Oncogenes
Multistep Carcinogenesis
Robert A. Weinberg
Cancer Res 1989;49:3713-3721.
Updated Version
Citing Articles
E-mail alerts
Reprints and
Subscriptions
Permissions
Access the most recent version of this article at:
http://cancerres.aacrjournals.org/content/49/14/3713.citation
This article has been cited by 62 HighWire-hostedarticles. Access the articles at:
http://cancerres.aacrjournals.org/content/49/14/3713.citation#related-urls
Sign up to receive free email-alerts related to this article or journal.
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
Department at pubs@aacr.org.
To request permission to re-use all or part of this article, contact the AACRPublications
Department at permissions@aacr.org.
Downloaded from cancerres.aacrjournals.org on September 23, 2012
Copyright © 1989 American Association for Cancer Research
(CANCER RESEARCH 49, 3713-3721, July IS, 1989]
Perspectivesin CancerResearch
Oncogenes, Antioncogenes, and the Molecular Bases of Multistep Carcinogenesis1
Robert A. Weinberg2
Whitehead Institute for Biomédical esearchand Massachusetts Institute of Technology, Cambridge, Massachusetts 02142
R
Tumorigenesis in humans and laboratory animals is a com
plex, mu 11
¡step
process (1, 2). In humans, in whom the process
has been studied only indirectly, measurements of age-depen
dent tumor incidence indicate kinetics dependent on the fifth
or sixth power of elapsed time (3). This suggests a succession
offive or six independent steps, each of which is rate limiting
on the process. In experimental models, such as mouse skin
tumorigenesis, the process has been broken down into at least
three distinct steps: initiation, promotion, and progression (4,
5). From the perspective of the organism, the multistep nature
of tumorigenesis is easily rationalized; each step in the process
represents aphysiological barrier that must be breached in
order for a cell to progress further toward the end point of
malignancy. Such multiple barriers conspire to ensure that
successful completion of the tumorigenic process is a rarely
achieved event.
An unanswered question concerns the natures of these bar
riers to tumor inception and growth. A portion of the defenses
may well derive from systemicdefenses against tumors; yet
others, confronted in this essay, reflect underlying mechanisms
governing the behavior of individual cells. Our cells and likely
those of all metazoa would seem to be constructed so as to
present multiple impediments to full malignant transformation.
Only recently has it been possible to search for the molecular
and cellular mechanisms that govern multisteptumorigenesis.
What are the rules that govern cell growth? How is the growthregulatory circuitry laid out within the cell? And how can
multiple physiological controls be overridden to produce the
deregulation of neoplasia?
induce part of the phenotypes required for full transformation.
Was this a peculiarity of these viral oncogenes or were the
principles transferable as well to the behavior ofoncogenes
derived from the cell genome?
The model was indeed extended to a number of oncogenes of
cellular origin. Thus, neither a ras nor a myc oncogene was
found able to induce full transformation while the two, cointroduced into rat embryo fibroblasts, achieved this end result
(7). Analogously, a ras oncogene was found to collaborate with
the adenovirus EIA oncogene in the fulltransformation of baby
rat kidney cells (8).
These rather simple experiments had a number of conceptual
ramifications that warrant mention. Like the polyomavirus
genes, the observed ability of ras and myc oncogenes to collab
orate with one another in the transformation process showed
that each acts in a distinct, complementary way on cell phenotype. Detailed studies in rodent cells showed that rus...
Regístrate para leer el documento completo.