Tackling major killers - Cancer

52 Pages·2004·1.173 MB·English

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Tackling Major Killers:
exclusive online issue no. 17
More than 1.36 million Americans will be diagnosed with cancer in 2004, and 563,700 will succumb to the disease, according to estimates
from the American Cancer Society. Accounting for one in four mortalities, cancer is second only to heart disease when it comes to cause of
death. These grim statistics notwithstanding, researchers have made great strides in understanding--and combating--the scourge. Thanks
to their efforts, a number of new cancer-fighting tactics are on the horizon.
In this exclusive online issue, comprised of articles published over the past five years, leading scientists and journalists explain recent
advances in cancer research. Learn how cells become malignant; how viruses, dendritic cells and light-sensitive pigments are finding work
as anti-cancer agents; and how researchers might one day be able to manipulate the formation of new blood vessels to treat the disease.
Other reports explain why hormone-replacement therapy may not be such a bad idea--and why alternative medicine is. In addition, two arti-
cles sketch Judah Folkman, who discovered that two natural compounds dramatically shrink tumors by cutting off their blood supply, and
Peter Duesberg, who has claimed that the scientific establishment has an incorrect theory of how cancer arises.—The Editors
TABLE OF CONTENTS
2 Untangling the Roots of Cancer
BY W. WAYT GIBBS; THE SCIENCE OF STAYING YOUNG
Recent evidence challenges long-held theories of how cells turn malignant--and suggests new ways to stop tumors before they
spread
11 Vessels of Death or Life
BY RAKESH K. JAIN AND PETER F. CARMELIET; DECEMBER 2001
Angiogenesis--the formation of new blood vessels--might one day be manipulated to treat disorders from cancer to heart disease.
First-generation drugs are now in the final phase of human testing
18 The Long Arm of the Immune System
BY JACQUES BANCHEREAU; NOVEMBER 2002
Dendritic cells catch invaders and tell the immune system when and how to respond. Vaccines depend on them, and scientists are
even employing the cells to stir up immunity against cancer
26 New Light on Medicine
BY NICK LANE; JANUARY 2003
Pigments that turn caustic on exposure to light can fight cancer, blindness and heart disease. Their light-induced toxicity may also
help explain the origin of vampire tales
33 Tumor-Busting Viruses
BY DIRK M. NETTELBECK AND DAVID T. CURIEL; OCTOBER 2003
A new technique called virotherapy harnesses viruses, those banes of humankind, to stop another scourge - cancer
41 Hormone Hysteria
BY DENNIS WATKINS; OCTOBER 2003
Hormone replacement therapy may not be so bad
42 Skeptic: What's the Harm?
BY MICHAEL SHERMER; DECEMBER 2003
Alternative medicine is not everything to gain and nothing to lose
43 Quiet Celebrity: Interview with Judah Folkman
BY SERGIO PISTOI AND CHIARA PALMERINI; NOVEMBER 4, 2002
The renowned medical researcher reflects on the promise of anti-angiogenesis drugs
45 Profile: Peter H. Duesberg, Dissident or Don Quixote?
BY W. WAYT GIBBS; AUGUST 2001
Challenging the HIV theory got virologist Peter H. Duesberg all but excommunicated from the scientific orthodoxy. Now he claims
that science has got cancer all wrong
1 SCIENTIFIC AMERICAN EXCLUSIVE ONLINE ISSUE OCTOBER 2004
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originally published in The Science of Staying Young
the roots of cancer
Recent evidence challenges
long-held theories of how cells
turn malignant—and suggests
new ways to stop tumors
before they spread
By W. Wayt Gibbs
WHAT CAUSES CANCER?
Tobacco smoke, most people would say. Probably too much alcohol, sunshine or
grilled meat; infection with cervical papillomaviruses; as- into an active state. Some researchers still take it as ax-
bestos. All have strong links to cancer, certainly. But they iomatic that such growth-promoting changes to a small
cannot be root causes. Much of the population is exposed number of cancer genes are the initial event and root cause
to these carcinogens, yet only a tiny minority suffers dan- of every human cancer.
gerous tumors as a consequence. A cause, by definition, Others, however, including a few very prominent on-
leads invariably to its effect. The immediate cause of can- cologists, are increasingly challenging that theory. No one
cer must be some combination of insults and accidents questions that cancer is ultimately a disease of the DNA.
that induces normal cells in a healthy human body to turn But as biologists trace tumors to their roots, they have dis-
malignant, growing like weeds and sprouting in unnat- covered many other abnormalities at work inside the nu-
ural places. clei of cells that, though not yet cancerous, are headed that
At this level, the cause of cancer is not entirely a mys- way. Whole chromosomes, each containing 1,000 or
tery. In fact, a decade ago many geneticists were confident more genes, are often lost or duplicated in their entirety.
n
o
ati that science was homing in on a final answer: cancer is the Pieces of chromosomes are frequently scrambled, trun-
m
ni result of cumulative mutations that alter specific locations cated or fused together. Chemical additions to the DNA,
A
al in a cell’s DNA and thus change the particular proteins en- or to the histone proteins around which it coils, somehow
c
di
Me coded by cancer-related genes at those spots. The muta- silence important genes—but in a reversible process quite
brid tions affect two kinds of cancer genes. The first are called different from mutation.
y
HN tumor suppressors. They normally restrain cells’ ability to The accumulating evidence has spawned at least three
O
S divide, and mutations permanently disable the genes. The hypotheses that compete with the standard dogma to ex-
N
H
F JO second variety, known as oncogenes, stimulate growth— plain what changes come first and which aberrations mat-
EF in other words, cell division. Mutations lock oncogenes ter most in the transformation of a cell and its descendants
J
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from well-behaved tissue to invasive tu- keep a human being healthy over the mands that are sent out by the adjacent
mor. The challengers dispute the domi- course of an 80-year life span. If any one tissues they squeeze and by their own in-
nant view of the disease as the product of of those myriad cells could give rise to a ternal aging mechanisms.
a defined genetic state. They argue that it tumor, why is it that less than half the All cancerous cells have serious
is more useful to think of cancer as the population will ever contract a cancer problems of some sort with their DNA,
consequence of a chaotic process, a com- that is serious enough to catch a doctor’s and as they double again and again,
bination of Murphy’s Law and Darwin’s attention? many cells in the resulting colony end up
Law: anything that can go wrong will, One explanation is that a cell must far from the blood vessels that supply
and in a competitive environment, the acquire several extraordinary skills to be oxygen and nutrients. Such stresses trig-
best adapted survive and prosper. malignant. “Five or six different regula- ger autodestruct mechanisms in healthy
Despite that shared underlying prin- tory systems must be perturbed in order cells. Tumor cells find some way to
ciple, the new theories make different for a normal cell to grow as a cancer,” avoid this kind of suicide. Then they
“If you look at most solid tumors in adults, it looks
set off a bomb
like someone in the nucleus.”
—William C. Hahn, Dana-Farber Cancer Institute
predictions about what kind of treat- asserts Robert A. Weinberg of the White- have to persuade nearby blood vessels
ments will work best. Some suggest that head Institute at the Massachusetts Insti- to build the infrastructure they need to
many cancers could be prevented alto- tute of Technology. In a November 2002 thrive.
gether by better screening, changes in review paper, he and William C. Hahn of A fifth superpower that almost all
diet, and new drugs—or even by old the Dana-Farber Cancer Institute in cancers acquire is immortality. A culture
drugs, such as aspirin. Other theories Boston argued that all life-threatening of normal human cells stops dividing af-
cast doubt on that hope. cancers manifest at least six special abil- ter 50 to 70 generations. That is more
ities, or “superpowers.” (Although Wein- than enough doublings to sustain a per-
Marks of Malignancy
berg is one of the founding proponents of son through even a century of healthy
A WORKABLE THEORY of cancer has the standard paradigm, even those who life. But the great majority of cells in tu-
to explain both why it is predominantly challenge that theory tend to agree with mors quickly die of their genetic defects,
a disease of old age and why we do not this view.) so those that survive must reproduce in-
all die from it. A 70-year-old is roughly For example, cancer cells continue di- definitely if the tumor is to grow. The
100 times as likely to be diagnosed with viding in situations in which normal cells survivors do so in part by manipulating
a malignancy as a 19-year-old is. Yet would quietly wait for a special chemical their telomeres, gene-free complexes of
most people make it to old age without signal—say, from an injured neighbor. DNA and protein that protect the ends
getting cancer. Somehow they counterfeit these pro- of each chromosome.
Biologists estimate that more than growth messages. Conversely, tumor Tumors that develop these five facul-
10 million billion cells must cooperate to cells must ignore “stop dividing” com- ties are trouble, but they are probably
not deadly. It is the sixth property, the
Overview/How Cancer Arises
ability to invade nearby tissue and then
metastasize to distant parts of the body,
■ Cancer is a genetic disease. Alterations to the DNA inside cells can endow cells that gives cancer its lethal character. Lo-
with morbid “superpowers,” such as the ability to grow anywhere and to cal invasions can usually be removed sur-
continue dividing indefinitely. gically. But nine of every 10 deaths from
■ Most cancer researchers have long focused on mutations to a relatively small the disease are the result of metastases.
set of cancer-related genes as the decisive events in the transformation Only an elite few cells in a tumor
of healthy cells to malignant tumors. seem to acquire this ability to detach
■ Recently, however, other theories have emerged to challenge this view. One from the initial mass, float through the
hypothesizes that a breakdown in DNA duplication or repair leads to many circulatory system and start a new
thousands of random mutations in cells. Another suggests that damage to a few colony in a different organ from the one
“master” genes mangles the chromosomes, which then become dangerous. that gave birth to them. Unfortunately,
A third challenger proposes that abnormal numbers of chromosomes in a cell by the time cancers are discovered, many
may be the first milestone on the road to cancer. have already metastasized—including, in
the U.S., 72 percent of lung cancers, 57
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SIX DIABOLICAL SUPERPOWERS OF CANCER
1. GROWTH EVEN IN THE ABSENCE OF NORMAL “GO” SIGNALS
Most normal cells wait for an external message before dividing. Cancer cells often counterfeit their own
pro-growth messages.
2. GROWTH DESPITE “STOP” COMMANDS ISSUED BY NEIGHBORING CELLS
As the tumor expands, it squeezes adjacent tissue, which sends out chemical messages that would
normally bring cell division to a halt. Malignant cells ignore the commands.
3. EVASION OF BUILT-IN AUTODESTRUCT MECHANISMS
In healthy cells, genetic damage above a critical level usually activates a suicide program. Cancerous cells
bypass this mechanism, although agents of the immune system can sometimes successfully order the
cancer cells to self-destruct.
4. ABILITY TO STIMULATE BLOOD VESSEL CONSTRUCTION
Tumors need oxygen and nutrients to survive. They obtain them by co-opting nearby blood vessels to form
new branches that run throughout the growing mass.
5. EFFECTIVE IMMORTALITY
Healthy cells can divide no more than 70 times. Malignant cells need more than that to make tumors. So
they work around systems—such as the telomeres at the end of chromosomes—that enforce the
reproductive limit.
6. POWER TO INVADE OTHER TISSUES AND SPREAD TO OTHER ORGANS
Cancers usually become life-threatening only after they somehow disable the cellular circuitry that
confines them to a specific part of the particular organ in which they arose. New growths appear and
eventually interfere with vital systems.
percent of colorectal, and 34 percent of deletes or disrupts a tumor suppressor another burst of growth.
breast cancers. By then the prognosis is gene—RB, p53 and APC are among Cells normally have two copies of
frequently grim. the best known—thereby suppressing every chromosome—one from the moth-
proteins that normally ensure the in- er, the other from the father—and thus
The Order of Disorder
tegrity of the genome and cell division. two copies, or alleles, of every gene. (In
DOCTORS COULD CATCH incipient Alternatively, a mutation may increase males, the single X and Y chromosomes
tumors sooner if scientists could trace the the activity of an oncogene—such as are notable exceptions.) A mutation to
steps that cells take down the road to BRAF, c-fosor c-erbb3—whose proteins just one allele is enough to activate an
cancer after the initial assault to their then stimulate the cell to reproduce. oncogene permanently. But it takes two
DNA by a carcinogen or some random Changes to cancer genes endow the hits to knock out both alleles of a tumor
biochemical mishap. Researchers broad- cell with one or more superpowers, al- suppressor gene. Four to 10 mutations in
ly agree on the traits of the diseased cells lowing it to outbreed its neighbors. The the right genes can transform any cell. Or
that emerge from the journey. It is the cell passes abnormalities in its DNA se- so the theory goes.
propelling force and the order of each quence on to its descendants, which be- The mutant-gene paradigm gained
milestone that are under active debate. come a kind of clone army that grows to almost universal acceptance because it
The dominant paradigm has been the limits of its capacity. Eventually an- explained very well what scientists saw
that tumors grow in spurts of mutation other random mutation to a cancer gene in their experiments on genetically engi-
and expansion. Genetic damage to a cell knocks down another obstacle, initiating neered mice and human cell cultures.
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But new technologies now allow re- cancers but not in any of several other
searchers to study the genomes of can- kinds of thyroid cancers. BRANCHING POINTS IN
cerous and precancerous cells taken di- Moreover, some of the most com-
rectly from people. Many recent obser- monly altered cancer genes have oddly
vations seem to contradict the idea that inconsistent effects. Bert E. Vogelstein’s
mutations to a few specific genes lie at the group at Johns Hopkins found that the
1927 Hermann J.
root of all cancers. much studied oncogenes c-fosand c-erbb3
Muller observes
are curiously less active in tumors than that radiation
Unexplained Phenomena they are in nearby normal tissues. The tu- mutates cells
IN APRIL 2003, for example, Muham- mor suppressor gene RB was recently
mad Al-Hajj of the University of Mich- shown to be hyperactive—not disabled—
1951 Muller
igan at Ann Arbor and his colleagues re- in some colon cancers, and, perversely, it
proposes
ported that they had identified distin- appears to protect those tumors from theory that
guishing marks for a rare subset of cells their autodestruct mechanisms. multiple
mutations
within human breast cancers that can The “two hit” hypothesis—that both turn a cell
form new tumors. As few as 100 cells of alleles of a tumor suppressor gene must malignant
this type quickly spawned disease when be deactivated—has also been upended
injected into mice lacking an immune sys- by the discovery of a phenomenon called
tem. Tens of thousands of other cells, har- haploinsufficiency. In some cancers, tu- 1914 Theodor Boveri suggests
that aberrant chromosomes
vested from the same nine breast malig- mor suppressors are not mutated at all.
may cause cancer
nancies but lacking the telltale marks, Their output is simply reduced, and that
failed to do so. “This is the first tumor- seems to be enough to push cells toward
initiating cell anyone has isolated for sol- malignancy. This effect has now been
id tumors,” says John E. Dick, a biologist seen for more than a dozen tumor sup-
1915 1920 1925 1930 1935
at the University of Toronto who has pressor genes. Searching for the mere
identified similar cells for leukemia. presence or absence of a gene’s protein
The tantalizing implication, Dick ex- is too simplistic. Dosage matters. with truncations, extensions or swapped
plains, is that just a small fraction of the segments.
Beyond Mutation
cells in a tumor are responsible for its Almost a century ago German biol-
growth and metastasis. If that is shown to RESEARCHERS ARE NOW looking ogist Theodor Boveri noticed the strange
be true for humans as well as mice, it more closely at other phenomena that imbalance in cancer cells between the
could pose a problem for the mutant-gene could dramatically alter the dosage of a numbers of maternal versus paternal
theory of cancer. If mutations, which are protein in a cell. Candidates include the chromosomes. He even suggested that
copied from a cell to its progeny, give tu- loss or gain of a chromosome (or part of aneuploid cells might cause the disease.
mor cells their powers, then shouldn’t all one) containing the gene; changes in the But scientists could find no recurrent pat-
clones in the army be equally powerful? concentration of other proteins that reg- tern to the chromosomal chaos—indeed,
In fact, most tumors are not masses ulate how the gene is transcribed from the genome of a typical cancer cell is not
of identical clones. On the contrary, clos- DNA to RNA and translated into a pro- merely aneuploid but is unstable as well,
er examination has revealed amazing ge- tein; even so-called epigenetic phenome- changing every few generations. So
netic diversity among their cells, some of na that alter gene activity by reversible Boveri’s idea was dropped as the search
which are so different from normal hu- means. All these changes are nearly ubiq- for oncogenes started to bear fruit. The
man cells (and from one another) that uitous in established cancers. aneuploidy and massive genomic insta-
they might fairly be called new species. “If you look at most solid tumors in bility inside tumor cells were dismissed as
A few cancer-related genes, such as adults, it looks like someone set off a side effects of cancer, not prerequisites.
p53,do seem to be mutated in the ma- bomb in the nucleus,” Hahn says. “In But the oncogene/tumor suppressor
jority of tumors. But many other cancer most cells, there are big pieces of chro- gene hypothesis has also failed, despite
genes are changed in only a small frac- mosomes hooked together and duplica- two decades of effort, to identify a par-
tion of cancer types, a minority of pa- tions or losses of whole chromosomes.” ticular set of gene mutations that occurs
tients, or a sprinkling of cells within a tu- Scientists have yet to settle on a term in every instance of any of the most com-
mor. David Sidransky of the Johns Hop- for the suite of chromosomal aberra- mon and deadly kinds of human cancer.
kins University School of Medicine and tions seen in cancer. The word “aneu- The list of cancer-related mutations has
his co-workers tested DNA from 476 tu- ploidy” once referred to an abnormal grown to more than 100 oncogenes and
mors of various kinds. They reported in number of chromosomes. But more re- 15 tumor suppressor genes. “The rate at
April 2003 that the oncogene BRAF was cently, it has been used in a broader which these molecular markers are be-
altered in two thirds of papillary thyroid sense that encompasses chromosomes ing identified continues to increase
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THE EVOLUTION OF CANCER THEORY
1997 Christoph Lengauer 2002 Thomas Ried 2003 The number of
and Vogelstein identifies recurrent identified cancer genes,
1971 Alfred G. Knudson demonstrate dramatic patterns of aneuploidy now well over 100,
explains different rates of increase in gain and loss in cervical and continues to grow rapidly
inherited and spontaneous of chromosomes in colon colon cancers
retinal cancer with the tumor cells and propose
hypothesis that two “hits,” that chromosomal
or damaging mutations, instability is a critical
are needed to disable early event that leads to
both alleles of the RB gene the mutation of
and that one mutation oncogenes and tumor
can be inherited suppressor genes
1990 Bert Vogelstein and
1974 Lawrence
Eric R. Fearon publish a model of
Loeb argues
that random sequential gene mutations that 1999 Peter Duesberg publishes
mutations must lead to colon cancer detailed theory of how aneuploidy
accumulate may be sufficient to cause cancer
fast in cells 1986 Robert Weinberg isolates RB, itself, even without mutations to any
1960 Discovery that an that become the first tumor suppressor gene particular set of genes
exchange of DNA between malignant
chromosomes 9 and 22 leads to
chronic myelogenous leukemia
1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000
rapidly,” lamented Weinberg and Hahn and repair machinery—must dramatical- chromosomal instability can occur ear-
in their 2002 review. “As a consequence,” ly accelerate the mutation rate, Loeb ar- ly on. The genetic flux then combines
they added, “it remains possible that each gues. “I think that is probably right,” forces with natural selection to produce
tumor is unique” in the pattern of its ge- Hahn concurs. Otherwise, he says, “cells a benign growth that may later be con-
netic disarray. wouldn’t accumulate a sufficient number verted to an invasive malignancy and
Hahn reflected on this possibility in of mutations to form a tumor.” life-threatening metastases.
his Boston office in January 2003. Along Loeb believes that “early during the In their hypothesis, there are several
with Weinberg, he has pioneered the genesis of cancer there are enormous “master” genes whose function is critical
construction of artificial tumors using numbers of random mutations—10,000 for a cell to reproduce correctly. If as few
mutant cancer genes. But he acknowl- to 100,000 per cell.” Evidence for the as one of these genes is disabled, either by
edged that they cannot be the whole sto- theory is still slim, he acknowledges. mutation or epigenetically, the cell stum-
ry. “The question is which comes first,” Counting random mutations is hard; sci- bles each time it attempts cell division,
he said. “Mutations or aneuploidy?” entists must compare the genomes of in- muddling some of the chromosomes into
There are at least three competing dividual cells letter by letter. Advances an aneuploid state. One result is to in-
answers. Let us call them the modified in biotechnology have only recently crease 100,000-fold the rate at which
dogma, the early instability theory and made that feasible. cells randomly lose one of the two alleles
the all-aneuploidy theory. Encouraging- The modified dogma thus adds a of their genes. For a tumor suppressor
ly, the theories seem to be converging as prologue to the accepted life history of gene, a lost allele may effectively put the
they bend to accommodate new experi- cancer. But the most important factors gene out of commission, either because
mental results. are still mutations to genes that serve to the remaining copy is already mutated or
The modified form of the standard increase the reproductive success of cells. because of the haploinsufficiency effect.
dogma revives an idea proposed in 1974 Mangled and ever changing chromo- Lengauer and Vogelstein still assume
by Lawrence A. Loeb, now at the Uni- somes are but fortuitous by-products. that some cancer genes must be altered
versity of Washington. He and others before a malignancy can erupt.
Unstable from the Outset
have estimated that random mutation In December 2002, together with
will affect just one gene in any given cell CRISTOPH LENGAUER and Vogel- Martin A. Nowak and Natalia L. Ko-
over a lifetime. Something—a carcino- stein of Johns Hopkins, both well- marova of the Institute for Advanced
gen, reactive oxidants, or perhaps a mal- known colon cancer specialists, have Study in Princeton, N.J., Lengauer and
function in the cell’s DNA duplication proposed an alternative theory in which Vogelstein published a mathematical
7 SCIENTIFIC AMERICAN EXCLUSIVE ONLINE ISSUE OCTOBER 2004
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THE GENESIS OF CANCER: FOUR THEORIES
FOR DECADES,the most widely accepted view of how cancer gained currency. One modifies the standard paradigm by
begins has been that mutations to a handful of special genes postulating a dramatic increase in the accumulation of
eliminate tumor suppressor proteins and activate random mutations throughout the genomes of precancerous
oncoproteins. More recently, three alternative theories have cells. Two other theories focus on the role of aneuploidy—
TUMOR SUPPRESSOR 2
Mutationsin tumor suppressor
GENES
genes cause growth-inhibiting
proteinsencoded by the genes to
A APC p53
M disappear, allowing the cell
G RB to survive and continue
O 1 dividing when it should not
D Carcinogens,
RD ssuucnhli gahst u alntrda violet 3At the same time, mutations to
A tobacco, directly oncogenescause oncoproteins
D alter the DNA to become hyperactive,
TAN BRAF scaeqnuceern-creel oaft ed genes pgrroowm pint isnigtu tahteio cnesll itno
S which it normally would not
c-fos
c-erbb3
ONCOGENES
1
Something disables one
or more genes needed to
A accurately synthesize or
M repair the DNA
G
O DNA-REPAIR GENE
D
2
D As the cell divides,
random mutations
E
I are introduced and
F
I go unrepaired,
D
O accumulating by the
Y M 1“fomrSa cosomtoeerrdt”hingineagnte esdsil cethenlacl ted asiv roeisn cieor iontirc malo re tEcgeaevnnensnce etsour fa- atrrhleelyol ahu ttishteaednds. Tchhero dmoossaogme oef p gieecneess ainre t haed dceeldl cohr adnegleetse das
T
I
L
I
B
A 2
T As the chromosomes are
NS duplicated, mistakes occur.
I Some daughter cells get the
LY wrong number of chromosomes or
R chromosomes with missing arms or
A extra segments. The aberrations
E
worsen with each generation
1 2
A mistake during cell division The misplaced or truncated
produces aneuploid cells chromosomes change the relative
Y amounts of thousands of genes. Teams of
D enzymes that normally cooperate to copy
OI or fix DNA begin to fail. Most aneuploid
L cells die as a result
P
U
E
N
A
-
L
L
A
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