CARCINOGENIC AGENTS AND TUMOR IMMUNOLOGY

DAVID LEWIN MD

OVERVIEW

Three Classes of Carcinogens

Chemical Radiation Viral Tumor Antigens Antitumor Effector Mechanisms Immunosurveillance Immunotherapy

Tumor Immunology

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 1-Acetyl-imidazole, Dimethylcarbamyl chloride

Acylating agents

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 Formed endogenously in acid environment of stomach GI cancers? Aspergillus in grains Hepatocellular cancer

Nitrosamines and amides

Aflatoxin B

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.e.. HNPCC

Radiation Carcinogenesis

Types of radiation

Ultraviolet rays of sunlight

Melanoma, 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, translocations and point mutations

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

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 BURKITTS 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 CARCINOMA
University of Utah Web Site

Epstein-Barr Virus (EBV)

Four cancers

Burkitts lymphoma B-cell lymphoma in immunosupressed Nasopharyngeal carcinoma Hodgkins 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 Burkitts

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) Destroying tumor cells without prior sensitization Ifn-gamma Via complement and NK cells

NK cells

Macrophages

Humoral Mechanisms

Antitumor Effector Mechanisms

Cytotoxic T-cell NK cell

Humoral Mechanisms

Macrophage

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 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)

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