How Cancer Arises
ow cancer develops is nolonger a mystery. During thepast two decades, investiga-tors have made astonishing progress inidentifying the deepest bases of the pro-cess
those at the molecular level. Thesediscoveries are robust: they will survivethe scrutiny of future generations of re-searchers, and they will form the foun-dation for revolutionary approaches totreatment. No one can predict exactlywhen therapies targeted to the molecu-lar alterations in cancer cells will ﬁndwide use, given that the translation of new understanding into clinical prac-tice is complicated, slow and expensive.But the effort is now under way.In truth, the term “cancer” refers tomore than 100 forms of the disease. Al-most every tissue in the body can spawnmalignancies; some even yield severaltypes. What is more, each cancer hasunique features. Still, the basic processesthat produce these diverse tumors ap-pear to be quite similar. For that reason,I will refer in this article to “cancer” ingeneric terms, drawing on one or anoth-er type to illustrate the rules that seemto apply universally.The 30 trillion cells of the normal,healthy body live in a complex, interde-pendent condominium, regulating oneanother’s proliferation. Indeed, normalcells reproduce only when instructed todo so by other cells in their vicinity. Suchunceasing collaboration ensures thateach tissue maintains a size and archi-tecture appropriate to the body’s needs.Cancer cells, in stark contrast, violatethis scheme; they become deaf to theusual controls on proliferation and fol-low their own internal agenda for re-production. They also possess an evenmore insidious property
the ability tomigrate from the site where they began,invading nearby tissues and formingmasses at distant sites in the body. Tu-mors composed of such malignant cellsbecome more and more aggressive overtime, and they become lethal when theydisrupt the tissues and organs needed forthe survival of the organism as a whole.This much is not new. But over thepast 20 years, scientists have uncovereda set of basic principles that govern thedevelopment of cancer. We now knowthat the cells in a tumor descend from acommon ancestral cell that at onepoint
usually decades before a tumorbecomes palpable
initiated a programof inappropriate reproduction. Further,the malignant transformation of a cellcomes about through the accumulationof mutations in speciﬁc classes of thegenes within it. These genes provide thekey to understanding the processes atthe root of human cancer.Genes are carried in the DNA mole-cules of the chromosomes in the cell nu-cleus. A gene speciﬁes a sequence of amino acids that must be linked togeth-er to make a particular protein; the pro-tein then carries out the work of thegene. When a gene is switched on, thecell responds by synthesizing the encod-ed protein. Mutations in a gene can per-turb a cell by changing the amounts orthe activities of the protein product.Two gene classes, which together con-stitute only a small proportion of the fullgenetic set, play major roles in trigger-ing cancer. In their normal conﬁgura-tion, they choreograph the life cycle of the cell
the intricate sequence of eventsby which a cell enlarges and divides.Proto-oncogenes encourage such growth,whereas tumor suppressor genes inhibitit.
Collectively these two gene classes ac-
How Cancer Arises
An explosion of research is uncovering the long-hidden molecular underpinningsof cancer
and suggesting new therapies
by Robert A. Weinberg
The altered cell and its descendantscontinue to look normal, but they re-produce too much—a conditiontermed hyperplasia. After years, onein a million of these cells (
) suf-fers another mutation that furtherloosens controls on cell growth.
In addition to proliferating excessively, the off-spring of this cell appear abnormal in shape and inorientation; the tissue is now said to exhibit dys-plasia. Once again, after a time, a rare mutationthat alters cell behavior occurs (
he creation of a malignant tumor in epithelial tissue is depicted schemat-ically below. Epithelial cancers are the most common malignancies andare called carcinomas. The mass seen here emerges as a result of mutationsin four genes, but the number of genes involved in real tumors can vary.
Tumor DevelopmentOccurs in Stages
HYPERPLASIAGENETICALLY ALTERED CELLDYSPLASIA
D A N A B U R N S - P I Z E R
Tumor development begins whensome cell (
) within a normalpopulation (
) sustains a genet-ic mutation that increases itspropensity to proliferate when itwould normally rest.
Copyright 1996 Scientific American, Inc.