Cancer is a complex genetic disorder exhibiting considerable variability, according to the National Cancer Institute. Inherited or acquired genetic mutations can cause cells to go haywire, turning normal cells into unregulated factories of mass cell production.
Unfettered cell growth upends the natural cell cycle, which can lead to human cancer formation unless tumor suppressor genes intervene.
TL;DR (Too Long; Didn't Read)
Tumor suppressor genes are the body’s natural army against tumor and cancer progression. Healthy tumor suppressor genes function to regulate cell activity. Mutated or missing tumor suppressor genes increase the risk of tumor formation.
Genes Linked to Human Cancer
The somatic cells of the human body contain thousands of genes normally located on 46 chromosomes. Genetic material in DNA determines hereditary characteristics, including rare genes for cancer. At the molecular level, genes work by synthesizing proteins that control cell differentiation, growth, reproduction and longevity.
Cancerous tumors result from adverse gene mutations replicated by the cells. Altered protein sequences send faulty messages to the cell that disrupt normal operations. When mutations occur, normal tumor suppressor genes can sometimes fix the DNA damage of affected cells or flag irreparably damaged cells for destruction.
Mutations to tumor suppressor genes can result in abnormal cell growth and tumor formation. Certain inherited mutations, such as BRCA1 and BRCA2, are linked to a higher risk of breast cancer, for instance. A common mutation in cancerous cells is an absent or impaired p53 gene.
Tumor Suppressor Genes in Cell Division
The nucleus operates as the cell’s command center, controlling gene expression and cell division. Rate of cell growth is determined by the organism’s age, condition and changing needs. Proto-oncogenes help cells divide in a normal fashion. Anti-division tumor suppressor genes prevent overgrowth through various strategies.
Oncogenes can cause the cell to grow erratically and out of control. Rapid, unregulated growth of cells is associated with tumor formation. Cancer can also occur when tumor suppression genes are turned off, leaving the body vulnerable to deleterious genetic mutations.
Within the human body, there are approximately 250 oncogenes and 700 tumor suppressor genes that regulate cell functioning, according to a 2015 article in EBioMedicine.
For example, p21CIP is a kinase inhibitor that plays an active role in tumor suppression. Specifically, p21CIP can suppress tumor growth, repair damaged DNA and inhibit cell death from causing tissue damage.
Tumor Suppression Genes and Genetic Mutations
Because cancer is a genetic disease, accumulated mutations throughout life increase the odds of tumor formation. Cancerous tumor cells are a “genetic train wreck” made up of pathogenic cell mutations, gene fusions and abnormal gene expression, as described in EBioMedicine. Tumor suppressor genes can help the cell respond to mutations before dividing and passing on altered DNA.
Protective actions of tumor suppression genes may include:
- Inhibiting the division of damaged cells
- Repairing mutated/damaged DNA
- Eliminating malfunctioning cells
For instance, p53 protein is a tumor suppressor gene – mapped on the 17th chromosome – that encodes for protein involved in cell regulation. It works by binding to a specific region DNA, which stimulates production of the p21 protein, which subsequently inhibits uncontrolled cell division and related tumors.
APC protein made by the APC gene partners with other proteins in the cell to manage cellular functions. APC is considered a tumor suppressor because APC keeps cells from dividing too fast and monitors the number of chromosomes following cell division. Mutations to the APC gene can increase the risk of polyps and colon cancer.
Tumor Suppressor Genes and Cell Death
The human body protects itself by killing off mutated or damaged cells that are potentially harmful. This process is called apoptosis, a type of programmed cell death.
Tumor suppressor proteins act as gatekeepers that put a stop to potential threats. Tumor suppressor gene p53 encodes proteins that tell damaged cells to self-destruct, for instance.
Located on chromosome 18, BCL-2 is a proto-oncogene that maintains a balance between living and dying cells. Subgroups of the protein serve a pro- or anti-apoptotic function. Mutations to the BCL-2 gene can lead to cancers like leukemia and lymphoma.
The Tumor Necrosis Factor (TNF) gene encodes a cytokine protein involved in the regulation of inflammation. TNF plays a part in apoptosis, cell differentiation and autoimmune disorders. TNF in macrophages can kill certain types of cancer cells in tumors.
Tumor Suppressor Genes and Senescence
Cells are finite and eventually enter senescence after repeated cell divisions. Senescence is a period of arrested growth. When cells enter senescence, they stop dividing as a way to stop aged, damaged genetic material from being passed to daughter cells.
If cells that are supposed to be in senescence keep dividing, that can contribute to tumor growth. During senescence, mature cells accumulate and secrete inflammatory chemicals into adjacent tissue, which increases the risk of age-related diseases like cancer.
Discovering drugs to coax malignant cells into senescence and reduce their secretion of inflammatory chemicals may expand options for cancer treatment.
Cyclin-dependent kinases (CDK1, CDK2) are proteins involved in cell growth. CDK inhibitors arrest cell division and have the potential to “become important weapons in the fight against cancer,” according to a 2015 article in Molecular Pharmacology.
CDK inhibitors could play a role in slowing tumors and triggering the demise of cancer cells. However, the variability of tumor DNA makes it difficult to engineer tumor-specific drugs that work for all tumors_._
Tumor Suppressor Genes and Angiogenesis
Solid tumors need abundant food and oxygen. Growing tumors start by developing their own blood vessels to supply fuel – a process called angiogenesis. Chemical signals stimulate the production of new blood vessels, thus ensuring a rich supply of nutrients to multiplying tumor cells.
Expanding tumors can then metastasize, or move, to other locations of the body and prove fatal. Promising new drugs are being tested to prevent tumor angiogenesis and starve the tumor, according to the National Cancer Institute. This approach to cancer treatment targets the blood supply instead of the tumor itself.
The PTEN gene activates enzymes that help control cell growth and prevent tumor formation. Other functions include controlling angiogenesis, cell movement and apoptosis. The p53 protein has been shown to inhibit angiogenesis in tumor formation, but the mechanism is not well-understood.
What Happens to Tumor Suppressor Genes During Cancer?
Tumor suppressor genes do not always win when waging war against cancer. Other mutations could mean the genes are silenced or less active.
When cancer invades the body, tumor suppression genes may be inactivated at the protein level and rendered defenseless. Aggressive cancers may even cause tumor suppressor genes to go extinct from the genome.
Moreover, "good" genes can go rogue. For instance, the job of the retinoblastoma protein (pRB) is to suppress tumors by blocking the growth of abnormal cells. However, mutation in the pRB gene can actually lead to uncontrolled cell growth and higher incidents of tumors.
Knudson’s Two-Hit Hypothesis
In 1971, Alfred Knudsen, Jr. published his “two-hit” hypothesis based on studies of inherited and non-inherited cases of childhood retinoblastoma (eye cancer). Knudson observed that tumors only developed when both copies of the RB1 gene in cells were missing or damaged.
He concluded that the mutated gene was recessive, and one healthy gene could act as a tumor suppressor.
Types of Human Cancer
The National Cancer Institute estimates that more than 100 types of cancer occur in humans. The most common type listed are carcinomas – cancers occurring in epithelial cells. Many familiar types of cancer fall in this category:
- Glandular tissues: Breast, prostate and colon cancer.
- Basal cells: Cancer in the outer layer of skin.
- Squamous cells: Cancer deep in the skin; also found in lining of certain organs.
- Transitional cells: Cancer in the lining of bladder, kidney and uterus.
Other types of cancer include soft tissue sarcoma, lung cancer, myeloma, melanoma and brain cancer. Li-Fraumeni syndrome is an inherited predisposition to rare cancers caused by a p53 mutation.
Without functioning p53 proteins, patients are at higher risk for multiple types of cancers.
- DNA Repair: Multiple Functions of p21 in Cell Cycle, Apoptosis and Transcriptional Regulation After DNA Damage
- EBioMedicine: Is Cancer a Genetic Disease or a Metabolic Disease?
- NCBI Bookshelf: Genes and Disease: The p53 Tumor Suppressor Protein
- Cancer Genetics: BCL2
- Sino Biological: What Is Tumor Necrosis Factor (TNF)
- Journal of Cell Biology: Senescence and Aging: Causes, Consequences, and Therapeutic Avenues
- Molecular Pharmacology: Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics
- National Cancer Institute: Angiogenesis Inhibitors
- U.S. National Library of Medicine: Genetics Home Reference: PTEN Gene
- U.S. National Library of Medicine: Genetics Home Reference: APC Gene
- LFSA Foundation: Li-Fraumeni Syndrome
- Fox Chase Cancer Center: Knudson's "Two-Hit" Theory of Cancer Causation