Origins of Metastatic Traits
2013; Cell Press; Volume: 24; Issue: 4 Linguagem: Inglês
10.1016/j.ccr.2013.09.007
ISSN1878-3686
AutoresSakari Vanharanta, Joan Massagué,
Tópico(s)Epigenetics and DNA Methylation
ResumoHow cancer cells acquire the competence to colonize distant organs remains a central question in cancer biology. Tumors can release large numbers of cancer cells into the circulation, but only a small proportion of these cells survive on infiltrating distant organs and even fewer form clinically meaningful metastases. During the past decade, many predictive gene signatures and specific mediators of metastasis have been identified, yet how cancer cells acquire these traits has remained obscure. Recent experimental work and high-resolution sequencing of human tissues have started to reveal the molecular and tumor evolutionary principles that underlie the emergence of metastatic traits. How cancer cells acquire the competence to colonize distant organs remains a central question in cancer biology. Tumors can release large numbers of cancer cells into the circulation, but only a small proportion of these cells survive on infiltrating distant organs and even fewer form clinically meaningful metastases. During the past decade, many predictive gene signatures and specific mediators of metastasis have been identified, yet how cancer cells acquire these traits has remained obscure. Recent experimental work and high-resolution sequencing of human tissues have started to reveal the molecular and tumor evolutionary principles that underlie the emergence of metastatic traits. The molecular and tumor evolutionary basis of metastasis is a long-standing problem that particularly in the past few years has started to move toward a resolution. Important elements of the biologically complex metastatic cascade (Talmadge and Fidler, 2010Talmadge J.E. Fidler I.J. 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Taken together, these developments have revealed a set of principles that illuminate fundamental questions on the origins of metastatic traits. We resort to specific examples in order to review here the nature and implications of these advances. The classical view of tumor progression, based on the clonal evolutionary theory of cancer (Nowell, 1976Nowell P.C. The clonal evolution of tumor cell populations.Science. 1976; 194: 23-28Crossref PubMed Google Scholar), postulated that the metastatic ability is conferred by random mutations in primary tumor cells that remain rare until clonally expanded and selected at secondary organ sites (Fidler and Kripke, 1977Fidler I.J. Kripke M.L. Metastasis results from preexisting variant cells within a malignant tumor.Science. 1977; 197: 893-895Crossref PubMed Google Scholar). This Darwinian view for metastatic progression was intuitively appealing and supported by evidence from cancer cell transplantation experiments in mice (Fidler and Kripke, 1977Fidler I.J. Kripke M.L. Metastasis results from preexisting variant cells within a malignant tumor.Science. 1977; 197: 893-895Crossref PubMed Google Scholar, Kripke et al., 1978Kripke M.L. Gruys E. Fidler I.J. Metastatic heterogeneity of cells from an ultraviolet light-induced murine fibrosarcoma of recent origin.Cancer Res. 1978; 38: 2962-2967PubMed Google Scholar). Clinical observations were also consistent with the view that metastasis is a rare achievement for cells in a primary tumor, although one that follows predictable patterns suggestive of specific mutations being responsible for its development (Hess et al., 2006Hess K.R. Varadhachary G.R. Taylor S.H. Wei W. Raber M.N. Lenzi R. Abbruzzese J.L. Metastatic patterns in adenocarcinoma.Cancer. 2006; 106: 1624-1633Crossref PubMed Scopus (141) Google Scholar). Identifying these driver mutations, however, remained an elusive goal. Indications that the clonal selection model alone was not sufficient to explain the development of metastatic traits emerged with the advent of genome-wide transcriptomic techniques and their application to tumor samples. It became evident that the likelihood of metastasis in many types of cancer could be predicted from the overall gene expression profile of primary tumors (van ’t Veer et al., 2002van ’t Veer L.J. Dai H. van de Vijver M.J. He Y.D. Hart A.A. Mao M. Peterse H.L. van der Kooy K. Marton M.J. Witteveen A.T. et al.Gene expression profiling predicts clinical outcome of breast cancer.Nature. 2002; 415: 530-536Crossref PubMed Scopus (4928) Google Scholar, van de Vijver et al., 2002van de Vijver M.J. He Y.D. van’t Veer L.J. Dai H. Hart A.A. Voskuil D.W. Schreiber G.J. Peterse J.L. Roberts C. 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Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL.Nature. 2003; 425: 307-311Crossref PubMed Scopus (513) Google Scholar). This view, however, had its problems too, as cancer so clearly was an evolutionary phenomenon (Greaves and Maley, 2012Greaves M. Maley C.C. Clonal evolution in cancer.Nature. 2012; 481: 306-313Crossref PubMed Scopus (202) Google Scholar). It was hard to imagine how metastasis could not be the end result of strong selection imposed by different microenvironments. A complementary view invoked the “seed-and-soil” hypothesis that was first enunciated by Paget in the 19th century and, in today’s language, stated that cancer cells may seed metastasis so long as they reach a compatible tissue microenvironment (Fidler, 2003Fidler I.J. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited.Nat. Rev. Cancer. 2003; 3: 453-458Crossref PubMed Scopus (1397) Google Scholar). Compelling evidence has since accumulated that partially supports each of these early ideas. The formation of clinically detectable metastasis is the end result of a series of stochastic events that first allow cancer cells to disperse and survive in distant sites and later to grow as secondary tumors (Figure 1). This process comprises steps of cancer cell migration, local invasion, entry into the circulation, arrest at secondary sites, extravasation, and colonization. The use of “colonization” as a single term belies the highly complex and demanding process that awaits infiltrated cancer cells in distant organs. Colonization can be parsed into steps of cancer cell survival upon entry into the tissue, formation of micrometastasis, adoption of latency states that can last up to decades, reactivation of growth in the latent micrometastases, aggressive overtaking of the host tissue, recirculation, and formation of tertiary lesions in the same or different organs (Figure 1). Viewing these steps as orderly cell biological phenomena akin to developmental programs has been useful for mechanistic dissection of the metastatic process and has allowed the identification of a number of metastasis promoting and suppressing genes and functions (Valastyan and Weinberg, 2011Valastyan S. Weinberg R.A. Tumor metastasis: molecular insights and evolving paradigms.Cell. 2011; 147: 275-292Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar). However, cancer is not a developmental program but an evolutionary process during which only a minority of malignant cells succeed. In this process, the mediators of metastasis function as factors that slightly increase, on a per cell basis, the probability of successful completion of one or more steps of the metastatic cascade. Biologically, metastasis is a highly inefficient process. Aggressive tumors are thought to release cancer cells into the circulation by the thousands each day, as can be inferred from the numbers of circulating tumor cells (CTCs) present in the blood of cancer patients (Baccelli et al., 2013Baccelli I. Schneeweiss A. Riethdorf S. Stenzinger A. Schillert A. Vogel V. Klein C. Saini M. Bäuerle T. Wallwiener M. et al.Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay.Nat. Biotechnol. 2013; 31: 539-544Crossref PubMed Scopus (17) Google Scholar, Nagrath et al., 2007Nagrath S. Sequist L.V. Maheswaran S. Bell D.W. Irimia D. Ulkus L. Smith M.R. Kwak E.L. Digumarthy S. Muzikansky A. et al.Isolation of rare circulating tumour cells in cancer patients by microchip technology.Nature. 2007; 450: 1235-1239Crossref PubMed Scopus (998) Google Scholar, Stott et al., 2010Stott S.L. Lee R.J. Nagrath S. Yu M. Miyamoto D.T. Ulkus L. Inserra E.J. Ulman M. Springer S. 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Pathol. 1998; 153: 865-873Abstract Full Text Full Text PDF PubMed Google Scholar). Even cell populations that are experimentally enriched for metastasis-initiating cells suffer extreme attrition in the organs that they invade (Chambers et al., 2002Chambers A.F. Groom A.C. MacDonald I.C. Dissemination and growth of cancer cells in metastatic sites.Nat. Rev. Cancer. 2002; 2: 563-572Crossref PubMed Scopus (1401) Google Scholar). For example, cancer stem cells isolated from patients with metastatic melanoma are capable of forming a tumor when individually implanted in the skin of a mouse (Quintana et al., 2008Quintana E. Shackleton M. Sabel M.S. Fullen D.R. Johnson T.M. Morrison S.J. Efficient tumour formation by single human melanoma cells.Nature. 2008; 456: 593-598Crossref PubMed Scopus (782) Google Scholar), but would probably not form a metastasis if individually inoculated in the general circulation. The same is true for colorectal cancer (CRC) cells when challenged to colonize the liver parenchyma (Calon et al., 2012Calon A. Espinet E. Palomo-Ponce S. Tauriello D.V. Iglesias M. Céspedes M.V. Sevillano M. Nadal C. Jung P. Zhang X.H. et al.Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation.Cancer Cell. 2012; 22: 571-584Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). The main bottlenecks for metastasis formation therefore seem to occur during the colonization of distant organs (Figure 1). The metastatic compatibility of certain tissues as envisioned by the seed-and-soil hypothesis is only relative. To infiltrating cancer cells, the best soil is still a deadly soil, just a bit less deadly than others. The stress of passing through endothelial barriers, a lack of survival signals and a supportive stroma in the host tissue, and an overexposure of solitary cancer cells to the perils of innate immunity challenge cancer cells that infiltrate distant organs (Chambers et al., 2002Chambers A.F. Groom A.C. MacDonald I.C. Dissemination and growth of cancer cells in metastatic sites.Nat. Rev. Cancer. 2002; 2: 563-572Crossref PubMed Scopus (1401) Google Scholar, Nguyen et al., 2009aNguyen D.X. Bos P.D. Massagué J. Metastasis: from dissemination to organ-specific colonization.Nat. Rev. Cancer. 2009; 9: 274-284Crossref PubMed Scopus (553) Google Scholar, Vesely et al., 2011Vesely M.D. Kershaw M.H. Schreiber R.D. Smyth M.J. Natural innate and adaptive immunity to cancer.Annu. Rev. Immunol. 2011; 29: 235-271Crossref PubMed Scopus (239) Google Scholar). Why cancer cells so easily die at distant sites is currently unknown, but this death en masse represents a major barrier to metastatic cancer progression. Clinically, it is also the most relevant barrier, because previous steps of cancer cell emigration from primary tumors and distribution to distant organs have already occurred for months at the time of cancer diagnosis. Identifying the natural mechanisms that eliminate disseminated cancer cells might facilitate the development of new therapeutic strategies to prevent or combat metastasis. Overt metastasis may eventually arise from residual populations of disseminated cancer cells that managed to survive in host tissues. Clinically, “metastatic latency” refers to the period elapsed between the diagnosis of a primary tumor and the emergence of detectable metastatic lesions. At the cell biological level, latency also refers to various states that disseminated cancer cells may adopt during this period of indolence. These states include growth arrest (“dormancy”) of solitary or micrometastatic cancer cells and unproductive micrometastatic growth with cell proliferation counterbalanced by cell death or loss of stem cell fitness (“stemness”). These various states could coexist in the population of disseminated cancer cells residing in a patient. The biology of metastatic latency and reactivation is largely unknown, at least partially due to the lack of suitable experimental systems that would model this aspect of metastasis. However, recent work in mouse models of breast cancer provides insights into the kind of differentiation signals and stromal interactions that may be involved (Gao et al., 2012Gao H. Chakraborty G. Lee-Lim A.P. Mo Q. Decker M. Vonica A. Shen R. Brogi E. Brivanlou A.H. Giancotti F.G. The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites.Cell. 2012; 150: 764-779Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, Lu et al., 2011Lu X. Mu E. 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Assessing the true temporal patterns of primary tumor, latent metastasis, and overt metastasis only based on clinical observation is challenging. For example, pancreatic adenocarcinoma was thought to metastasize early because in many cases metastasis is already present at the time of disease diagnosis. However, mathematical modeling of exome sequencing data from matched primary and metastatic lesions suggests that this may be due to late diagnosis, not early metastasis, and the development of metastatic pancreatic cancer may in fact take decades (Yachida et al., 2010Yachida S. Jones S. Bozic I. Antal T. Leary R. Fu B. Kamiyama M. Hruban R.H. Eshleman J.R. Nowak M.A. et al.Distant metastasis occurs late during the genetic evolution of pancreatic cancer.Nature. 2010; 467: 1114-1117Crossref PubMed Scopus (450) Google Scholar). Nevertheless, the fact that some tumor types, such as estrogen-positive breast cancer (Lim et al., 2012Lim E. Metzger-Filho O. Winer E.P. The natural history of hormone receptor-positive breast cancer.Oncology (Huntingt.). 2012; 26 (696): 688-694PubMed Google Scholar) and prostate cancer (Popiolek et al., 2013Popiolek M. Rider J.R. Andrén O. Andersson S.O. Holmberg L. Adami H.O. Johansson J.E. Natural history of early, localized prostate cancer: a final report from three decades of follow-up.Eur. Urol. 2013; 63: 428-435Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar), are associated with long latency periods between primary tumor resection and the development of metastasis indicates that cancer cells in these tumors are disseminated long before they acquire the capabilities of metastatic colonization. Solid tumors display dramatic variation in the pattern of metastasis. Some mainly relapse in one particular organ (e.g., prostate cancers in bone, ocular melanomas in liver, sarcomas in lungs) whereas others relapse in multiple organs (e.g., triple-negative breast cancers, skin melanomas, lung cancers, renal carcinomas). Blood circulation patterns can direct cancer cells to a particular organ, as in the case of the mesenteric circulation directing CRC cells to the liver. However, most solid tumors release cells into the general circulation reaching many organs. The fenestrated endothelium of bone marrow and liver capillaries is more permissive than are the contiguous capillary walls in other organs, particularly in the brain. The capacity of circulating cancer cells to pass through endothelial walls may, therefore, influence the organ tropism of tumors. 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