The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

and malignant states into invasive cancers (Foulds, 1954). These observations have been rendered more con-Hormone Research Institute University of California at San Francisco crete by a large body of work indicating that the genomes of tumor cells are invariably altered at multiple San Francisco, California 94143 † Whitehead Institute for Biomedical Research and sites, having suffered disruption through lesions as subtle as point mutations and as obvious as changes in Department of Biology Massachusetts Institute of Technology chromosome complement (e.g., Kinzler and Vogelstein, 1996). Transformation of cultured cells is itself a Cambridge, Massachusetts 02142 multistep process: rodent cells require at least two introduced genetic changes before they acquire tumorigenic competence, while their human counterparts are more After a quarter century of rapid advances, cancer redifficult to transform (Hahn et al., 1999). Transgenic search has generated a rich and complex body of knowlmodels of tumorigenesis have repeatedly supported the edge, revealing cancer to be a disease involving dyconclusion that tumorigenesis in mice involves multiple namic changes in the genome. The foundation has been rate-limiting steps (Bergers et al., 1998; see Oncogene, set in the discovery of mutations that produce onco-1999, R. DePinho and T. E. Jacks, volume 18[38], pp. genes with dominant gain of function and tumor sup-5248-5362). Taken together, observations of human pressor genes with recessive loss of function; both cancers and animal models argue that tumor developclasses of cancer genes have been identified through ment proceeds via a process formally analogous to Dartheir alteration in human and animal cancer cells and winian evolution, in which a succession of genetic by their elicitation of cancer phenotypes in experimental changes, each conferring one or another type of growth models (Bishop and Weinberg, 1996). advantage, leads to the progressive conversion of nor-Some would argue that the search for the origin and mal human cells into cancer cells (Foulds, 1954; Nowell, treatment of this disease will continue over the next 1976). quarter century in much the same manner as it has in the recent past, by adding further layers of complexity to a scientific literature that is already complex almost An Enumeration of the Traits beyond measure. But we anticipate otherwise: thoseThe barriers to development of cancer are embodied researching the cancer problem will be practicing a drain a teleology: cancer cells have defects in regulatory matically different type of science than we have expericircuits that govern normal cell proliferation and homeoenced over the past 25 years. Surely much of this change stasis. There are more than 100 distinct types of cancer, will be apparent at the technical level. But ultimately, and subtypes of tumors can be found within specific the more fundamental change will be conceptual.organs. This complexity provokes a number of ques-We foresee cancer research developing into a logical tions. How many dis...

The epithelial-mesenchymal transition (EMT) is a key developmental program that is often activated during cancer invasion and metastasis. We here report that the induction of an EMT in immortalized human mammary epithelial cells (HMLEs) results in the acquisition of mesenchymal traits and in the expression of stem-cell markers. Furthermore, we show that those cells have an increased ability to form mammospheres, a property associated with mammary epithelial stem cells. Independent of this, stem cell-like cells isolated from HMLE cultures form mammospheres and express markers similar to those of HMLEs that have undergone an EMT. Moreover, stem-like cells isolated either from mouse or human mammary glands or mammary carcinomas express EMT markers. Finally, transformed human mammary epithelial cells that have undergone an EMT form mammospheres, soft agar colonies, and tumors more efficiently. These findings illustrate a direct link between the EMT and the gain of epithelial stem cell properties.