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CARCINOGENIC AGENTS AND TUMOR IMMUNOLOGY DAVID LEWIN MD
OVERVIEW Three Classes of Carcinogens
Chemical Radiation Viral
Tumor Immunology Tumor Antigens Antitumor Effector Mechanisms Immunosurveillance Immunotherapy
CHEMICAL CARCINOGENS Natural and Synthetic Agents Highly reactive electrophiles
(electron deficient) React with RNA, DNA or cellular
proteins Direct –Acting Indirect-Acting
CHEMICAL CARCINOGENS
Direct Acting Agents Weak carcinogens Require no chemical transformation
Chemotherapeutic drugs Alkylating agents
Cyclophosphamide, chlorambucil, nitrosoureas Second malignancy decades later
Acylating agents 1-Acetyl-imidazole, Dimethylcarbamyl
chloride
Indirect Agents Require metabolic conversion before they become active.
Procarcinogen- initial chemical Ultimate carcinogen: active end product
Examples Polycyclic hydrocarbons: fossil fuels, active epoxides bind DNA
Benz[a]anthracene: skin cancer Benzo[a]pyrene: cigarette smoke- lung cancer
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
Nitrosamines and amides Formed endogenously in acid environment of
stomach GI cancers?
Aflatoxin B Aspergillus in grains
Hepatocellular cancer
Mechanism of Action of Chemical Carcinogens Mutagenic
Ras mutations in rodents Promoter
Augmenting agents by themselves not carcinogenic
Produce cell proliferation Must follow mutagenic chemical “initiator”
Tetra-decanoylphorbol-acetate (TPA) Activate protein kinase C
Patients at High risk Genetic disorders i.e.. HNPCC
Radiation Carcinogenesis Types of radiation
Ultraviolet rays of sunlight
Melanoma, Squamous cell carcinoma, basal cell carcinoma
X-rays Early developers: skin
cancer ENT ca with irradiation:
thyroid cancer Nuclear fission
Survivors of nuclear bomb: leukemia
Radionuclides Miners: lung cancer Ionizing radiation: chromosome breakage,
translocations and point mutations
MECHANISMS OF VIRAL CARCINOGENESIS
ONCOGENES Carry oncogenes in viral DNA
INSERTIONAL MUTAGENESIS Altering structure and/or function of
host genome.
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
PROTOTYPE RETROVIRUS: GAG (CORE PROTEINS) POL (REVERSE TRANSCRIPTASE) ENV (ENVELOPE PROTEINS)
MECHANISMS OF RETROVIRAL TRANSFORMATION
ACUTE TRANSFORMING RETROVIRUS CONTAINS ACTIVE ONCOGENE
SLOW TRANSFORMING RETROVIRUS INSERTIONAL MUTAGENESIS
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
HTLV-1 and ATL
Proliferation
Malignancy
Kumar et al. Basic Pathology 6th ed. Figure 6-31
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
HPV AND CERVICAL CANCER EPIDEMIOLOGY CO-EXISTING INFECTIONS SPECIFIC TYPES (16, 18) HPV INTEGRATED DNA IN SOME
CELLS CAN TRANSFORM CELLS IN
CULTURE
THE “GRADUAL” DEVELOPMENT OF MALIGNANCY
CARCINOMA OF THE UTERINE CERVIX HPV INFECTION (KOILOCYTOSIS) CONDYLOMA DYSPLASIA (CIN) CARCINOMA IN SITU INVASIVE CARCINOMAUniversity
of Utah Web Site
Epstein-Barr Virus (EBV) Four cancers
Burkitt’s lymphoma B-cell lymphoma in immunosupressed Nasopharyngeal carcinoma Hodgkin’s disease
Mechanism LMP-1: cell growth and survival ( bcl-2) EBNA-2: activates cyclin D and src genes
Association with Burkitt’s High antibody titer DNA clonally present in tumor cells EBV transforms cultured lymphocytes
University of Kansas Web site
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
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, however are generally not expressed by normal tissue
Melanoma-associated antigen-1 (MAGE-1): Embryonal protein normally expressed in testis
Melanomas, breast ca, lung ca
Tumor Antigens Tumor Associated Antigens
Not unique to tumors, shared by normal cells
Differentiation- specific antigens CALLA (CD10) in early B cells Prostate specific antigen PSA
Antitumor Effector Mechanisms Cytotoxic T-cells
MHC restricted CD-8 cells (viruses) NK cells
Destroying tumor cells without prior sensitization
Macrophages Ifn-gamma
Humoral Mechanisms Via complement and NK cells
Antitumor Effector Mechanisms
Cytotoxic T-cell NK cell
MacrophageHumoralMechanisms
Kumar et al. Basic Pathology 6th ed. Figure 6-32
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
TGF-b)
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)
Cytokine Therapy Activate specific and nonspecific
(inflammatory) host defenses. Interferon-a, TNF-a, Il-2, IFN-g
IFN-a activates NK cells, increase MHC expression on tumor cells
Used for hairy cell leukemia
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