1. Fundamental Understandings
become more and more aggressive over
How Cancer Arises time, and they become lethal when they
disrupt the tissues and organs needed for
the survival of the organism as a whole.
This much is not new. But over the
An explosion of research is uncovering past 20 years, scientists have uncovered
the long-hidden molecular underpinnings a set of basic principles that govern the
development of cancer. We now know
of cancer— and suggesting new therapies that the cells in a tumor descend from a
common ancestral cell that at one
point—usually decades before a tumor
becomes palpable—initiated a program
by Robert A. Weinberg
of inappropriate reproduction. Further,
the malignant transformation of a cell
comes about through the accumulation
of mutations in specific classes of the
H ow cancer develops is no
longer a mystery. During the
past two decades, investiga-
tors have made astonishing progress in
identifying the deepest bases of the pro-
pear to be quite similar. For that reason,
I will refer in this article to “cancer” in
generic terms, drawing on one or anoth-
er type to illustrate the rules that seem
to apply universally.
genes within it. These genes provide the
key to understanding the processes at
the root of human cancer.
Genes are carried in the DNA mole-
cules of the chromosomes in the cell nu-
cess—those at the molecular level. These The 30 trillion cells of the normal, cleus. A gene specifies a sequence of
discoveries are robust: they will survive healthy body live in a complex, interde- amino acids that must be linked togeth-
the scrutiny of future generations of re- pendent condominium, regulating one er to make a particular protein; the pro-
searchers, and they will form the foun- another’s proliferation. Indeed, normal tein then carries out the work of the
dation for revolutionary approaches to cells reproduce only when instructed to gene. When a gene is switched on, the
treatment. No one can predict exactly do so by other cells in their vicinity. Such cell responds by synthesizing the encod-
when therapies targeted to the molecu- unceasing collaboration ensures that ed protein. Mutations in a gene can per-
lar alterations in cancer cells will find each tissue maintains a size and archi- turb a cell by changing the amounts or
wide use, given that the translation of tecture appropriate to the body’s needs. the activities of the protein product.
new understanding into clinical prac- Cancer cells, in stark contrast, violate Two gene classes, which together con-
tice is complicated, slow and expensive. this scheme; they become deaf to the stitute only a small proportion of the full
But the effort is now under way. usual controls on proliferation and fol- genetic set, play major roles in trigger-
In truth, the term “cancer” refers to low their own internal agenda for re- ing cancer. In their normal configura-
more than 100 forms of the disease. Al- production. They also possess an even tion, they choreograph the life cycle of
most every tissue in the body can spawn more insidious property—the ability to the cell—the intricate sequence of events
malignancies; some even yield several migrate from the site where they began, by which a cell enlarges and divides.
types. What is more, each cancer has invading nearby tissues and forming Proto-oncogenes encourage such growth,
unique features. Still, the basic processes masses at distant sites in the body. Tu- whereas tumor suppressor genes inhibit
that produce these diverse tumors ap- mors composed of such malignant cells it. Collectively these two gene classes ac-
Tumor Development
Occurs in Stages T he creation of a malignant tumor in epithelial tissue is depicted schemat-
ically below. Epithelial cancers are the most common malignancies and
are called carcinomas. The mass seen here emerges as a result of mutations
in four genes, but the number of genes involved in real tumors can vary.
GENETICALLY ALTERED CELL
HYPERPLASIA
DYSPLASIA
2 The altered cell and its descendants
1 Tumor development begins when continue to look normal, but they re-
DANA BURNS-PIZER
some cell (orange ) within a normal produce too much—a condition 3 In addition to proliferating excessively, the off-
population (beige) sustains a genet- termed hyperplasia. After years, one spring of this cell appear abnormal in shape and in
ic mutation that increases its in a million of these cells (pink) suf- orientation; the tissue is now said to exhibit dys-
propensity to proliferate when it fers another mutation that further plasia. Once again, after a time, a rare mutation
would normally rest. loosens controls on cell growth. that alters cell behavior occurs (purple).
62 Scientific American September 1996 Copyright 1996 Scientific American, Inc. How Cancer Arises

2. count for much of the uncontrolled cell when a mutation in one of its proto-on- other cancer types secrete too much
proliferation seen in human cancers. cogenes energizes a critical growth-stim- transforming growth factor alpha. These
When mutated, proto-oncogenes can ulatory pathway, keeping it continu- factors act, as usual, on nearby cells,
become carcinogenic oncogenes that ously active when it should be silent. but, more important, they may also
drive excessive multiplication. The mu- These pathways within a cell receive turn back and drive proliferation of the
tations may cause the proto-oncogene to and process growth-stimulatory signals same cells that just produced them.
yield too much of its encoded growth- transmitted by other cells in a tissue. Researchers have also identified on-
stimulatory protein or an overly active Such cell-to-cell signaling usually begins cogenic versions of receptor genes. The
form of it. Tumor suppressor genes, in when one cell secretes growth factors. aberrant receptors specified by these on-
contrast, contribute to cancer when they After release, these proteins move cogenes release a flood of proliferative
are inactivated by mutations. The result- through the spaces between cells and signals into the cell cytoplasm even when
ing loss of functional suppressor pro- bind to specific receptors—antennalike no growth factors are present to urge
teins deprives the cell of crucial brakes molecules—on the surface of other cells the cell to replicate. For instance, breast
that prevent inappropriate growth. nearby. Receptors span the outer mem- cancer cells often display Erb-B2 recep-
For a cancerous tumor to develop, brane of the target cells, so that one end tor molecules that behave in this way.
mutations must occur in half a dozen or protrudes into the extracellular space, Still other oncogenes in human tumors
more of the founding cell’s growth-con- and the other end projects into the cell’s perturb parts of the signal cascade found
trolling genes. Altered forms of yet oth- interior, its cytoplasm. When a growth- in the cytoplasm. The best understood
er classes of genes may also participate stimulatory factor attaches to a recep- example comes from the ras family of
in the creation of a malignancy, by spe- tor, the receptor conveys a proliferative oncogenes. The proteins encoded by
cifically enabling a proliferating cell to signal to proteins in the cytoplasm. normal ras genes transmit stimulatory
become invasive or capable of spread- These downstream proteins then emit signals from growth factor receptors to
ing (metastasizing) throughout the body. stimulatory signals to a succession of other proteins farther down the line.
other proteins, in a chain that ends in The proteins encoded by mutant ras
Signaling Systems Go Awry the heart of the cell, its nucleus. Within genes, however, fire continuously, even
the nucleus, proteins known as tran- when growth factor receptors are not
V ital clues to how mutated proto-
oncogenes and tumor suppressor
genes contribute to cancer came from
scription factors respond by activating
a cohort of genes that help to usher the
cell through its growth cycle.
prompting them. Hyperactive Ras pro-
teins are found in about a quarter of all
human tumors, including carcinomas
studying the roles played within the cell Some oncogenes force cells to over- of the colon, pancreas and lung. (Carci-
by the normal counterparts of these produce growth factors. Sarcomas and nomas are by far the most common
genes. After almost two decades of re- gliomas (cancers, respectively, of con- forms of cancer; they originate in epi-
search, we now view the normal genet- nective tissues and nonneuronal brain thelial cells, which line the body cavities
ic functions with unprecedented clarity cells) release excessive amounts of plate-
and detail. let-derived growth factor. A number of
Many proto-oncogenes code for pro-
teins in molecular “bucket brigades” that
relay growth-stimulating signals from INVASIVE CANCER
outside the cell deep into its interior. The
growth of a cell becomes deregulated
IN SITU CANCER
5 If the genetic changes allow the tu-
4 The affected cells become still more mor to begin invading underlying tis-
abnormal in growth and appearance. If sue and to shed cells into the blood
the tumor has not yet broken through or lymph, the mass is considered to
any boundaries between tissues, it is have become malignant. The rene- BLOOD VESSEL
called in situ cancer. This tumor may gade cells are likely to establish new
remain contained indefinitely; however, tumors (metastases) throughout the
some cells may eventually acquire ad- body; these may become lethal by
ditional mutations (blue ). disrupting a vital organ.
How Cancer Arises Copyright 1996 Scientific American, Inc. Scientific American September 1996 63

3. Fundamental Understandings
STIMULATORY INHIBITORY
PATHWAYS Normal cell PATHWAYS
Growth factor Inhibitor
(“go” signal) (“stop” signal)
Neighboring Receptors Neighboring
cells release at cell surface cells release
growth-stimulatory growth-inhibitory
factors factors
No growth Cytoplasmic relay proteins
factor attaches Receptor
Transcription Relay
factors molecule
Nucleus is lost
Receptor DNA
fires Signaling
anyway stops
Proteins Proteins that Cell divides
Cell divides that trigger inhibit cell when it
DIMITRY SCHIDLOVSKY
in the absence cell division division should not,
of stimulation Cell cycle because
by external clock decides inhibitory
growth factors whether cell signal fails
should to reach nucleus
proliferate
EXAMPLE OF EXAMPLE OF
STIMULATORY INHIBITORY
ABNORMALITY ABNORMALITY
SIGNALING PATHWAYS in normal cells convey growth-con- convey “stop” signals. A stimulatory pathway will become hy-
trolling messages from the outer surface deep into the nucleus. peractive if a mutation causes any component, such as a growth
There a molecular apparatus known as the cell cycle clock col- factor receptor (box at left), to issue stimulatory messages au-
lects the messages and decides whether the cell should divide. tonomously, without waiting for commands from upstream.
Cancer cells often proliferate excessively because genetic muta- Conversely, inhibitory pathways will shut down when some
tions cause stimulatory pathways ( green) to issue too many constituent, such as a cytoplasmic relay (box at right), is elimi-
“go” signals or because inhibitory pathways (red) can no longer nated and thus breaks the signaling chain.
and form the outer layer of the skin.) peutics. In an exciting turn of events, as to the nucleus much as stimulatory sig-
Yet other oncogenes, such as those in many as half a dozen pharmaceutical nals do—via molecular bucket brigades.
the myc family, alter the activity of tran- companies are working on drugs de- In cancer cells, these inhibitory brigades
scription factors in the nucleus. Cells signed to shut down aberrantly firing may be disrupted, thereby enabling the
normally manufacture Myc transcrip- growth factor receptors. At least three cell to ignore normally potent inhibitory
tion factors only after they have been other companies are attempting to devel- signals at the surface. Critical compo-
stimulated by growth factors impinging op compounds that block the synthesis nents of these brigades, which are speci-
on the cell surface. Once made, Myc of aberrant Ras proteins. Both groups of fied by tumor suppressor genes, are ab-
proteins activate genes that force cell agents halt excessive signaling in cultured sent or inactive in many types of cancer
growth forward. But in many types of cancer cells, but their utility in blocking cells.
cancer, especially malignancies of the the growth of tumors in animals and A secreted substance called transform-
blood-forming tissues, Myc levels are humans remains to be demonstrated. ing growth factor beta (TGF-ß) can stop
kept constantly high even in the ab- the growth of various kinds of normal
sence of growth factors. Tumor Suppressors Stop Working cells. Some colon cancer cells become
Discovery of trunk lines that carry oblivious to TGF-ß by inactivating a
proliferative messages from the cell sur-
face to its nucleus has been more than
intellectually satisfying. Because these
T o become malignant, cells must do
more than overstimulate their
growth-promoting machinery. They
gene that encodes a surface receptor for
this substance. Some pancreatic cancers
inactivate the DPC4 gene, whose pro-
pathways energize the multiplication of must also devise ways to evade or ig- tein product may operate downstream
malignant cells, they constitute attrac- nore braking signals issued by their nor- of the growth factor receptor. And a va-
tive targets for scientists intent on de- mal neighbors in the tissue. Inhibitory riety of cancers discard the p15 gene,
veloping new types of anticancer thera- messages received by a normal cell flow which codes for a protein that, in re-
64 Scientific American September 1996 Copyright 1996 Scientific American, Inc. How Cancer Arises

4. sponse to signals from TGF-ß, normally
shuts down the machinery that guides Some Genes Involved in Human Cancers
the cell through its growth cycle.
enes known as proto-oncogenes code for proteins that stimulate cell division;
Tumor suppressor proteins can also
restrain cell proliferation in other ways.
G mutated forms, called oncogenes, can cause the stimulatory proteins to be over-
active, with the result that cells proliferate excessively. Tumor suppressor genes code
Some, for example, block the flow of
for proteins that inhibit cell division. Mutations can cause the proteins to be inacti-
signals through growth-stimulatory cir- vated and may thus deprive cells of needed restraints on proliferation. Investigators
cuits. One such suppressor is the prod- are still trying to decipher the specific functions of many tumor suppressor genes.
uct of the NF-1 gene. This cytoplasmic
molecule ambushes the Ras protein be- ONCOGENES
fore it can emit its growth-promoting Genes for growth factors or their receptors
directives. Cells lacking NF-1, then, are
missing an important counterbalance PDGF Codes for platelet-derived growth factor. Involved in glioma
(a brain cancer)
to Ras and to unchecked proliferation.
Various studies have shown that the erb-B Codes for the receptor for epidermal growth factor. Involved in
glioblastoma (a brain cancer) and breast cancer
introduction of a tumor suppressor gene
into cancer cells that lack it can restore erb-B2 Also called HER-2 or neu. Codes for a growth factor receptor. Involved
a degree of normalcy to the cells. This in breast, salivary gland and ovarian cancers
response suggests a tantalizing way of RET Codes for a growth factor receptor. Involved in thyroid cancer
combating cancer—by providing cancer Genes for cytoplasmic relays in stimulatory signaling pathways
cells with intact versions of tumor sup-
Ki-ras Involved in lung, ovarian, colon and pancreatic cancers
pressor genes they lost during tumor de-
velopment. Although the concept is at- N-ras Involved in leukemias
tractive, this strategy is held back by the Genes for transcription factors that activate growth-promoting genes
technical difficulties still encumbering c-myc Involved in leukemias and breast, stomach and lung cancers
gene therapy for many diseases. Current N-myc Involved in neuroblastoma (a nerve cell cancer) and glioblastoma
procedures fail to deliver genes to a large
L-myc Involved in lung cancer
proportion of the cells in a tumor. Until
this logistical obstacle is surmounted, Genes for other kinds of molecules
the use of gene therapy to cure cancer Bcl-2 Codes for a protein that normally blocks cell suicide. Involved
will remain a highly appealing but un- in follicular B cell lymphoma
fulfilled idea. Bcl-1 Also called PRAD1. Codes for cyclin D1, a stimulatory component of the
cell cycle clock. Involved in breast, head and neck cancers
The Clock Is Struck MDM2 Codes for an antagonist of the p53 tumor suppressor protein. Involved
in sarcomas (connective tissue cancers) and other cancers
O ver the past five years, impressive
evidence has uncovered the desti-
nation of stimulatory and inhibitory
TUMOR SUPPRESSOR GENES
Genes for proteins in the cytoplasm
pathways in the cell. They converge on APC Involved in colon and stomach cancers
a molecular apparatus in the cell nucle-
DPC4 Codes for a relay molecule in a signaling pathway that inhibits
us that is often referred to as the cell cy- cell division. Involved in pancreatic cancer
cle clock. The clock is the executive de-
NF-1 Codes for a protein that inhibits a stimulatory (Ras) protein. Involved
cision maker of the cell, and it appar-
in neurofibroma and pheochromocytoma (cancers of the peripheral
ently runs amok in virtually all types of nervous system) and myeloid leukemia
human cancer. In the normal cell, the
NF-2 Involved in meningioma and ependymoma (brain cancers) and
clock integrates the mixture of growth- schwannoma (affecting the wrapping around peripheral nerves)
regulating signals received by the cell
and decides whether the cell should pass Genes for proteins in the nucleus
through its life cycle. If the answer is MTS1 Codes for the p16 protein, a braking component of the cell cycle clock.
positive, the clock leads the process. Involved in a wide range of cancers
The cell cycle is composed of four RB Codes for the pRB protein, a master brake of the cell cycle. Involved in
stages. In the G 1 (gap 1) phase, the cell retinoblastoma and bone, bladder, small cell lung and breast cancer
increases in size and prepares to copy its p53 Codes for the p53 protein, which can halt cell division and induce
DNA. This copying occurs in the next abnormal cells to kill themselves. Involved in a wide range of cancers
stage, termed S (for synthesis), and en- WT1 Involved in Wilms’ tumor of the kidney
ables the cell to duplicate precisely its
Genes for proteins whose cellular location is not yet clear
complement of chromosomes. After the
chromosomes are replicated, a second BRCA1 Involved in breast and ovarian cancers
gap period, termed G 2 , follows during BRCA2 Involved in breast cancer
which the cell prepares itself for M (mi- VHL Involved in renal cell cancer
tosis)—the time when the enlarged par-
How Cancer Arises Copyright 1996 Scientific American, Inc. Scientific American September 1996 65

5. Fundamental Understandings
ent cell finally divides in half to produce of a variety of molecules. Its two essen- This action releases the braking effect
its two daughters, each of which is en- tial components, cyclins and cyclin-de- of pRB and enables the cell to progress
dowed with a complete set of chromo- pendent kinases (CDKs), associate with into late G 1 and thence into S (DNA
somes. The new daughter cells immedi- one another and initiate entrance into synthesis) phase [see b in box below].
ately enter G 1 and may go through the the various stages of the cell cycle. In Various inhibitory proteins can re-
full cycle again. Alternatively, they may G 1, for instance, D-type cyclins bind to strain forward movement through the
stop cycling temporarily or permanently. CDKs 4 or 6, and the resulting complex- cycle. Among them are p15 (mentioned
The cell cycle clock programs this es act on a powerful growth-inhibitory earlier) and p16, both of which block
elaborate succession of events by means molecule—the protein known as pRB. the activity of the CDK partners of cy-
The Cell Cycle Clock and Cancer driven to a large extent by rising levels of proteins called cyclins:
first the D type, followed by E, A and then B.
M ost, perhaps all, human cancers grow inappropriately not
only because signaling pathways in cells are perturbed
but also because the so-called cell cycle clock becomes deranged.
A crucial step in the cycle occurs late in G1 at the restriction
point (R), when the cell decides whether to commit itself to com-
pleting the cycle. For the cell to pass through R and enter S, a
The clock—composed of an assembly of interacting proteins in molecular “switch” must be flipped from “off” to “on.” The switch
the nucleus—normally integrates messages from the stimulatory works as follows (b ): As levels of cyclin D and, later, cyclin E rise,
and inhibitory pathways and, if the stimulatory messages win these proteins combine with and activate enzymes called cyclin-
out, programs a cell’s advance through its cycle of growth and di- dependent kinases (1 ). The kinases (acting as part of cyclin-ki-
vision. Progression through the four stages of the cell cycle (a ) is nase complexes) grab phosphate groups (2 ) from molecules of
a c
STAGES OF THE CELL CYCLE THE CELL CYCLE CLOCK IN ACTION
Growth-
Beginning promoting
Cell of cycle
divides signals
(mitosis) issued by
M Cell enlarges neighboring
and makes cells
Cell prepares new proteins
to divide
G G
2 1
Growth-
Cell rests inhibitory
G signals
0
issued by
neighboring
cells
DIMITRY SCHIDLOVSKY
R
Cell Restriction point: cell p27 Inactive
replicates S decides whether pRB
its DNA to commit itself to protein
the complete cycle
Cyclin D*
b Cyclin D–
CDK4/6
A MOLECULAR “SWITCH” complex
Cyclin-
1 2 Inactive 3 Active dependent
transcription transcription kinase 4* or 6 p15*
ATP Active factor factor
Cyclin D or E (CDK4/6)
pRB
(master
brake)
Proteins Transforming
Phosphate needed growth
Gene for cell’s factor beta
advance (an inhibitor)
Active through its
complex cycle
Cyclin-
dependent Early G
1
kinase
Inactive pRB PHASES OF CELL CYCLE
66 Scientific American September 1996 Copyright 1996 Scientific American, Inc. How Cancer Arises

6. clin D, thus preventing the advance of Breast cancer cells often produce ex- quently disabled, eliminating two of the
the cell from G1 into S. Another inhibi- cesses of cyclin D and cyclin E. In many clock’s most vital restraints. The end re-
tor of CDKs, termed p21, can act cases of melanoma, skin cells have lost sult in all these cases is that the clock
throughout the cell cycle. P21 is under the gene encoding the braking protein begins to spin out of control, ignoring
control of a tumor suppressor protein, p16. Half of all types of human tumors any external warnings to stop. If investi-
p53, that monitors the health of the lack a functional p53 protein. And in gators can devise ways to impose clamps
cell, the integrity of its chromosomal cervical cancers triggered by infection on the cyclins and CDKs active in the
DNA and the successful completion of of cells with a human papillomavirus, cell cycle, they may be able to halt can-
the different steps in the cycle. both the pRB and p53 proteins are fre- cer cells in their tracks.
ATP (adenosine triphosphate) and transfer them to a protein called it releases the factors, freeing them to act on genes (3; top). The
pRB, the master brake of the cell cycle clock. When pRB lacks liberated factors then spur production of various proteins required
phosphates, it actively blocks cycling (and keeps the switch in for continued progression through the cell cycle.
the “off” position) by sequestering other proteins termed tran- In figure c below, the switch is placed in the larger context of
scription factors. But after the cyclin-kinase complexes add the many molecular interactions that regulate the cell cycle. Flip-
enough phosphates to pRB, the brake stops working (3; bottom ); ping of the switch to “on” can be seen above the R point. Overac-
tivity of the stimulatory proteins cyclin D, cyclin E and CDK4 have
been implicated in certain human cancers. Inactivation of various
inhibitory proteins has also been documented. The affected pro-
DNA damage teins include p53 (lost or ineffective in more than half of all tumor
or oxygen
deprivation types), pRB, p16 and p15. The net effect of any of these changes
is deregulation of the clock and, in turn, excessive proliferation of
the cell. —R.A.W.
Cell suicide
p53* (apoptosis)
MDM2
p21
Cyclin E* Proteins
Cyclin E– DNA
CDK2 complex involved in DNA
synthesis synthesis
CDK2
CDC25A
Cell
Liberated division
transcription
factors Cyclin A
Cyclin A–CDK1 Cyclin B
complex
Cyclin B–
CDK1 complex
Active
pRB protein* CDK1
complexed
with inactive
transcription
factors
(master brake) green Activity that promotes red Activity that discourages Positive signal (increasing the amount
cell division cell division or activity of the target molecule)
p16*
Main path leading to External signal that Negative signal (decreasing the amount
cell division discourages cell division or activity of the target molecule)
External signal that Feedback loop
promotes cell division
Mutation or deregulation of gene for this
* protein has been found in human tumors
Late G S G M
1 2
R
How Cancer Arises Copyright 1996 Scientific American, Inc. Scientific American September 1996 67

7. Fundamental Understandings
I have so far discussed two ways that whole: the potential dangers posed to evade apoptosis will be far less respon-
our tissues normally hold down cell pro- the organism by carcinogenic mutations sive to treatment. By the same token, it
liferation and avoid cancer. They pre- are far greater than the small price paid suggests that therapies able to restore a
vent excess multiplication by depriving in the loss of a single cell. The tumors cell’s capacity for suicide could combat
a cell of growth-stimulatory factors or, that emerge in our tissues, then, would cancer by improving the effectiveness of
conversely, by showering it with antipro- seem to arise from the rare, genetically existing radiation and chemotherapeu-
liferative factors. Still, as we have seen, disturbed cell that somehow succeeds tic treatment strategies.
cells on their way to becoming cancerous in evading the apoptotic program hard- A second defense against runaway
often circumvent these controls: they wired into its control circuitry. proliferation, quite distinct from the
MERRYN MACVILLE AND THOMAS REID National Center for Human Genome Research, NIH
stimulate themselves and turn a deaf ear Developing cancer cells devise several apoptotic program, is built into our cells
NORMAL CELL
8 9 10 11 12 13 14 15
CANCER CELL
8q
8q
8 9 10 11 12 13 14 15
Truncated copies
HUMAN CHROMOSOMES from a normal dividing cell (top) occur as identical as well. This mechanism counts and lim-
pairs; those numbered 8 to 18 are shown. Chromosomes from a cervical cancer cell, in its the total number of times cells can
contrast, display many abnormalities (bottom). Chromosome 8, for instance, exhibits
three disturbances: gain of copy number; deletion of genetic material from individual
reproduce themselves.
copies; and breakage followed by joining of segments that do not belong together ( far
right in 8 ). Copy loss, as in chromosome 13, is also common. These various changes Cells Become Immortal
can favor tumor progression if they activate an oncogene, increase the copies of an
oncogene or eliminate a tumor suppressor gene. The images were generated by spectral
karyotyping, a new method for analyzing chromosomes. M uch of what is known about this
safeguard has been learned from
studies of cells cultured in a petri dish.
When cells are taken from a mouse or
to inhibitory signals. Prepared for such means of evading apoptosis. The p53 human embryo and grown in culture,
eventualities, the human body equips protein, among its many functions, helps the population doubles every day or so.
cells with certain backup systems that to trigger cell suicide; its inactivation by But after a predictable number of dou-
guard against runaway division. But many tumor cells reduces the likelihood blings—50 to 60 in human cells—growth
additional mutations in the cell’s genet- that genetically troubled cells will be stops, at which point the cells are said to
ic repertoire can overcome even these eliminated. Cancer cells may also make be senescent. That, at least, is what hap-
defenses and contribute to cancer. excessive amounts of the protein Bcl-2, pens when cells have intact RB and p53
which wards off apoptosis efficiently. genes. Cells that sustain inactivating mu-
Fail-Safe Systems Fail Recently scientists have realized that tations in either of these genes continue
this ability to escape apoptosis may en- to divide after their normal counterparts
O ne such backup system, present in
each human cell, provokes the cell
to commit suicide (undergo “apopto-
danger patients not only by contributing
to the expansion of a tumor but also by
making the resulting tumors resistant to
enter senescence. Eventually, though, the
survivors reach a second stage, termed
crisis, in which they die in large num-
sis”) if some of its essential components therapy. For years, it was assumed that bers. An occasional cell in this dying
are damaged or if its control systems radiation therapy and many chemother- population, however, will escape crisis
are deregulated. For example, injury to apeutic drugs killed malignant cells di- and become immortal: it and its descen-
chromosomal DNA can trigger apopto- rectly, by wreaking widespread havoc dants will multiply indefinitely.
sis. Further, recent work from a num- in their DNA. We now know that the These events imply the existence of a
ber of laboratories indicates that crea- treatments often harm DNA to a rela- mechanism that counts the number of
tion of an oncogene or the disabling of tively minor extent. Nevertheless, the doublings through which a cell popula-
a tumor suppressor gene within a cell affected cells perceive that the inflicted tion has passed. During the past several
can also induce this response. Destruc- damage cannot be repaired easily, and years, scientists have discovered the mo-
tion of a damaged cell is bad for the cell they actively kill themselves. This dis- lecular device that does this counting.
itself but makes sense for the body as a covery implies that cancer cells able to DNA segments at the ends of chromo-
68 Scientific American September 1996 Copyright 1996 Scientific American, Inc. How Cancer Arises

8. somes, known as telomeres, tally the cells to replicate endlessly. The resulting flicted with early-onset colonic tumors,
number of replicative generations cell immortality can be troublesome in preordained by an inherited gene. In the
through which cell populations pass a couple of ways. Obviously, it allows sporadic cases, a rare mutation silences
and, at appropriate times, initiate senes- tumors to grow large. It also gives pre- a tumor suppressor gene called APC in
cence and crisis. In so doing, they cir- cancerous or already cancerous cells an intestinal epithelial cell. The resulting
cumscribe the ability of cell populations time to accumulate additional mutations proliferation of the mutant cell yields a
to expand indefinitely [see “Telomeres, that will increase their ability to repli- benign polyp that may eventually pro-
Telomerase and Cancer,” by Carol W. cate, invade and ultimately metastasize. gress to a malignant carcinoma. But de-
Greider and Elizabeth H. Blackburn; From the point of view of a cancer fective forms of APC may pass from
Scientific American, February]. cell, production of a single enzyme is a parents to children in certain families.
clever way to topple the mortality bar- Members of these families develop hun-
rier. Yet dependence on one enzyme dreds, even thousands of colonic polyps
may represent an Achilles’ heel as well. during the first decades of life, some of
If telomerase could be blocked in can- which are likely to become transformed
cer cells, their telomeres would once into carcinomas.
again shrink whenever they divided, The list of familial cancer syndromes
pushing these cells into crisis and death. that are now traceable directly to inher-
16 17 18
For that reason, a number of pharma- itance of mutant tumor suppressor genes
ceutical firms are attempting to develop is growing. For instance, inherited defec-
drugs that target telomerase. tive versions of the gene for pRB often
lead to development of an eye cancer—
Why Some Cancers Appear Early retinoblastoma—in children; later in life
16 17 18 the mutations account for a greatly in-
I t normally takes decades for an incip-
ient tumor to collect all the muta-
tions required for its malignant growth.
creased risk of osteosarcomas (bone can-
cers). Mutant inherited versions of the
p53 tumor suppressor gene yield tumors
In some individuals, however, the time at multiple sites, a condition known as
Like the plastic tips on shoelaces, the for tumor development is clearly com- the Li-Fraumeni syndrome (named in
telomere caps protect chromosomal ends pressed; they contract certain types of part for Frederick Li, co-author of
from damage. In most human cells, telo- cancer decades before the typical age of “What Causes Cancer?”, page 80).
meres shorten a bit every time chromo- onset of these cancers. How can tumor And the recently isolated BRCA1 and
somes are replicated during the S phase formation be accelerated? BRCA2 genes seem to account for the
of the cell cycle. Once the telomeres In many cases, this early onset is ex- bulk of familial breast cancers, encom-
shrink below some threshold length, they plained by the inheritance from one or passing as many as 20 percent of all pre-
sound an alarm that instructs cells to the other parent of a mutant cancer- menopausal breast cancers in this coun-
enter senescence. If cells bypass senes- causing gene. As a fertilized egg begins try and a substantial proportion of fa-
cence, further shrinkage of the telomere to divide and replicate, the set of genes milial ovarian cancers as well.
will eventually trigger crisis: extreme provided by the sperm and egg is cop- Early onset of tumors is sometimes
shortening of the telomeres will cause ied and distributed to all the body’s explained by inheritance of mutations
the chromosomes in a cell to fuse with cells. Now a typically rare event—a mu- in another class of genes as well. As I
one another or to break apart, creating tation in a critical growth-controlling implied earlier, most people avoid can-
genetic chaos that is fatal to the cell. gene—becomes ubiquitous, because the cer until late in life or indefinitely be-
If the telomere-based counting system mutation is implanted in all the body’s cause they enter the world with pristine
operated properly in cancerous cells, cells, not merely in some randomly genes. During the course of a lifetime,
their excessive proliferation would be stricken cell. In other words, the process however, our genes are attacked by car-
aborted long before tumors became very of tumor formation leapfrogs over one cinogens imported into our bodies from
large. Dangerous expansion would be of its early, slowly occurring steps, ac- the environment and also by chemicals
stemmed by the senescence program or, celerating the process as a whole. As a produced in our own cells. And genetic
if the cell evaded that blockade, by dis- consequence, tumor development, which errors may be introduced when the en-
ruption of the chromosomal array at usually requires three or four decades zymes that replicate DNA during cell
crisis. But this last defense is breached to reach completion, may culminate in cycling make copying mistakes. For the
during the development of most cancer one or two. Because such mutant genes most part, such errors are rapidly cor-
cells, overcome by activation of a gene can pass from generation to generation, rected by a repair system that operates
that codes for the enzyme telomerase. many members of a family may be at in every cell. Should the repair system
This enzyme, virtually absent from risk for the early development of cancer. slip up and fail to erase an error, the
most healthy cell types but present in An inherited form of colon cancer pro- damage will become a permanent mu-
almost all tumor cells, systematically re- vides a dramatic example. Most cases of tation in one of the cell’s genes and in
places telomeric segments that are usu- colon cancer occur sporadically, the re- that same gene in all descendant cells.
ally trimmed away during each cell cy- sults of random genetic events occurring The system’s high repair efficiency is
cle. In so doing, it maintains the integri- during a person’s lifetime. In certain fam- one reason many decades can pass be-
ty of the telomeres and thereby enables ilies, however, many individuals are af- fore all the mutations needed for a ma-
How Cancer Arises Copyright 1996 Scientific American, Inc. Scientific American September 1996 69

9. Fundamental Understandings
lignancy to develop will, by chance, will enable us to predict which members cinomas. Very likely, many of the solu-
come together within a single cell. Cer- of cancer-prone families are at high risk tions to these mysteries will flow from
tain inherited defects, though, can ac- and which have, through good fortune, research in developmental biology (em-
celerate tumor development through a inherited intact copies of these genes. bryology). After all, the genes that gov-
particularly insidious means: they im- ern embryonic development are, much
pair the operation of proteins that re- Beyond Proliferation later, the sources of our malignancies.
pair damaged DNA. As a result, muta- By any measure, the amount of infor-
tions that would normally accumulate
slowly will appear with alarming fre-
quency throughout the DNA of cells.
A lthough we have learned an enor-
mous amount about the genetic
basis of runaway cell proliferation, we
mation gathered over the past two de-
cades about the origins of cancer is with-
out parallel in the history of biomedical
Among the affected genes are inevitably still know rather little about the mutant research. Some of this knowledge has
those controlling cell proliferation. genes that contribute to later stages of already been put to good use, to build
Such is the case in another inherited tumor development, specifically those molecular tools for detecting and deter-
colon cancer, hereditary nonpolyposis that allow tumor cells to attract blood mining the aggressiveness of certain types
colon cancer. Afflicted individuals make vessels for nourishment, to invade nearby of cancer, as David Sidransky discusses
defective versions of a protein responsi- tissues and to metastasize. But research in “Advances in Cancer Detection,” on
ble for repairing the copying mistakes in these areas is moving rapidly. ( Judah page 104. Still, despite so much insight
made by the DNA replication appara- Folkman describes the ingenuity of tu- into cause, new curative therapies have
tus. Because of this impairment, colonic mor cells in generating their own blood so far remained elusive. One reason is
cells cannot fix DNA damage efficiently; supply in “Fighting Cancer by Attack- that tumor cells differ only minimally
they therefore collect mutations rapidly, ing Its Blood Supply,” on page 150. from healthy ones; a minute fraction of
accelerating cancer development by two Erkki Ruoslahti takes up metastasis in the tens of thousands of genes in a cell
decades or more. People affected by an- “How Cancer Spreads” on page 72.) suffers damage during malignant trans-
other familial cancer syndrome, xero- We are within striking distance of formation. Thus, normal friend and
derma pigmentosum, have inherited a writing the detailed life histories of many malignant foe are woven of very similar
defective copy of a gene that directs the human tumors from start to life-threat- cloth, and any fire directed against the
repair of DNA damaged by ultraviolet ening finish. These biographies will be enemy may do as much damage to nor-
rays. These patients are prone to sever- written in the language of genes and mal tissue as to the intended target.
al types of sunlight-induced skin cancer. molecules. Within a decade, we will Yet the course of the battle is chang-
Similarly, cells of people born with a know with extraordinary precision the ing. The differences between normal and
defective ATM gene have difficulty rec- succession of events that constitute the cancer cells may be subtle, but they are
ognizing the presence of certain lesions complex evolution of normal cells into real. And the unique characteristics of
in the DNA and mobilizing the appro- highly malignant, invasive derivatives. tumors provide excellent targets for in-
priate repair response. These people are By then, we may come to understand tervention by newly developed drugs
susceptible to neurological degeneration, why certain localized masses never pro- [see the section “Therapies of the Fu-
blood vessel malformation and a variety gress beyond their benign, noninvasive ture,” beginning on page 135]. The de-
of tumors. Some researchers have pro- form to confront us with aggressive ma- velopment of targeted anticancer thera-
posed that as many as 10 percent of in- lignancy. Such benign growths can be peutics is still in its infancy. This enter-
herited breast cancers may arise in pa- found in almost every organ of the body. prise will soon move from hit-or-miss,
tients with a defective copy of this gene. Perhaps we will also discern why certain serendipitous discovery to rational de-
Over the next decade, the list of can- mutant genes contribute to the formation sign and accurate targeting. I suspect
cer susceptibility genes will grow dra- of some types of cancer but not others. that the first decade of the new century
matically, one of the fruits of the Human For example, mutant versions of the RB will reward us with cancer therapies
Genome Project (which seeks to identify tumor suppressor gene appear often in that earlier generations could not have
every gene in the human cell). Together retinoblastoma, bladder carcinoma and dreamed possible. Then this nation’s
with the increasingly powerful tools of small cell lung carcinoma but are seen long investment in basic cancer research
DNA analysis, knowledge of these genes only occasionally in breast and colon car- will begin to pay off handsomely. SA
The Author Further Reading
ROBERT A. WEINBERG is Member of the Whitehead Insti- Cancer: Science and Society. J. Cairns. W. H. Freeman, 1978.
tute for Biomedical Research and a professor of biology at the Genes and the Biology of Cancer. H. Varmus and R. A. Wein-
Massachusetts Institute of Technology, where he earned his doc- berg. Scientific American Library (distributed by W. H. Freeman),
toral degree in biology in 1969. His laboratory was instrumen- 1993.
tal in isolating the first human oncogene and the first human tu- The Multistep Nature of Cancer. B. Vogelstein and K. W. Kinzler
mor suppressor gene. Weinberg, a member of the National Acad- in Trends in Genetics, Vol. 9, No. 4, pages 138–141; April 1993.
emy of Sciences, has won many awards for his contributions to Cancer: The Rise of the Genetic Paradigm. J. M. Bishop in Genes
the understanding of cancer genetics, most recently the G.H.A. and Development, Vol. 9, No. 11, pages 1309–1315; June 1, 1995.
Clowes Memorial Award of the American Association for Can- Oncogenes. Second edition. G. M. Cooper. Jones and Bartlett Pub-
cer Research. This is his fourth article for Scientific American. lishers, Boston, 1995.
70 Scientific American September 1996 Copyright 1996 Scientific American, Inc. How Cancer Arises