1. بسم الله الرحمن الرحيم

2. 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

3. 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

5. 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

6. Oncogenic Transformation of Normal 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. The transformation of normal cells into malignant cells: Chemical Carcinogens Physical Carcinogens Viral Oncogenes Cellular Oncogenes

11. 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

12. Oncogenes in Tumor Development

13. Cancer-associated Genes

14. 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.

15. Immunotherapy

16. 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

17. Tumor Antigens 1) Mutated Proteins oncogenic - abnormal function: p53, p21Ras, β- catenin, CDK-4 - translocation: BCR-Abl (CML) secondary to genomic instability 2) Viral Proteins oncogenic - EBV: EBNA1, LMP1, LMP2 (Hodgkin ’ s disease, nasopharyngeal cancer) - HPV: E6, E7 (cervical cancer) 3) Cancer-testes (germ cell antigens) expressed only in germ cells and tumors unknown function - MAGE family: MAGE1, MAGE3, NY- ESO (melanoma, breast, glioma) 4) Differentiation Antigens overexpressed in tumor, but also found in tissue of origin - melanosomal proteins: tyrosinase, gp100, Mart 1 (melanoma) unique to tumor - rearranged Ig and TCR genes (B and T cell lymphoma) 5) 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

18. Mechanisms for Generating Tumor-specific Transplantation Antigens (TSTA) and Tumor- associated Transplantation Antigens (TATA)

19. Utilization of Antigens Techniques for defining tumor antigens Techniques for defining tumor antigens Antigens purified from cancer cells and identified by physicochemical techniques 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 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 Synthetic peptides constructed to precisely identify antigenic site or epitope Immunodiagnosis Immunodiagnosis TATA as useful tumor markers TATA as useful tumor markers Released only from tumor tissue Released only from tumor tissue Specific for a given tumor type Specific for a given tumor type Detectable at low levels of tumor burden Detectable at low levels of tumor burden Has direct relationship to the tumor cell burden Has direct relationship to the tumor cell burden Present in all patients with tumor Present in all patients with tumor Tumors release antigen macromolecules that can be detected in vivo and in vitro Tumors release antigen macromolecules that can be detected in vivo and in vitro

20. Immunodiagnosis Examples of TATA used for markers Examples of TATA used for markers Alpha-Fetoprotein Alpha-Fetoprotein Beta-subunit of human chorionic gonadotropin Beta-subunit of human chorionic gonadotropin(B-HCG) Prostate-specific antigen (PSA) Prostate-specific antigen (PSA) CA 125 CA 125 Radio-labeled monoclonal antibody B72.3 Radio-labeled monoclonal antibody B72.3 Carcinoembryonic Antigen (CEA) Carcinoembryonic Antigen (CEA) Protein-polysaccharide complex in colon carcinomas Protein-polysaccharide complex in colon carcinomas Immunoassay can detect increased levels in blood Immunoassay can detect increased levels in blood Specificity is low in certain cases, such as heavy cigarette smokers and other cancers Specificity is low in certain cases, such as heavy cigarette smokers and other cancers

21. Diagnostics Ideal Tumor Marker 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.

22. Prognostic roles of tumor markers

23. CONCLUSION AFPCA125CA153CA199CA72-4CEA CYFRA 21-1 HCGNSE Free PSA Total PSA cholangiocarcinoma★ breast carcinoma ★★ Islet cell carcinoma ★ uterine cervix cancer ★ chorionic carcinoma ★ intestinal carcinoma ★★ esophageal carcinoma ★ germinocarcinoma★★ hepatoma★ SCLC★ NSCLC★★ ovarian cancer ★★ pancreatic carcinoma ★★ prostatic carcinoma ★★ gastric carcinoma ★★★

25. 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

26. 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

27. Tumor Immunology Cancer immunosurveilance: 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)

32. 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

41. 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