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Tumor and Onset of Cancer
This Sqadia video is the demonstration of Cancer. Cancer cells acquire a drive to proliferate that does not require an external inducing signal. They fail to sense signals that restrict cell division and continue to live when they should die. During carcinogenesis, six fundamental cellular properties are altered to give rise to the complete, most destructive cancer phenotype. Less dangerous tumors arise when only some of these changes occur i.e. Self-sufficiency in growth signals, Insensitivity to antigrowth signals, tissue invasion and metastasis, Limitless replicative potential, sustained angiogenesis, and Evasion of apoptosis. Cancer cells usually arise from stem cells and other proliferating cells and bear more resemblance to these cells than to more mature differentiated cell types. Tumors, whether primary or secondary, require recruitment of new blood vessels in order to grow to a large mass. Cultured Cells can be transformed into tumor cells. Successive oncogenic mutations can be seen in colon cancers. Transformation of mouse cells with DNA from a human cancer cell permits identification and molecular cloning of the rasD oncogene. A mutation in the APC tumor-suppressor gene in a single epithelial cell causes the cell to divide, although surrounding cells do not, forming a mass of localized benign tumor cells, or polyp. Subsequent mutations leading to expression of a constitutively active Ras protein and loss of two tumor-suppressor genes—an unidentified gene in the vicinity of DCC and p53—generate a malignant cell carrying all four mutations.
The Genetic Basis of Cancer
Among the proteins encoded by proto-oncogenes are growth-promoting signaling proteins and their receptors, signal-transduction proteins, transcription factors, and apoptotic proteins. An activating mutation of one of the two alleles of a protooncogene converts it to an oncogene. This can occur by point mutation, gene amplification, and gene translocation. The first tumor-suppressor gene to be recognized, RB, is mutated in retinoblastoma and some other tumors. Inheritance of a single mutant allele of RB greatly increases the probability that a specific kind of cancer will develop, as is the case for many other tumor-suppressor genes (e.g., APC and BRCA1). In individuals born heterozygous for a tumor-suppressor gene, a somatic cell can undergo loss of heterozygosity (LOH) by mitotic recombination, chromosome mis-segregation, mutation, or deletion. Many genes that regulate normal developmental processes encode proteins that function in various signaling pathways. Their normal roles in regulating where and when growth occurs are reflected in the character of the tumors that arise when the genes are mutated. DNA microarray analysis can identify differences in gene expression between types of tumor cells that are indistinguishable by traditional criteria.
Oncogenic Mutations in Growth Promoting Proteins
Mutations or chromosomal translocations that permit RTKs for growth factors to dimerize in the absence of their normal ligands lead to constitutive receptor activity. Such activation ultimately induces changes in gene expression that can transform cells. Overproduction of growth factor receptors can have the same effect and lead to abnormal cell proliferation. Certain virus-encoded proteins can bind to and activate host-cell receptors for growth factors, thereby stimulating cell proliferation in the absence of normal signals. The activity of Src, a cytosolic signal-transducing protein tyrosine kinase, normally is regulated by reversible phosphorylation and dephosphorylation of a tyrosine residue near the C-terminus. The unregulated activity of Src oncoproteins that lack this tyrosine promotes abnormal proliferation of many cells.
Mutations Causing Loss of Cell Cycle Controls
Binding of TGFβ, an antigrowth factor, causes activation of Smad transcription factors. In the absence of TGFβ signaling due to either a receptor mutation or a SMAD mutation, cell proliferation and invasion of the surrounding extracellular matrix (ECM) increase. Unphosphorylated Rb protein binds transcription factors collectively called E2F and thereby prevents E2F-mediated transcriptional activation of many genes whose products are required for DNA synthesis. The kinase activity of cyclin D-CDK4 phosphorylates Rb, thereby activating E2F; this kinase activity is inhibited by p16. The kinase activity of ATM is activated in response to DNA damage due to various stresses (e.g., UV irradiation, heat). Activated ATM then triggers two pathways leading to arrest in G1. Phosphorylation of p53 stabilizes it, permitting p53-activated expression of genes encoding proteins that cause arrest in G1 and in some cases G2, promote apoptosis, or participate in DNA repair. In the other pathway phosphorylated Chk2 in turn phosphorylates Cdc25A, thereby marking it for degradation and blocking its role in CDK2 activation.
Role of Carcinogens and DNA Repair in Cancer
Changes in the DNA sequence result from copying errors and the effects of various physical and chemical agents, or carcinogens. All carcinogens are mutagens; that is, they alter one or more nucleotides in DNA. Many copying errors that occur during DNA replication are corrected by the proofreading function of DNA polymerases that can recognize incorrect bases at the 3’ end of the growing strand and then remove them by an inherent 3’n5’ exonuclease activity. If the resulting T-G base pair is not restored to the normal C-G base pair by base excision-repair mechanisms, it will lead to a permanent change in sequence following DNA replication. A DNA glycosylase specific for G-T mismatches, usually formed by deamination of 5-methyl C residues, flips the thymine base out of the helix and then cuts it away from the sugar-phosphate DNA backbone, leaving just the deoxyribose. An endonuclease specific for the resultant baseless site then cuts the DNA backbone, and the deoxyribose phosphate is removed by an endonuclease associated with DNA polymerase. The gap is then filled in by DNA Pol and sealed by DNA ligase. MSH6 proteins binds to a mispaired segment of DNA in such a way as to distinguish between the template and newly synthesized daughter strands. This triggers binding of the MLH1 endonuclease, as well as other proteins such as PMS2, which has been implicated in oncogenesis through mismatch-repair mutations, although its specific function is unclear. Finally, as with base excision repair, the gap is then filled in by a DNA polymerase and sealed by DNA ligase. The most common type of DNA damage caused by UV irradiation, thymine-thymine dimers can be repaired by an excision-repair mechanism. A double-strand DNA break forms in the chromatids. The double-strand break activates the ATM kinase; this leads to activation of a set of exonucleases that remove nucleotides at the break first from the 3’ and then from the 5’ ends of both broken strands, ultimately creating single stranded 3’ ends.