Despite recognizing the devastating consequences of metastasis, we are not yet able to effectively treat cancer that has spread to vital organs. The inherent complexity of genomic alterations in late-stage cancers, coupled with numerous heterotypic interactions that occur between tumour and stromal cells, represent fundamental challenges in our quest to understand and control metastatic disease. The incorporation of genomic and other systems level approaches, as well as technological breakthroughs in imaging and animal modelling, have galvanized the effort to overcome gaps in our understanding of metastasis. Future research carries with it the potential to translate the wealth of new knowledge and conceptual advances into effective targeted therapies.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Context dependent isoform specific PI3K inhibition confers drug resistance in hepatocellular carcinoma cells
BMC Cancer Open Access 24 March 2022
Nuclear pore protein NUP210 depletion suppresses metastasis through heterochromatin-mediated disruption of tumor cell mechanical response
Nature Communications Open Access 13 December 2021
Signal Transduction and Targeted Therapy Open Access 22 November 2021
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Fidler, I. J. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nature Rev. Cancer 3, 453–458 (2003).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Chambers, A. F., Groom, A. C. & MacDonald, I. C. Dissemination and growth of cancer cells in metastatic sites. Nature Rev. Cancer 2, 563–572 (2002).
Gupta, G. P. & Massague, J. Cancer metastasis: building a framework. Cell 127, 679–695 (2006).
Nguyen, D. X., Bos, P. D. & Massague, J. Metastasis: from dissemination to organ-specific colonization. Nature Rev. Cancer 9, 274–284 (2009).
Paget, S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 8, 98–101 (1989).
Chaffer, C. L. & Weinberg, R. A. A perspective on cancer cell metastasis. Science 331, 1559–1564 (2011).
Klein, C. A. Parallel progression of primary tumours and metastases. Nature Rev. Cancer 9, 302–312 (2009).
Ding, L. et al. Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464, 999–1005 (2010).
Navin, N. et al. Tumour evolution inferred by single-cell sequencing. Nature 472, 90–94 (2011).
Joyce, J. A. & Pollard, J. W. Microenvironmental regulation of metastasis. Nature Rev. Cancer 9, 239–252 (2009).
Nguyen, D. X. & Massague, J. Genetic determinants of cancer metastasis. Nature Rev. Genet. 8, 341–352 (2007).
Karnoub, A. E. et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449, 557–563 (2007).
Bhowmick, N. A., Neilson, E. G. & Moses, H. L. Stromal fibroblasts in cancer initiation and progression. Nature 432, 332–337 (2004).
Orimo, A. et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121, 335–348 (2005).
Scheel, C. et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell States in the breast. Cell 145, 926–940 (2011).
Weilbaecher, K. N., Guise, T. A. & McCauley, L. K. Cancer to bone: a fatal attraction. Nature Rev. Cancer 11, 411–425 (2011).
Kang, Y. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003).
Bos, P. D. et al. Genes that mediate breast cancer metastasis to the brain. Nature 459, 1005–1009 (2009).
Minn, A. J. et al. Genes that mediate breast cancer metastasis to lung. Nature 436, 518–524 (2005).
Sahai, E. Illuminating the metastatic process. Nature Rev. Cancer 7, 737–749 (2007).
Kienast, Y. et al. Real-time imaging reveals the single steps of brain metastasis formation. Nature Med. 16, 116–122 (2010).
Kedrin, D. et al. Intravital imaging of metastatic behavior through a mammary imaging window. Nature Methods 5, 1019–1021 (2008).
Condeelis, J. & Segall, J. E. Intravital imaging of cell movement in tumours. Nature Rev. Cancer 3, 921–930 (2003).
Schena, M., Shalon, D., Davis, R. W. & Brown, P. O. Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270, 467–470 (1995).
Bentley, D. R. et al. Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456, 53–59 (2008).
Olsen, J. V. et al. Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 127, 635–648 (2006).
Irish, J. M. et al. Single cell profiling of potentiated phospho-protein networks in cancer cells. Cell 118, 217–228 (2004).
Hynes, R. O. Metastatic potential: generic predisposition of the primary tumor or rare, metastatic variants-or both? Cell 113, 821–823 (2003).
Kouros-Mehr, H. et al. GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. Cancer Cell 13, 141–152 (2008).
Liu, W. et al. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nature Med. 15, 559–565 (2009).
Campbell, P. J. et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467, 1109–1113 (2010).
Yachida, S. et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114–1117 (2010).
Jones, S. et al. Comparative lesion sequencing provides insights into tumor evolution. Proc. Natl Acad. Sci. USA 105, 4283–4288 (2008).
Cairns, J. Mutation selection and the natural history of cancer. Nature 255, 197–200 (1975).
Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).
Sorlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl Acad. Sci. USA 98, 10869–10874 (2001).
van't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).
van de Vijver, M. J. et al. A gene-expression signature as a predictor of survival in breast cancer. N. Engl. J. Med. 347, 1999–2009 (2002).
Wang, X. et al. A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature 461, 495–500 (2009).
Lim, E. et al. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nature Med. 15, 907–913 (2009).
Molyneux, G. et al. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 7, 403–417 (2010).
Ince, T. A. et al. Transformation of different human breast epithelial cell types leads to distinct tumor phenotypes. Cancer Cell 12, 160–170 (2007).
Li, F., Tiede, B., Massague, J. & Kang, Y. Beyond tumorigenesis: cancer stem cells in metastasis. Cell Res. 17, 3–14 (2007).
Johnson, R. A. et al. Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature 466, 632–636 (2010).
Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).
Goldstein, A. S., Huang, J., Guo, C., Garraway, I. P. & Witte, O. N. Identification of a cell of origin for human prostate cancer. Science 329, 568–571 (2010).
Sutherland, K. D. et al. Cell of origin of small cell lung cancer: inactivation of Trp53 and rb1 in distinct cell types of adult mouse lung. Cancer Cell 19, 754–764 (2011).
Youssef, K. K. et al. Identification of the cell lineage at the origin of basal cell carcinoma. Nature Cell Biol. 12, 299–305 (2010).
Wang, G. Y., Wang, J., Mancianti, M. L. & Epstein, E. H. Jr. Basal cell carcinomas arise from hair follicle stem cells in Ptch1+/− mice. Cancer Cell 19, 114–124 (2011).
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).
Hunter, K., Welch, D. R. & Liu, E. T. Genetic background is an important determinant of metastatic potential. Nature Genet. 34, 23–24 (2003).
Hunter, K. W. et al. Predisposition to efficient mammary tumor metastatic progression is linked to the breast cancer metastasis suppressor gene Brms1. Cancer Res. 61, 8866–8872 (2001).
Park, Y. G. et al. Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1. Nature Genet. 37, 1055–1062 (2005).
Clark, E. A., Golub, T. R., Lander, E. S. & Hynes, R. O. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406, 532–535 (2000).
Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004).
Gumireddy, K. et al. In vivo selection for metastasis promoting genes in the mouse. Proc. Natl Acad. Sci. USA 104, 6696–6701 (2007).
Cook, L. M., Hurst, D. R. & Welch, D. R. Metastasis suppressors and the tumor microenvironment. Semin. Cancer Biol. 21, 113–122 (2011).
Smith, S. C. & Theodorescu, D. Learning therapeutic lessons from metastasis suppressor proteins. Nature Rev. Cancer 9, 253–264 (2009).
Steeg, P. S. et al. Evidence for a novel gene associated with low tumor metastatic potential. J. Natl Cancer Inst. 80, 200–204 (1988).
Hu, G. et al. MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer. Cancer Cell 15, 9–20 (2009).
Kim, M. et al. Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene. Cell 125, 1269–1281 (2006).
Ji, H. et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807–810 (2007).
Carretero, J. et al. Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors. Cancer Cell 17, 547–559 (2010).
Meyerson, M., Gabriel, S. & Getz, G. Advances in understanding cancer genomes through second-generation sequencing. Nature Rev. Genet. 11, 685–696 (2010).
Alkan, C., Coe, B. P. & Eichler, E. E. Genome structural variation discovery and genotyping. Nature Rev. Genet. 12, 363–376 (2011).
Kaminker, J. S., Zhang, Y., Watanabe, C. & Zhang, Z. CanPredict: a computational tool for predicting cancer-associated missense mutations. Nucleic Acids Res. 35, W595–W598 (2007).
Ng, P. C. & Henikoff, S. Predicting deleterious amino acid substitutions. Genome Res. 11, 863–874 (2001).
Adzhubei, I. A. et al. A method and server for predicting damaging missense mutations. Nature Methods 7, 248–249 (2010).
Leth-Larsen, R. et al. Metastasis-related plasma membrane proteins of human breast cancer cells identified by comparative quantitative mass spectrometry. Mol. Cell. Proteomics 8, 1436–1449 (2009).
Yao, H. et al. Identification of metastasis associated proteins in human lung squamous carcinoma using two-dimensional difference gel electrophoresis and laser capture microdissection. Lung Cancer 65, 41–48 (2009).
Li, D. J. et al. Identification of 14-3-3 sigma as a lymph node metastasis-related protein in human lung squamous carcinoma. Cancer Lett. 279, 65–73 (2009).
Xue, H. et al. Identification of serum biomarkers for colorectal cancer metastasis using a differential secretome approach. J. Proteome Res. 9, 545–555 (2010).
Luque-Garcia, J. L. et al. Differential protein expression on the cell surface of colorectal cancer cells associated to tumor metastasis. Proteomics 10, 940–952 (2010).
Sreekumar, A. et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 457, 910–914 (2009).
Kulasingam, V. & Diamandis, E. P. Strategies for discovering novel cancer biomarkers through utilization of emerging technologies. Nature Clin. Pract. Oncol. 5, 588–599 (2008).
Petricoin, E. F., Zoon, K. C., Kohn, E. C., Barrett, J. C. & Liotta, L. A. Clinical proteomics: translating benchside promise into bedside reality. Nature Rev. Drug Discovery 1, 683–695 (2002).
Bandyopadhyay, S. et al. A human MAP kinase interactome. Nature Methods 7, 801–805 (2010).
Chan, C. T., Paulmurugan, R., Reeves, R. E., Solow-Cordero, D. & Gambhir, S. S. Molecular imaging of phosphorylation events for drug development. Mol. Imaging Biol. 11, 144–158 (2009).
Lamb, J. et al. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313, 1929–1935 (2006).
Pichiorri, F. et al. Downregulation of p53-inducible microRNAs 192,194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development. Cancer Cell 18, 367–381 (2010).
Bueno, M. J. et al. Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression. Cancer Cell 13, 496–506 (2008).
Fazi, F. et al. Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein. Cancer Cell 12, 457–466 (2007).
Varambally, S. et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 322, 1695–1699 (2008).
Iliopoulos, D., Hirsch, H. A. & Struhl, K. An epigenetic switch involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 139, 693–706 (2009).
Ma, L., Teruya-Feldstein, J. & Weinberg, R. A. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449, 682–688 (2007).
Tavazoie, S. F. et al. Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451, 147–152 (2008).
Nicoloso, M. S., Spizzo, R., Shimizu, M., Rossi, S. & Calin, G. A. MicroRNAs-the micro steering wheel of tumour metastases. Nature Rev. Cancer 9, 293–302 (2009).
Korpal, M. et al. Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nature Med. 17, 1101–1108 (2011).
Baek, D. et al. The impact of microRNAs on protein output. Nature 455, 64–71 (2008).
Lim, L. P. et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433, 769–773 (2005).
Gupta, R. A. et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071–1076 (2010).
Brower, V. Epigenetics: unravelling the cancer code. Nature 471, S12–S13 (2011).
Esteller, M. Epigenetics in cancer. N. Engl. J. Med. 358, 1148–1159 (2008).
Jones, P. A. & Baylin, S. B. The epigenomics of cancer. Cell 128, 683–692 (2007).
Niwa, T. & Ushijima, T. Induction of epigenetic alterations by chronic inflammation and its significance on carcinogenesis. Adv. Genet. 71, 41–56 (2010).
Ju, H. X. et al. Distinct profiles of epigenetic evolution between colorectal cancers with and without metastasis. Am. J. Pathol. 178, 1835–1846 (2011).
Raghavan, K., Ruskin, H. J., Perrin, D., Goasmat, F. & Burns, J. Computational micromodel for epigenetic mechanisms. PLoS ONE 5, e14031 (2010).
Psaila, B. & Lyden, D. The metastatic niche: adapting the foreign soil. Nature Rev. Cancer 9, 285–293 (2009).
Bissell, M. J. & Radisky, D. Putting tumours in context. Nature Rev. Cancer 1, 46–54 (2001).
Bierie, B. & Moses, H. L. Tumour microenvironment: TGFβ: the molecular Jekyll and Hyde of cancer. Nature Rev. Cancer 6, 506–520 (2006).
Wiseman, B. S. & Werb, Z. Stromal effects on mammary gland development and breast cancer. Science 296, 1046–1049 (2002).
Shekhar, M. P., Pauley, R. & Heppner, G. Host microenvironment in breast cancer development: extracellular matrix-stromal cell contribution to neoplastic phenotype of epithelial cells in the breast. Breast Cancer Res. 5, 130–135 (2003).
Tlsty, T. D. & Hein, P. W. Know thy neighbor: stromal cells can contribute oncogenic signals. Curr. Opin. Genet. Dev. 11, 54–59 (2001).
Quante, M. et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 19, 257–272 (2011).
Tlsty, T. D. & Coussens, L. M. Tumor stroma and regulation of cancer development. Annu. Rev. Pathol. 1, 119–150 (2006).
Sessa, C., Guibal, A., Del Conte, G. & Ruegg, C. Biomarkers of angiogenesis for the development of antiangiogenic therapies in oncology: tools or decorations? Nature Clin. Pract. Oncol. 5, 378–391 (2008).
Reinacher-Schick, A., Pohl, M. & Schmiegel, W. Drug insight: antiangiogenic therapies for gastrointestinal cancers-focus on monoclonal antibodies. Nature Clin. Pract. Gastroenterol. Hepatol. 5, 250–267 (2008).
Banerjee, S., Dowsett, M., Ashworth, A. & Martin, L. A. Mechanisms of disease: angiogenesis and the management of breast cancer. Nature Clin. Pract. Oncol. 4, 536–550 (2007).
Miller, K. et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N. Engl. J. Med. 357, 2666–2676 (2007).
Ebos, J. M. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15, 232–239 (2009).
Paez-Ribes, M. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15, 220–231 (2009).
Robert, N. J. et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J. Clin. Oncol. 29, 1252–1260 (2011).
Miles, D. W. et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J. Clin. Oncol. 28, 3239–3247 (2010).
Miles, D. et al. Disease course patterns after discontinuation of bevacizumab: pooled analysis of randomized phase III trials. J. Clin. Oncol. 29, 83–88 (2011).
Gonzalez-Angulo, A. M., Hortobagyi, G. N. & Ellis, L. M. Targeted therapies: peaking beneath the surface of recent bevacizumab trials. Nature Rev. Clin. Oncol. 8, 319–320 (2011).
Wyckoff, J. et al. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res. 64, 7022–7029 (2004).
Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).
Rolny, C. et al. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19, 31–44 (2011).
Chen, J. et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell 19, 541–555 (2011).
Erez, N. & Coussens, L. M. Leukocytes as paracrine regulators of metastasis and determinants of organ-specific colonization. Int. J. Cancer 128, 2536–2544 (2011).
DeNardo, D. G. et al. CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16, 91–102 (2009).
Schmid, M. C. et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3Kγ, a single convergent point promoting tumor inflammation and progression. Cancer Cell 19, 715–727 (2011).
Calbo, J. et al. A functional role for tumor cell heterogeneity in a mouse model of small cell lung cancer. Cancer Cell 19, 244–256 (2011).
Gay, L. J. & Felding-Habermann, B. Contribution of platelets to tumour metastasis. Nature Rev. Cancer 11, 123–134 (2011).
Allard, W. J. et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin. Cancer Res. 10, 6897–6904 (2004).
Nagrath, S. et al. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450, 1235–1239 (2007).
Slade, M. J. & Coombes, R. C. The clinical significance of disseminated tumor cells in breast cancer. Nature Clin. Pract. Oncol. 4, 30–41 (2007).
Braun, S. et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N. Engl. J. Med. 353, 793–802 (2005).
Singletary, S. E., Greene, F. L. & Sobin, L. H. Classification of isolated tumor cells: clarification of the 6th edition of the American Joint Committee on Cancer Staging Manual. Cancer 98, 2740–2741 (2003).
Harris, L. et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J. Clin. Oncol. 25, 5287–5312 (2007).
Maheswaran, S. et al. Detection of mutations in EGFR in circulating lung-cancer cells. N. Engl. J. Med. 359, 366–377 (2008).
Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).
Comen, E., Norton, L. & Massague, J. Clinical implications of cancer self-seeding. Nature Rev. Clin. Oncol. 8, 369–377 (2011).
Kim, M. Y. et al. Tumor self-seeding by circulating cancer cells. Cell 139, 1315–1326 (2009).
Hiratsuka, S., Watanabe, A., Aburatani, H. & Maru, Y. Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nature Cell Biol. 8, 1369–1375 (2006).
Hiratsuka, S. et al. The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nature Cell Biol. 10, 1349–1355 (2008).
Ara, T. & Declerck, Y. A. Interleukin-6 in bone metastasis and cancer progression. Eur. J. Cancer 46, 1223–1231 (2010).
Seike, T. et al. Interaction between lung cancer cells and astrocytes via specific inflammatory cytokines in the microenvironment of brain metastasis. Clin. Exp. Metastasis 28, 13–25 (2011).
Sethi, N., Dai, X., Winter, C. G. & Kang, Y. Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell 19, 192–205 (2011).
Ara, T. et al. Interleukin-6 in the bone marrow microenvironment promotes the growth and survival of neuroblastoma cells. Cancer Res. 69, 329–337 (2009).
Cabodi, S. & Taverna, D. Interfering with inflammation: a new strategy to block breast cancer self-renewal and progression? Breast Cancer Res. 12, 305 (2010).
Sethi, N. & Kang, Y. Dysregulation of developmental pathways in bone metastasis. Bone 48, 16–22 (2011).
Guise, T. A. Molecular mechanisms of osteolytic bone metastases. Cancer 88, 2892–2898 (2000).
Yin, J. J. et al. TGF-β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J. Clin. Invest. 103, 197–206 (1999).
Buijs, J. T. et al. Bone morphogenetic protein 7 in the development and treatment of bone metastases from breast cancer. Cancer Res. 67, 8742–8751 (2007).
Buijs, J. T. et al. TGF-β and BMP7 interactions in tumour progression and bone metastasis. Clin. Exp. Metastasis 24, 609–617 (2007).
Buijs, J. T. et al. BMP7, a putative regulator of epithelial homeostasis in the human prostate, is a potent inhibitor of prostate cancer bone metastasis in vivo. Am. J. Pathol. 171, 1047–1057 (2007).
Dai, J. et al. Bone morphogenetic protein-6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism. Cancer Res. 65, 8274–8285 (2005).
Feeley, B. T. et al. Overexpression of noggin inhibits BMP-mediated growth of osteolytic prostate cancer lesions. Bone 38, 154–166 (2006).
Katsuno, Y. et al. Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway. Oncogene 27, 6322–6333 (2008).
Bu, G. et al. Breast cancer-derived Dickkopf1 inhibits osteoblast differentiation and osteoprotegerin expression: implication for breast cancer osteolytic bone metastases. Int. J. Cancer 123, 1034–1042 (2008).
Chen, G. et al. Up-regulation of Wnt-1 and β-catenin production in patients with advanced metastatic prostate carcinoma: potential pathogenetic and prognostic implications. Cancer 101, 1345–1356 (2004).
Dai, J. et al. Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent and independent mechanisms. Cancer Res. 68, 5785–5794 (2008).
Hall, C. L., Bafico, A., Dai, J., Aaronson, S. A. & Keller, E. T. Prostate cancer cells promote osteoblastic bone metastases through Wnts. Cancer Res. 65, 7554–7560 (2005).
Oshima, T. et al. Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2. Blood 106, 3160–3165 (2005).
Tian, E. et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N. Engl. J. Med. 349, 2483–2494 (2003).
Pratap, J. et al. Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells. Cancer Res. 68, 7795–7802 (2008).
Sterling, J. A. et al. The hedgehog signaling molecule Gli2 induces parathyroid hormone-related peptide expression and osteolysis in metastatic human breast cancer cells. Cancer Res. 66, 7548–7553 (2006).
Zunich, S. M. et al. Paracrine sonic hedgehog signalling by prostate cancer cells induces osteoblast differentiation. Mol. Cancer 8, 12 (2009).
Nguyen, D. X. et al. WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell 138, 51–62 (2009).
Oskarsson, T. et al. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nature Med. 17, 867–874 (2011).
Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).
Huntington, J. T. et al. Overexpression of collagenase 1 (MMP-1) is mediated by the ERK pathway in invasive melanoma cells: role of BRAF mutation and fibroblast growth factor signaling. J. Biol. Chem. 279, 33168–33176 (2004).
Klein, R. M. & Aplin, A. E. Rnd3 regulation of the actin cytoskeleton promotes melanoma migration and invasive outgrowth in three dimensions. Cancer Res. 69, 2224–2233 (2009).
Old, W. M. et al. Functional proteomics identifies targets of phosphorylation by B-Raf signaling in melanoma. Mol. Cell 34, 115–131 (2009).
Arozarena, I. et al. Oncogenic BRAF induces melanoma cell invasion by downregulating the cGMP-specific phosphodiesterase PDE5A. Cancer Cell 19, 45–57 (2011).
Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010).
Bollag, G. et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467, 596–599 (2010).
Turke, A. B. et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17, 77–88 (2010).
Guix, M. et al. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J. Clin. Invest. 118, 2609–2619 (2008).
Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007).
Poulikakos, P. I. & Rosen, N. Mutant BRAF melanomas-dependence and resistance. Cancer Cell 19, 11–15 (2011).
Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M. & Rosen, N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464, 427–430 (2010).
Hatzivassiliou, G. et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464, 431–435 (2010).
Heidorn, S. J. et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140, 209–221 (2010).
Martin, R. W., Connell, P. P. & Bishop, D. K. The Yin and Yang of treating BRCA-deficient tumors. Cell 132, 919–920 (2008).
Edwards, S. L. et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451, 1111–1115 (2008).
Shah, N. P. et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2, 117–125 (2002).
Shah, N. P. et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305, 399–401 (2004).
Burgess, M. R., Skaggs, B. J., Shah, N. P., Lee, F. Y. & Sawyers, C. L. Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance. Proc. Natl Acad. Sci. USA 102, 3395–3400 (2005).
Nazarian, R. et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468, 973–977 (2010).
Johannessen, C. M. et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468, 968–972 (2010).
Karlou, M., Tzelepi, V. & Efstathiou, E. Therapeutic targeting of the prostate cancer microenvironment. Nature Rev. Urol. 7, 494–509 (2010).
Emmenegger, U. & Kerbel, R. S. Cancer: chemotherapy counteracted. Nature 468, 637–638 (2010).
Williams, R. T., den Besten, W. & Sherr, C. J. Cytokine-dependent imatinib resistance in mouse BCR-ABL+, Arf-null lymphoblastic leukemia. Genes Dev. 21, 2283–2287 (2007).
Francia, G. et al. Comparative impact of trastuzumab and cyclophosphamide on HER-2-positive human breast cancer xenografts. Clin. Cancer Res. 15, 6358–6366 (2009).
Man, S. et al. Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res. 62, 2731–2735 (2002).
Fizazi, K. et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377, 813–822 (2011).
Stopeck, A. T. et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J. Clin. Oncol. 28, 5132–5139 (2010).
Lymperi, S., Ferraro, F. & Scadden, D. T. The HSC niche concept has turned 31. Has our knowledge matured? Ann. N. Y Acad. Sci. 1192, 12–18 (2010).
Premsrirut, P. K. et al. A rapid and scalable system for studying gene function in mice using conditional RNA interference. Cell 145, 145–158 (2011).
Ellwood-Yen, K. et al. Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell 4, 223–238 (2003).
Sweet-Cordero, A. et al. An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis. Nature Genet. 37, 48–55 (2005).
Graeber, T. G. & Sawyers, C. L. Cross-species comparisons of cancer signaling. Nature Genet. 37, 7–8 (2005).
Francia, G., Cruz-Munoz, W., Man, S., Xu, P. & Kerbel, R. S. Mouse models of advanced spontaneous metastasis for experimental therapeutics. Nature Rev. Cancer 11, 135–141 (2011).
Vogelstein, B. et al. Genetic alterations during colorectal-tumor development. N. Engl. J. Med. 319, 525–532 (1988).
Foulds, L. The experimental study of tumor progression: a review. Cancer Res. 14, 327–339 (1954).
Fidler, I. J. & Lieber, S. Quantitative analysis of the mechanism of glucocorticoid enhancement of experimental metastasis. Res. Commun. Chem. Pathol. Pharmacol. 4, 607–613 (1972).
Koscielny, S. et al. Breast cancer: relationship between the size of the primary tumour and the probability of metastatic dissemination. Br. J. Cancer 49, 709–715 (1984).
Kinouchi, T. et al. Impact of tumor size on the clinical outcomes of patients with Robson State I renal cell carcinoma. Cancer 85, 689–695 (1999).
Collins, V. P., Loeffler, R. K. & Tivey, H. Observations on growth rates of human tumors. Am. J. Roentgenol. Radium Ther. Nucl. Med. 76, 988–1000 (1956).
Friberg, S. & Mattson, S. On the growth rates of human malignant tumors: implications for medical decision making. J. Surg. Oncol. 65, 284–297 (1997).
Husemann, Y. et al. Systemic spread is an early step in breast cancer. Cancer Cell 13, 58–68 (2008).
Ellis, M. J. et al. Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. JAMA 302, 774–780 (2009).
Ben-Haim, S. & Ell, P. 18F-FDG PET and PET/CT in the evaluation of cancer treatment response. J. Nucl. Med. 50, 88–99 (2009).
Iagaru, A. et al. Novel strategy for a cocktail 18F-fluoride and 18F-FDG PET/CT scan for evaluation of malignancy: results of the pilot-phase study. J. Nucl. Med. 50, 501–505 (2009).
McCann, T. E. et al. Molecular imaging of tumor invasion and metastases: the role of MRI. NMR Biomed. 12 Dec 2010 (doi:10.1002/nbm.1590).
Ren, G. et al. Melanin-targeted preclinical PET imaging of melanoma metastasis. J. Nucl. Med. 50, 1692–1699 (2009).
Chishima, T. et al. Cancer invasion and micrometastasis visualized in live tissue by green fluorescent protein expression. Cancer Res. 57, 2042–2047 (1997).
Liu, H. et al. Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. Proc. Natl Acad. Sci. USA 107, 18115–18120 (2010).
Hatta, K., Tsujii, H. & Omura, T. Cell tracking using a photoconvertible fluorescent protein. Nature Protoc. 1, 960–967 (2006).
Gligorijevic, B., Kedrin, D., Segall, J. E., Condeelis, J. & van Rheenen, J. Dendra2 photoswitching through the Mammary Imaging Window. J. Vis. Exp. 5 Jun 2009 (doi:10.3791/1278).
Ewald, A. J., Werb, Z. & Egeblad, M. Dynamic, long-term in vivo imaging of tumor-stroma interactions in mouse models of breast cancer using spinning-disk confocal microscopy. Cold Spring Harb. Protoc. 2011, pdb.top97 (2011).
Massoud, T. F., Paulmurugan, R. & Gambhir, S. S. A molecularly engineered split reporter for imaging protein-protein interactions with positron emission tomography. Nature Med. 16, 921–926 (2010).
Korpal, M. et al. Imaging transforming growth factor-β signaling dynamics and therapeutic response in breast cancer bone metastasis. Nature Med. 15, 960–966 (2009).
Wistuba, II, Gelovani, J. G., Jacoby, J. J., Davis, S. E. & Herbst, R. S. Methodological and practical challenges for personalized cancer therapies. Nature Rev. Clin. Oncol. 8, 135–141 (2011).
Lu, X. et al. ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling cascade for bone metastasis. Genes Dev. 23, 1882–1894 (2009).
Zhang, X. H. et al. Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 16, 67–78 (2009).
Park, B. K. et al. NF-κB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF. Nature Med. 13, 62–69 (2007).
Gupta, G. P. et al. Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446, 765–770 (2007).
Padua, D. et al. TGFβ primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133, 66–77 (2008).
Brown, D. M. & Ruoslahti, E. Metadherin, a cell surface protein in breast tumors that mediates lung metastasis. Cancer Cell 5, 365–374 (2004).
Gupta, G. P. et al. ID genes mediate tumor reinitiation during breast cancer lung metastasis. Proc. Natl Acad. Sci. USA 104, 19506–19511 (2007).
Gumireddy, K. et al. KLF17 is a negative regulator of epithelial-mesenchymal transition and metastasis in breast cancer. Nature Cell Biol. 11, 1297–1304 (2009).
Hiratsuka, S. et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2, 289–300 (2002).
Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001).
Xie, T. X. et al. Activation of stat3 in human melanoma promotes brain metastasis. Cancer Res. 66, 3188–3196 (2006).
Stein, U. et al. MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis. Nature Med. 15, 59–67 (2009).
Erler, J. T. et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15, 35–44 (2009).
Erler, J. T. et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440, 1222–1226 (2006).
Kuperwasser, C. et al. A mouse model of human breast cancer metastasis to human bone. Cancer Res. 65, 6130–6138 (2005).
Yonou, H. et al. Establishment of a novel species- and tissue-specific metastasis model of human prostate cancer in humanized non-obese diabetic/severe combined immunodeficient mice engrafted with human adult lung and bone. Cancer Res. 61, 2177–2182 (2001).
Nemeth, J. A. et al. Severe combined immunodeficient-hu model of human prostate cancer metastasis to human bone. Cancer Res. 59, 1987–1993 (1999).
Shtivelman, E. & Namikawa, R. Species-specific metastasis of human tumor cells in the severe combined immunodeficiency mouse engrafted with human tissue. Proc. Natl Acad. Sci. USA 92, 4661–4665 (1995).
Rasmussen, H. H., Mortz, E., Mann, M., Roepstorff, P. & Celis, J. E. Identification of transformation sensitive proteins recorded in human two-dimensional gel protein databases by mass spectrometric peptide mapping alone and in combination with microsequencing. Electrophoresis 15, 406–416 (1994).
Centonze, V. E. & White, J. G. Multiphoton excitation provides optical sections from deeper within scattering specimens than confocal imaging. Biophys. J. 75, 2015–2024 (1998).
Xu, C., Zipfel, W., Shear, J. B., Williams, R. M. & Webb, W. W. Multiphoton fluorescence excitation: new spectral windows for biological nonlinear microscopy. Proc. Natl Acad. Sci. USA 93, 10763–10768 (1996).
Kan, Z. & Liu, T. J. Video microscopy of tumor metastasis: using the green fluorescent protein (GFP) gene as a cancer-cell-labeling system. Clin. Exp. Metastasis 17, 49–55 (1999).
Scherbarth, S. & Orr, F. W. Intravital videomicroscopic evidence for regulation of metastasis by the hepatic microvasculature: effects of interleukin-1α on metastasis and the location of B16F1 melanoma cell arrest. Cancer Res. 57, 4105–4110 (1997).
Chambers, A. F. et al. Steps in tumor metastasis: new concepts from intravital videomicroscopy. Cancer Metastasis Rev. 14, 279–301 (1995).
MacDonald, T. J., Tabrizi, P., Shimada, H., Zlokovic, B. V. & Laug, W. E. Detection of brain tumor invasion and micrometastasis in vivo by expression of enhanced green fluorescent protein. Neurosurgery 43, 1437–1443 (1998).
Farina, K. L. et al. Cell motility of tumor cells visualized in living intact primary tumors using green fluorescent protein. Cancer Res. 58, 2528–2532 (1998).
Kononen, J. et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nature Med. 4, 844–847 (1998).
Monoclonal antibody approved for metastatic breast cancer. Oncology 12, 1727 (1998).
Ren, B. et al. Genome-wide location and function of DNA binding proteins. Science 290, 2306–2309 (2000).
Blat, Y. & Kleckner, N. Cohesins bind to preferential sites along yeast chromosome III, with differential regulation along arms versus the centric region. Cell 98, 249–259 (1999).
Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).
Alizadeh, A. A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000).
Virtaneva, K. et al. Expression profiling reveals fundamental biological differences in acute myeloid leukemia with isolated trisomy 8 and normal cytogenetics. Proc. Natl Acad. Sci. USA 98, 1124–1129 (2001).
Paweletz, C. P. et al. Reverse phase protein microarrays which capture disease progression show activation of pro-survival pathways at the cancer invasion front. Oncogene 20, 1981–1989 (2001).
Ramaswamy, S., Ross, K. N., Lander, E. S. & Golub, T. R. A molecular signature of metastasis in primary solid tumors. Nature Genet. 33, 49–54 (2003).
Wang, W. et al. Single cell behavior in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling. Cancer Res. 62, 6278–6288 (2002).
Margulies, M. et al. Genome sequencing in microfabricated high-density picolitre reactors. Nature 437, 376–380 (2005).
Shendure, J. et al. Accurate multiplex polony sequencing of an evolved bacterial genome. Science 309, 1728–1732 (2005).
Domon, B. & Aebersold, R. Mass spectrometry and protein analysis. Science 312, 212–217 (2006).
Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).
Nagalakshmi, U. et al. The transcriptional landscape of the yeast genome defined by RNA sequencing. Science 320, 1344–1349 (2008).
Wilhelm, B. T. et al. Dynamic repertoire of a eukaryotic transcriptome surveyed at single-nucleotide resolution. Nature 453, 1239–1243 (2008).
Mortazavi, A., Williams, B. A., McCue, K., Schaeffer, L. & Wold, B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nature Methods 5, 621–628 (2008).
Lister, R. et al. Highly integrated single-base resolution maps of the epigenome in Arabidopsis. Cell 133, 523–536 (2008).
Cloonan, N. et al. Stem cell transcriptome profiling via massive-scale mRNA sequencing. Nature Methods 5, 613–619 (2008).
Marioni, J. C., Mason, C. E., Mane, S. M., Stephens, M. & Gilad, Y. RNA-seq: an assessment of technical reproducibility and comparison with gene expression arrays. Genome Res. 18, 1509–1517 (2008).
Lee, W. et al. The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature 465, 473–477 (2010).
Ley, T. J. et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 456, 66–72 (2008).
Mardis, E. R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009).
Shah, S. P. et al. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 461, 809–813 (2009).
Pleasance, E. D. et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463, 191–196 (2010).
Barton, M. K. Denosumab an option for patients with bone metastasis from breast cancer. CA Cancer J. Clin. 61, 135–136 (2011).
Lipton, A. & Goessl, C. Clinical development of anti-RANKL therapies for treatment and prevention of bone metastasis. Bone 48, 96–99 (2011).
Vultur, A., Villanueva, J. & Herlyn, M. BRAF inhibitor unveils its potential against advanced melanoma. Cancer Cell 18, 301–302 (2010).
Kim, T., Kim, J. & Lee, M. G. Inhibition of mutated BRAF in melanoma. N. Engl. J. Med. 363, 2261 (2010).
The authors would like to thank members of their laboratory, particularly M. A. Blanco, for helpful discussions and critical comments on this manuscript. They apologize to those colleagues whose work is not cited owing to space limitations. The authors' research is funded by the Brewster Foundation, Champalimaud Foundation, American Cancer Society, Komen for the Cure, New Jersey Commission on Cancer Research, the US Department of Defense and the US National Institutes of Health (R01CA134519 and R01CA141062).
The authors declare no competing financial interests.
About this article
Cite this article
Sethi, N., Kang, Y. Unravelling the complexity of metastasis — molecular understanding and targeted therapies. Nat Rev Cancer 11, 735–748 (2011). https://doi.org/10.1038/nrc3125
This article is cited by
Context dependent isoform specific PI3K inhibition confers drug resistance in hepatocellular carcinoma cells
BMC Cancer (2022)
Molecular Cancer (2021)
Signal Transduction and Targeted Therapy (2021)
Nuclear pore protein NUP210 depletion suppresses metastasis through heterochromatin-mediated disruption of tumor cell mechanical response
Nature Communications (2021)