Understanding how cancer begins and then grows is fundamental to one day preventing the disease. Here, we explain three new theories for how cancer may form.
For the last decade cancer research has been guided by a common vision of how a single cell, outcompeting its neighbors, evolves into a malignant tumor.
Through a series of random mutations, genes that encourage cellular division are pushed into overdrive, while genes that normally send growth-restraining signals are taken offline.
With the accelerator floored and the brake lines cut, the cell and its progeny are free to rapidly multiply. More mutations accumulate, allowing the cancer cells to elude other safeguards and to invade neighboring tissue and metastasize.
These basic principles — laid out 11 years ago in a landmark paper, "The Hallmarks of Cancer," by Douglas Hanahan and Robert A. Weinberg, and revisited in a follow-up article this year — still serve as the reigning paradigm, a kind of Big Bang theory for the field.
But recent discoveries have been complicating the picture with tangles of new detail. Cancer appears to be even more willful and calculating than previously imagined.
Most DNA, for example, was long considered junk — a netherworld of detritus that had no important role in cancer or anything else. Only about 2 percent of the human genome carries the code for making enzymes and other proteins, the cogs and scaffolding of the machinery that a cancer cell turns to its own devices.
These days "junk" DNA is referred to more respectfully as "noncoding" DNA, and researchers are finding clues that "pseudogenes" lurking within this dark region may play a role in cancer.
"We've been obsessively focusing our attention on 2 percent of the genome," said Dr. Pier Paolo Pandolfi, a professor of medicine and pathology at Harvard Medical School. This spring, at the annual meeting of the American Association for Cancer Research in Orlando, Fla., he described a new "biological dimension" in which signals coming from both regions of the genome participate in the delicate balance between normal cellular behavior and malignancy.
As they look beyond the genome, cancer researchers are also awakening to the fact that some 90 percent of the protein-encoding cells in our body are microbes. We evolved with them in a symbiotic relationship, which raises the question of just who is occupying whom.
"We are massively outnumbered," said Jeremy K. Nicholson, chairman of biological chemistry and head of the department of surgery and cancer at Imperial College London. Altogether, he said, 99 percent of the functional genes in the body are microbial.
In Orlando, he and other researchers described how genes in this microbiome — exchanging messages with genes inside human cells — may be involved with cancers of the colon, stomach, esophagus and other organs.
These shifts in perspective, occurring throughout cellular biology, can seem as dizzying as what happened in cosmology with the discovery that dark matter and dark energy make up most of the universe: Background suddenly becomes foreground and issues once thought settled are up in the air. In cosmology the Big Bang theory emerged from the confusion in a stronger but more convoluted form. The same may be happening with the science of cancer.
Exotic Players
According to the central dogma of molecular biology, information encoded in the DNA of the genome is copied by messenger RNA and then carried to subcellular structures called ribosomes, where the instructions are used to assemble proteins. Lurking behind the scenes, snippets called microRNAs once seemed like little more than molecular noise. But they have been appearing with increasing prominence in theories about cancer.
By binding to a gene's messenger RNA, microRNA can prevent the instructions from reaching their target — essentially silencing the gene — and may also modulate the signal in other ways. One presentation after another at the Orlando meeting explored how microRNAs are involved in the fine-tuning that distinguishes a healthy cell from a malignant one.
Ratcheting the complexity a notch higher, Dr. Pandolfi, the Harvard Medical School researcher, laid out an elaborate theory involving microRNAs and pseudogenes. For every pseudogene there is a regular, protein-encoding gene. (Both are believed to be derived from a common ancestral gene, the pseudogene shunted aside in the evolutionary past when it became dysfunctional.) While normal genes express their will by sending signals of messenger RNA, the damaged pseudogenes either are mute or speak in gibberish.
Or so it was generally believed. Little is wasted by evolution, and Dr. Pandolfi hypothesizes that RNA signals from both genes and pseudogenes interact through a language involving microRNAs. (These signals are called ceRNAs, pronounced "sernas," meaning "competing endogenous RNAs.")
His lab at Beth Israel Deaconess Medical Center in Boston is studying how this arcane back channel is used by genes called PTEN and KRAS, commonly implicated in cancer, to confer with their pseudotwins. The hypothesis is laid out in more detail this month in an essay in the journal Cell.
Fueled by the free espresso offered by pharmaceutical companies hawking their wares, scientists at the Orlando meeting moved from session to session and browsed corridors of posters, looking for what might have recently been discovered about other exotic players: lincRNA, (for large intervening noncoding), siRNA (small interfering), snoRNA (small nucleolar) and piRNA (Piwi-interacting (short for "P-element induced wimpy testis" (a peculiar term that threatens to pull this sentence into a regress of nested parenthetical explanations))).
In their original "hallmarks" paper — the most cited in the history of Cell — Dr. Hanahan and Dr. Weinberg gathered a bonanza of emerging research and synthesized it into six characteristics. All of them, they proposed, are shared by most and maybe all human cancers. They went on to predict that in 20 years the circuitry of a cancer cell would be mapped and understood as thoroughly as the transistors on a computer chip, making cancer biology more like chemistry or physics — sciences governed by precise, predictable rules.
Now there appear to be transistors inside the transistors. "I still think that the wiring diagram, or at least its outlines, may be laid out within a decade," Dr. Weinberg said in an e-mail. "MicroRNAs may be more like minitransistors or amplifiers, but however one depicts them, they still must be soldered into the circuit in one way or another."
In their follow-up paper, "Hallmarks of Cancer: The Next Generation," he and Dr. Hanahan cited two "emerging hallmarks" that future research may show to be crucial to malignancy — the ability of an aberrant cell to reprogram its metabolism to feed its wildfire growth and to evade destruction by the immune system.
Unwitting Allies
Even if all the lines and boxes for the schematic of the cancer cell can be sketched in, huge complications will remain. Research is increasingly focused on the fact that a tumor is not a homogeneous mass of cancer cells. It also contains healthy cells that have been conscripted into the cause.
Cells called fibroblasts collaborate by secreting proteins the tumor needs to build its supportive scaffolding and expand into surrounding tissues. Immune system cells, maneuvered into behaving as if they were healing a wound, emit growth factors that embolden the tumor and stimulate angiogenesis, the generation of new blood vessels. Endothelial cells, which form the lining of the circulatory system, are also enlisted in the construction of the tumor's own blood supply.
All these processes are so tightly intertwined that it is difficult to tell where one leaves off and another begins. With so much internal machinery, malignant tumors are now being compared to renegade organs sprouting inside the body.
As the various cells are colluding, they may also be trading information with cells in another realm — the micro-organisms in the mouth, skin, respiratory system, urogenital tract, stomach and digestive system. Each microbe has its own set of genes, which can interact with those in the human body by exchanging molecular signals.
"The signaling these microbes do is dramatically complex," Dr. Nicholson said in an interview at Imperial College. "They send metabolic signals to each other — and they are sending chemicals out constantly that are stimulating our biological processes.
"It's astonishing, really. There they are, sitting around and doing stuff, and most of it we don't really know or understand."
People in different geographical locales can harbor different microbial ecosystems. Last year scientists reported evidence that the Japanese microbiome has acquired a gene for a seaweed-digesting enzyme from a marine bacterium. The gene, not found in the guts of North Americans, may aid in the digestion of sushi wrappers. The idea that people in different regions of the world have co-evolved with different microbial ecosystems may be a factor — along with diet, lifestyle and other environmental agents — in explaining why they are often subject to different cancers.
The composition of the microbiome changes not only geographically but also over time. With improved hygiene, dietary changes and the rising use of antibiotics, levels of the microbe Helicobacter pylori in the human gut have been decreasing in developing countries, and so has stomach cancer. At the same time, however, esophageal cancer has been increasing, leading to speculation that H. pylori provides some kind of protective effect.
At the Orlando meeting, Dr. Zhiheng Pei of New York University suggested that the situation is more complex. Two different types of microbial ecosystems have been identified in the human esophagus. Dr. Pei's lab has found that people with an inflamed esophagus or with a precancerous condition called Barrett's esophagus are more likely to harbor what he called the Type II microbiome.
"At present, it is unclear whether the Type II microbiome causes esophageal diseases or gastro-esophageal reflux changes the microbiome from Type I to II," Dr. Pei wrote in an e-mail. "Either way, chronic exposure of the esophagus to an abnormal microbiome could be an essential step in esophageal damage and, ultimately, cancer."
Unseen Enemies
At a session in Orlando on the future of cancer research, Dr. Harold Varmus, the director of the National Cancer Institute, described the Provocative Questions initiative, a new effort to seek out mysteries and paradoxes that may be vulnerable to solution.
"In our rush to do the things that are really obvious to do, we're forgetting to pay attention to many unexplained phenomena," he said.
Why, for example, does the Epstein-Barr virus cause different cancers in different populations? Why do patients with certain neurological diseases like Parkinson's, Huntington's, Alzheimer's and Fragile X seem to be at a lower risk for most cancers? Why are some tissues more prone than others to developing tumors? Why do some mutations evoke cancerous effects in one type of cell but not in others?
With so many phenomena in search of a biological explanation, "Hallmarks of Cancer: The Next Generation" may conceivably be followed by a second sequel — with twists as unexpected as those in the old "Star Trek" shows. The enemy inside us is every bit as formidable as imagined invaders from beyond. Learning to outwit it is leading science deep into the universe of the living cell.
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yellowdog VT
burlington, vt
As a working cancer scientist who was lucky enough to attend meeting, I can attest to the exciting nature of the work, and to the paradox that, the more we learn, the more the knotty the problem appears.With reference to some of the comments made by other readers, rest assured that, (1) the Cancer Stem Cell theory is alive and well and is being actively investigated in many tumors; that (2) epigenetics is being actively investigated; non coding RNAs are in fact epigenetic in nature; (3) big Pharma is actually trying to develop new drugs to cure cancers, and that so far, nobody has discovered a miracle drug that cures all cancers and can't be patented.
What the article does not say is that the current desire to make huge cuts in the "discretionary" component of the Federal budget will be devastating to cancer researchers, and indeed all biomedical scientists. Don't look to industry, all of our Pharma colleagues are losing their jobs in the rush to outsource basic science to laboratories in India and China. If the current trends continue, the only scientists able to maintain labs will be those funded by the Howard Hughes Medical Institute. There will be no discoveries and miracle cures to move out of the lab and into hospitals.
And to all those politicians who chide scientists for not speaking up, I am sorry, we are too busy writing grants, teaching classes, training students, and performing all the tasks our overpaid administrators have dumped on us. And we don't have the hedge fund sized contributions to get your attention anyway.
W.A. Spitzer
Faywood, New Mexico
It is a sad commentary that one frequently reads comments that suggest that large pharmaceutical companies would withhold useful cancer treatments from the public because they are not profitable. I worked as a research scientist for a major pharmaceutical company for nearly 30 years. The scientific community is not immune - our friends, our colleagues, our family members die from cancer just as surely as everyone else. There are literally thousands of scientists working for pharmaceutical companies trying to find a more effective treatment for cancer. They spend their entire careers dedicated to the possibility that their work might one day make a difference; that their research might save one life - it is the reason they get up and go to work everyday. To imply that somehow they would bypass a successful cancer treatment because it was not hugely profitable is deeply insulting. Anyone who would even imagine that kind of large scale scientific conspiracy coupled with such a complete absence of morality needs to pause and look within themselves.
MJR
Stony Brook, NY
As this article admirably summarizes, we are now on the cusp of major advances in understanding and, in our life time, curing many types of cancer. Tragically America will not be leading the world towards this marvelous goal. Driven by austerity crazed politicians and others - America has not been training and funding enough new scientists for years and its scientific infrastructure is now crumbling (indeed it is becoming a laugh stock) and so America is neither prepared to exploit these new discoveries, nor actually translate these advances into new therapies. And don't look to industry to invest here! They're realizing a lot more profits from treating chronic life style diseases than cancer. As a researcher for the past 30 years, I have witnessed many of these discoveries, but also the soul crushing budget cuts of the past twenty - both in academics and in industry. Also I have observed the heedless squabbling in Pharma and Biotech over intellectual property control and profits. Congress, CEO's and the other wealthy citizens of our nation need to ask themselves: would I be so happy with a tax break if it means my wife or daughter would not benefit from a highly effective treatment or cure for breast cancer?? Would I gladly place on the tomb stone of a young father who died needlessly of lung cancer or a child who unnecessarily succumbed to a brain tumor - they died for smaller government and lower taxes?!
LKF
NY
Absolutely fascinating.
I would point out that anthropomorphising cancer as something to be outwitted is perhaps part of the problem we have in solving this disease. Cancer is not an enemy in any traditional sense and as far as we know has no evil intent. Cancer is a very complex system more akin in some ways to a "black box" problem. When we solve it, we will also, of necessity, solved many other biological mysteries which will undoubtedly form the foundation for wide ranging scientific breakthroughs.
Freeman
Memphis, TN
For those who think scientists, including those in Big Pharma, are uninterested in finding a cure for cancer, realize that a number of us entered the field because family members died of cancer. We might someday get cancer and we are almost assured that friends and relatives will get cancer. Why wouldn't we want to cure it?
Greenpa
Minnesota
"Most DNA, for example, was long considered junk — a netherworld of detritus that had no important role in cancer or anything else. Only about 2 percent of the human genome carries the code for making enzymes and other proteins, the cogs and scaffolding of the machinery that a cancer cell turns to its own devices."
HEAR ME. Hear me well. That statement- so often repeated as a pet idea by the press- has ALWAYS been considered GARBAGE science- by all first class evolutionists and geneticists.
It's an idiotic idea- with an abundance of hard data that have always contradicted it. If the scientist you are interviewing repeats that nonsense giving it any credence whatsoever- you know you are talking to a second rate intellect. And the rest of what they have to offer is likely second rate, also.
Rankin Fyle
Atlanta
60% of all cancers are environmental in origin. Improve public health and reduce cancer-duh
sas
new york
although i support continuing research to understand cancer at a cellular level, i am deeply suspicious of a mindset that refuses to acknowledge the likely possible preponderance of cancer cures and preventatives -- simply because they might not be profitable to big pharma/big medicine.
are cancer researachers REALLY interested in finding low-cost, low technology winners in the 'war' on cancer?
i doubt it.
sas
new york
here's a 4th theory: whether by mechanism 1, 2 or 3, our bodies are CONSTANTLY subjected to cell abnormalities -- cancers! -- that may result in life-threatening disease. however, properly nourished and healthy cell tissue normally resists such growth and metastasis. isolating and promoting to the public the foods that resist -- and, in fact may obliterate such cancers at an early stage of growth -- is the most effective artillery in the 'war' on cancer.
Sylvia
Ridge, NY
If you look at the ads for ridiculous products devised and sold by the pharmaceutical companies, it's hard to imagine that the industry would really like to see a cure for cancer. By sticking to an M.O. of "never kill 'em and never cure 'em," they can rest assured of their continued financial success. To the extent that research depends on the support of big pharma, it is limited in its scope.
Tortuga
Colorado
Sooner or later, "science" will realize that health begins and ends in the human microbiome. Take heed now: support your microbiome with supplemental beneficial microbes (e.g., acidophilus) and then feed your microbes with probiotics.
pierre
nyc
It's great, fascinating and also, of course, amazing to see top scientists enjoying themselves with "something" that is killing people Something that is...preventable. More screens to catch tumors early and ending the production of cigarettes would, for the most part, solve the problem. But no, let's keep alive that horrible disease, let's wait until it becomes deadly and incurable in one's body. That is SO interesting to observe...This is the exact same thing with sociologists enjoying studying poor and dangerous ghettos instead of calling for their destruction.
MMG
Puerto Rico
When I was growing up I was taught to wash my hands before eating to keep microbes from entering my stomach. Later on I learned about helpful bacteria. Then I learned about cancer causing bacteria and viruses. Now I have learned that I AM bacteria. I think maybe I no longer need to wash my hands before eating since I do not need to prevent the owners of my body from entering it.
It is mind blowing to think how little we really know. How humbling.
Winfield J. Abbe
Athens, GA
To: Yellowdog, #38: Your unenlightening propaganda comment has not only been posted but highlighted by the prejudiced anonymous censors to these comments, but neither of my two posts, which answer your comment even with references, have been posted.
How long should the cancer generals be paid billions of public and private dollars to beat a dead horse? At some point one must admit they have dismally failed and are dismally failing. They have squandered over $105 billion according to a NYTimes article last year, but some estimates rise to $1 trillion, but the cancer generals cannot even tell us what cancer is, let alone how to cure and prevent it!
Big Pharma is not the answer, but the problem. It has obstructed, or is behind the obstruction by the FDA Gestapo, of every non orthodox less toxic treatment, which is why none are legally available. All orthodox cancer treatments are life threatening and can and do kill patients every day. One cancer victim in the U.S. dies every minute either from cancer, treatment or both.
No, the cancer generals don't need more support, they need to be fired and prosecuted for scientific misconduct, fraud, medical quackery and crimes against humanity.
Unlightening propaganda comments like yours and unenlightening propaganda articles like this one are not helpful. The pharmaceutical companies have so much money they can and do buy anything, any lawmaker and any government. They are secret corrupt cesspools. They are just as corrupt as the illegal drug trade except they are legal and kill about 270 unwitting victims every day.
Winfield J. Abbe, Ph.D., Physics
References:
"The Truth about Hydrazine Sulfate-Dr. Gold Speaks", www.hydrazinesulfate.org.
"The Hidden Story of Cancer", B. Peskin, Pinnacle Press, Houston, 2010.
"The Cancer Industry" by Ralph W. Moss, Ph.D., Equinox Press, NY, 1996, 1989, or 1980 as The Cancer Syndrome.
www.preventcancer.com
"Cancer and the Search for ...biochemical inhibitors,E.J. Hoffman
NJBOY234
Paramus, NJ
@Med Student Boston, MA comment #52 - I find it very hard to trust people like you when all you want to do is get rid of those with a differing view. I find it rather sad that most Medical Doctors are not trained in nutrition and have a very weak understanding of it.
While some people go overboard with the vitamin theories, one must have enough sense to realize that of course diet and nutrition has an effect on our health. And, because you and your colleagues do not know what causes cancer or can stop it (you admitted that yourself) you should take more time looking into nutritional factors and how it can help in the fight against cancer and terrible diseases.
Don't you agree?
sarah Dixon
Malibu, California
Well, well, well! Didn't we already know that we're, among other elements, a collection of microbes, friendly and otherwise, parasites, enzymes, a small universe, healthy when in balance, ill when out of balance? And, knowing this we submit ourselves to all sorts of way to kill our friendly bacteria. Knowing that our friendly bacteria are required for digestion of nutrients (and who knows what other activities), we thoughtlessly lace our food and the soil in which it grows with agents that kill those vital bacteria! Why do we do that? We do that because farmers, stockmen, and purveyors of the nutrients we require and enjoy want the easy way. They even convince us that they protect us with preservatives, insecticides, grains laced with herbicides, sugars that throw our systems out of balance. Think about it. This is why more and more people are trying to build soil, grow organically, avoid additives in our diets, and fight for clean air and water.
S.E.H.
Massachusetts
The much praised "Hallmarks of Cancer" article, however beautifully written,does more harm than good. It cements misconceptions, another mirror in the hall of mirrors that the cancer community is.
It reflects a reductionist, uni-dimensional, linear deterministic mindset when cancer is a complex, non-linear stochastic process with auto-causative loops that help sustain itself and defies our linear thinking.
Believing that we need just to identify and attack the central molecular pathway that causes any of these "hallmarks" (unlimited cell proliferation, immune evasion etc), so to speak, target cancer's Achilles heel, is akin to solving an economic crisis solely by cutting spending or solely by or with a single financial bailout. Economic crises are self-sustained deviations from the norm utilizing a newly rewired network of elementary transactions inherent to the system, trapped in a dynamics in which the rich get richer - mathematically this is precisely like cancer!
People tend to reduce complex dynamics to a singular cause that epitomizes a point of attack. This somehow brings a type of emotional gratification that is misguiding. But this is precisely what modern drug company do when they develop drugs that target a single faulty pathway. Yet big pharma continues to do so because such target-selective drugs can be patented (whereas the advice to eat more vegetables cannot) and are expensive, and their simplistic mechanism of action is music to the ear of the FDA. Such target specific drugs typically, when approved, generate > $ 1 billions revenue/year (e.g. Genentech's Avastin(R) ) - just to extend life by a couple of month...
However, if the "hallmarks" article continue to set the standard of thinking and if drugs based on such naive-reductionist theories that extend life by merely 3 month can bring $1 billion revenues - who then is motivated to look outside the box and develop new drugs based on novel holistic embrace of the very complexity of cancer?
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