Open Questions: Cancer

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See also: Cell biology -- Molecular biology and genetics

Cancer is getting broken down into more and more separate diseases as we're able to subdivide the diagnostics and the genes associated with them, but we're starting to take a different view of viewing cancer as an overall disease, and we're looking at gene space where we think it can be targeted to deal with cancer as a whole.

J. Craig Venter


Introduction

Causes of cancer

Cellular biology of cancer

DNA damage and repair

Cancer and inflammation

Cancer stem cells

Cancer precursors

Metastasis

Stages of cancer

Natural defenses against cancer

Cancer therapies

Open questions


Recommended references: Web sites

Recommended references: Magazine/journal articles

Recommended references: Books

Introduction

Even though there is just one name, "cancer", it is sometimes helpful to think of the name as referring to a number of different diseases. Or, perhaps, if you wish, it may be useful to think of "cancer" as a type of disease, and there are a number of different varieties of the disease within the type.

In fact, there are about 200 anatomically different types of cancer. And if further distinctions are made based on the underlying molecular causes, it is estimated there may be 250,000 different types. Indeed, each individual case of cancer may arise through a slightly different sequence of cellular changes.

There are certainly many similarities among the diseases of this type. For example:

  • A cancer generally involves the unchecked and harmful proliferation of cells of a particular kind, such as cells in the skin, lungs, breast, or prostate gland.
  • This unchecked proliferation always results from damage to cellular DNA, which becomes unable to keep normal control over cell division.
  • Cells that have become cancerous usually cease to be able to perform their normal function in the body as a part of some specific organ type.
  • Cancer becomes fatal either when the organ where it occurs ceases to be able to perform its normal function, or when cancer cells "metastasize" and spread their uncontrolled proliferation to other parts of the body.

At the same time, it is helpful to regard different types of cancer as distinct diseases for various reasons:

There are various ways to classify the different diseases which are types of cancer. The most common way, and perhaps the most useful to begin with, is simply by the part of the body or the organ which is affected.

Here is a table of the most common types of cancer, further broken down by estimated new cases and estimated deaths (in 2004), and even further by sex. (The percentages refer to relative frequency in a particular column.)

Cancer types
Estimated new cases Estimated deaths
Male Female Male Female
Prostate - 33% Breast - 32% Lung & bronchus - 32% Lung & bronchus - 25%
Lung & bronchus - 13% Lung & bronchus - 12% Prostate - 10% Breast - 15%
Colon & rectum - 11% Colon & rectum - 11% Colon & rectum - 10% Colon & rectum - 10%
Urinary bladder - 6% Uterine corpus - 6% Pancreas - 5% Ovary - 6%
Melanoma - 4% Ovary - 4% Leukemia - 5% Pancreas - 6%
Non-Hodgkin lymphoma - 4% Non-Hodgkin lymphoma - 4% Non-Hodgkin lymphoma - 4% Leukemia - 4%
Kidney - 3% Melanoma - 4% Esophagus - 4% Non-Hodgkin lymphoma - 3%
Leukemia - 3% Thyroid - 3% Liver - 3% Uterine corpus - 3%
Oral caviity - 3% Pancreas - 2% Urinary bladder - 3% Multiple myeloma - 2%
Pancreas - 2% Urinary bladder - 2% Kidney - 3% Brain - 2%
All other - 18% All other - 20% All other - 21% All other - 24%
Source: American Cancer Society - Cancer Statistics Presentation 2004


Causes of cancer:


Open questions

What makes environmental and dietary substances carcinogenic?
At what points in the development of a cancer is the process most easily interrupted?
How do very large animals like elephants and whales avoid cancer?
Are there blood tests which can detect cancer at an early stage?
What is the role of the immune system in dealing with cancer?
Why is it so hard to develop therapeutic drugs to treat cancer, even though we know so much about the signaling pathways that facilitate cancer?


Recommended references: Web sites

Site indexes

Open Directory Project: Cancer
Categorized and annotated links. A version of this list is at Google, with entries sorted in "page rank" order. May also be found at Netscape.
Galaxy: Cancer
Categorized site directory. Entries usually include descriptive annotations.

Sites with general resources

MedlinePlus: Cancers Topics
MelinePlus provides links to many types of information on almost every medical topic -- news, overviews, symptoms and diagnosis, genetics, research, etc. This page gives links to pages on specific types of cancer.
OncoLink
A general portal for cancer-related information. Many links are classified by types of cancer. Other features include news, discussion forums, FAQs, and other services for patients and medical specialists.
National Cancer Institute
This U. S. government site provides a huge mine of resources on cancer, including many overview articles, fact sheets, recent news, information on clinical trials, and general cancer information.
Plans and Priorities for Cancer Research
This is the budget proposal of the U. S. National Cancer Institute for 2004. It has special emphasis on important areas of cancer research. Similar but more recent information can be found in the budget proposals for 2005, 2006, and 2007.
New Scientist Special Report on Cancer
Primarily offers links to many news articles from the past several years of New Scientist magazine. But there are also other features, including facts and figures, external links, frequently-asked questions, and a short bibliography.
Nature Cancer Update
Excellent portal/gateway for cancer research. Provides general and specialist news on cancer research, and other services for professionals.
BioOncology OnLine
"The Web resource for biologic oncology". Sponsored by Genentech.
Compute Against Cancer
Cooperative distributed computing project to assist in cancer research.
Intel-United Devices Cancer Research Project
Another Cooperative distributed computing project to assist in cancer research.
The Cancer Genome Atlas
Web site of TCGA project of the U. S. National Cancer Institue. "The Cancer Genome Atlas (TCGA) is a comprehensive and coordinated effort to accelerate our understanding of the molecular basis of cancer through the application of genome analysis technologies, including large-scale genome sequencing."
The Cancer Genome Project
"The Cancer Genome Project is using the human genome sequence and high throughput mutation detection techniques to identify somatically acquired sequence variants/mutations and hence identify genes critical in the development of human cancers." Web site includes news, external links, lists of publications, and databases of accumulated data, such as the Cancer Gene Census, Catalog of Somatic Mutations in Cancer (COSMIC), and the CGP Copy Number Analysis.
Cancer Prevention and Control
Site maintained by the U. S. Centers for Disease Control and Prevention. Provides information on different types of cancer, fact sheets, and some scientific articles.
Cancer Research UK - Science and Research
Web pages of a UK organization that helps coordinate and fund cancer research, part of the Cancer Research UK site.
National Toxicology Program Report on Carcinogens
This is the U. S. government's official list of known carcinogens. See in particular the 10th Report on Carcinogens, which lists details of 228 substances "known" or "reasonably anticipated" to pose a cancer risk. (Individual sections are in PDF format.)
American Institute for Cancer Research
Home page of an organization which "supports research into the role of diet and nutrition in the prevention and treatment of cancer". It advocates a predominantly plant-based diet and consuming more vegetables, fruits, whole grains and beans. Further explanation of this position is provided in the section of general information on diet & cancer.
Memorial Sloan-Kettering Cancer Center
Web site of a major cancer research and treatment center. The site provides extensive information on all types of cancer, genetics of cancer, and cancer risk reduction.
The Oral Cancer Foundation
"The Oral Cancer Foundation is a national public service, non-profit entity designed to reduce suffering and save lives through prevention, education, research, advocacy, and support." The site contains a lot of information pertaining to oral and other cancers, especially here.

Surveys, overviews, tutorials

Category: Oncology
Topic category from Wikipedia.
Cancer
Article from Wikipedia. See also Oncology.
Cancer (ClearlyExplained.com)
Overview in several parts by Richard Conan-Davies.
Understanding Cancer Series
A series of tutorials in slide format on topics related to cancer, such as cancer genomics, molecular diagnostics, and angiogenesis
DNA's repair system studied in hopes of better cancer treatments
July 2009 article about how problems in the cell's natural systems for detecting and repairing damage to DNA can lead to cancer.
Can you catch cancer?
January 2006 article at Guardian Unlimited about types of infections that can cause cancer.
Biology of Cancer
A ScienceWeek "symposium" consisting of excerpts and summaries of articles from various sources.
Cancer Medicine
Complete online textbook. Index. Part of the NCBI Bookshelf.
Cancer Death -- Causes & Prevention
Detailed survey by Ben Best.
Cancer: diet and physical activity's impact
An informative article published by the World Health Organization.
Genetic Tests May Reveal Source of Mystery Tumors
March 2009 New York Times news feature about new tests being developed to determine the origin of metastatic tumors.
Leukemia Cells Flash Fake Protein "ID" to Dupe the Immune System
Short August 2009 Scientific American article "A crucial protein on the surfaces of malignant cells shields them from destruction, but it could also provide a new way to attack cancer."
Cancer Vaccine: Looking Beyond Tumor Size
November 2008 Scientific American article. "Proponents see hope in changing cancer vaccines' bad reputation."
What makes pancreatic cancer so deadly?
August 2008 Scientific American "Ask the Experts" article on the reasons why pancreatic cancer is so difficult to treat.
Lung Cancer
December 2006 Scientific American Sidebar about the experimental lung cancer vaccine Stimuvax.
Leafy Letdown
April 2005 Scientific American In Focus article, subtitled "Eating vegetables seems to do little in warding off cancer."
New Light on Breast Cancer
August 2002 Scientific American In Focus article, subtitled "Laser light and thermal heat could help improve the accuracy of mammograms"
Cancer in the Crosshairs
Brief September 2001 Scientific American article about the new cancer drug Gleevec.
Breast Cancer: Knocking Out a Killer
June 2001 Scientific American In Focus article, subtitled "Test-tube studies have uncovered key facts about the breast cancer gene BRCA1, but new animal models of the disease promise to reveal much more."
Solid Proof of Immunity against Cancer
April 2001 Scientific American news article about how the immune system can prevent tumor formation.
A New Skin Cancer Culprit
February 2001 Scientific American news article about a mutation implicated in squamous cell carcinoma.
How Breast Cancer Starts and Spreads
February 2001 Scientific American new article about how breast cancer starts when cells become able to avoid senescence.
New Target for Melanoma Treatment?
January 2001 Scientific American news story about a new gene found to be involved in the resistance of melanoma to chemotherapy.
Do the telomeres in cancer cells shrink?
January 2001 Scientific American "Ask the Experts" article. Response by Jerry W. Shay.
Coffee Reduces Risk of Bladder Cancer
December 2000 Scientific American news article about epidemiological evidence that coffee may protect against bladder cancer in smokers.
Clue to Cancer in Cell-Death Proteins
October 2000 Scientific American news article about proteins involved with apoptosis of T cells.
How close are we to developing an effective gene therapy for treating cancer?
October 1999 Scientific American "Ask the Experts" article.
Soy Estrogens: Too Much of a Good Thing
June 2001 news article in Science News, about how genistein, an isoflavone that is a chemical analog of estrogen found in soy-based foods, seemed to promote cancer in mice.
Anticancer Protein Locks onto DNA
May 2001 news article in Science News, about how mutations of the BRCA1 gene lead to risk of breast cancer by interfering with DNA repair function of the BRCA1 protein.
Silencing the BRCA1 gene spells trouble
April 2000 news article in Science News about how an epigenetic change (hypermethylation) interfers with the promoter region for BRCA1, resulting in inhibition of BRCA1 protein production.
Fused cells hold promise of cancer vaccines
March 2000 news article in Science News about an experimental cancer vaccine that uses tumor cells fused to immune system cells.
Soy Slashes Cancer-fostering Hormones
March 2001 news article in Science News, about how large quantities of soy in a woman's diet reduces blood concentrations of female sex hormones.
Progestin Adds to Breast Cancer Risk
March 2000 news article in Science News, about how hormone replacement therapy using estrogen and progestin may raise the risk of breast cancer.
Is Your Stomach Bugging You?
October 1999 news article in Science News, about controversy over whether the benefits of Helicobacter pylori outweigh the problems (stomach ulcers, cancer).
Nighttime illumination might elevate cancer risk
October 1998 news article in Science News, about a possible relationship among exposure to light, melatonin production, and cancer.
Missing Enzyme Incites Cancer Debate
October 1997 news article in Science News, about how tumors can form from cells even of mice which are deficient in telomerase.
Can a pineal hormone head off everything from breast cancer to aging?
May 1995 news article in Science News, about possible links between melatonin and various pathologies, including cancer.
Taking Aim at p53
January 1999 news article from The Scientist. "Researchers are targeting the tumor suppressor with vectors, viruses, and small molecules."
Heartburn link to cancer
April 2001 news article about how gastro-esophageal reflux disease may be associated with esophageal cancer.
Enzyme can block tumour-feeding blood vessels
December 2000 news article about discovery of an enzyme that inhibits angiogenesis.
New cancer drug starves tumours
October 2000 news article about a potential drug (glutathionarsenoxide) to inhibit tumor angiogenesis.
New research links breast cancer to genetics
October 2000 news article about discovery of a gene (CYP-17) that may indicate increased risk of breast cancer.
Testicular cancer linked to male infertility
September 2000 news article about discovery of a correlation between infertility problems and risk for testicular cancer.
New targets to stop cancer growth
August 2000 news article about genes in the blood vessels of tumors that may lead to a way to inhibit tumor angiogenesis.
Drinking while smoking doubles lung troubles
June 2000 news article about the discovery of an association between the long term smoking and drinking habits of lung cancer patients and mutations in the tumor-suppressing p53 gene.
New protein a natural defence against cancer
April 2000 news article about a chemokine protein that can slow tumor growth.
Skin cancer test gives early warning
April 2000 news article about a genetic test that indicates susceptibility to skin cancer.
Gene for testicular cancer found
February 2000 news article about discovery of a gene on the X chromosome that increases risk of testicular cancer.
Turning to Telomerase As Antisense Strategies Emerge, Basic Questions Persist
January 1999 news article in The Scientist about the possibility of using antisense technology to reduce the expression of telomerase in cancer cells.
More accurate test for cervical cancer
December 1998 news article about a new test for cervical cancer that uses antibodies to detect abnormal cells.


Recommended references: Magazine/journal articles

It's a Cell-Eat-Cell World
Jef Akst
The Scientist, August 2011
For more than 100 years, pathologists have observed cancer cells engulfing other live cells, but scientists are only now beginning to understand how it happens and what it means for tumorigenesis.
An Aspirin for your Cancer?
Giorgio Trinchieri
The Scientist, April 2011
Can tumors - which can originate from, and often resemble, chronically inflamed tissue - be curtailed using familiar anti-inflammatory agents, without their side effects?
Taking Aim at Melanoma
Keith T. Flaherty
The Scientist, April 2011
Understanding oncogenesis at the molecular level offers the prospect of tailoring treatments much more precisely for patients with advanced cases of this deadliest of skin cancers.
Epigenetic Changes in Cancer
Manuel Esteller
The Scientist, March 2011
The study of how covalent marks on DNA and histones are involved in the origin and spread of cancer cells is also leading to new therapeutic strategies.
Interfering with Cancer
Katherine Hyde; Paul Liu
The Scientist, January 2011
MicroRNAs may drive the development of leukemia.
The Immune System vs. Cancer
Mark J. Smyth
The Scientist, November 2009
The comeback of an old idea in immunology prompts a rethink of cancer progression and approaches to treatment.
New Smoking Gun?
Jef Akst
The Scientist, April 2010
Teams come together to target the genes behind lung cancer, but the hunt is far from over.
Cancer's culprit
Elie Dolgin
The Scientist, April 2009
Breast cancer's genetic profile calls the cancer stem cell hypothesis into question.
Do White Blood Cells Make Cancer Deadly?
Charles Q. Choi
Scientific American, January 2009
Could Our Own Proteins Be Used to Help Us Fight Cancer?
Pramod K. Srivastava
Scientific American, July 2008
New Breast Cancer Treatments Help Sufferers Gain Ground
Francisco J. Esteva; Gabriel N. Hortobagyi
Scientific American, May 2008
Taming Vessels to Treat Cancer
Rakesh K. Jain
Scientific American, January 2008
Restoring order to the chaotic blood vessels inside a tumor opens a window of opportunity for attacking it. Surprisingly, drugs meant to destroy vasculature can make the repairs and may help reverse conditions that lead to cardiovascular disease and blindness.
Taking a Jab at Cancer
Patrick Barry
Science News, August 11, 2007
Combined with drugs, vaccines against tumors may finally be working.
Is Chronic Inflammation the Key to Unlocking the Mysteries of Cancer?
Gary Stix
Scientific American, July 2007
Understanding chronic inflammation, which contributes to heart disease, Alzheimer's and a variety of other ailments, may be a key to unlocking the mysteries of cancer. [Originally published as A Malignant Flame.]
Chemo Control
Jeneen Interlandi
Scientific American, April 2007
Mapping the Cancer Genome
Francis S. Collins; Anna D. Barker
Scientific American, March 2007
Deadly Dialogue
Christine Soares
Scientific American, February 2007
Cancer Clues from Pet Dogs
David J. Waters; Kathleen Wildasin
Scientific American, November 2006
Stem Cells: The Real Culprits in Cancer?
Michael F. Clarke; Michael W. Becker
Scientific American, July 2006
A dark side of stem cells--their potential to turn malignant--is at the root of a handful of cancers and may be the cause of many more. Eliminating the disease could depend on tracking down and destroying these elusive killer cells.
Overcoming Self
Gary Stix
Scientific American, July 2004
A company tries to turn the immune system against cancer.
The Ecology of Tumors
Parauc A. Kenny; Celeste M. Nelson; Mina J. Bissell
The Scientist, April 2006
By perturbing the microenvironment, wounds and infection may be key to tumor development.
Leukemia and Cancer Stem Cells
Irving Weissman; Michael Clarke
The Scientist, April 2006
Cancers and normal tissue stem cells have much in common: Both have self-renewal capacity, and both develop into differentiated progeny. But do true cancer stem cells exist? We believe that they do and that this realization will have a major impact on the understanding and treatment of cancers.
Stem cells for brain cancer
Peter B. Dirks
The Scientist, April 2006
Several groups showed that isolating stem cells from brain tumors yielded cells that could clonally form colonies of cells in vitro that expressed neural precursor markers and that could be replated to reform colonies demonstrating self-renewal.
The Root of BRCA1's Evil
Nicole Johnson
The Scientist, March 2006
Uncovering the mechanism of cancer-causing defects in a notorious oncogene.
Bright Lights, Big Cancer
Ben Harder
Science News, January 7, 2006
Melatonin-depleted blood spurs tumor growth.
Does Telomerase Moonlight?
Jerry W. Shay; Woodring E. Wright
The Scientist, February 2005
The enzyme may do more than maintain telomere length, but the verdict is still out.
Breast Cancer: The Big Picture Emerges
Ricki Lewis
The Scientist, October 2003
It's not just about BRCA genes anymore.
Tumor-Busting Viruses
Dirk M. Nettelbeck; David T. Curiel
Scientific American, October 2003
There is a sidebar: Targeting Melanoma
Untangling the Roots of Cancer
W. Wayt Gibbs
Scientific American, July 2003
T Cell Triumph
Diane Martindale
Scientific American, February 2003
Telomeres as the Key to Cancer
Jeffrey M. Perkel
The Scientist, May 2002
Could hundreds of mouse models be wrong?
Tracking Tumors
Damaris Christensen
Science News, March 2, 2002
DNA Chips Target Cancer
Marc Wortman
Technology Review, July/August 2001, pp. 50-55
By enabling the rapid identification of all of the many types of genes that may be expressed in cancerous cells, DNA microarrays should soon make diagnosis of cancer much more rapid and accurate. The same chips also play an important role in identification and testing of effective cancer drugs.
Understanding Cancer's Spread
Damaris Christensen
Science News, June 2, 2001, pp. 350-351
Discovering the mechanisms of cellular movement and growth is a key step to developing successful cancer therapies.
[References]
DNA Vaccines as Cancer Treatment
Edward P. Cohen, Edwin F. de Zoeten, Morton Schatzman
American Scientist, July-August 1999, pp. 328-335
"No longer limited to warding against infectious agents, vaccines may help treat diseases after they have been diagnosed."
Immune Attack on Cancer
Kathleen Fackelmann
Science News, June 13, 1998
Researchers spur the immune system to rout malignancies.
Metastasis
Cornelis J. F. VanNoorden, Linda C. Meade-Tollin, Fred T. Bosman
American Scientist, March-April 1998, pp. 130-141
Metastasis of cancer cells represents a major malfunction of the normal cell life cycle. Genetic abnormalities play a significant role.
How Cancer Arises
Robert A. Weinberg
Scientific American, September 1996, pp. 62-70
Distinctive chemical and genetic differences of cancer cells from normal cells have been identified.
How Cancer Spreads
Erkki Ruoslahti
Scientific American, September 1996, pp. 72-77
Various control mechanisms prevent normal cells from surviving anywhere other than where they "belong". Cancers metastasize by evading these controls.
Immunotherapy for Cancer
Lloyd J. Old
Scientific American, September 1996, pp. 136-143
Rapidly increasing knowledge of how the immune system works should lead to a variety of possible treatments for cancer. Among the more promising are vaccines that stimulate the immune system and monoclonal antibodies which can deliver toxic agents specifically to cancer cells.
New Molecular Targets for Cancer Therapy
Allen Oliff; Jackson B. Gibbs; Frank McCormick
Scientific American, September 1996, pp. 144-149
Cancer cells are characterized by specific DNA mutations which either produce a tendency to excessive proliferation or else disable mechanisms that resist this proliferation. Drugs that target such mutations specifically are therapeutically promising.
Fighting Cancer by Attacking Its Blood Supply
Judah Folkman
Scientific American, September 1996, pp. 150-154
Solid tumors such as occur in most forms of cancer consist of masses of cells which require a blood supply in order to grow. Cancer cells have mutations which allow them to turn on the development of capillaries to supply the needed blood. Drugs that inhibit this process of angiogenesis should be useful in treating cancers of this sort.
Sunlight and Skin Cancer
David J. Leffell; Douglas E. Brash
Scientific American, July 1996, pp. 52-59
The mechanism by which the ultraviolet component of sunlight induces skin cancer is a good example of carcinogenesis in general. The ultraviolet light causes a mutation in the p53 tumor-suppressor gene and also causes premature death of other cells which leads to selective favoring of cells with already damaged DNA.
Taxoids: New Weapons against Cancer
Nicolaou, Guy, Potier
Scientific American, June 1996
Taxol, a natural substance originally extracted from the bark of yew trees, was found to be very effective as a treatment for ovarian cancer. It can now be manufactured semisynthetically and appears to be very effective also with breast cancer, lung cancer, and melanoma.
Uncovering New Clues to Cancer Risk
Frederica P. Perera
Scientific American, May 1996, pp. 54-62
Now that we know much more about the molecular and cellular mechanisms by which cancer develops, we can use sensitive tests to detect risk factors like exposure to carcinogens or genetic defects. This new discipline is known as molecular epidemology.
Telomeres, Telomerase and Cancer
Carol W. Greider, Elizabeth H. Blackburn
Scientific American, February 1996, pp. 92-97
Chromosomal features known as telomeres seem to govern cell division in normal cells. The enzyme telomerase plays a fundamental role in the function of telomeres.
The Genetic Basis of Cancer
Webster K. Cavenee; Raymond L. White
Scientific American, March 1995, pp. 72-79
Two types of genetic defects contribute to the development of cancer -- defects that encourage cell proliferation and defects that weaken the inhibition of uncontrolled proliferation. An accumulation of such defects in a single cell must occur before cancerous growth commences.


Recommended references: Books

Mel Greaves -- Cancer: The Evolutionary Legacy
Oxford University Press, 2000
Greaves is a professor of cell biology and director of a major cancer research center. His book tackles the seemingly intractable question of what "causes" cancer, which has eluded any simple answer in terms of infection, genetic factors, or the like. The author proposes to apply new insights from evolutionary theory to the understanding of cancer. The book is relatively brief, yet it manages to deal very clearly with the nature of cancer, the etiology of the main types of cancer, and prospects for reducing the incidence of cancer and finding ways to treat it. This is highly recommended, and is one of the finest books around about any topic in science.
Gary D. Kruh; Kenneth D. Tew, eds. – Basic Science of Cancer
Current Medicine, 2000
This is not an easy volume to find, and it's intended for medical professionals. But scientifically-minded readers who peruse the 13 separately-authored papers in the book will be rewarded with at least a general understanding of the plethora of factors that subvert normal cell biology to produce a cancer cell. Readers should come equipped with a working knowledge of molecular cell biology, but need not memorize all the biochemical details presented here, if they aren't studying for an exam.
Robert A. Weinberg -- One Renegade Cell: How Cancer Begins
Basic Books, 1998
Weinberg is directory of the Oncology Research Laboratory at the Whitehead Institute, where much of the most significant research on cancer has been done. His book is relatively brief, yet covers most of the factors that are known to play a role in a cell's becoming cancerous. In brief, cancer results from mutations in cellular DNA which either lead to uncontrolled cell division or the failure to limit such division. Other factors which contribute to the metastasis of cancer are also discussesd.

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