Carcinogenic Agents

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

Carcinogenic Agents

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CARCINOGENIC AGENTS AND TUMOR IMMUNOLOGY

Three Classes of Carcinogens

Natural and Synthetic Agents Highly reactive electrophiles (electron deficient)

React with RNA, DNA or cellular proteins Direct Acting Indirect-Acting

Direct Acting Agents

Weak carcinogens Require no chemical transformation

Cyclophosphamide, chlorambucil, nitrosoureas

Second malignancy decades later 1-Acetyl-imidazole, Dimethylcarbamyl chloride

Require metabolic conversion before they become active.

Procarcinogen- initial chemical Ultimate carcinogen: active end product

Polycyclic hydrocarbons: fossil fuels, active epoxides bind DNA

Benz[a]anthracene: skin cancer Benzo[a]pyrene: cigarette smoke- lung cancer

Indirect Agents Continued

Aromatic amines and azo dyes

Converted in liver by P-450

Nitrosamines and amides

Mechanism of Action of Chemical Carcinogens

Ras mutations in rodents

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

Ultraviolet rays of sunlight

Ionizing radiation: chromosome breakage, translocations and point mutations

MECHANISMS OF VIRAL CARCINOGENESIS

Carry oncogenes in viral DNA

RNA TUMOR VIRUSES

ONLY CANCER CAUSING RNA VIRUSES

MECHANISMS OF RETROVIRAL TRANSFORMATION

ACUTE TRANSFORMING RETROVIRUS

CONTAINS ACTIVE ONCOGENE

SLOW TRANSFORMING RETROVIRUS

DOES NOT CARRY AN ONCOGENE ITSELF

OTHER MECHANISMS (HTLV-I)

HTLV AND ADULT T-CELL LEUKEMIA

HTLV-1 and ATL

DNA TUMOR VIRUSES

DNA REPLICATION / GENE EXPRESSION

CAPSID, PACKAGING TO PRODUCE VIRAL PARTICLES

EARLY GENES = CANCER CAUSING

DNA VIRUS LIFE CYCLE

EARLY AND LATE GENES

NON-PRODUCTIVE CYCLE (LYSOGENIC)

ONLY EARLY GENES

CELL SURVIVES MOST IMPORTANT FOR CARCINOGENESIS

DNA TUMOR VIRUSES ASSOCIATED WITH HUMAN CANCER

HPV AND CERVICAL CANCER

THE GRADUAL DEVELOPMENT OF MALIGNANCY

CARCINOMA OF THE UTERINE CERVIX

Epstein-Barr Virus (EBV)

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

Association with Burkitts

HBV AND HEPATOMA

Tumors not entirely self

Express non-self proteins

Tumor Specific Antigens

Present only on Tumor cells Recognized by cytotoxic T cells

Bound by class I MHC

Melanoma-associated antigen-1 (MAGE-1):