Basis Genetic of Cancer
Cancer Is a Genetic Disease
Cancer cells share two properties: uncontrolled cell proliferation and metastatic spread. All cancer cells in primary and secondary tumors are clonal, meaning that they originated from a common ancestral cell that accumulated numerous specific mutations. All lymphoma cells in each patient with Burkitt's lymphoma, for example, contain identical translocation breakpoints. Cancer is a multistep process requiring multiple mutations. Age-related cancer is an indication that cancer develops from the accumulation of several mutagenic events
Figure 18-2
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The multistep nature of cancer development is supported by the observation that cancers often develop in progressive steps, as occurs for cervical cancer. In a normal cervix, cells in the basal layer divide and differentiate into quiescent (nondividing) cells that are eventually shed from the surface of the cervix. Basal layer cells sometimes acquire mutations that allow them to grow abnormally, and these cells appear to lose part of their ability to differentiate and become quiescent. These areas of abnormally dividing cells are known as dysplasia. If areas of dysplasia progress over a period of years--with cells further proliferating, acquiring mutations and failing to differentiate--they become known as carcinomas in situ.
Cancer Cells Contain Genetic Defects Affecting Genomic Stability and DNA Repair
Cancer cells show higher than normal rates of mutation, chromosomal abnormalities, and genomic instability. The high level of genomic instability in cancer cells is known as the mutator phenotype. The genomic instability in cancer cells manifests itself in gross defects such as translocations, aneuploidy, chromosome loss, DNA amplification, and chromosomal deletions
Figure 18-1
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Figure 18-4
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A number of inherited cancers are caused by defects in genes that control DNA repair, including chronic myelogenous leukemia (CML) (involving the Philadelphia chromosome), xeroderma pigmentosum, and hereditary nonpolyposis colorectal cancer (HNPCC)
Cancer Cells Contain Genetic Defects Affecting Cell Cycle Regulation
Growth and differentiation of cells are strictly regulated. In cancer cells, many of the genes that control these functions are mutated or aberrantly expressed, leading to uncontrolled cell proliferation. Mutations in cycle cycle control proteins have two differing consequences 1) promote cell cycle, cell division and proliferation and 2) inhibit cell cycle checkpoints, thus cell divide when not supposed to (such as when harboring DNA damage)
Cells halt progress through the cell cycle if DNA replication, repair, or chromosome assembly are aberrant. If DNA damage is so severe that repair is impossible, the cell may initiate apoptosis, or programmed cell death. Mediates by proteases called caspases that degrade intracellular proteins. Cancer cells also have defects in apoptotic promoting proteins.
Bcl-2 overexpressed in cancer cells
Two types of cancer control genes-ProtoOncogenes (normal)/Oncogenes (altered version) and Tumor Suppressor Genes
Proto-oncogenes are genes whose products promote cell growth and division. In cancer cells, their activity is upregulated by mutation or overexpression and are called oncogenes. Tumor suppressor genes negatively regulate cell proliferation. Their activity is loosed in cancer cells.
Table 2006 18-2
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Cancer Is a Genetic Disorder Affecting CellCell Contact
To metastasize from the primary tumor, cancer cells must digest components of the extracellular matrix and basal lamina that normally inhibit migration of cells. Metastasis is thought to be controlled by a large number of genes, including those that encode cell adhesion molecules and proteolytic enzymes.
Predisposition to Some Cancers Can Be Inherited
Most cancers result from somatic cell mutations, but 50 forms of hereditary cancer are known. Most inherited cancer-susceptibility genes are not sufficient in themselves to trigger cancer development. At least one other somatic mutation in the other copy of the gene must occur to drive a cell toward tumorigenesis- the Two hit hypothesis.
Table 18-3
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Mutations in other genes are also usually necessary to fully express the cancer phenotype. An example is the development of familial adenomatous polyposis (FAP). Individuals inherit one defective copy of the APC gene
Viruses Contribute to Cancer in Both Humans and Animals
Most animal viruses that cause cancer are retroviruses. Viruses that cause cancer in animals are known as acute transforming retroviruses because they transform cells into cancer cells. Retroviruses integrate into the host genome as a provirus that is replicated with the host's DNA during the normal cell cycle . A retrovirus can cause cancer by integrating near a proto-oncogene or by integrating a copy of a host proto-oncogene into its genome.
Environmental Agents Contribute to Human Cancers
Any substance or event that damages DNA has the potential to be carcinogenic if it causes mutations to occur in proto-oncogenes or tumor suppressor genes. Carcinogens include chemicals, radiation, some viruses, and chronic infections.
Although multiple alterations are present in cancer cells, tumors display "oncogeneaddiction" -require the activity of a single/small subset for survival-gives great hope for therapeutic intervention
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Chin et al., Nature 1999
BCR-ABL and Gleevac (STI-571)
BCR-ABL oncogene fusion protein, derived from the "Philadelphia Chromosome" is a constitutively active cytoplasmic tyrosine kinase present in virtually all patients with CML STI0571 was originally isolated in a high throughput screen for small molecule inhibitors of the PDGF receptor tyrosine kinase. Studies of STI-571 showed activity of the drug against tumor cells expressing BCR-ABL and primary cancer cells isolated from the bone marrow of CML patients A phase I clinical trial showed a 98% response rate in CML patients in the chronic phase of the disease and a 60-70% response rate in end stage disease patients. Little, if any, toxicity May 10th 2001-FDA approves GLEEVEC for treatment of CLL patients Relapse patients harbor mutations in amino acids of BCR-ABL that result in lack of STI-571 binding but preserve kinase activity
How do we beat the diseases?
Prevention:
For viral-induced cancers such as HPV and cervical cancer, vaccines Reduce risks (smoking, sun exposure, diet, ect.) Better and early detection
Treatment: Find more cancer specific targets for each type of cancer Find drugs that specifically block their activity Improve cancer profiling, I.e. identify which targets are present in individual patients Match cancer profile with a cocktail therapy approach