n e w e ng l a n d j o u r na l
m e dic i n e
Molecular Origins of Cancer
Molecular Basis of Metastasis
Anne C. Chiang, M.D., Ph.D., and Joan Massagué, Ph.D.
From the Department of Medicine (A.C.C.), the Cancer Biology and Genetics Program (J.M.), and the Howard Hughes Medical Institute (J.M.), Memorial Sloan-Kettering Cancer Center, New York. Addressreprint requests to Dr. Massagué at Box 116, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065, or at firstname.lastname@example.org. N Engl J Med 2008;359:2814-23.
Copyright © 2008 Massachusetts Medical Society.
etastasis is the end product of an evolutionary process in which diverse interactions between cancer cells and their microenvironment yield alterations that allow these cellsto transcend their programmed behavior. Tumor cells thus populate and flourish in new tissue habitats and, ultimately, cause organ dysfunction and death. Understanding the many molecular players and processes involved in metastasis could lead to effective, targeted approaches to prevent and treat cancer metastasis. The tumor–node–metastasis (TNM) staging system used for most solid tumors considersthe tumor size and degree of local invasion (T), the number, size, and location of lymph nodes (N), and the presence or absence of distant metastases (M).1 Metastases of tumors originating in different sites, such as the breast or lung, are treated differently because they are thought to behave like the tissue of origin, with characteristic patterns and kinetics of spread, and distinct profilesof chemosensitivity. Lymph nodes are of paramount importance in current staging practices, but it is hard to interpret the clinical significance of the distance of metastases from the primary site (e.g., a supraclavicular N3 vs. a mediastinal N2 lymph node in lung cancer). Indeed, the distance from the primary tumor to the organ of metastasis does not affect staging. For this reason, the real valueof staging is to serve as an indicator of the primary cancer’s composite capability to metastasize, rather than to ensure that the tumor lies within the prescribed limits of a local intervention. Recent advances bring hope for characterizing the metastatic behavior of cancer cells beyond the simplistic TNM stage. In the future, staging could include identification of subpopulations of tumor cellsthat have different metastatic behavior. A deeper understanding of the molecular and genetic concepts and processes involved in metastasis may pave the way toward new prognostic models and ways of planning treatment.
B a sic C oncep t s of Me ta s ta sis
Origins of Cellular Heterogeneity
Primary tumors consist of heterogeneous populations of cells with genetic alterations that allowthem to surmount physical boundaries, disseminate, and colonize a distant organ. Metastasis is a succession of these individual processes2-4 (Fig. 1), and fully metastatic cells are rare clones in the primary tumor. In animal models, 0.01% or fewer of the cancer cells entering the circulation develop into metastases.5,6 The intrinsic genomic instability of cancer cells increases the frequency ofalterations necessary to acquire metastatic capacity. The genomic instability and heterogeneity of tumor cells are apparent in the chromosomal gains, losses, and rearrangements associated with cancer. DNA integrity can be compromised by aberrant cell-cycle progression, telomeric crisis (i.e., telomere dysfunction characterized by cytogenetic abnormalities and chromosomal instability), inactivationof DNA repair
n engl j med 359;26
december 25, 2008
The New England Journal of Medicine as published by New England Journal of Medicine. Downloaded from www.nejm.org on August 2, 2010. For personal use only. No other uses without permission. Copyright © 2008 Massachusetts Medical Society. All rights reserved.
Molecular Origins of Cancer