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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
References
Paget, S. The distribution of secondary growths in cancer of the breast. Lancet 1, 571–573 (1889).
Welch, D. Technical considerations for studying cancer metastasis in vivo. Clin. Exp. Metastasis 15, 272–306 (1997).
Khanna, C. & Hunter, K. Modeling metastasis in vivo. Carcinogenesis 26, 513–523 (2005).
Clifford, C.A., Mackin, A.J. & Henry, C.J. Treatment of canine hemangiosarcoma: 2000 and beyond. J. Vet. Intern. Med. 14, 479–485 (2000).
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).
Guo, W. & Giancotti, F.G. Integrin signalling during tumour progression. Nat. Rev. Mol. Cell Biol. 5, 816–826 (2004).
Cavallaro, U. & Christofori, G. Cell adhesion and signalling by cadherins and IG-CAMs in cancer. Nat. Rev. Cancer 4, 118–132 (2004).
Friedl, P. & Wolf, K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat. Rev. Cancer 3, 362–374 (2003).
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).
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).
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).
Balkwill, F. Chemokine biology in cancer. Semin. Immunol. 15, 49–55 (2003).
McLean, G. et al. The role of focal-adhesion kinase in cancer- a new therapeutic opportunity. Nat. Rev. Cancer 5, 505–514 (2005).
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).
Playford, M. & Schaller, M. The interplay between Src and integrins in normal and tumor biology. Oncogene 23, 7928–7946 (2004).
Birchmeier, C., Birchmeier, W., Gherardi, E. & Vande Woude, G.F. Met, metastasis, motility and more. Nat. Rev. Mol. Cell Biol. 4, 915–925 (2003).
Gao, C.F. et al. Proliferation and invasion: plasticity in tumor cells. Proc. Natl. Acad. Sci. USA 102, 10528–10533 (2005).
Zhan, M., Zhao, H. & Han, Z.C. Signalling mechanisms of anoikis. Histol. Histopathol. 19, 973–983 (2004).
Weiss, L. et al. Haematogenous metastatic patterns in colonic carcinoma: an analysis of 1541 necropsies. J. Pathol. 150, 195–203 (1986).
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).
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).
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).
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).
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).
Brown, D. & Ruoslahti, E. Metadherin, a cell surface protein in breast tumors that mediates lung metastasis. Cancer Cell 5, 365–374 (2004).
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).
Kaplan, R.N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).
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).
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).
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).
Rak, J. & Yu, J.L. Oncogenes and tumor angiogenesis: the question of vascular “supply” and vascular “demand”. Semin. Cancer Biol. 14, 93–104 (2004).
Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).
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).
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).
O'Reilly, M.S. et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277–285 (1997).
Asahara, T. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275, 964–967 (1997).
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).
Senger, D.R. et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219, 983–985 (1983).
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).
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).
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).
Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004).
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).
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).
Strumberg, D. Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment. Drugs Today (Barc.) 41, 773–784 (2005).
Weis, S.M. & Cheresh, D.A. Pathophysiological consequences of VEGF-induced vascular permeability. Nature 437, 497–504 (2005).
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).
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).
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).
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).
Mundy, G. Metastasis to the bone: Causes, consequences and therapeutic opportunities. Nat. Rev. Cancer 2, 584–593 (2002).
Logothetis, C.J. & Lin, S.H. Osteoblasts in prostate cancer metastasis to bone. Nat. Rev. Cancer 5, 21–28 (2005).
Roodman, G. Mechanisms of disease. Mechanisms of bone metastasis. N. Engl. J. Med. 350, 1655–1664 (2004).
Roodman, G. Role of stromal-derived cytokines and growth factors in bone metastasis. Cancer 97 Suppl.3, 733–738 (2003).
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).
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).
Kang, Y. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003).
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).
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).
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).
Isaacs, J., Xu, W. & Neckers, L. Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell 3, 213–217 (2003).
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).
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).
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).
Dalton, W. The tumor microenvironment as a determinant of drug response and resistance. Drug Resist. Updat. 2, 285–288 (1999).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Takeda, A. et al. Role of angiogenesis in the development and growth of liver metastasis. Ann. Surg. Oncol. 9, 610–616 (2002).
Saha, S. et al. A phosphatase associated with metastasis of colorectal cancer. Science 294, 1343–1346 (2001).
Zeng, Q. et al. PRL-3 and PRL-1 promote cell migration, invasion, and metastasis. Cancer Res. 63, 2716–2722 (2003).
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).
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).
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).
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).
Lassman, A. & DeAngelis, L. Brain Metastases. Neurol. Clin. 21, 1–23, vii (2003).
Bendell, J. et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 97, 2972–2977 (2003).
Clayton, A. et al. Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br. J. Cancer 91, 639–643 (2004).
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).
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).
Xie, T.X. et al. Activation of stat3 in human melanoma promotes brain metastasis. Cancer Res. 66, 3188–3196 (2006).
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).
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).
Minn, A.J. et al. Genes that mediate breast cancer metastasis to lung. Nature 436, 518–524 (2005).
Khanna, C. et al. The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat. Med. 10, 182–186 (2004).
Yu, Q. & Stamenkovic, I. Transforming growth factor-beta facilitates breast carcinoma metastasis by promoting tumor cell survival. Clin. Exp. Metastasis 21, 235–242 (2004).
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).
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).
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).
Inbal, B. et al. DAP kinase links the control of apoptosis to metastasis. Nature 390, 180–184 (1997).
Wong, C. et al. Apoptosis: an early event in metastatic inefficiency. Cancer Res. 61, 333–338 (2001).
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).
Jiang, Y. et al. Inhibition of anchorage-independent growth and lung metastasis of A549 lung carcinoma cells by IkappaBbeta. Oncogene 20, 2254–2263 (2001).
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).
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).
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).
Park, Y.G. et al. Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1. Nat. Genet. 37, 1055–1062 (2005).
Chekmareva, M. et al. Chromosome 17-mediated dormancy of AT6.1 prostate cancer micrmetastases. Cancer Res. 58, 4963–4969 (1998).
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).
Steeg, P. Metastasis suppressors alter the signal transduction of cancer cells. Nat. Rev. Cancer 3, 55–63 (2003).
Shevde, L. & Welch, D. Metastasis suppressor pathways - an evolving paradigm. Cancer Lett. 198, 1–20 (2003).
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).
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).
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).
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).
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).
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).
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).
D'Angelo, A. et al. Prune cAMP phosphodiesterase binds nm23-H1 and promotes cancer metastasis. Cancer Cell 5, 137–149 (2004).
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).
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).
Titus, B. et al. Endothelin axis is a target of the lung metastasis suppressor gene RhoGDI2. Cancer Res. 65, 7320–7327 (2005).
Ramaswamy, S., Ross, K., Lander, E. & Golub, T. A molecular signature of metastasis in primary solid tumors. Nat. Genet. 33, 49–54 (2003).
Hunter, K., Welch, D. & Liu, E. Genetic background as a determinant of metastatic potential. Nat. Genet. 34, 23–24 (2003).
Weigelt, B. et al. Gene expression profiles of primary breast tumors maintained in distant metastases. Proc. Natl. Acad. Sci. USA 100, 15901–15905 (2003).
Perou, C.M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).
Poste, G. & Fidler, I. The pathogenesis of cancer metastasis. Nature 283, 139–146 (1980).
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).
Crowley, N.J. & Seigler, H.F. Relationship between disease-free interval and survival in patients with recurrent melanoma. Arch. Surg. 127, 1303–1308 (1992).
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).
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).
Pantel, K. & Brakenhoff, R.H. Dissecting the metastatic cascade. Nat. Rev. Cancer 4, 448–456 (2004).
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).
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).
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).
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).
Al-Hajj, M. & Clarke, M.F. Self-renewal and solid tumor stem cells. Oncogene 23, 7274–7282 (2004).
Reya, T., Morrison, S.J., Clarke, M.F. & Weissman, I.L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).
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).
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).
Dean, M., Fojo, T. & Bates, S. Tumour stem cells and drug resistance. Nat. Rev. Cancer 5, 275–284 (2005).
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).
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).
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).
Piccart-Gebhart, M.J. et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 353, 1659–1672 (2005).
Romond, E.H. et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 353, 1673–1684 (2005).
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).
Coussens, L., Fingleton, B. & Matrisian, L. Cancer Therapy - Matrix metalloproteinase inhibitors and cancer: Trials and tribulations. Science 295, 2387–2392 (2002).
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).
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).
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).
Shannon, K.E. et al. Anti-metastatic properties of RGD-peptidomimetic agents S137 and S247. Clin. Exp. Metastasis 21, 129–138 (2004).
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).
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).
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).
Nasulewicz, A. et al. Magnesium deficiency inhibits primary tumor growth but favors metastasis in mice. Biochim. Biophys. Acta 1739, 26–32 (2004).
Epstein, R.J. Maintenance therapy to suppress micrometastasis: the new challenge for adjuvant cancer treatment. Clin. Cancer Res. 11, 5337–5341 (2005).
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).
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).
Messerli, S.M. et al. A novel method for imaging apoptosis using a caspase-1 near-infrared fluorescent probe. Neoplasia 6, 95–105 (2004).
Joyce, J.A. et al. Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis. Cancer Cell 5, 443–453 (2004).
Chang, E. et al. Protease-activated quantum dot probes. Biochem. Biophys. Res. Commun. 334, 1317–1321 (2005).
Jiang, T. et al. Tumor imaging by means of proteolytic activation of cell-penetrating peptides. Proc. Natl. Acad. Sci. USA 101, 17867–17872 (2004).
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).
Seymour, L. The design of clinical trials for new molecularly targeted compounds: progress and new initiatives. Curr. Pharm. Des. 8, 2279–2284 (2002).
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).
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.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The author declares no competing financial interests.
Rights and permissions
About this article
Cite this article
Steeg, P. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12, 895–904 (2006). https://doi.org/10.1038/nm1469
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1469
This article is cited by
-
5-Methoxytryptophan enhances the sensitivity of sorafenib on the inhibition of proliferation and metastasis for lung cancer cells
BMC Cancer (2024)
-
Functionalized tetrahedral DNA frameworks for the capture of circulating tumor cells
Nature Protocols (2024)
-
Pharmacological Properties of White Mulberry (Morus alba L.) Leaves: Suppressing Migratory and Invasive Activities Against A549 Lung Cancer Cells
Plant Foods for Human Nutrition (2024)
-
The promoting effect and mechanism of Nrf2 on cell metastasis in cervical cancer
Journal of Translational Medicine (2023)
-
Dual mode imaging guided multi-functional bio-targeted oxygen production probes for tumor therapy
Journal of Nanobiotechnology (2023)