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What is it?

A cancer is an uncontrolled proliferation of cells.
See Cancer Cells in Culture for other properties of cancer cells.

Cancer is a Genetic Disease

Cancer cells contain many mutated genes, in some cases over 100. Most of these are "passenger" mutations probably having no effect on the malignant process. They are just as likely to be found in healthy cells. However tumor cells also contain a small number (2–8) of mutant genes that are found so frequently in tumors that they are probably responsible for the malignancy. These are called "driver" mutations.

Some 300 driver mutations have been identified. These fall into several categories.

Progression to Cancer

What probably happens is:

So even though all the malignant cells in a cancer are descended from a single original cell — and thus are members of a single clone — they are no longer genetically-identical. As the tumor develops, its various cells develop a variety of additional mutations, and these give rise to "subclones" of varying degrees of malignancy with varying

These findings should stimulate a reexamination of the use of chemotherapy. Evidence: In a group of patients with chronic lymphocytic leukemia, those receiving chemotherapy survived for shorter periods than those that did not.

Cancer Stem Cells

Stem cells are cells that divide by mitosis to form either

There is growing evidence that most of the cells in leukemias, breast, brain, skin, ovarian, and colon cancers are not able to proliferate out-of-control (and to metastasize). Only those members of the clone that retain their stem-cell-like properties (~2.5% of the cells in a tumor of the colon) can do so.

There is a certain logic to this. Most terminally-differentiated cells have limited potential to divide by mitosis and, seldom passing through S phase of the cell cycle, are limited in their ability to accumulate the new mutations that predispose to becoming cancerous. Furthermore, they often have short life spans — being eliminated by apoptosis (e.g., lymphocytes) or being shed from the tissue (e.g., epithelial cells of the colon). The adult stem cell pool, in contrast, is long-lived, and its members have many opportunities to acquire new mutations as they produce differentiating daughters as well as daughters that maintain the stem cell pool.

Colon Cancer

Colon cancer: Examination of the cells at the earliest, polyp, stage, reveals that they contain one or two mutations associated with cancer. Frequently these include

Note that each of the mutations shown probably occurs in one cell of the type affected. This cell then develops into the next stage of the progression. The mutations do not necessarily occur in the order shown, although they often do.

The cells in the later stages of the disease show a wide variety of additional mutations including point mutations, deletions, translocations, and duplications. A handful (2–8) of these are "driver" mutations playing significant roles in the malignancy. The others are probably "passenger" mutations that play no role in the process.

A similar stepwise genetic progression occurs in

It is becoming clear that this is what one should expect. What distinguishes one cancer from another is not the tissue of origin, but the particular accumulation of mutations that drive its growth. Once these are identified, it will eventually be possible to choose chemotherapeutic agents that target the particular pathways in a given cancer — personalized therapy. [Link to an example.]

Cancer is more common in men than in women.

Over a lifetime, men are half-again more likely to develop cancer than women. This effect seems not to be caused by any differences in lifestyle or exposure to carcinogens.

Why this bias?

One possibility is the presence of a few tumor suppressor genes on the X chromosome. As men have only a single X chromosome, they have only one copy of each of these tumor suppressor genes and thus a mutation in one of them would remove the brake on tumor formation. Women, with their two X chromosomes, would still have a functioning copy.

But there is a problem with this explanation. The phenomenon of X-chromosome inactivation causes every cell in the woman's body to contain one active and one inactive X chromosome seemingly putting her in the same situation as males. As it turns out, however, not all the genes on the inactive chromosome are actually inactive. Some 50 of the approximately 800 genes on the X chromosome continue to be active and these include some tumor suppressor genes. So females retain their advantage in avoiding cancer.

Cancers become more common as one gets older.

The graph shows the death rate from cancer in the United States as a function of age. The graph can best be explained by the need for an accumulation of several "hits" to genes that control the cell cycle before a cell can become cancerous.

Sequencing of the genomes of a sample of single cells from different parts (including metastases) of a tumor in a single patient reveals in each a suite of mutations some of which are found in all samples, others in some, others in only a single sample. The gene or genes found in all samples represent those that began the malignant process. Estimating the mutation rate in these clones and subclones indicates that these tumors actually got their start 20–30 years before.

The graph also explains why cancer has become such a common cause of death during the twentieth century. It probably has very little to do with exposure to the chemicals of modern living and everything to do with the increased longevity that has been such a remarkable feature of the 20th century. A population whose members increasingly survive accidents and infectious disease is a population increasingly condemned to death from such "organic" diseases as cancer.

Causes of Cancer

Cancers are caused by

Viruses and Cancer

Many viruses have been studied that reliably cause cancer when laboratory animals are infected with them. What about humans? The evidence obviously is indirect but some likely culprits are:

But note! Clearly viral infection only contributes to the development of cancer.

So again it appears that only if an infected cell is unlucky enough to suffer several other types of damage will it develop into a tumor.

Nevertheless, widespread vaccination against these viruses should not only prevent disease but lower the incidence of the cancers associated with them.

Are Cancers Contagious?

The short answer is NO.

The reason: Cancer cells, like all cells in the body, express histocompatibility molecules on their surface. So like any organ or tissue transplant between two people (other than identical twins), they are allografts and are recognized and destroyed by the recipient's immune system [Link].

However, there are some exceptions.
  1. Although tumors are not transmissible, viruses are. So any of the viruses described in the previous section can be spread from person to person and predispose them to the relevant cancers.
  2. There have been a number of cases where, unbeknownst to the surgeon, an organ (e.g., a kidney) from a donor with melanoma has allowed the growth of the same melanoma in the recipient. Transplant recipients must have their immune system suppressed if the transplant is not to be rejected, but their immunosuppression also prevents their immune system from attacking the melanoma cells. Stopping immune suppression cures the recipient (but also causes loss of the kidney).
  3. Canine transmissible venereal tumor (CTVT). This tumor spreads from dog to dog during copulation. Although MHC molecules are only weakly expressed on the tumor cells, they do eventually cause the tumor to be rejected.
  4. Devil facial tumor disease (DFTD). The carnivorous Tasmanian devil is a marsupial living in Tasmania, Australia. The population is threatened by a facial cancer that is spread through bites. The population is highly inbred, thus closely-related genetically, and Class I MHC molecules are not expressed on the tumor cells. So it may be these factors that allow the tumor to grow unchecked.
  5. The soft-shell clam, Mya arenaria, along the North Atlantic coast of North America is being devastated by a leukemia that spreads from animal to animal perhaps as these filter feeders ingest sea water in which leukemic cells have been shed. These mollusks are invertebrates and lack powerful tissue rejection molecules like the MHC of vertebrates.
  6. There are extremely rare cases where a pregnant woman with cancer (usually leukemia, lymphoma or melanoma) has transmitted the cancer across the placenta to her fetus (whose immune system has yet to develop). In the months after they are born, they may succumb to the disease, but occasionally, an infant will be able to reject the cancer.

The Hallmarks of Cancer

In the year 2000 Douglas Hanahan and Robert Weinberg published a paper — The Hallmarks of Cancer — outlining 6 characteristics that are acquired as a cell progresses toward becoming a full-blown cancer. In the 4 March 2011 issue of Cell, they add 4 other features.

  1. Uncontrolled proliferation. See above.
  2. Evasion of growth suppressors. Among the many mutations found in cancers, one or more inactivate tumor suppressor genes. [Link to a discussion.]
  3. Resistance to apoptosis (programmed cell death). Link to a discussion.
  4. Develop replicative immortality; i.e., avoid the normal process of cell senescence. Link to a discussion.
  5. Induce angiogenesis; that is, promote the development of a blood supply. Link to a discussion.
  6. Invasion and metastasis — the ability of tumor cells to invade underlying tissue and then to be carried to other parts of the body where secondary tumors develop (metastasis). During this process, the normal adhesion of cells to each other and to the underlying extracellular matrix (ECM) are disrupted.
  7. Genomic instability. Cancer cells develop chromosomal aberrations and many (hundreds) of mutations. Most of the latter are "passenger" mutations, but as many as 10 may be "drivers" of the cancerous transformation.
  8. Inflammation. Tumors are invaded by cells of the immune system, which promote inflammation. One effect of inflammation is the production of reactive oxygen species (ROS). These damage DNA and other molecules.
  9. Changed energy metabolism. Even if well-supplied with oxygen, cancer cells get most of their ATP from glycolysis not cellular respiration.
  10. Evade the immune system. This is described in the page Immune Surveillance. Efforts to manipulate the immune system to combat cancer are described in the page Cancer Immunotherapy.

Summary: A Unifying View of Cancer

All cancers are genetic diseases characterized by an uncontrolled proliferation of their cells.

These cells arose from a single cell that began to lose control of its rate of division because of an accumulation of certain mutated genes (DNA).

A cell destined to give rise to a cancer can have acquired the mutations

  1. by inheritance (e.g., APC, BRCA1)
  2. spontaneously — mutations that arise every time the over 6 billion “letters” of our DNA are copied in preparation for making two cells from one. This explains why cancers are more common in tissues that have high rates of cell division (e.g., blood) than in tissues that do not (e.g., heart).

    Although copying DNA is remarkably accurate, every newly-formed cell probably contains some 3 new errors (mutations). Most of these (“passenger” mutations) occur in regions of our DNA that play no role in cell division. But mutations (“driver” mutations) in two dozen or so genes that do control cell division can propel the cell along the path to cancer.

  3. induced by external (environmental) agents that increase the rate of mutation. These include:
Current estimates are that only one-third of human cancers arise from category 3 and thus could be avoided by changes in life-style (e.g., smoking, diet, workplace safety). The rest (two-thirds) are "bad luck".

Other Pages on Cancer

"The Causes and Prevention of Cancer" by Bruce Ames
Three cancers of special biological interest: [Burkitt's lymphoma] [ Chronic Myelogenous Leukemia] [lung cancer]
The role of the oncogene BCL-2 in B-cell leukemia and lymphoma.
Estimating the risk of cancer from radiation and chemicals in the environment.
Cancer Chemotherapy
Immunotherapy of Cancer
Immune Surveillance of Cancers
Fighting cancer with angiogenesis inhibitors.

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11 January 2021