A.J. et al. Genes that mediate breast cancer metastasis to lung. Nature 436, 518–524 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Khanna, C. et al. The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat. Med. 10, 182–186 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Yu, Q. & Stamenkovic, I. Transforming growth factor-beta facilitates breast carcinoma metastasis by promoting tumor cell survival. Clin. Exp. Metastasis 21, 235–242 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Siegel, P.M., Shu, W., Cardiff, R.D., Muller, W.J. & Massague, J. Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc. Natl. Acad. Sci. USA 100, 8430–8435 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Pinkas, J., Martin, S.S. & Leder, P. Bcl-2-mediated cell survival promotes metastasis of EpH4 betaMEKDD mammary epithelial cells. Mol. Cancer Res. 2, 551–556 (2004).

    CAS  PubMed  Google Scholar 

  96. Martin, S.S. et al. A cytoskeleton-based functional genetic screen identifies Bcl-xL as an enhancer of metastasis, but not primary tumor growth. Oncogene 23, 4641–4645 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Inbal, B. et al. DAP kinase links the control of apoptosis to metastasis. Nature 390, 180–184 (1997).

    Article  CAS  PubMed  Google Scholar 

  98. Wong, C. et al. Apoptosis: an early event in metastatic inefficiency. Cancer Res. 61, 333–338 (2001).

    CAS  PubMed  Google Scholar 

  99. Sweeney, C.J. et al. The sesquiterpene lactone parthenolide in combination with docetaxel reduces metastasis and improves survival in a xenograft model of breast cancer. Mol. Cancer Ther. 4, 1004–1012 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Jiang, Y. et al. Inhibition of anchorage-independent growth and lung metastasis of A549 lung carcinoma cells by IkappaBbeta. Oncogene 20, 2254–2263 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. Ladeda, V., Adam, A., Puricello, L. & Joffe, E. Apoptotic cell death in mammary adenocarcinoma cells is prevented by soluble factors present in the target organ of metastasis. Breast Cancer Res. Treat. 69, 39–51 (2001).

    Article  CAS  PubMed  Google Scholar 

  102. Chen, Y., Wang, J., Chen, S. & Yang, B. Granulocytes mediates the Fas-L-associated apoptosis during lung metastasis of melanoma that determines the metastatic behavior. Br. J. Cancer 87, 359–365 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lifsted, T. et al. Identification of inbred mouse strains harboring genetic modifiers of mammary tumor age of onset and metastatic progression. Int. J. Cancer 77, 640–644 (1998).

    Article  CAS  PubMed  Google Scholar 

  104. Park, Y.G. et al. Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1. Nat. Genet. 37, 1055–1062 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Chekmareva, M. et al. Chromosome 17-mediated dormancy of AT6.1 prostate cancer micrmetastases. Cancer Res. 58, 4963–4969 (1998).

    CAS  PubMed  Google Scholar 

  106. Goldberg, S., Harms, J., Quon, K. & Welch, D. Metastasis suppressed C8161 melanoma cells arrest in lung but fail to proliferate. Clin. Exp. Metastasis 17, 601–607 (1999).

    Article  CAS  PubMed  Google Scholar 

  107. Steeg, P. Metastasis suppressors alter the signal transduction of cancer cells. Nat. Rev. Cancer 3, 55–63 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Shevde, L. & Welch, D. Metastasis suppressor pathways - an evolving paradigm. Cancer Lett. 198, 1–20 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Vander Griend, D. et al. Suppression of metastatic colonization by the context-dependent activation of the c-jun NH2-terminal kinase kinases JNKK1/MKK4 and MKK7. Cancer Res. 65, 10984–10991 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. DeWald, D.B. et al. Metastasis suppression by breast cancer metastasis suppressor 1 involves reduction of phosphoinositide signaling in MDA-MB-435 breast carcinoma cells. Cancer Res. 65, 713–717 (2005).

    CAS  PubMed  Google Scholar 

  111. Saunders, M. et al. Breast cancer metastastic potential correlates with a breakdown in homospecific and heterospecific gap junctionalintercellular communication. Cancer Res. 61, 1765–1767 (2001).

    CAS  PubMed  Google Scholar 

  112. Hartsough, M. et al. Nm23–H1 metastasis suppressor phosphorylation of Kinase suppressor of ras (KSR), via a histidine protein kinase pathway. J. Biol. Chem. 277, 32389–32399 (2002).

    Article  CAS  PubMed  Google Scholar 

  113. Engel, M., Mazurek, S., Eigenbrodt, E. & Welter, C. Phosphoglycerate mutase-derived polypeptide inhibits glycolytic flux and induces cell growth arrest in tumor cell lines. J. Biol. Chem. 279, 35803–35812 (2004).

    Article  CAS  PubMed  Google Scholar 

  114. Palacios, F., Schweitzer, J., Boshans, R. & D'Souza-Schorey, C. ARF6-GTP recruits Nm23–H1 to facilitate dynamin-mediated endocytosis during adherens junctions disassembly. Nat. Cell Biol. 4, 929–936 (2002).

    Article  CAS  PubMed  Google Scholar 

  115. Fournier, H. et al. Integrin cytoplasmic domain-associated protein 1a (ICAP-1a) interacts directly with the metastasis suppressor nm23–H2, and both proteins are targeted to newly formed cell adhesion sites upon integrin engagement. J. Biol. Chem. 277, 20895–20902 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. D'Angelo, A. et al. Prune cAMP phosphodiesterase binds nm23-H1 and promotes cancer metastasis. Cancer Cell 5, 137–149 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Ouatas, T., Halverson, D. & Steeg, P. Dexamethasone and medroxyprogesterone acetate elevate Nm23–H1 metastasis suppressor expression in metastatic human breast carcinoma cells: New uses for old compounds. Clin. Cancer Res. 9, 3763–3772 (2003).

    CAS  PubMed  Google Scholar 

  118. Palmieri, D. et al. Medroxyprogesterone acetate elevation of Nm23–H1 metastasis suppressor expression in hormone receptor-negative breast cancer. J. Natl. Cancer Inst. 97, 632–642 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Titus, B. et al. Endothelin axis is a target of the lung metastasis suppressor gene RhoGDI2. Cancer Res. 65, 7320–7327 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Ramaswamy, S., Ross, K., Lander, E. & Golub, T. A molecular signature of metastasis in primary solid tumors. Nat. Genet. 33, 49–54 (2003).

    Article  CAS  PubMed  Google Scholar 

  121. Hunter, K., Welch, D. & Liu, E. Genetic background as a determinant of metastatic potential. Nat. Genet. 34, 23–24 (2003).

    Article  CAS  PubMed  Google Scholar 

  122. Weigelt, B. et al. Gene expression profiles of primary breast tumors maintained in distant metastases. Proc. Natl. Acad. Sci. USA 100, 15901–15905 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Perou, C.M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).

    Article  CAS  PubMed  Google Scholar 

  124. Poste, G. & Fidler, I. The pathogenesis of cancer metastasis. Nature 283, 139–146 (1980).

    Article  CAS  PubMed  Google Scholar 

  125. Demicheli, R., Abbattista, A., Miceli, R., Valagussa, P. & Bonadonna, G. Time distribution of the recurrence risk for breast cancer patients undergoing mastectomy: further support about the concept of tumor dormancy. Breast Cancer Res. Treat. 41, 177–185 (1996).

    Article  CAS  PubMed  Google Scholar 

  126. Crowley, N.J. & Seigler, H.F. Relationship between disease-free interval and survival in patients with recurrent melanoma. Arch. Surg. 127, 1303–1308 (1992).

    Article  CAS  PubMed  Google Scholar 

  127. Naumov, G. et al. Persistence of solitary mammary carcinoma cells in a secondary site: A possible contributor to dormancy. Cancer Res. 62, 2162–2168 (2002).

    CAS  PubMed  Google Scholar 

  128. Goodison, S. et al. Prolonged dormancy and site-specific growth potential of cancer cells spontaneously disseminated from nonmetastatic breast tumors as revealed by labeling with green fluorescent protein. Clin. Cancer Res. 9, 3808–3814 (2003).

    CAS  PubMed  Google Scholar 

  129. Pantel, K. & Brakenhoff, R.H. Dissecting the metastatic cascade. Nat. Rev. Cancer 4, 448–456 (2004).

    Article  CAS  PubMed  Google Scholar 

  130. Lindemann, F., Schlimok, G., Dirschedl, P., Witte, J. & Riethmuller, G. Prognostic significance of micrometastatic tumour cells in bone marrow of colorectal cancer patients. Lancet 340, 685–689 (1992).

    Article  CAS  PubMed  Google Scholar 

  131. Holmgren, L., O'Reilly, M. & Folkman, J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat. Med. 1, 149–153 (1995).

    Article  CAS  PubMed  Google Scholar 

  132. Naumov, G. et al. Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late developing metastases. Breast Cancer Res. Treat. 82, 199–206 (2003).

    Article  CAS  PubMed  Google Scholar 

  133. Cao, Y. et al. Expression of angiostatin cDNA in a murine fibrosarcoma suppresses primary tumor growth and produces long-term dormancy of metastases. J. Clin. Invest. 101, 1055–1063 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Al-Hajj, M. & Clarke, M.F. Self-renewal and solid tumor stem cells. Oncogene 23, 7274–7282 (2004).

    Article  CAS  PubMed  Google Scholar 

  135. Reya, T., Morrison, S.J., Clarke, M.F. & Weissman, I.L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).

    Article  CAS  PubMed  Google Scholar 

  136. Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J. & Clarke, M.F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA 100, 3983–3988 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Al-Hajj, M., Becker, M.W., Wicha, M., Weissman, I. & Clarke, M.F. Therapeutic implications of cancer stem cells. Curr. Opin. Genet. Dev. 14, 43–47 (2004).

    Article  CAS  PubMed  Google Scholar 

  138. Dean, M., Fojo, T. & Bates, S. Tumour stem cells and drug resistance. Nat. Rev. Cancer 5, 275–284 (2005).

    Article  CAS  PubMed  Google Scholar 

  139. Liang, Y. et al. Selection with melphalan or paclitaxel (Taxol) yields variants with different patterns of multidrug resistance, integrin expression and in vitro invasiveness. Eur. J. Cancer 37, 1041–1052 (2001).

    Article  CAS  PubMed  Google Scholar 

  140. Wang, Z., Goulet, R., III, Stanton, K.J., Sadaria, M. & Nakshatri, H. Differential effect of anti-apoptotic genes Bcl-xL and c-FLIP on sensitivity of MCF-7 breast cancer cells to paclitaxel and docetaxel. Anticancer Res. 25, 2367–2379 (2005).

    CAS  PubMed  Google Scholar 

  141. Slamon, D. et al. Use of chemotherapy plus a monoclonal antibody against Her2 for metastatic breast cancer that overexpresses Her2. N. Engl. J. Med. 344, 783–792 (2001).

    Article  CAS  PubMed  Google Scholar 

  142. Piccart-Gebhart, M.J. et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 353, 1659–1672 (2005).

    Article  CAS  PubMed  Google Scholar 

  143. Romond, E.H. et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 353, 1673–1684 (2005).

    Article  CAS  PubMed  Google Scholar 

  144. Barlesi, F. et al. Gefitinib (ZD1839, Iressa) in non-small-cell lung cancer: a review of clinical trials from a daily practice perspective. Fundam. Clin. Pharmacol. 19, 385–393 (2005).

    Article  CAS  PubMed  Google Scholar 

  145. Coussens, L., Fingleton, B. & Matrisian, L. Cancer Therapy - Matrix metalloproteinase inhibitors and cancer: Trials and tribulations. Science 295, 2387–2392 (2002).

    Article  CAS  PubMed  Google Scholar 

  146. Xue, C. et al. Epidermal growth factor receptor overexpression results in increased tumor cell motility in vivo coordinately with enhanced intravasation and metastasis. Cancer Res. 66, 192–197 (2006).

    Article  CAS  PubMed  Google Scholar 

  147. Nagle, J.A., Ma, Z., Byrne, M.A., White, M.F. & Shaw, L.M. Involvement of insulin receptor substrate 2 in mammary tumor metastasis. Mol. Cell. Biol. 24, 9726–9735 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Lang, J.Y. et al. Antimetastatic effect of salvicine on human breast cancer MDA-MB-435 orthotopic xenograft is closely related to Rho-dependent pathway. Clin. Cancer Res. 11, 3455–3464 (2005).

    Article  CAS  PubMed  Google Scholar 

  149. Shannon, K.E. et al. Anti-metastatic properties of RGD-peptidomimetic agents S137 and S247. Clin. Exp. Metastasis 21, 129–138 (2004).

    Article  CAS  PubMed  Google Scholar 

  150. Manni, A. et al. Effects of alpha-difluoromethylornithine on local recurrence and pulmonary metastasis from MDA-MB-435 breast cancer xenografts in nude mice. Clin. Exp. Metastasis 20, 321–325 (2003).

    Article  CAS  PubMed  Google Scholar 

  151. Cairns, R.A. & Hill, R.P. Acute hypoxia enhances spontaneous lymph node metastasis in an orthotopic murine model of human cervical carcinoma. Cancer Res. 64, 2054–2061 (2004).

    Article  CAS  PubMed  Google Scholar 

  152. Lovey, J., Fazekas, K., Ladanyi, A., Nemeth, G. & Timar, J. Low-dose irradiation and short-exposure suboptimal-dose paclitaxel adversely modulate metastatic potential of squamous carcinoma cells. Strahlenther. Onkol. 179, 812–818 (2003).

    Article  PubMed  Google Scholar 

  153. Nasulewicz, A. et al. Magnesium deficiency inhibits primary tumor growth but favors metastasis in mice. Biochim. Biophys. Acta 1739, 26–32 (2004).

    Article  CAS  PubMed  Google Scholar 

  154. Epstein, R.J. Maintenance therapy to suppress micrometastasis: the new challenge for adjuvant cancer treatment. Clin. Cancer Res. 11, 5337–5341 (2005).

    Article  CAS  PubMed  Google Scholar 

  155. Miller, J.C., Pien, H.H., Sahani, D., Sorensen, A.G. & Thrall, J.H. Imaging angiogenesis: applications and potential for drug development. J. Natl. Cancer Inst. 97, 172–187 (2005).

    Article  CAS  PubMed  Google Scholar 

  156. Sharma, V., Prior, J.L., Belinsky, M.G., Kruh, G.D. & Piwnica-Worms, D. Characterization of a 67Ga/68Ga radiopharmaceutical for SPECT and PET of MDR1 P-glycoprotein transport activity in vivo: validation in multidrug-resistant tumors and at the blood-brain barrier. J. Nucl. Med. 46, 354–364 (2005).

    CAS  PubMed  Google Scholar 

  157. Messerli, S.M. et al. A novel method for imaging apoptosis using a caspase-1 near-infrared fluorescent probe. Neoplasia 6, 95–105 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Joyce, J.A. et al. Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis. Cancer Cell 5, 443–453 (2004).

    Article  CAS  PubMed  Google Scholar 

  159. Chang, E. et al. Protease-activated quantum dot probes. Biochem. Biophys. Res. Commun. 334, 1317–1321 (2005).

    Article  CAS  PubMed  Google Scholar 

  160. Jiang, T. et al. Tumor imaging by means of proteolytic activation of cell-penetrating peptides. Proc. Natl. Acad. Sci. USA 101, 17867–17872 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Funovics, M.A., Weissleder, R. & Mahmood, U. Catheter-based in vivo imaging of enzyme activity and gene expression: feasibility study in mice. Radiology 231, 659–666 (2004).

    Article  PubMed  Google Scholar 

  162. Seymour, L. The design of clinical trials for new molecularly targeted compounds: progress and new initiatives. Curr. Pharm. Des. 8, 2279–2284 (2002).

    Article  CAS  PubMed  Google Scholar 

  163. Parulekar, W. & Eisenhauer, E. Phase I trial design for solid tumor studies of targeted, non-cytotoxic agents: Theory and practice. J. Natl. Cancer Inst. 96, 990–997 (2004).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

I apologize to the many authors whose work is not cited due to space limitations. This work was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, US National Institutes of Health.

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Steeg, P. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12, 895–904 (2006). https://doi.org/10.1038/nm1469

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