Oncogenes and Tumor Suppressor Genes

MOLECULAR ONCOLOGY

Lecture № 1.

Genes and Cancer. Oncogenes and Tumor Suppressor Genes. Angiogenesis

Oncogenes and Tumor Suppressor Genes

Chemicals (e.g., from smoking), radiation, viruses, and heredity all contribute to the development of cancer by triggering changes in a cell’s genes. Chemicals and radiation act by damaging genes, viruses introduce their own genes into cells, and heredity passes on alterations in genes that make a person more susceptible to cancer. Genes are inherited instructions that reside within a person’s chromosomes. Each gene instructs a cell how to build a specific product--in most cases, a particular kind of protein. Genes are altered, or “mutated,” in various ways as part of the mechanism by which cancer arises.

One group of genes implicated in the development of cancer are damaged genes, called “oncogenes.” Oncogenes are genes whose PRESENCE in certain forms and/or overactivity can stimulate the development of cancer. When oncogenes arise in normal cells, they can contribute to the development of cancer by instructing cells to make proteins that stimulate excessive cell growth and division.

Oncogenes are related to normal genes called proto-oncogenes that encode components of the cell’s normal growth-control pathway. Some of these components are growth factors, receptors, signaling enzymes, and transcription factors. Growth factors bind to receptors on the cell surface, which activate signaling enzymes inside the cell that, in turn, activate special proteins called transcription factors inside the cell’s nucleus. The activated transcription factors “turn on” the genes required for cell growth and proliferation.

Oncogenes arise from the mutation of proto-oncogenes. They resemble proto-oncogenes in that they code for the production of proteins involved in growth control. However, oncogenes code for an altered version (or excessive quantities) of these growth-control proteins, thereby disrupting a cell’s growth-signaling pathway.

By producing abnormal versions or quantities of cellular growth-control proteins, oncogenes cause a cell’s growth-signaling pathway to become hyperactive. To use a simple metaphor, the growth-control pathway is like the gas pedal of an automobile. The more active the pathway, the faster cells grow and divide. The presence of an oncogene is like having a gas pedal that is stuck to the floorboard, causing the cell to continually grow and divide. A cancer cell may contain one or more oncogenes, which means that one or more components in this pathway will be abnormal.

A second group of genes implicated in cancer are the “tumor suppressor genes.” Tumor suppressor genes are normal genes whose ABSENCE can lead to cancer. In other words, if a pair of tumor suppressor genes are either lost from a cell or inactivated by mutation, their functional absence might allow cancer to develop. Individuals who inherit an increased risk of developing cancer often are born with one defective copy of a tumor suppressor gene. Because genes come in pairs (one inherited from each parent), an inherited defect in one copy will not lead to cancer because the other normal copy is still functional. But if the second copy undergoes mutation, the person then may develop cancer because there no longer is any functional copy of the gene.

Tumor suppressor genes are a family of normal genes that instruct cells to produce proteins that restrain cell growth and division. Since tumor suppressor genes code for proteins that slow down cell growth and division, the loss of such proteins allows a cell to grow and divide in an uncontrolled fashion. Tumor suppressor genes are like the brake pedal of an automobile. The loss of a tumor suppressor gene function is like having a brake pedal that does not function properly, thereby allowing the cell to grow and divide continually.

One particular tumor suppressor gene codes for a protein called “p53” that can trigger cell suicide (apoptosis). In cells that have undergone DNA damage, the p53 protein acts like a brake pedal to halt cell growth and division. If the damage cannot be repaired, the p53 protein eventually initiates cell suicide, thereby preventing the genetically damaged cell from growing out of control.

A third type of genes implicated in cancer are called “DNA repair genes.” DNA repair genes code for proteins whose normal function is to correct errors that arise when cells duplicate their DNA prior to cell division. Mutations in DNA repair genes can lead to a failure in repair, which in turn allows subsequent mutations to accumulate. People with a condition called xeroderma pigmentosum have an inherited defect in a DNA repair gene. As a result, they cannot effectively repair the DNA damage that normally occurs when skin cells are exposed to sunlight, and so they exhibit an abnormally high incidence of skin cancer. Certain forms of hereditary colon cancer also involve defects in DNA repair.

Each cell, when it divides, generates two identical new ones. So, when a cell acquires a mutation, it passes that mutation on to its progeny during cell growth and division. Because cells with cancer-linked mutations tend to proliferate more than normal cells, cellular candidates for additional mutations grow in number. Mutations continue to accumulate and are copied to descendant cells. If one cell finally acquires enough mutations to become cancerous, subsequent cancer cells will be derived from that one single transformed cell. So all tumors are clonal, which means that they originate from a single parent cell, whether that first mutant cell was of germline or somatic origin.

The cell cycle is a critical process that a cell undergoes in order to copy itself exactly. Most cancers have mutations in the signals that regulate the cell’s cycle of growth and division. Normal cell division is required for the generation of new cells during development and for the replacement of old cells as they die.

Most cells remain in interphase, the period between cell divisions, for at least 90 percent of the cell cycle. The first part of the interphase is called G1 (for first gap), followed by the S phase (for DNA synthesis), then G2 (for second gap). During G1, there is rapid growth and metabolic activity, including synthesis of RNA and proteins. Cell growth continues during the S phase, and DNA is replicated. In G2, the cell continues to grow and prepares for cell division. Cell division (mitosis) is referred to as the M phase. Cells that do not divide for long periods do not replicate their DNA and are considered to be in G0.

In normal cells, tumor suppressor genes act as braking signals during G1 to stop or slow the cell cycle before S phase. DNA repair genes are active throughout the cell cycle, particularly during G2 after DNA replication and before the chromosomes prepare for mitosis.

Most cancers have mutations in proto-oncogenes, the normal genes involved in the regulation of controlled cell growth. These genes encode proteins that function as growth factors, growth factor receptors, signal-relaying molecules, and nuclear transcription factors (proteins that bind to genes to start transcription). When the proto-oncogene is mutated or overregulated, it is called an oncogene and results in unregulated cell growth and transformation. At the cellular level, only one mutation in a single allele is enough to trigger an oncogenic role in cancer development. The chance that such a mutation will occur increases as a person ages.

Most cancer susceptibility genes are tumor suppressor genes. Tumor suppressor genes are just one type of the many genes malfunctioning in cancer. These genes, under normal circumstances, suppress cell growth. Some do so by encoding transcription factors for other genes needed to slow growth. For example, the protein product of the suppressor gene TP53 is called p53 protein. It binds directly to DNA and leads to the expression of genes that inhibit cell growth or trigger cell death. Other tumor suppressor genes code for proteins that help control the cell cycle.

Both copies of a tumor suppressor gene must be lost or mutated for cancer to occur. A person who carries a germline mutation in a tumor suppressor gene has only one functional copy of the gene in all cells. For this person, loss or mutation of the second copy of the gene in any of these cells can lead to cancer.

Cancer may begin because of the accumulation of mutations involving oncogenes, tumor suppressor genes, and DNA repair genes. For example, colon cancer can begin with a defect in a tumor suppressor gene that allows excessive cell proliferation. The proliferating cells then tend to acquire additional mutations involving DNA repair genes, other tumor suppressor genes, and many other growth-related genes. Over time, the accumulated damage can yield a highly malignant, metastatic tumor. In other words, creating a cancer cell requires that the brakes on cell growth (tumor suppressor genes) be released at the same time that the accelerators for cell growth (oncogenes) are being activated.

While the prime suspects for cancer-linked mutations are the oncogenes, tumor suppressor genes, and DNA repair genes, cancer conspires even beyond these. Mutations also are seen in the genes that activate and deactivate carcinogens, and in those that govern the cell cycle, cell senescence (or “aging”), cell suicide (apoptosis), cell signaling, and cell differentiation. And still other mutations develop that enable cancer to invade and metastasize to other parts of the body.

In addition to all the molecular changes that occur within a cancer cell, the environment around the tumor changes dramatically as well. The cancer cell loses receptors that would normally respond to neighboring cells that call for growth to stop. Instead, tumors amplify their own supply of growth signals. They also flood their neighbors with other signals called cytokines and enzymes called proteases. This action destroys both the basement membrane and surrounding matrix, which lies between the tumor and its path to metastasis--a blood vessel or duct of the lymphatic system.

Angiogenesis

The walls of blood vessels are formed by vascular endothelial cells. These cells rarely divide, doing so only about once every 3 years on average. However, when the situation requires it, angiogenesis can stimulate them to divide.

Angiogenesis is regulated by both activator and inhibitor molecules. Normally, the inhibitors predominate, blocking growth. Should a need for new blood vessels arise, angiogenesis activators increase in number and inhibitors decrease. This prompts the growth and division of vascular endothelial cells and, ultimately, the formation of new blood vessels.

VEGF and bFGF are first synthesized inside tumor cells and then secreted into the surrounding tissue. When they encounter endothelial cells, they bind to specific proteins, called receptors, sitting on the outer surface of the cells. The binding of either VEGF or bFGF to its appropriate receptor activates a series of relay proteins that transmit a signal into the nucleus of the endothelial cells. The nuclear signal ultimately prompts a group of genes to make products needed for new endothelial cell growth.

The activation of endothelial cells by VEGF or bFGF sets in motion a series of steps toward the creation of new blood vessels. First, the activated endothelial cells produce matrix metalloproteinases (MMPs), a special class of degradative enzymes. These enzymes are then released from the endothelial cells into the surrounding tissue. The MMPs break down the extracellular matrix--support material that fills the spaces between cells and is made of proteins and polysaccharides. Breakdown of this matrix permits the migration of endothelial cells. As they migrate into the surrounding tissues, activated endothelial cells begin to divide. Soon they organize into hollow tubes that evolve gradually into a mature network of blood vessels.

Date: 2015-12-24; view: 1085