CARCINOGENIC AGENTS AND TUMOR IMMUNOLOGY

DAVID LEWIN MD

OVERVIEW

Three Classes of Carcinogens
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Chemical Radiation Viral Tumor Antigens Antitumor Effector Mechanisms Immunosurveillance Immunotherapy

Tumor Immunology
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CHEMICAL CARCINOGENS
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Natural and Synthetic Agents Highly reactive electrophiles (electron deficient)
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React with RNA, DNA or cellular proteins Direct –Acting Indirect-Acting

Basic Pathology 6th ed. Table 6-7 .CHEMICAL CARCINOGENS Kumar et al.

Direct Acting Agents   Weak carcinogens Require no chemical transformation  Chemotherapeutic drugs  Alkylating agents  Cyclophosphamide. chlorambucil. Dimethylcarbamyl chloride  Acylating agents  . nitrosoureas  Second malignancy decades later 1-Acetyl-imidazole.

  Procarcinogen. active epoxides bind DNA   Benz[a]anthracene: skin cancer Benzo[a]pyrene: cigarette smoke.lung cancer .Indirect Agents  Require metabolic conversion before they become active.initial chemical Ultimate carcinogen: active end product  Examples  Polycyclic hydrocarbons: fossil fuels.

Indirect Agents Continued  Examples  Aromatic amines and azo dyes  Converted in liver by P-450   Beta-naphthylamine: Bladder ca in rubber factories Azo dyes: developed for food color Formed endogenously in acid environment of stomach  GI cancers? Aspergillus in grains  Hepatocellular cancer  Nitrosamines and amides   Aflatoxin B  .

HNPCC .e..Mechanism of Action of Chemical Carcinogens  Mutagenic  Ras mutations in rodents Augmenting agents by themselves not carcinogenic    Promoter  Produce cell proliferation Must follow mutagenic chemical “initiator”  Tetra-decanoylphorbol-acetate (TPA)  Activate protein kinase C  Patients at High risk  Genetic disorders i.

translocations and point mutations  . Squamous cell carcinoma. basal cell carcinoma Early developers: skin cancer ENT ca with irradiation: thyroid cancer Survivors of nuclear bomb: leukemia Miners: lung cancer  X-rays    Nuclear fission   Radionuclides  Ionizing radiation: chromosome breakage.Radiation Carcinogenesis  Types of radiation  Ultraviolet rays of sunlight  Melanoma.

MECHANISMS OF VIRAL CARCINOGENESIS  ONCOGENES  Carry oncogenes in viral DNA Altering structure and/or function of host genome.  INSERTIONAL MUTAGENESIS  .

TUMOR VIRUSES    RNA VIRUSES (RETROVIRUSES) DNA VIRUSES Important for both types of viruses is that the infection not kill the cell .

RNA TUMOR VIRUSES  RETROVIRUSES  ONLY CANCER CAUSING RNA VIRUSES GAG (CORE PROTEINS) POL (REVERSE TRANSCRIPTASE) ENV (ENVELOPE PROTEINS)  PROTOTYPE RETROVIRUS:    .

MECHANISMS OF RETROVIRAL TRANSFORMATION  ACUTE TRANSFORMING RETROVIRUS  CONTAINS ACTIVE ONCOGENE INSERTIONAL MUTAGENESIS   SLOW TRANSFORMING RETROVIRUS  DOES NOT CARRY AN ONCOGENE ITSELF  OTHER MECHANISMS (HTLV-I) .

HTLV AND ADULT T-CELL LEUKEMIA     GEOGRAPHIC DISTRIBUTION ALL ATL PATIENTS ARE INFECTED VIRUS FOUND IN TUMOR CELLS VIRUS TRANSFORMS T CELLS IN CULTURE .

Figure 6-31 .HTLV-1 and ATL Proliferation Malignancy Kumar et al. Basic Pathology 6th ed.

DNA TUMOR VIRUSES  EARLY GENES  DNA REPLICATION / GENE EXPRESSION  LATE GENES  CAPSID. PACKAGING TO PRODUCE VIRAL PARTICLES  EARLY GENES = CANCER CAUSING .

DNA VIRUS LIFE CYCLE  PRODUCTIVE CYCLE  EARLY AND LATE GENES  CELL DEATH  NON-PRODUCTIVE CYCLE (LYSOGENIC)  ONLY EARLY GENES   CELL SURVIVES MOST IMPORTANT FOR CARCINOGENESIS .

DNA TUMOR VIRUSES ASSOCIATED WITH HUMAN CANCER    HUMAN PAPILLOMA VIRUS (HPV) AND CERVICAL CANCER HEPATITIS B (HBV) AND LIVER CANCER (HEPATOMA) EPSTEIN-BARR VIRUS (EBV) AND BURKITT’S LYMPHOMA .

18) HPV INTEGRATED DNA IN SOME CELLS CAN TRANSFORM CELLS IN CULTURE .HPV AND CERVICAL CANCER      EPIDEMIOLOGY CO-EXISTING INFECTIONS SPECIFIC TYPES (16.

THE “GRADUAL” DEVELOPMENT OF MALIGNANCY  CARCINOMA OF THE UTERINE CERVIX      HPV INFECTION (KOILOCYTOSIS) CONDYLOMA DYSPLASIA (CIN) CARCINOMA IN SITU INVASIVE CARCINOMA University of Utah Web Site .

Epstein-Barr Virus (EBV)  Four cancers     Burkitt’s lymphoma B-cell lymphoma in immunosupressed Nasopharyngeal carcinoma Hodgkin’s disease LMP-1: cell growth and survival ( bcl-2) EBNA-2: activates cyclin D and src genes High antibody titer DNA clonally present in tumor cells EBV transforms cultured lymphocytes University of Kansas Web site  Mechanism    Association with Burkitt’s    .

HBV AND HEPATOMA     GEOGRAPHIC DISTRIBUTION (EPIDEMIOLOGY) CHRONIC INFECTION.RR 200X WOODCHUCKS (ANIMAL MODEL) INTEGRATED VIRAL DNA .

Tumor Immunity  General Principles  Tumors not entirely self  Express non-self proteins  Immune-mediated recognition of tumor cells may be “positive mechanism of eliminating transformed cells  Immune surveillance .

however are generally not expressed by normal tissue  Melanoma-associated antigen-1 (MAGE-1):  Embryonal protein normally expressed in testis  Melanomas. lung ca .Tumor Antigens  Tumor Specific Antigens   Present only on Tumor cells Recognized by cytotoxic T cells  Bound by class I MHC  Several antigens in humans found that are not unique for tumor. breast ca.

shared by normal cells  Differentiation.Tumor Antigens  Tumor Associated Antigens  Not unique to tumors.specific antigens   CALLA (CD10) in early B cells Prostate specific antigen PSA .

Antitumor Effector Mechanisms  Cytotoxic T-cells  MHC restricted CD-8 cells (viruses) Destroying tumor cells without prior sensitization Ifn-gamma Via complement and NK cells  NK cells   Macrophages   Humoral Mechanisms  .

Figure 6-32 . Basic Pathology 6th ed.Antitumor Effector Mechanisms Cytotoxic T-cell NK cell Humoral Mechanisms Macrophage Kumar et al.

IMMUNOSURVAILLANCE  Argument for:  Increased cancer in immunodeficient hosts  200x increase in immunodeficiencies (lymphoma)  X-linked lymphoproliferative disorder (XLP  EBV related  Escape Mechanism Theories    Selective outgrowth of antigen-negative variants Loss or reduction of HLA (escape T-cells) Immunosuppression (Tumors secrete factors TGFb) .

IMMUNOTHERAPY  Replace suppressed components of immune system or stimulate endogenous responses  Adoptive Cellular Therapy  Incubation of lymphocytes with IL-2 to generate lymphokine activated killer (LAK) cells with potent antitumor activity  Enriched tumor specific cytotoxic T cells  Tumor infiltrating lymphocytes (TIL) .

Il-2. increase MHC expression on tumor cells  Used for hairy cell leukemia .  Interferon-a. IFN-g  IFN-a activates NK cells.Cytokine Therapy  Activate specific and nonspecific (inflammatory) host defenses. TNF-a.

Antibody-Based Therapy   Antibodies as targeting agents for delivery of cell toxins “magic bullet” Direct use of antibodies to activate host immune system  Her-2/neu in advance breast cancer .

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