Neoplasia 2 PDF

Neoplasia 2 Dr. MAHA ELTINGARI Cancer Incidence 9.2 million deaths from cancer by 2018 Cancer is 2nd leading cause of death (after heart disease) Most common cancers Men: Prostate Women: Breast Dea...

Neoplasia 2 Dr. MAHA ELTINGARI Cancer Incidence 9.2 million deaths from cancer by 2018 Cancer is 2nd leading cause of death (after heart disease) Most common cancers Men: Prostate Women: Breast Deadliest cancers Men: Lung Women: Lung Cancer Incidence Death rates have changed over last years by Recognition of risk factors change habits and screening programs Decrease in death rates for: Cervical cancer (pap smears) Colon cancer (earlier detection)Hemiocculta Breast cancer (earlier detection) mamography Lung cancer in men (less smokers) Some types of leukemia (new treatment) Increase in death rates for: Lung cancer in women (more smokers) EPIDEMIOLOGY; relate particularly to: environmental racial (possibly hereditary), and cultural influences to the occurrence of specific neoplasms. Interactions between environmental factors and genetic factors may be important determinants of cancer risk. Environmental Variables Sunlight: skin cancer Smoking: lung cancer Alcohol: liver, breast cancers HPV: cervical carcinoma Variables Cancer is most frequent at the two extremes of age. Elderly Frequency of cancer increases with age Most cancer deaths occur between 55-75 Children 10% of all childhood deaths Leukemia/lymphoma, CNS tumors, sarcoma Acquired conditions that predispose to cancer include; chronic inflammation, Immunodeficiency states precursor lesions Heredity cancers Three categories of hereditary cancer Inherited cancer syndromes Dominantly inherited Retinoblastoma Familial polyposis coli Heredity cancers Three categories of hereditary cancer Inherited cancer syndromes Familial cancers Most common sporadic cancers have familial forms too Breast, colon, ovary, brain Occur earlier, are often deadlier Heredity cancers Three categories of hereditary cancer Inherited cancer syndromes Familial cancers Syndromes of defective DNA repair Recessively inherited Xeroderma pigmentosum Acquired Preneoplastic Syndromes Persistent regenerative cell replication CF Chronic skin fistula → squamous cell carcinoma Cirrhosis → Liver cancer Hyperplastic and dysplastic proliferations Atypical endometrial hyperplasia → endometrial cancer Dysplastic bronchial mucosa → lung cancer Chronic atrophic gastritis → stomach cancer Chronic ulcerative colitis → colon cancer Leukoplakia → squamous cell carcinoma (Precursor) Carcinogenesis Cancer formation is initiated by damage to DNA of stem cells. The damage overcomes DNA repair mechanisms, but is not lethal. A tumor is formed by the clonal expansion of a single precursor cell (monoclonal) Carcinogens are agents that damage DNA, increasing the risk for cancer. Carcinogenesis genetic Four kinds of normal genes are damaged: Genes that promote growth (“proto-oncogenes”) Genes that inhibit growth (“tumor-suppressor genes”) Genes that regulate apoptosis Genes involved in DNA repair Carcinogenesis is a multistep process How do all these genetic mutations arise? We are constantly exposed to mutagenic agents (sunlight, radiation, chemicals)!! We don’t get very many cancers because normal cells are able to REPAIR DNA damage!! Many systems for DNA repair exist. If you inherit a defect in any of these systems, you’ll be more likely to get cancer. Hallmarks of cancer “Cancer genes” cause bad things in cells: 1. Autonomous growth 2. Insensitivity to growth-inhibitory signals 3. Evasion of apoptosis 4. Limitless replication 5. Sustained angiogenesis hallmarks of cancer AllAH AKBER The Cell Cycle p53 activated p53 not activated Hallmarks of cancer “Cancer genes” cause bad things in cells: 1. Autonomous growth 2. Insensitivity to growth-inhibitory signals 3. Evasion of apoptosis 4. Limitless replication 5. Sustained angiogenesis  Autonomous growth
Mutated growth signal is always on… Autonomous growth oncogenes Insensitivity to growth-inhibitory signals Tumor-suppressor genes Autonomous growth
ACTIVE ONCOGENES Are MUTATIONS of NORMAL genes (PROTO-oncogenes) Growth Factors Growth Factor Receptors Signal Transduction Proteins (RAS) Nuclear Regulatory Proteins Cell Cycle Regulators Oncogenes code for  Oncoproteins Insensitivity to growth-inhibitory signals No Tumor-suppressor genes
Tumor suppressor genes normally prevent uncontrolled growth and, both alleles must be damaged. Tumor suppressor Genes are two groups: 1. “governors”; that act as important brakes on cellular proliferation.RB 2. “guardians”; that are responsible for sensing genomic damage. P53, GUARDIAN OF THE GENOME
The p53 protein is the central monitor of stress in the cell and can be activated by anoxia, inappropriate signaling by mutated oncoproteins, or DNA damage.  p53 controls the expression and activity of proteins involved in cell cycle arrest, DNA repair, cellular senescence, and apoptosis. Active p53 increase expression of proteins such as the cyclin-dependent kinase inhibitor p21, thereby causing cell-cycle arrest at the G1/S checkpoint. This pause allows cells to repair DNA damage. If DNA damage cannot be repaired, p53 induces additional events that lead to cellular senescence or apoptosis. The majority of human cancers demonstrate loss-of function mutations in TP53. Like RB, p53 is inactivated by viral oncoproteins, such as the E6 protein of HPV.. Hallmarks of cancer “Cancer genes” cause bad things in cells: Autonomous growth Insensitivity to growth-inhibitory signals Evasion of apoptosis Evasion of APOPTOSIS REGULATORS OF APOPTOSIS Prevent apoptosis in normal cells, but promote apoptosis in mutated cells whose DNA cannot be repaired (e.g., Bcl2) DNA REPAIR GENE DEFECTS (DNA repair is like a spell checker) HNPCC Xeroderma Pigmentosum Ataxia Telangiectasia Bloom Syndrome Fanconi anemia Hallmarks of cancer
“Cancer genes” cause bad things in cells: Autonomous growth Insensitivity to growth-inhibitory signals Evasion of apoptosis Limitless replication 60-70 doublings by shorter telomere TELOMERES determine the limited number of duplications a cell will have cancer cells use telomerase to maintain telomere length Hallmarks of cancer “Cancer genes” cause bad things in cells: Autonomous growth Insensitivity to growth-inhibitory signals Evasion of apoptosis Limitless replication Sustained angiogenesis Activation of VEGF and FGF-b Hallmarks of cancer
“Cancer genes” cause bad things in cells: Autonomous growth Insensitivity to growth-inhibitory signals Evasion of apoptosis Limitless replication Sustained angiogenesis Invasion and metastasis Invasion Factors Detachment ("loosening up") of the tumor cells from each other Attachment to matrix components Degradation of ECM, e.g., collagenase, etc. Migration of tumor cells  Carcinogenesis is “MULTISTEP” NO single oncogene causes cancer BOTH several oncogenes AND several tumor suppressor genes must be involved Gatekeeper/Caretaker concept Gatekeepers: ONCOGENES and TUMOR SUPPRESSOR GENES Caretakers: DNA REPAIR GENES Tumor “PROGRESSION” ANGIOGENESIS HETEROGENEITY from original single cell Carcinogenesis: Initiation/Promotion concept: BOTH initiators AND promotors are needed NEITHER can cause cancer by itself INITIATORS (carcinogens) cause MUTATIONS PROMOTORS are NOT carcinogenic by themselves, and MUST take effect AFTER initiation, NOT before PROMOTORS enhance the proliferation of initiated cells, i.e., HYPERPLASTIC AGENTS!!! Carcinogenic Agents Chemicals Direct-acting agents Indirect-acting agents Radiation Ionizing radiation UV light Viruses HPV Squamous Cervical Carcinoma EBV Burkitt Lymphoma HBV Hepatocellular Carcinoma (Hepatoma) CHEMICAL CARCINOGENS:
INITIATORS PROMOTORS Acylating Agents Natural Plant and Microbial HORMONES Products PHORBOL ESTERS (TPA), Aflatoxin B1 Hepatomas Griseofulvin Antifungal activate kinase C PHENOLS DRUGS, many “Initiated” cells respond and proliferate FASTER to promotors than normal cells  How do tumor cells
escape immune surveillance? Mutation, like microbes A. ↓ MHC molecules on tumor cell surface B. Lack of immune stimulation molecules C. Immunosuppressive agents D. Antigen masking E. Apoptosis of cytotoxic T-Cells (CD8), i.e., tumor cell KILLS the T-cell. Grading and Staging Grading = microscopic Is the degree of differentiation Well diff Moderately G1 G2 Poorly Anaplastic G3 G4 Staging = clinical Is description of tumor spread Staging is more useful. GRADING/STAGING GRADING: HOW “DIFFERENTIATED” ARE THE CELLS? STAGING: HOW MUCH ANATOMIC EXTENSION? TNM Which one of the above do you think is more important? Cancer is still an enigma
-Never stop fighting it!!!! THANK YOU