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Cigarette Consumption and Lung Cancer Figure 11.2 The Biology of Cancer (© Garland Science 2007) Tissue organization and protection of the stem cell genome Figure 12.1 The Biology of Cancer (© Garland Science 2007) Stem cells and the organization of GIT 4-6 actual stem cells (red) Emigration of transit-amplifying cell from the crypt can be traced by thymidine labeling. Figure 12.2a The Biology of Cancer (© Garland Science 2007) Figure 12.3a The Biology of Cancer (© Garland Science 2007) Hematopoietic differentiation Figure 12.4 The Biology of Cancer (© Garland Science 2007) Conserved DNA strand and the stem cell genome Figure 12.5a The Biology of Cancer (© Garland Science 2007) Proofreading by DNA polymerase and Cancer incidence: Death due to malignancy in mice containing Mutation in DNA pol d (D400A)> Heterozygous and homozygous in a wid type p53 background Figure 12.7 The Biology of Cancer (© Garland Science 2007) Oxidation of bases in DNA Figure 12.12a The Biology of Cancer (© Garland Science 2007) Metabolic rate and DNA oxidation: Thymidine glycol is an excretory product of DNA oxidation measured in urine. Figure 12.13 The Biology of Cancer (© Garland Science 2007) Product of UV radiation Figure 12.14a The Biology of Cancer (© Garland Science 2007) Action of cytochromes on pro-carcinogen: Natural Detoxification on benzoapyrene leads to the production of carcinogen Polycyclic aromatic hydrocarbons (PAHs) from tobacco smoke, broiled food and polution. Figure 12.15b The Biology of Cancer (© Garland Science 2007) DNA adduct produced by BPDE Figure 12.16 The Biology of Cancer (© Garland Science 2007) Aflatoxin (fungal toxin) and Liver carcinogenesis: Incidence of hepatocellular carcinoma (HCC) is 8 times higher in the very humid southestern Qidong penisula Figure 12.18a The Biology of Cancer (© Garland Science 2007) Figure 12.18b The Biology of Cancer (© Garland Science 2007) Table 12.1 The Biology of Cancer (© Garland Science 2007) Xeroderma pigmentosum patient: Caused by Mutation in nucleotide excision repair genes. These patients are very sensitive to UV light and have 1000 fold higher rate of incidence of melanoms, squamous and basal cell carcinoma. Figure 12.25 The Biology of Cancer (© Garland Science 2007) Multi-step tumorigenesis in variety of organ sites Figure 11.7 The Biology of Cancer (© Garland Science 2007) Evidence of adenoma to carcinoma progression Figure 11.8b The Biology of Cancer (© Garland Science 2007) The ErB signaling network: Figure 5.1 The Biology of Cancer (© Garland Science 2007) Table 5.1 The Biology of Cancer (© Garland Science 2007) Table 5.3 The Biology of Cancer (© Garland Science 2007) Figure 5.24 The Biology of Cancer (© Garland Science 2007) How a cancer develops? 1. Uncontrolled cell division a. mutation leading to activation or overproduction of oncogenes (cell division promoting signaling molecules. And/or b. By mutation leading to inactivation or underproduction of cell cycle blocking genes or anti-oncogemnes or tumor suppressor genes. 2. Blockage of cell death mechanisms caused by DNA abnormalities, leading to the growth of cells with mutated genes, thus encouraging more mutations. This is achieved by mutation in p53 genes, over production of Bcl2 genes etc. 3. Acquiring immortality: all mammalian cells can divide to a limited number of population doublings, after which they become senescent. Recent work suggests that a check on the number of cell division is achieved by telomere length at the end of chromosomes that keeps getting shorter in each replication cycle. In many cancers there is production of an enzyme called telomerase (a reverse transcriptase). This enzyme keeps the telomere length constant and cells become virtually immortal. 4. Induction of blood capillary formation or angiogenesis. 5. Detachment from the tissue, invasion of other tissues. 6. Mutations leading to escape from immune system, immuno-supression, expression of decoy receptors etc. Chromosomal aberrations in a cervical cancer cells (bottom) compared to the normal (top) Ch. 8: three abnormalities, a. number, b. deletion of genetic material and c. mismatch joining of two fragments. Ch. 13: Copy loss, Ch. 12, 17, and 18; copy number. APC gene mutation: Adenoma polyposis coli: found mutated or truncated in all polyps and advance colon cancers. Oncogenic mutations of a Ras gene, followed by loss of p53 and DCC are present in successive stages of colon carcinoma. Figure 11.10 The Biology of Cancer (© Garland Science 2007) 1. Chromosome 17 in almost all the brain tumors. Later on the gene on this chromosome was identified to be p53 gene. 2. In the later advanced stage of the brain tumors, loss of chromosome 9 was observed. The region of chromosome 9 that was deleted contained a cluster of genes encoding interferons, the proteins involved in triggering immune response. Thus these mutations may help the cancer cells escape the immune system. This region may also include the multiple tumor supressors -1 and 2 (MTS-1, MTS-2). The protein products of these genes in involved in regulating cell division. 3. In most aggressive form of tumors, there was loss of one copy of chr. 10 (we do not know the role of any important gene on this chromosome in advancement of tumor) and there was multiplication of Figure 11.17 The Biology of Cancer (© Garland Science 2007) K-ras mutation and tumor initiation Figure 11.22a The Biology of Cancer (© Garland Science 2007) Toxic and mitogenic agents can act as human tumor promoters: e.g. TPA or phorbol 12 myristate 13 acetate (phorbol ester) Figure 11.27 The Biology of Cancer (© Garland Science 2007) Infammation contributes to carcinogenesis in gastrointestinal tract Human ulcerative colitis Figure 11.34a The Biology of Cancer (© Garland Science 2007) Chronic Inflammation leading to cancer Carcinoma of epithellial lining of gallbladder associated with gallstones. Inflammation due to Hepatitis B or c virus infection leads to 100 fold incresased risk of cancer Figure 11.35a The Biology of Cancer (© Garland Science 2007) In vivo model of chronic liver inflammation and hepatocellular carcinoma: Loss of MDR gene leads to chronic inflammation Figure 11.37a The Biology of Cancer (© Garland Science 2007) Figure 11.37b The Biology of Cancer (© Garland Science 2007) Action of Cox-2 enzyme and their inhibition by aspirin Figure 11.38b The Biology of Cancer (© Garland Science 2007) Figure 11.40e The Biology of Cancer (© Garland Science 2007) Figure 11.41 The Biology of Cancer (© Garland Science 2007) Table 11.3 The Biology of Cancer (© Garland Science 2007) Therapeutic strategies: There are more than a million new cases of cancers diagnosed in 1994 in united states. The major cancers were, Lung carcinoma, 172,000, Colorectal cancer 149,000, breast cancer 183,000, prostate cancer 200,000, various lymphomas and leukemia >90,000, cervical, uterine and ovarian >70,000, Bladder and Kidney 80,000 and melanoma 32000. The first challenge is to diagnose the cancer in early stage: Physical examination and some physiological symptoms are used in combination to tissue pathology: mostly can reveal only late stage stagecancers. Some tumors diagnosed by scanning and the processes mentioned above are cured by surgical procedures. New developments are needed for early diagnosis: Gene Microarrays Protein microarrays e.g. prostrate cancer diagnosis The treatments: Prevention: Avoid mutagens eg radiations (radio active, and UV), smoking and tobacco, carcinogen in food, vaccination against viral diseases, dietary intake of fruits, vegetable, fiber containing diets etc. Surgery Chemo therapy Radiotherapy Both the chemo and radio therapies induce apoptosis in fast dividing cells. Most of the drugs are DNA damaging agents which induce apoptosis by DNA damage. Obviously, the treatment kills other normal dividing cells, and the collateral damage is significant. Other drugs like taxol disrupt the tubulin polymerization and inhibit growth and induce cell death in dividing cells. Since the discovery of different pathways of apoptosis, a new hope is there to induce the cell death program targeted specifically to cell cells. Followings are the cutting edge research and developments in the therapeutic development of cancers: Targeted delivery of chemotherapeutic agents via liposomes containing specific anticancer antibodies. Delivery of photo-sensitive chemotherapeutic agents conjugated to specific targets. Localized laser targeted radiotherapy Many of the tumors have p53 mutations, and they do not respond to DNA damage-inducing agent. Researchers are trying to restore p53 function by gene therapy or by chemical modulator. Some companies are developing antagonists to epidermal growth factor to neutralize its effect and control tumor growth in brain. A smart approach is being developed by a chemist Dr. Taylor at Washington University St. Louis. He plans to make specific probes for mutated genes in cancer and conjugate it to a drug release system. PNA: Peptide nucleic acid synthesized complimentary to mutated mRNA (or over-expressed mRNA). Then this specific PNA is tagged on to a drug delivery vesicle, which is catalytically released only when PNA binds to the target. This way killing the cancer cells specifically can be achieved.