Cancer

What is it?
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. 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).

Index to this page Cancer Genetics Progression to Cancer Colon Cancer Aging and Cancer Causes of Cancer Viruses and Cancer The Hallmarks of Cancer Other Pages on Cancer

See Cancer Cells in Culture for other properties of cancer cells.

Cancer is a Genetic Disease

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. o Oncogenes. Their mutated or over-expressed products stimulate mitosis even though normal growth signals are absent. Examples: SIS, the gene for platelet-derived growth factor (PDGF) and

EGFR, the gene encoding the receptor for epidermal growth factor (EGF) (EGFR is also known as HER1.)

These genes act as dominants; that is, only one of the pair need be mutated to predispose the cell to cancer.
Link to discussion of oncogenes.
o

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].
Link to discussion of tumor suppressor genes.

Genes that regulate apoptosis. Mutations in these enable the cell to ignore signals telling it that it is irreparably damaged and should commit suicide.
Link to apoptosis.

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.
Link to a discussion of angiogenesis inhibitors that may provide weapons against cancer.

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: o mutations in genes whose products normally keep the cells of a tissue adhering to one another. Example: the E-cadherin genes that help hold epithelial cells together (the most common cancers are carcinomas cancers of epithelial cells).
o

mutations in genes whose products normally keep the cells adhering to their substrate. Example: integrin genes

elevated expression of genes that encode proteases which can break down the proteinaceous extracellular material that normally holds cells in place.

Progression to Cancer
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.
Link to an analysis of the mutations in a lung cancer.

Sequencing samples from several areas in a primary tumor, as well as from some of its metastases, reveals a different collection of mutations from sample to sample. This finding is reinforced by the sequencing of the genome of individual cells from a single tumor each of which shows a unique pattern of shared and unique mutations.

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 geneticallyidentical. 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

propensity to metastasize; susceptibility to treatment by anticancer drugs; propensity to relapse after apparently-successful therapy.

Recent advances have enabled the coding portions of the genome of single cells to be sequenced. Early results indicate than even normal cells in an adult have accumulated a suite of somatic mutations that differs from cell to cell. However, the rate of somatic mutations in these normal cells is only a fourth of that in cancer cells.

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
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: 1. One of the functions of the APC gene product is to destroy the transcription factor -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. 2. 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). deletion and/or mutation of the tumor suppressor gene p53

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 dozen or more 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

lung cancer [Link] breast cancer cancer of the mouth and pharynx.

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.]

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. 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.

Causes of Cancer
Cancers are caused by

anything that damages DNA; that is anything that is mutagenic o radiation that can penetrate to the nucleus and interact with DNA
see Radiation Is there a safe dose of radiation?
o

chemicals that can penetrate to the nucleus and damage DNA. Chemicals that cause cancer are called carcinogens.
see Ames test Is there a safe dose of a potential carcinogen?

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. o certain hormones (e.g., hormones that stimulate mitosis in tissues like the breast and the prostate gland) o chronic tissue injury (which increases mitosis in the stem cells needed to repair the damage) o agents that cause inflammation (which generates DNAdamaging oxidizing agents in the cell) o certain other chemicals; some the products of technology [example] o 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!)

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:

two papilloma viruses that infect the reproductive organs and cause cervical cancer
How these viruses deregulate the cell cycle

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 lymphotropic 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.

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.

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 proto-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. Welcome&Next Search

9 August 2012