Causes and Progression of Cancer

Causes/Risks of Cancer

Links of Interest: Mesothelioma (asbestos Cancer or Mesothelioma)

Some known causes include the following:

• Chemical carcinogens: There is evidence that some chemical carcinogens do not serve as cancer causing agents alone but rather as tumor initiators. Then upon repeated exposure to other substances called tumor promoters which are not themselves mutagenic, promoters cause cancer to develop in skin previously exposed to the tumor initiator.
• physical carcinogenesis: by such things as radiation has long been known to be a cause of cancer. In normal cells, the cell cycle can be stopped in response to such damage and the damaged either repaired or the cell destroyed if damage is too extensive to repair. This cycle arrest breaks down in certain cells.
• viral carcinogenesis: DNA tumor viruses can cause cancer by interfering with cell cycle controls. This occurs, for example, with papillomavirueses which are the cause of human warts. In papillomaviruses, the products of the viral genes, E6 and E7 interfere with the key tumor suppressor genes of the host cell p53 and Rb respectively.
• Immunosupression increases cancer risk: Cancer is a disease of the elderly. Immunodeficient mice (ones which lack T, B, NKT cells, IFNg-) develop cancer.
• Some cancers are associated with Chronic inflammation: This is different then a strong Th1 response which is beneficial. Here, see abundant pro-inflammatory chemokines (these such as CXCR4 are in fact very high in cancers) and cytokines. It is believed that one has these growth factors which call in tissue stem cells which become genetically unstable. Free radicals are also believed to be caused by this inflamation.

How Cancer Develops

Although it is important to know which environmental factors can lead to cancer, an equally important question is how such cancers developed. Understanding mechanisms can lead to treatment strategies. Some answers as to how certain cells go from the normal to the cancerous state are as follows:

• importance of telomerase: There is evidence that the enzyme, telomerase, may provide one answer as to why certain cells turn cancerous. Most human cells seem to have a built-in limit to their proliferation. This replicative cell senescence is thought to be caused by changes in the structure of telomeres which are synthesized and maintained by a mechanisms that requires telomerase. In most human cells, other than those of the germ line and some stem cells, expression of the gene coding for the catalytic subunit of telomerase is switched off. As a result, the telomeres in these cells shorten with each round of cell division until eventually a danger signal is generated, arresting the cell cycle.  This is not the case in most cancer cells which continue to express telomerase.
• importance of oncogenes and tumor supressor genes: Cancer is a genetic disease in that it results from mutations in somatic cells. More than 100 genes have been identified as genes which are repeatedly altered in human cancer. These cancer critical genes can be groups into two classes according to whether the cancer risk arises form too much activity of the gene product or too little. Genes of the first class for which a gain of function mutation drives a cell toward cancer are called proto-oncogenes and their mutant overactive forms are termed "oncogenes." Genes of the second class, for which a loss-of-function mutation creates the danger are called "tumor supressor genes."

Gain-of-function mutations or pro-oncogenes stimulate cells to increase their numbers when they should not. These mutations have a dominant effect. The types of genetic changes which can make a gene into an oncogene can be  1) point mutations, 2) partial deletions of sequences or 3) even by a chromosomal translocation that involves the breakage and rejoining of the DNA helix. These changes in turn can 1) occur in the protein coding region so as to yield a hyperactive product, 2) can occur in adjacent control regions so that the gene is simply expressed at higher concentrations or 3) can be due to extra copies of the gene due to gene amplification events caused by errors in DNA replication which also results in higher expression of the gene.

• down-regulation of signals essential for the activation of immune cells: Tumor cells may down-regulate the expression of signals that are essential for the activation of host T cells. The mechanisms include defective expression of MHC Ags, absence of costimulatory or adhesion molecules, and alteration of Ag-processing or transport, resulting in an inability to present tumor-associated Ags. Strategies to augemnt the host immune response to tumor have included introduction of genes encoding MHC Ags, costimulatory molecules, or cytokines into tumor cells. The goal of these approoahces is to improve the immunogenicity and the Ag-presenting capability of tumor cells. Tumor cells have a lower capacity for antigen presentation, thus evading immune surveillance.