The Hallmarks Of Cancer

Cell, Vol. 100, 57–70, January 7, 2000, Copyright ©2000 by Cell Press

The Hallmarks of Cancer

Douglas Hanahan* and Robert A. Weinberg†
* Department of Biochemistry and Biophysics and
Hormone Research Institute
University of California at San Francisco
San Francisco, California 94143
† Whitehead Institute for Biomedical Research and
Department of Biology
Massachusetts Institute ofTechnology
Cambridge, Massachusetts 02142

After a quarter century of rapid advances, cancer research has generated a rich and complex body of knowledge, revealing cancer to be a disease involving dynamic changes in the genome. The foundation has been
set in the discovery of mutations that produce oncogenes with dominant gain of function and tumor suppressor genes with recessive loss of function;both
classes of cancer genes have been identified through
their alteration in human and animal cancer cells and
by their elicitation of cancer phenotypes in experimental
models (Bishop and Weinberg, 1996).
Some would argue that the search for the origin and
treatment of this disease will continue over the next
quarter century in much the same manner as it has in
the recent past, by addingfurther layers of complexity
to a scientific literature that is already complex almost
beyond measure. But we anticipate otherwise: those
researching the cancer problem will be practicing a dramatically different type of science than we have experienced over the past 25 years. Surely much of this change
will be apparent at the technical level. But ultimately,
the more fundamental change willbe conceptual.
We foresee cancer research developing into a logical
science, where the complexities of the disease, described in the laboratory and clinic, will become understandable in terms of a small number of underlying principles. Some of these principles are even now in the
midst of being codified. We discuss one set of them in
the present essay: rules that govern the transformation
ofnormal human cells into malignant cancers. We suggest that research over the past decades has revealed
a small number of molecular, biochemical, and cellular
traits—acquired capabilities—shared by most and perhaps all types of human cancer. Our faith in such simplification derives directly from the teachings of cell biology
that virtually all mammalian cells carry a similar molecular machineryregulating their proliferation, differentiation, and death.
Several lines of evidence indicate that tumorigenesis
in humans is a multistep process and that these steps
reflect genetic alterations that drive the progressive
transformation of normal human cells into highly malignant derivatives. Many types of cancers are diagnosed
in the human population with an age-dependent incidenceimplicating four to seven rate-limiting, stochastic
events (Renan, 1993). Pathological analyses of a number
of organ sites reveal lesions that appear to represent
the intermediate steps in a process through which cells

Review

evolve progressively from normalcy via a series of premalignant states into invasive cancers (Foulds, 1954).
These observations have been rendered more concrete by a largebody of work indicating that the genomes of tumor cells are invariably altered at multiple
sites, having suffered disruption through lesions as subtle as point mutations and as obvious as changes in
chromosome complement (e.g., Kinzler and Vogelstein,
1996). Transformation of cultured cells is itself a
multistep process: rodent cells require at least two introduced genetic changes before theyacquire tumorigenic
competence, while their human counterparts are more
difficult to transform (Hahn et al., 1999). Transgenic
models of tumorigenesis have repeatedly supported the
conclusion that tumorigenesis in mice involves multiple
rate-limiting steps (Bergers et al., 1998; see Oncogene,
1999, R. DePinho and T. E. Jacks, volume 18[38], pp.
5248–5362). Taken together, observations of...