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Oncogenes and Cancer Induction - IV
Cancer has become the second leading cause of death. From an immunologic perspective, cancer cells can be viewed as altered self-cells that have escaped normal growth-regulating mechanisms. The Sqadia lecture ´´Cancer and the Immune System – II´´ examines the unique properties of cancer cells and the oncogenes, especially those properties that can be recognized by the immune system. The development from a normal cell to a cancerous cell is a multistep process of clonal evolution driven by a series of somatic mutations. These mutations progressively convert the cell from normal growth to a precancerous state and finally a cancerous state. The presence of myriad chromosomal abnormalities in precancerous and cancerous cells lends support to the role of multiple mutations in the development of cancer. Colon cancer begins as small, benign tumors called adenomas in the colorectal epithelium. Model of sequential genetic alterations leading to metastatic colon cancer have different stages, allowing researchers to determine the sequence of genetic alterations. In this sequence, benign colorectal polyps progress to carcinoma following mutations resulting in the inactivation or loss of three tumor-suppressor genes (APC, DCC, and TP53) and the activation of one oncogene linked to cellular proliferation (K-ras). Studies with transgenic mice also support the role of multiple steps in the induction of cancer. Tumors of the immune system are classified as lymphomas or leukemias. Lymphomas proliferate as solid tumors within a lymphoid tissue. They include Hodgkin’s and non-Hodgkin’s lymphomas.
Oncogenes and Cancer Induction - V
Leukemias were classified as acute or chronic according to the clinical progression of the disease. Acute leukemia appear suddenly and progress rapidly, tend to arise in less mature cells. Chronic leukemia are much less aggressive. They develop slowly as mild, barely symptomatic diseases and arise in mature cells. A proto-oncogene that has been translocated into immunoglobulin genes and T-cell receptor genes, the best characterized is the translocation of c-MYC in Burkitt’s lymphoma in mouse plasmacytomas.
In 75% of Burkitt’s lymphoma patients, c-MYC is translocated from chromosome 8 to the Ig heavy-chain gene cluster on chromosome 14. Kappa-gene translocations from chromosome 2 to chromosome 8 occur 9% of the time. γ-gene translocations from chromosome 22 to chromosome 8 occur 16% of the time. In other cases, exons 1, 2, and 3 or exons 2 and 3 of c-MYC translocated head-to head to the Sμ or Sα switch site. The translocation removes the MYC coding exons from the regulatory mechanisms operating in chromosome 8 and places them in the immunoglobulin-gene region.
Tumor Antigens - I
Two types of tumor antigens have been identified on tumor cells i.e.
- Tumor-specific transplantation antigens (TSTAs)
- Tumor-associated transplantation antigens (TATAs)
Tumor Specific Transplantation Antigens (TSTAs) are unique to tumor cells. They do not occur on normal cells in the body. They may result from mutations in tumor cells that generate altered cellular proteins. Cytosolic processing of these proteins give rise to novel peptides That are presented with class I MHC molecules. Tumor Associated Transplantation Antigens (TATAs) are not unique to tumor cells. These represent normal cellular proteins typically expressed only during specific developmental stages, such as in the fetus. Those derived from mutation-induced reactivation of certain fetal or embryonic genes, called oncofetal tumor antigens, normally only appear early in embryonic development, before the immune system acquires immunocompetence. Different mechanisms generate tumor specific antigens (TSAs) and tumor-associated antigens (TAAs). Tumor antigens recognized by human T cells fall into one of four major categories:
- Antigens encoded by genes exclusively expressed by tumors
- Antigens encoded by variant forms of normal genes that have been altered by mutation
- Antigens normally expressed only at certain stages of differentiation
- Antigens that are overexpressed in particular tumors.
Many tumor antigens are cellular proteins, give rise to peptides presented with MHC molecules.
Tumor Antigens - II
Tumor-specific antigens have been identified on tumors induced with chemical carcinogens, physical carcinogens, and virally induced tumors. Demonstrating the presence of tumor specific antigens on spontaneously occurring tumors is particularly difficult. Immune response to such tumors eliminates all of the tumor cells bearing sufficient numbers of the antigens. In this way selects for cells bearing low levels of the antigens. Methyl cholanthrene and UV light are two carcinogens that are extensively used to generate lines of tumor cells. Syngeneic animals are injected with killed cells from a carcinogen-induced tumor-cell line. The TSTAs of chemically induced tumors have been difficult to characterize because they can’t be identified by induced antibodies but only by their T-cell–mediated rejection. Experimental approach allowed identification of genes encoding some TSTAs. Most tum– variants have been shown to express TSTAs. When tum– cells are injected into syngeneic mice, unique TSTAs that the tum– cells express are recognized by specific CTLs. To identify the genes encoding the TSTAs that are expressed on a tum– cell line, a cosmid DNA library is prepared from the tum– cells.
Tumor Antigens - III
Most TSTAs can be detected only by the cell-mediated rejection they elicit. Initially a non-tumorigenic (tum–) cell line is generated. This cell line expresses a TSTA that is recognized by syngeneic mice which mount a cell-mediated response against it. To isolate the gene encoding the TSTA, a cosmid gene library is prepared from the tum- cell line, the genes are transfected into tumorigenic tum+ cells, and the transfected cells are incubated with TSTA-specific CTLs. The transfected tum+ cells are tested for the expression of the tum- TSTAs by their ability to activate cloned CTLs specific for the tum- TSTA. A number of diverse TSTAs have been identified by this method. In the past few years, two methods have facilitated the characterization of TSTAs. In the 1st Method, peptides bound to class I MHC molecules on the membranes of the tumor cells are eluted with acid and purified by HPLC to allow its sequence to be deduced by Edman degradation. In the 2nd Method, cDNA libraries are prepared from tumor cells. These cDNA libraries are transfected transiently into COS cells. The genes that encode some TSTAs have been shown to differ from normal cellular genes by a single point mutation. Further characterization of TSTAs has demonstrated that many of them are not cell-membrane proteins, they are short peptides derived from cytosolic proteins processed and presented together with class I MHC molecules.