A cancer is an uncontrolled proliferation of cells.
- In some the rate is fast; in others, slow; but in all cancers the cells never stop dividing.
- This distinguishes cancers — malign tumors or malignancies — from benign growths like moles where their cells eventually stop dividing.
- Cancers are clones. No matter how many trillions of cells are present in the cancer, they are all descended from a single ancestral cell. Evidence: Although normal tissues of a woman are a mosaic of cells in which one X chromosome or the other has been inactivated [Link], all her tumor cells — even if from multiple sites — have the same X chromosome inactivated.
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Cancers begin as a primary tumor. Most (maybe all) solid tumors shed cells into the lymph and blood. Most of these lack the potential to develop into tumors. However, some of the shed cells are able to take up residence and establish secondary tumors — metastases — in other locations of the body. Metastasis is what usually kills the patient.
- Cancer cells are usually less differentiated than the normal cells of the tissue where they arose. Many people feel that this reflects a process of dedifferentiation, but I doubt it. Rather, evidence is accumulating that cancers arise in precursor cells — stem cells or "progenitor cells" — of the tissue: cells that are dividing by mitosis producing daughter cells that are not yet fully differentiated (see below).
Cancer cells contain many mutated genes. These almost always include:
- mutations in genes that are involved in mitosis; that is, in genes that control the cell cycle.
- Oncogenes. Their mutated or over-expressed products stimulate mitosis even though normal growth signals are absent.
Examples:
These genes act as dominants; that is, only one of the pair need be mutated to predispose the cell to cancer.
- Tumor suppressor genes. These genes normally inhibit mitosis.
Example: the p53 gene product normally senses DNA damage and either halts the cell cycle until it can be repaired or, if the damage is too massive; triggers apoptosis.
Example: The MAD (="mitotic arrest defective") gene encodes a protein that binds to kinetochores until spindle fibers attach to them. If there is any failure to attach, MAD remains and blocks entry into anaphase (by inhibiting the anaphase promoting complex (APC).
Mutations in MAD produce a defective protein and failure of the checkpoint. The cell finishes mitosis but produces daughter cells with too many or too few chromosomes (aneuploidy). Aneuploidy is one of the hallmarks of cancer cells (> 90% of human cancers are aneuploid) suggesting that failure of the spindle checkpoint is a major step in the conversion of a normal cell into a cancerous one.
More on checkpoint genes.
Tumor suppressor genes are recessive; that is, either both copies must be mutated for their function to be lost or — more commonly — the healthy copy of the gene has been lost [More].
- Genes that regulate apoptosis. Mutations in these enable the cell to ignore signals telling it that it is irreparably damaged and should commit suicide.
- Genes that stimulate angiogenesis. Tumors, like any tissue, need a blood supply to bring food and oxygen and to take away wastes. So as it grows, a developing cancer must be able to stimulate the growth of new blood vessels into itself. This is done by the release of angiogenesis stimulants, e.g., vascular endothelial growth factor (VEGF), perhaps as an additional effect of mutated oncogenes or tumor suppressor genes.
- Metastasis genes: genes that enable cells of the tumor to separate from the primary tumor and migrate to other parts of the body. These can be:
What probably happens is:
- A single cell — perhaps an adult stem cell or progenitor cell — in a tissue suffers a mutation (red line) in a gene involved in the cell cycle, e.g., an oncogene or tumor suppressor gene.
- This results in giving that cell a slight growth advantage over other dividing cells in the tissue.
- As that cell develops into a clone, some if its descendants suffer another mutation (red line) in another cell-cycle gene.
- This further deregulates the cell cycle of that cell and its descendants.
- As the rate of mitosis in that clone increases, the chances of further DNA damage increases.
- Eventually, so many mutations have occurred that the growth of that clone becomes completely unregulated.
- The result: full-blown cancer. (Genetic analysis reveals an average of 63 mutations in pancreatic cancers; almost as many in one type of adult brain cancer, but only 11 somatic mutations in a case of brain cancer in a child.
Note that 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.
Cancer Stem Cells
Stem cells are cells that divide by mitosis to form either
- two stem cells, thus increasing the size of the stem cell "pool",
or
- one daughter that goes on to differentiate, and
one daughter that retains its stem-cell properties.
There is growing evidence that most of the cells in leukemias, breast, brain, skin, 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:
- begins with the development of polyps in the epithelium of the colon.
Polyps are benign growths.
- As time passes, the polyps may get bigger.
- At some point, nests of malignant cells may appear within the polyps
- If the polyp is not removed, some of these malignant cells will escape from the primary tumor and metastasize throughout the body.
Examination of the cells at the earliest, polyp, stage, reveals that they contain one or two mutations associated with cancer. Frequently these include- the deletion of a healthy copy of the APC (adenomatous polyposis coli) gene on chromosome 5 leaving behind a mutant copy of this tumor suppressor gene
Two results:
- One of the functions of the APC gene product is to destroy the transcription factor β-catenin thus preventing it from turning on genes that cause the cell to divide [Link]. With no, or a defective, APC protein, the normal brakes on cell division are lifted.
- Another function of the APC protein is to help attach the microtubules of the mitotic spindle to the kinetochores of the chromosomes. With no, or a defective, APC product available, chromosomes are lost from the spindle producing aneuploid progeny.
- a mutant proto-oncogene (often RAS).
The cells in the later stages of the disease show additional types of damage such as deletions of p53 and another tumor-suppressor gene.
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.
A similar stepwise genetic progression occurs in
- lung cancer [Link]
- breast cancer
- cancer of the mouth and pharynx.
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.
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 this century.
A population whose members increasingly survive accidents and infectious disease is a population increasingly condemned to death from such "organic" diseases as cancer.
Cancers are caused by
- anything that damages DNA; that is anything that is mutagenic
- radiation that can penetrate to the nucleus and interact with DNA
- chemicals that can penetrate to the nucleus and damage DNA. Chemicals that cause cancer are called carcinogens.
- anything that stimulates the rate of mitosis. This is because a cell is most susceptible to mutations when it is replicating its DNA during the S phase of the cell cycle.
- certain hormones (e.g., hormones that stimulate mitosis in tissues like the breast and the prostate gland)
- chronic tissue injury (which increases mitosis in the stem cells needed to repair the damage)
- agents that cause inflammation (which generates DNA-damaging oxidizing agents in the cell)
- certain other chemicals; some the products of technology [example]
- certain viruses
(Considering that from conception to death, an estimated 1016 mitotic cell divisions occur in humans, it is remarkable that cancer is not more common than it is!)
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:
- two papilloma viruses that infect the reproductive organs and cause cervical cancer
- the hepatitis B and hepatitis C viruses, which infect the liver and are closely associated with liver cancer (probably because of the chronic inflammation they produce)
- some herpes viruses such as the Epstein-Barr virus (implicated in Burkitt's lymphoma) and KSHV that is associated with Kaposi's sarcoma (a malignancy frequently seen in the late stages of AIDS)
- two human T-cell leukemia viruses, HTLV-1 and HTLV-2 [Link]
But note! Clearly viral infection only contributes to the development of cancer.
- Many people are infected by these viruses and do not develop cancer.
- When cancers do arise in infected people, they still follow our rule of clonality. Many cells have been infected, but only one (usually) develops into a tumor.
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.
- A vaccine against hepatitis B is available as are
- two vaccines (Gardasil® and Cervarix®) against the most dangerous papilloma viruses.
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.
- Uncontrolled proliferation. See above.
- Evasion of growth suppressors. Among the many mutations found in cancers, one or more inactivate tumor suppressor genes. [Link to a discussion.]
- Resistance to apoptosis (programmed cell death). Link to a discussion.
- Develop replicative immortality; i.e., avoid the normal process of cell senescence. Link to a discussion.
- Induce angiogenesis; that is, promote the development of a blood supply. Link to a discussion.
- 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.
- 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.
- 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.
- Changed energy metabolism. Even if well-supplied with oxygen, cancer cells get most of their ATP from glycolysis not cellular respiration.
- 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.
26 October 2011