Neoplasia Lecture 5 PDF

Neoplasia Lecture 5 Dr. Mohanad Al-Hindawi Eight fundamental changes in cell physiology are considered the hallmarks of cancer. 1. Self-sufficiency in growth signals 2. Insensitivity to growth-inhibitory signals 3. Altered cellular metabolism 4. Evasion of apoptosis 5. Limitless replicat...

Neoplasia Lecture 5 Dr. Mohanad Al-Hindawi Eight fundamental changes in cell physiology are considered the hallmarks of cancer. 1. Self-sufficiency in growth signals 2. Insensitivity to growth-inhibitory signals 3. Altered cellular metabolism 4. Evasion of apoptosis 5. Limitless replicative potential (immortality) 6. Sustained angiogenesis 7. Invasion and metastasis 8. Evasion of immune surveillance  6. Sustained Angiogenesis: Most cancers cannot grow more than 1 to 2 mm in diameter or thickness unless they are vascularized. Angiogenesis has many effects on tumor growth: 1. Supplies nutrients & oxygen. 2. Newly formed endothelial cells during angiogenesis, will stimulate the growth of adjacent tumor cells by secretion of polypeptides (like platelets growth factor). 3. Angiogenesis is also important for the development of metastasis. Cells of malignant tumors are the main inducer of angiogenesis by their production of growth factors (Angiogenetic factors); the two most important ones are Vascular endothelial growth factor and Fibroblast growth factor. Eight fundamental changes in cell physiology are considered the hallmarks of cancer. 1. Self-sufficiency in growth signals 2. Insensitivity to growth-inhibitory signals 3. Altered cellular metabolism 4. Evasion of apoptosis 5. Limitless replicative potential (immortality) 6. Sustained angiogenesis 7. Invasion and metastasis 8. Evasion of immune surveillance 7. Invasion and metastasis The Metastatic pathway of cancer can be divided into two phases: 1. Invasion of Extracellular matrix 2. Vascular dissemination and homing of tumor cells Both of these phases were discussed previously Eight fundamental changes in cell physiology are considered the hallmarks of cancer. 1. Self-sufficiency in growth signals 2. Insensitivity to growth-inhibitory signals 3. Altered cellular metabolism 4. Evasion of apoptosis 5. Limitless replicative potential (immortality) 6. Sustained angiogenesis 7. Invasion and metastasis 8. Evasion of immune surveillance 8. Evasion of immune surveillance Cancer cells express Despite the antigenicity various antigens that of cancer cells, the stimulate the host immune response to immune system, which established tumors is appears to have an ineffective, due to important role in acquired changes that preventing the allow cancer cells to development of avoid anti-tumor cancers. responses. Genomic Instability due to defects in DNA repair  Genomic Instability due to defects in DNA repair Although humans swim in environmental agents that are mutagenic (e.g.,chemicals, radiation, sunlight), cancers are relatively rare outcomes because the cell is able to repair DNA damage and the death of cells with unrepairable damage. Defects in three types of DNA-repair systems contribute to different types of cancers; 1.Defect in DNA mismatch repair gene: When a strand of DNA is being repaired, these genes act as ―spell checkers. For example, if there is an erroneous pairing of G with T rather than the normal A with T, the mismatch-repair genes correct the defect. Without these checkers, errors accumulate at an increased rate. Ex. HNPCC (Hereditary nonpolyposis colon carcinoma (Lynch syndrome) Characterized by familial carcinomas of the colon affecting predominantly the cecum and proximal colon. A characteristic finding in the genome of patients with mismatch repair defects is microsatellite instability (MSI). Microsatellites are repeats of one to six nucleotides found throughout the genome. In normal people, the length of these microsatellites remains constant. In patients with HNPCC, these satellites are unstable and increase or decrease in length.  Xeroderma pigmentosum is an autosomal recessive disorder caused by a 2. Defect in defect in DNA repair that is associated with a greatly increased risk for nucleotide cancers arising in sun-exposed skin. excision repair UV radiation causes cross-linking of pyrimidine residues, preventing normal gene: Ex. DNA replication. Such DNA damage is repaired by the nucleotide excision Xeroderma repair system. Pigmentosum Several proteins are involved in nucleotide excision repair, and an inherited loss of anyone can give rise to xeroderma pigmentosum.  3. Defects in DNA Repair by Homologous Recombination Germ line mutations in two genes, BRCA1 and BRCA2, account for 50% of familial breast cancer cases. In addition to breast cancer, women with BRCA1 mutations have a higher risk of developing epithelial ovarian cancers, and men have a slightly higher risk of developing prostate cancer. Likewise, germline mutations in the BRCA2 gene increase the risk of developing breast cancer in both men and women, as well as cancers originating from the ovary, prostate, pancreas, etc. Cells that lack these genes develop chromosomal breaks. Both genes seem to function in the homologous recombination DNA repair pathway. ETIOLOGY OF CANCER: CARCINOGENIC AGENTS CARCINOGENIC AGENTS Carcinogenic agents cause genetic damage, which lies at the heart of carcinogenesis. Three classes of carcinogenic agents have been identified: 1. Chemicals 2. Radiant energy 3. Microbial products. Initiation and promotion 1-Initiation: results from exposure of the cell to The steps of cancer an appropriate dose of carcinogen (initiator). development are: Those factors cause permanent DNA damage (mutation), so it is irreversible. 2-Promotion: means induction of tumor in the initiated cell but the promoters are non-tumorigenic by themselves. Initiator: 1. it is the first step in the development of a tumor and it should be followed by a promoter. Initiator alone ---no tumor. Promoter alone ---no tumor. 2. It is rapid (within minutes), and it does not need time to get permanent irreversible damage. G. atomic bomb exposure---the damage will occur immediately and last for 2,3 generations. 3. It is dose-independent: i.e. even small doses may lead to damage e.g. pregnant female is avoided from having an XR although the radiological amount is small. 4. Initiators should be followed by promoters. Promoters: 1-Comes after the initiator. 2-It is dose-dependent. e.g. increase in the amount of estrogen hormone to a certain level will produce the changes. 3-It is reversible. 4-Induce tumors in initiated cells, but they are non-tumorigenic by themselves. e.g. on promoters are: (drugs, hormones, phenol). 1-Chemical carcinogens classified into two categories: I. Direct acting agents Require no metabolic conversion to become carcinogenic. They are typically weak carcinogens but are important because some of them are cancer chemotherapy drugs (e.g., alkylating agents) used in regimens that may cure certain types of cancer (e.g., Hodgkin lymphoma), only to evoke a subsequent, second form of cancer, usually leukemia. This situation is even more tragic when the initial use of such agents has been for non- neoplastic disorders, such as rheumatoid arthritis or granulomatosis with polyangiitis. The associated risk for induced cancer is low, but its existence dictates the cautious use of such agents.  II. Indirect-acting agents Need transformation inside the body by liver enzymes to become active (ultimate carcinogens). Examples include: a. Polycyclic aromatic hydrocarbon. benzo[a]pyrene in cigarette smoke, and smoked meat. b. Aromatic amines, amides &azo dyes. (βnaphthylamine) Carcinoma of the urinary bladder  Chemical carcinogens-continue c-Natural plant and microbial products Aflatoxin B1 (a substance present in stored grains produced from certain fungi)hepatocellular carcinoma. d-Others Nitrosamine &amides; in preservatives and can cause gastric carcinoma. Asbestos bronchogenic carcinomas. Vinyl chlorideangiosarcoma. Chromiumlung carcinoma. Nickelnasopharyngeal carcinoma. Cadmiumprostatic carcinoma  Mechanism of Chemical carcinogenesis: Most chemical carcinogens are mutagenic (initiators). these carcinogens contain highly reactive electrophile groups that form chemical adducts with DNA, as well as with proteins and RNA. Any gene may be the target of chemical carcinogens, but understandably it is the mutation of important cancer genes, such as RAS and TP53 Some chemicals’ carcinogenesis is augmented by promoters (drugs, hormones, phenol) non-mutagenic but increase proliferation. Repeated & and sustained exposure to promoters must follow the exposure to chemical mutagenic agent or initiator 2-Radiation Carcinogenesis: Radiation, whatever its source (UV rays of sunlight, radiographs, nuclear fission, radionuclides), is a well- established carcinogen. A. Ionizing radiation e.g. XR, gamma ray, proton, neutron. Those at risk are: 1. Radiologists. 2. Unprotected miners of radioactive elements. 3. Survivors of atomic bomb. 4. Therapeutic irradiation. Even therapeutic irradiation can induce cancer e.g.(Therapeutic irradiation of the head and neck can give rise to papillary, thyroid cancers years later).  Examples of cancers induced by ionizing radiation are (leukemia, Thyroid cancer, and pulmonary cancer). Mechanism: The oncogenic properties of ionizing radiation are related to its mutagenic effects (initiator); it causes chromosome breakage (commonest), translocation, & and less commonly point mutation. There is a long latent period associated with radiation-induced cancer & this cancer occurs in initially damaged cells by other environmental factor.  Natural UV radiation derived from the sun can 2. Ultraviolet light cause skin cancers (melanomas, squamous cell in sunlight carcinomas, and basal cell carcinomas). At greatest risk are fair-skinned people who live in locales such as Australia and New Zealand that receive a great deal of sunlight. Mechanism Ability to damage DNA by forming pyrimidine dimers. This type of DNA damage is repaired by the nucleotide excision repair pathway. With extensive exposure to UV light, the repair systems may be overwhelmed, and skin cancer results. As mentioned earlier, patients with the inherited disease xeroderma pigmentosum have a defect in the nucleotide excision repair pathway and are predisposed to skin cancers  3-Viral & Microbial carcinogenesis Oncogenic viruses are of two types: 1.RNA oncogenic viruses: Only one human retrovirus, human T-cell leukemia virus type 1 (HTLV-1), is firmly implicated in the pathogenesis of cancer in humans. It causes T-cell Leukemia / Lymphoma(endemic in japan). Similar to the human immunodeficiency virus, which causes AIDS, HTLV-1 has tropism for CD4+ T cells, and this subset of T cells is the major target for neoplastic transformation. 2. DNA oncogenic viruses: Include 4 viruses: 1. Human Papillomavirus (HPV): Causes many types of tumors: 1. Benign squamous papilloma of skin (Wart) (by virus type 1, 2, 4, 7). 2. Genital warts have low malignant potential and are also associated with low-risk HPVs, predominantly HPV-6 and HPV-11. 3. Squamous cell carcinoma of the cervix and anogenital region. Caused by high-risk HPVs (e.g., types 16 and 18) 4. Oropharyngeal carcinomas: at least 20% of these are associated with HBV. HPV can cause cancer by production of two viral genes E6 and E7. The E7protein binds to the RBprotein and displaces the E2F transcription factors that are normally sequestered by RB, promoting progression through the cell cycle. The E6protein binds to and mediates the degradation of p53and BAX (pro-apoptotic member). However, infection with HPV itself is not sufficient for carcinogenesis, and full-blown transformation requires the acquisition of mutations in host cancer genes, such as RAS.