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...

Colorectal cancer (CRC) is a frequently lethal disease with heterogeneous outcomes and drug responses. To resolve inconsistencies among the reported gene expression–based CRC classifications and facilitate clinical translation, we formed an international consortium dedicated to large-scale data sharing and analytics across expert groups. We show marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMS) with distinguishing features: CMS1 (MSI Immune, 14%), hypermutated, microsatellite unstable, strong immune activation; CMS2 (Canonical, 37%), epithelial, chromosomally unstable, marked WNT and MYC signaling activation; CMS3 (Metabolic, 13%), epithelial, evident metabolic dysregulation; and CMS4 (Mesenchymal, 23%), prominent transforming growth factor β activation, stromal invasion, and angiogenesis. Samples with mixed features (13%) possibly represent a transition phenotype or intra-tumoral heterogeneity. We consider the CMS groups the most robust classification system currently available for CRC – with clear biological interpretability – and the basis for future clinical stratification and subtype–based targeted interventions.

Factors that affect the probability of genetic transformation of Escherichia coli by plasmids have been evaluated. A set of conditions is described under which about one in every 400 plasmid molecules produces a transformed cell. These conditions include cell growth in medium containing elevated levels of Mg 2+. and incubation of the cells at 0~ in a solution of Mn 2+, ("a 2+, Rb + or K +, dimethyl sulfoxide, dithiothreitol, and hexamine cobalt (III). Transibrmation efficiency declines linearly with increasing plasmid size. Relaxed and supercoiled plasmids transfol'm with similar probabilities. Non-transforming DNAs compete consistent with mass. No significant variation is observed between competing DNAs of difi~rent source, complexity, length or form. Competition with both transforming and nontransforming plasmids indicates that each cell is capable of taking up many DNA molecules, and that the establishment of a transformation event is neither helped nor hindered significantly by the presence of multiple plasmids.

avascular site, the cornea of a rabbit eye (Gimbrone et al., 1972). The implants attracted new capillaries that Boston, Massachusetts 02115 ‡ Depts. of Surgery and Cell Biology grew in from the limbus to vascularize the expanding tumor mass. If the capillaries were physically prevented Harvard Medical School Boston, Massachusetts 02115 from reaching the implant or were inhibited from undergoing angiogenesis, tumor growth was dramatically impaired, restricting the tumor nodule to a diameter of approximately 0.4 mm. Subsequent experiments have

Mutationally corrupted cancer (stem) cells are the driving force of tumor development and progression. Yet, these transformed cells cannot do it alone. Assemblages of ostensibly normal tissue and bone marrow-derived (stromal) cells are recruited to constitute tumorigenic microenvironments. Most of the hallmarks of cancer are enabled and sustained to varying degrees through contributions from repertoires of stromal cell types and distinctive subcell types. Their contributory functions to hallmark capabilities are increasingly well understood, as are the reciprocal communications with neoplastic cancer cells that mediate their recruitment, activation, programming, and persistence. This enhanced understanding presents interesting new targets for anticancer therapy.

A major challenge for cancer medicine involves the remarkable variability of the disease, at all levels. The hallmarks of cancer constitute an organizing principle that may provide a rational basis for distilling this complexity so as to better understand mechanisms of the disease in its diverse manifestations. The conceptualization involves eight acquired capabilities—the hallmarks of cancer—and two generic characteristics of neoplastic disease that facilitate their acquisition during the multistage process of neoplastic development and malignant progression. The integration of these hallmark capabilities in symptomatic disease involves multiple cell types populating the tumor microenvironment, including heterogeneous populations of cancer cells, in particular cancer stem cells, and three prominent classes of stromal support cells. A premise is that the hallmarks of cancer constitute a useful heuristic tool for understating the mechanistic basis and interrelationships between different forms of human cancer, with potential applications to cancer therapy.

Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signalling pathways are affording demonstrable therapeutic efficacy in mouse models of cancer and in an increasing number of human cancers. However, in both preclinical and clinical settings, the benefits are at best transitory and are followed by a restoration of tumour growth and progression. Emerging data support a proposition that two modes of unconventional resistance underlie such results: evasive resistance, an adaptation to circumvent the specific angiogenic blockade; and intrinsic or pre-existing indifference. Multiple mechanisms can be invoked in different tumour contexts to manifest both evasive and intrinsic resistance, motivating assessment of their prevalence and importance and in turn the design of pharmacological strategies that confer enduring anti-angiogenic therapies.The long-standing proposition that induction of chronic angiogenesis is a hallmark of cancer is now solidly grounded in a substantial body of research involving genetic and pharmacological perturbation of elements in the vascular regulatory circuitry. The 'angiogenic switch'1 is increasingly recognized as a rate-limiting secondary event in multistage carcinogenesis 2 , as documented in animal models of cancer and correlated in advanced pre malignant stages, as well as their malignant derivatives, in a growing list of human cancer types. That this acquired capability is functionally important for manifestation of the disease has been further validated by the approval of angiogenesis inhibitors as cancer therapeutics, most notably ones targeting the vascular endothelial growth factor (VEGF) pro-angiogenic signalling pathways 3 . The pioneers of the clinical proof-of-concept for angiogenesis inhibitors are bevacizumab (Avastin, Genentech/Roche), a ligand-trapping monoclonal antibody, and two kinase inhibitors (sorafenib (Nexavar, Bayer) and sunitinib (Sutent, Pfizer)) targeting the VEGF receptor (VEGFR) tyrosine kinases, principally VEGFR2 (also known as KDR). Since March 2008, bevacizumab has been approved for treating patients with late-stage colon cancer, non-small-cell lung cancer and breast cancer, all in combination with chemotherapy. Sorafenib and sunitinib have both been approved for treating renal carcinoma, a highly vascularized (and angiogenic) tumour type. In addition, sunitinib has been approved for treating gastrointestinal stromal tumours, and sorafenib for hepatocel-lular carcinomas3 -6. Numerous ongoing clinical trials seek to expand the applications of each of these VEGF pathway inhibitors, and dozens of other angiogenesis inhibitors (many also targeting VEGF signalling) are being clinically evaluated (see Angiogenesis Inhibitors Therapy URL and clinical trials URLs in Further information). Moreover, two VEGF pathway inhibitors (the RNA aptamer pegaptanib and a Fab derivative of bevacizumab) have been approved for treating the angiogenic (wet) form of macular degeneration 7-9.Many of the demonstrable clinical benefits and side ef...