Neoplasia5-Carcinogenesis

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NEOPLASIA - 5:

NEOPLASIA - 5 Dr. R. Sasank

Neoplasia - 5 Lesson Plan:

Neoplasia - 5 Lesson Plan Definitions Nomenclature Benign Vs Malignant Invasion, Metastasis, Epidemiology Molecular basis of cancer Carcinogenic Agents & cellular interaction Host Defense , tumor immunity Clinical Aspects

Molecular Basis of tumors - an over view :

Molecular Basis of tumors - an over view 1. NON-lethal genetic damage to cell 2. Tumors are formed by clonal expansion of a single precursor cell (monoclonal) 3. Defects in regulatory genes PROTO-oncogenes Oncogenes  Oncoproteins DNA repair genes Apoptosis genes 4. Carcinogenesis is a multi-step process

Transformation of normal Cell:

Transformation of normal Cell

The hallmarks of Transformed cell:

The hallmarks of Transformed cell Six hallmarks of cancer cell. Most cancer cells acquire these properties during their development, typically by mutations in the relevant genes .

Functions of Cellular Proto-Oncogenes:

4. Nuclear Proteins: Transcription Factors 5. Cell Growth Genes 3. Cytoplasmic Signal Transduction Proteins 1. Secreted Growth Factors 2. Growth Factor Receptors Functions of Cellular Proto-Oncogenes

Carcinogenesis:

Carcinogenesis

The Carcinogenic agents:

The Carcinogenic agents Chemical Carcinogens Physical Carcinogens Biological Carcinogens

Biological carcinogens:

Biological carcinogens Viruses DNA VIRUSES RNA VIRUSES Bacteria FUNGI

Viruses and Human Cancer:

Viruses and Human Cancer Despite of so many viral oncogenes, the cancers associated with viral infections is limited Viral infections are responsible for some 15% of all human cancers.

Association between viruses & cancer …some examples:

Association between viruses & cancer … some examples Virus Name Cancer caused Human T-cell leukemia virus type I (HTLV-I) (RNA retrovirus) T-cell leukemia/lymphoma Hepatitis C virus (HCV-RNA) Hepato-cellular carcinoma HPV (DNA virus) Carcinoma of the cervix Hepatitis B virus (HBV-DNA virus) Hepato-cellular carcinoma Epstein-Barr virus (EBV-DNA virus) Lymphoma and nasopharyngeal carcinoma HHV 8 (DNA virus) Kaposi sarcoma.

Human T-Cell Leukemia Virus-I (HTLV-I) is a Lymphotropic Agent:

Human T-Cell Leukemia Virus-I (HTLV-I) is a Lymphotropic Agent Firmly linked to infection with an RNA retrovirus it is endemic in south Japan and Caribbean basin. HTLV-I, is tropic for CD4 + T lymphocytes Leukemia in > 5% of persons infected with HTLV-I and exhibits a latency period of 40 years. Oncogenic stimulation is mediated by viral transcriptional activation protein tax . Tax protein increases the transcription from its own viral genome & also promotes the activity of other genes involved in host cell proliferation.

HTLV-1-induced T-cell leukemia/lymphoma:

HTLV-1-induced T-cell leukemia/lymphoma HTLV-1 causes polyclonal proliferation by autocrine & paracrine pathways triggered by the TAX gene. TAX neutralizes growth-inhibitory signals by affecting p53 and CDKN2A/p16 genes. Ultimately, a monoclonal T-cell leukemia/lymphoma results when one proliferating T cell suffers additional mutations

DNA Viruses Encode Proteins that Bind Regulatory Proteins:

DNA Viruses Encode Proteins that Bind Regulatory Proteins Four DNA viruses (HPV, EBV, HBV, and HHV 8) are incriminated in the development of human cancers. The transforming genes of oncogenic DNA viruses exhibit virtually no homology with cellular genes, whereas those of RNA retroviruses (oncogenes) are derived from, and are homologous with, their cellular counterparts (protooncogenes). Oncogenic DNA viruses encode protein products that bind to, and inactivate, specific host proteins (tumor suppressor genes, e.g., Rb, p53) involved in the regulation of cell proliferation and apoptosis.

Human Papilloma Viruses (HPVs):

Human Papilloma Viruses (HPVs) Papillomaviruses manifest tropism for epithelial cells, and their life cycle occurs only in squamous cells. HPVs induce lesions that progress to squamous cell carcinoma. At least 20 HPV types are associated with cancer of the uterine cervix, especially HPV 16 and 18. The major oncoproteins encoded are E6 and E7. E6 binds to p53 and targets it for degradation. E7 binds to Rb, thereby releasing its inhibitory effect on cell cycle progression.

HPV Mechanism:

HPV Mechanism

Epstein-Barr Virus (EBV):

Epstein-Barr Virus (EBV) EBV is a human herpesvirus infects B lymphocytes and transform them into lymphoblasts with an indefinite lifespan. In some, this transformation is manifested as infectious mononucleosis- a short-lived disease. EBV genes implicated in lymphocyte immortalization, including EBNuclear Antigens and latent-infection associated membrane proteins (LMPs). The EBNAs activate the transcription of viral and cellular genes. LMP1 interacts with signal transduction from the TNF receptor

Burkitt Lymphoma-Oncogenesis:

Burkitt Lymphoma-Oncogenesis African Burkitt lymphoma is a B-cell tumor, all neoplastic lymphocytes contain EBVgenome Non-Africans, contain only 20% of EBV genome. Burkitt lymphoma ’ s localization to equatorial Africa is attributed to prolonged stimulation of the immune system by endemic malaria. It is associated with a chromosomal translocation, in which the c-myc protooncogene is deregulated by being brought into proximity with an immunoglobulin promoter region. Ultimately, this leads to uncontrolled proliferation of a malignant clone of B lymphocytes.

Pathogenesis Burkitt lymphoma:

Pathogenesis Burkitt lymphoma

Nasopharyngeal Carcinoma:

Nasopharyngeal Carcinoma Its a variant of sq. cell carcinoma common in certain parts of Africa and Asia. EBV DNA and EBNA are present in virtually all of these cancers. The pathogenesis may be related to infection with EBV in early childhood, with reactivation at 40 to 50 years of age Fortunately, 70% of patients with this disease are cured by radiation therapy alone.

Hepatitis B virus (HBV-DNA) & Hepatitis C virus (HCV-RNA):

Hepatitis B virus (HBV-DNA) & Hepatitis C virus (HCV-RNA) There is strong association between chronic infection of HBV and hepatocellular carcinoma. Similarly HCV hepatitis ,HCV cirrhosis and hepatocellular carcinoma. Two mechanisms of carcinogenesis in virus-related liver cancer. One theory holds that the continued liver cell proliferation that accompanies chronic liver injury eventually leads to transformation. A second theory implicates a virally encoded protein the HBx gene product, which inactivates p53

HHV 8 (Human herpesviruses 8) or Kaposi's Sarcoma-Associated HerpesVirus:

HHV 8 (Human herpesviruses 8) or Kaposi's Sarcoma-Associated HerpesVirus Kaposi sarcoma is a vascular neoplasm originally described in east European men & in central African blacks Today its very common tumor in AIDS. The neoplastic cells contain sequences of a novel herpes virus, HHV 8. Interestingly, HHV 8 ts also demonstrated in Kaposi sarcoma with HIV-negative patients.

Helicobacter pylori:

Helicobacter pylori Gastric infection linked to gastric lymphomas and adenocarcinomas Detection of H pylori in majority of cases of gastric lymphomas Antibiotic treatment results in gastric lymphoma regression in most cases

Fungus and cancer:

Fungus and cancer Some Fungi produce Mycotoxins Aflatoxin (From aspergillus) Ochratoxin (From pencillium) Trichothecenes(From fusarium) Mechanism of toxicity Inhibit protein synthesis, Inhibit DNA synthesis, Inhibit mitochondrial protein synthesis. Cause immunosuppression

Mycotoxins and cancer:

Mycotoxins and cancer Ochratoxin from Aspergillus & Penicillium , causes Astrocytomas Breast carcinoma Mesothelioma Renal Cell Carcinoma Aflatoxin from Aspergillus Causes: Astrocytomas Lung Adenocarcinoma Liver cancer Trichotecenes from Fusarium causes : Uterine carcinoma

Physical Carcinogens:

Physical Carcinogens Ionizing radiation (X-rays) Ultraviolet light Asbestos

Solar Specrum :

Solar Specrum

RADIATION CARCINOGENS:

RADIATION CARCINOGENS UV: BasalCellCa, SqCellCa, MaligMelanoma IONIZING: photons and particulate Hematopoetic and Thyroid (90%/15yrs) tumors in fallout victims Solid tumors either less susceptible or require a longer latency period than LEUK/LYMPH BCCs in Therapeutic Radiation

Carcinogenic Agents- Radiation:

Carcinogenic Agents- Radiation Ionizing radiation Causes chromosome breakage, translocations Examples: Unprotected miners: lung cancer Atomic bomb survivors: leukemia, other cancers Therapeutic head/neck radiation: thyroid cancer

Carcinogenic Agents-UV light:

Carcinogenic Agents- UV light UV light Causes formation of pyrimidine dimers Repair pathways usually fix – but can become overwhelmed Examples: squamous cell carcinoma, melanoma

DNA hit by ionizing radiation:

normal DNA DNA with pyrimidine dimers DNA hit by ionizing radiation

Artist’s view of DNA damage & Repair:

Artist ’ s view of DNA damage & Repair

Ionizing Radiation-- historical:

Ionizing Radiation-- historical Death of pioneer radiation researchers from neoplasms High incidence of leukemia among radiologists recognized in 1940s Osteosarcoma incidence in radium dial painters

Skin cancer is one of the most common human cancer and one of the most preventable:

Skin cancer is one of the most common human cancer and one of the most preventable ~10 6 cases of BCC and SCC are diagnosed per year This is more than all other types of cancer combined Most of these will be caused by exposure to ultraviolet (UV) irradiation

Asbestos:

Asbestos Widely used in construction, insulation, and manufacturing Family of related fibrous silicates Chrysotile Crocidolite

Asbestos Fibers:

Asbestos Fibers

Malignant Mesothelioma:

Malignant Mesothelioma Mainly occurs in pleural and peritoneal cavities Rare in general population Latent period of ≥20 years

Chemical Carcinogenesis :

Chemical Carcinogenesis

Chemical Carcinogenesis Historical aspect:

Chemical Carcinogenesis Historical aspect Firstly described by Sir Percival Pott in 1775 More than 200 years ago, the London surgeon Sir Percival Pott correctly attributed scrotal skin cancer in chimney sweeps to chronic exposure to soot. Based on this observation, the Danish Chimney Sweeps Guild ruled that its members must bathe daily

Initiators and promotors:

Initiators and promotors

Events in Chemical carcinogenesis :

Events in Chemical carcinogenesis

Chemical Carcinogens:

Chemical Carcinogens Direct-acting Chemicals Indirect-acting Chemicals (must be metabolized to activated metabolic forms) Mechanism Highly reactive electrophile groups bind to DNA Important targets: RAS and p53

Direct-acting Carcinogens:

Direct-acting Carcinogens Carcinogenic as-is Most are chemotherapy drugs Cause secondary malignancies (e.g., leukemia) Nitrogen mustards, Nitrosomethylurea, Benzyl chloride

Indirect-acting Carcinogens:

Indirect-acting Carcinogens Require conversion to become carcinogenic Examples: Polycyclic aromatic hydrocarbons (PAH) Produced by incomplete combustion of organic materials Present in chimney soot, charcoal-grilled meats, auto exhaust, cigarette smoke Aflatoxin B (from Aspergillus-infected grains, nuts) Nitrites (food preservative)

Electrophiles:

Electrophiles Direct-acting carcinogens are already electrophilic Indirect-acting carcinogens are metabolically activated into electrophilic species

Electrophilic Theory of Chemical Carcinogenesis:

Electrophilic Theory of Chemical Carcinogenesis Electrophilic (electron-seeking) molecules will bind to nucleophilic (electron-rich) macromolecules in the cell DNA RNA Proteins

Ames Test:

Ames Test Developed by Bruce Ames and his colleagues in the 1970s. Many synthetic and natural compounds in our environment have been screened by the Ames test Test is based upon correlation between carcinogenicity and mutagenicity

Ames Test - Qualitative Method:

Ames Test - Qualitative Method A suspension of a histidine-requiring (His−) strain of Salmonella typhimurium has been plated with a mixture of rat liver enzymes on agar lacking histidine. The disk of filter paper has been impregnated with 10µg of 2-aminofluorene, a known carcinogen. The mutagenic effect of the chemical has caused many bacteria to regain the ability to grow without histidine, forming the colonies seen around the disk.

Characteristics of mutants strains of S.typhimurium used for Ames Test:

Characteristics of mutants strains of S.typhimurium used for Ames Test cannot synthesize histidine. are very susceptible to additional mutations because they lack the normal repair mechanisms found in bacteria. more permeable than wild-type bacteria to external chemicals, including potential mutagens.

Human carcinogens - environmental :

Human carcinogens - environmental Aflatoxins Asbestos Benzene Cadmium Coal tar Creosote DDT Polycyclic aromatic hydrocarbons Radon Solar radiation

Human carcinogens - drugs/therapeutic agents:

Human carcinogens - drugs/therapeutic agents Adriamycin (doxorubicin) Androgenic steroids Chlorambucil Cisplatin Cyclophosphamide Cyclosporin A Diethylstilbestrol Ethylene oxide Melphalan Tamoxifen

Thank you:

Thank you

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