بسم الله الرحمن الرحيم 1
•Cancer Origin and Terminology •Malignant Transformation of Cells •Oncogenes and Cancer Induction •Tumor Antigens •Immune Responses to Tumors •Tumor Evasion of the Immune System •Cancer Immunotherapy
•Cancer Origin and Terminology •Malignant Transformation of Cells •Oncogenes and Cancer Induction •Tumor Antigens •Immune Responses to Tumors •Tumor Evasion of the Immune System •Cancer Immunotherapy
•Cancer Origin and Terminology •Malignant Transformation of Cells •Oncogenes and Cancer Induction •Tumor Antigens •Immune Responses to Tumors •Tumor Evasion of the Immune System •Cancer Immunotherapy
Oncogenic Transformation of Normal Cells The transformation of normal cells into malignant cells: Spontaneously arising transformants resulting from random mutations or gene rearrangements during the normal processes of cell growth. The action of carcinogens, which may be chemical, physical or viral in nature. Chemical Carcinogens Physical Carcinogens Viral Oncogenes Cellular Oncogenes
•Cancer Origin and Terminology •Malignant Transformation of Cells •Oncogenes and Cancer Induction •Tumor Antigens •Immune Responses to Tumors •Tumor Evasion of the Immune System •Cancer Immunotherapy
Oncogenes in Tumor Development
Cancer-associated Genes
Cancer-associated Genes
Cancer-associated Genes
Cancer-associated Genes
Cancer-associated Genes
Cancer-associated Genes
Process of Oncogenic Transformation Model of sequential genetic alterations leading to metastatic colon cancer. Each of the stages indicated is morphologically distinct, allowing for the determination of the sequence of genetic alterations.
Immunotherapy
•Cancer Origin and Terminology •Malignant Transformation of Cells •Oncogenes and Cancer Induction •Tumor Antigens •Immune Responses to Tumors •Tumor Evasion of the Immune System •Cancer Immunotherapy
Tumor Antigens New Antigens : Tumor Specific Antigens (TSAs) Autologous Tissue Antigens: Tumor Associated Antigens (TAAs)
Tumor Specific Antigens (TSAs) 1) Mutated Proteins oncogenic abnormal function: p53, p21Ras, β-catenin, CDK-4 translocation: BCR-Abl (CML) secondary to genomic instability 2) Viral Proteins EBV: EBNA1, LMP1, LMP2 (Hodgkin’s disease, nasopharyngeal cancer) HPV: E6, E7 (cervical cancer)
Tumor Specific Antigens (TSAs) 1) Mutated Proteins oncogenic abnormal function: p53, p21Ras, β-catenin, CDK-4 translocation: BCR-Abl (CML) secondary to genomic instability 2) Viral Proteins EBV: EBNA1, LMP1, LMP2 (Hodgkin’s disease, nasopharyngeal cancer) HPV: E6, E7 (cervical cancer)
Tumor Associated Antigens (TAAs) 1) Cancer-testes (germ cell antigens) expressed only in germ cells and tumors unknown function MAGE family: MAGE1, MAGE3, NY-ESO (melanoma, breast, glioma) 2) Differentiation Antigens overexpressed in tumor, but also found in tissue of origin melanosomal proteins: tyrosinase, gp100, Mart 1 (melanoma) rearranged Ig and TCR genes (B and T cell lymphoma) 3) Overexpressed Oncogenic Proteins may reflect critical step in oncogenesis WT1 -- regulates transcription/ MDM-2 -- blocks p53 function survivin -- inhibits apoptosis/ HER2/neu -- growth factor receptor Telomerase-- prevents senescence
Tumor Associated Antigens (TAAs) 1) Cancer-testes (germ cell antigens) expressed only in germ cells and tumors unknown function MAGE family: MAGE1, MAGE3, NY-ESO (melanoma, breast, glioma) 2) Differentiation Antigens overexpressed in tumor, but also found in tissue of origin melanosomal proteins: tyrosinase, gp100, Mart 1 (melanoma) rearranged Ig and TCR genes (B and T cell lymphoma) 3) Overexpressed Oncogenic Proteins may reflect critical step in oncogenesis WT1 -- regulates transcription/ MDM-2 -- blocks p53 function survivin -- inhibits apoptosis/ HER2/neu -- growth factor receptor Telomerase-- prevents senescence
Tumor Associated Antigens (TAAs) 1) Cancer-testes (germ cell antigens) expressed only in germ cells and tumors unknown function MAGE family: MAGE1, MAGE3, NY-ESO (melanoma, breast, glioma) 2) Differentiation Antigens overexpressed in tumor, but also found in tissue of origin melanosomal proteins: tyrosinase, gp100, Mart 1 (melanoma) rearranged Ig and TCR genes (B and T cell lymphoma) 3) Overexpressed Oncogenic Proteins may reflect critical step in oncogenesis WT1 -- regulates transcription/ MDM-2 -- blocks p53 function survivin -- inhibits apoptosis/ HER2/neu -- growth factor receptor Telomerase-- prevents senescence
Mechanisms for Generating Tumor-specific Transplantation Antigens (TSTA) and Tumor-associated Transplantation Antigens (TATA)
Utilization of Antigens Techniques for defining tumor antigens Antigens purified from cancer cells and identified by physicochemical techniques Tumor-specific T-cell clones tested against antigen negative cells that express the antigen via transfection by plasmids Synthetic peptides constructed to precisely identify antigenic site or epitope Immunodiagnosis TATA as useful tumor markers Released only from tumor tissue Specific for a given tumor type Detectable at low levels of tumor burden Has direct relationship to the tumor cell burden Present in all patients with tumor Tumors release antigen macromolecules that can be detected in vivo and in vitro
Immunodiagnosis Examples of TATA used for markers Alpha-Fetoprotein Beta-subunit of human chorionic gonadotropin (B-HCG) Prostate-specific antigen (PSA) CA 125 Radio-labeled monoclonal antibody B72.3 Carcinoembryonic Antigen (CEA) Protein-polysaccharide complex in colon carcinomas Immunoassay can detect increased levels in blood Specificity is low in certain cases, such as heavy cigarette smokers and other cancers
Diagnostics Ideal Tumor Marker 1. Specific for tumor type. 2. Released only in response to tumor. 3. Results proportional to tumor mass. 4. Quantitatively reflects tumor response. 5. Elevated with low tumor burden.
Prognostic roles of tumor markers
•Cancer Origin and Terminology •Malignant Transformation of Cells •Oncogenes and Cancer Induction •Tumor Antigens •Immune Responses to Tumors •Tumor Evasion of the Immune System •Cancer Immunotherapy
Host Immune Response to Tumor Circumstantial and Experimental Evidence of a Host Immune Response to Tumor Circumstantial Spontaneous regression Regression of tumor after sub-lethal doses of chemotherapy Regression of metastasis after resection of primary tumor Mononuclear cell infiltration of tumor High incidence of tumor after clinical immunosuppression High incidence of tumor in immunodeficiency diseases Increased incidence of tumors in aging Experimental Colony inhibition of tumors by sensitized lymphocytes Lymphocyte blast transformation in presence of tumor extracts Lymphocyte-enhanced cytotoxicity in patients with tumor Macrophage-enhanced phagocytosis in patients with tumor
Tumor Immunology Cancer immunosurveilance: Cancer immunoediting: immune system can recognize and destroy nascent transformed cells Cancer immunoediting: immune system kill and also induce changes in the tumor resulting in tumor escape and recurrence (epigenetic changes or Darwinian selection)
•Cancer Origin and Terminology •Malignant Transformation of Cells •Oncogenes and Cancer Induction •Tumor Antigens •Immune Responses to Tumors •Tumor Evasion of the Immune System •Cancer Immunotherapy
•Cancer Origin and Terminology •Malignant Transformation of Cells •Oncogenes and Cancer Induction •Tumor Antigens •Immune Responses to Tumors •Tumor Evasion of the Immune System •Cancer Immunotherapy
•Cancer Origin and Terminology •Malignant Transformation of Cells •Oncogenes and Cancer Induction •Tumor Antigens •Immune Responses to Tumors •Tumor Evasion of the Immune System •Cancer Immunotherapy
امتحان كلاسي 95/2/4 داروسازي كدام يك از سلول هاي دفاعي در از بين بردن سلولهاي توموري كارآمدتر هستند؟ الف) DC ب) NK ج)CTL د) Th1