Classify carcinogens /enumerate the types of carcinogens.

A carcinogen is an agent known or suspected to cause tumors and such agents are said to be carcinogenic (cancer
causing).

Carcinogenic agents : (1) chemicals, (2) microbial agents, and (3) radiation

Chemical Carcinogenesis
Classification of Chemical Carcinogens

Chemical carcinogens may be classified into two categories : Direct acting and indirect acting.

1. Direct-acting Agents
Direct-acting chemical agents do not require metabolic conversion to become carcinogenic, but most of them are weak
carcinogens

• Alkylating agents:

Mechanism of action:

 Alkylating agents contain electron-deficient atoms that react with electron-rich atoms in DNA.
 These drugs not only destroy cancer cells by damaging DNA, but also injure normal cells.
 Cancers produced: Solid and hematological malignancies.
 2. Indirect-acting Agents (Procarcinogens) Q. Write short note on polycyclic
hydrocarbons.
Polycyclic hydrocarbons: Lung cancer.

Workers exposed to polyvinyl chloride may develop angiosarcoma of liver.

Indirect-acting carcinogen needs metabolic activation for their conversion into DNA-damaging agent.

Aromatic amines: Bladder and liver cancers.

Aflatoxin: Hepatocellular carcinoma.

Mechanism of Action of Chemical Carcinogens

Molecular targets of chemical carcinogens: Most chemical carcinogens are mutagenic

• All direct and ultimate carcinogens (of indirect carcinogens) contain highly reactive electrophilic groups → form
adducts with DNA, RNA and proteins.

• Genes affected: Any gene may be affected but commonly involved are proto-oncogenes (RAS) and tumor suppressor
genes (p53).

Multistep Hypothesis:
Microbial Carcinogenesis
Microbial carcinogens: Viruses > bacteria > parasites

VIRUS
Oncogenic RNA Viruses
Human T-cell leukemia virus type 1: It is a retrovirus.

Major target for neoplastic transformation: CD4+ T lymphocytes.

• Tumor caused: Adult T-cell leukemia/lymphoma— develops after a long latent period (20–50 years).
• Mode of infection: Sexual intercourse, blood products and breast feeding.

• Mechanism of oncogenesis
Oncogenic DNA Viruses
Oncogenic DNA viruses:

1. Human papillomavirus (HPV)

2. Epstein-Barr virus (EBV)

3. Hepatitis B virus (HBV)

4. Kaposi sarcoma herpes virus (KSHV), also called human herpes virus 8 (HHV-8)

5. Merkel cell polyomavirus causing Merkel cell carcinomas.

HCV is not a DNA virus and found to be associated with cancer.

Human Papillomavirus (HPV)

Cell infected:
 only the immature squamous cells but its replication occurs in the maturing, nonproliferating squamous cells.
 Thus, their full productive life cycle occurs only in squamous cells.
 The physical state of the virus differs in different lesions.

Types of HPV and associated lesions:

 More than 70 genetically different types of HPV have been identified.
 They are divided into low-risk and high-risk HPVs.

Mode of action
Episomal form:

 In benign lesions such as benign warts, condylomata and most precancerous lesions;
 the HPV genome is present as nonintegrated, free (episomal) viral DNA.

Integration:

 In cancers, the HPV genome is integrated into the host genome and is essential for malignant transformation.
 Integration results in overexpression of the two viral genes E6 and E7.
 Protein products of E6 and E7 (oncoproteins) are important for the oncogenic effects of HPV.

Epstein-Barr Virus (EBV)

EBV is a human herpesvirus, which infects B lymphocytes.

manifest as a short-lived infectious mononucleosis or develop few human cancers

The list of cancers produced include:

1. African form of Burkitt lymphoma.

2. B-cell lymphomas in immunosuppressed (e.g. HIV infection or immunosuppressive therapy after organ
transplantation).
3. A subset of Hodgkin lymphoma.
4. Nasopharyngeal carcinoma (T-cell tumor).
5. Some gastric carcinomas.
6. Rare forms of T-cell lymphomas and natural killer (NK) cell lymphomas.
7. Very rarely sarcomas.

Pathogenesis:
EBV: Genes involved—
1. LMP1

2. EBNA2

3. VIL-10

4. c-MYC in Burkitt lymphoma.

 EBV-related oncogenesis: Evasion of immune system is the key step.

 LMP-1 gene plays a role in oncogenesis induced by: Epstein-Barr virus.
 Burkitt lymphoma: EBV is not directly oncogenic, but acts as a polyclonal B-cell mitogen → favors
t(8;14) translocation → activate the c-MYC oncogene → release the cells from normal growth
regulation.

Hepatitis B and C Viruses

 HBV is a DNA virus whereas HCV is RNA virus
HBV:

 HBV genome contains a viral regulatory gene known as HBx.

 Various actions of HBx are: – Direct or indirect activation of many transcription factors and signal transduction
pathways. – Inactivation of p53 – HBV DNA can be integrated within the human genome and can cause multiple
deletions, which may harbor unknown tumor suppressor genes.

HCV: HCV genome, such as the HCV core protein, may activate many growth-promoting signal transduction
pathways and cause tumor.

Human Herpesvirus 8 (HHV 8)

Neoplasm produced:

• Kaposi sarcoma: It is a vascular neoplasm, which is the most common neoplasm, associated with AIDS. HHV 8
has also been found in Kaposi sarcoma from HIV-negative patients.

• B-cell lymphoid malignancies: Two uncommon lymphoid malignancies,

1. primary effusion lymphoma

2. multicentric Castleman disease are associated with HHV 8

 HHV 8 viral genome encodes proteins, which interfere with the p53 and RB tumor suppressor pathways.
 HHV 8 also encodes gene products, which downregulate class I major histocompatibility complex (MHC)
expression → infected cells escape recognition by cytotoxic T lymphocytes.
Bacteria
Helicobacter Pylori : (1) peptic ulcers, (2) gastric adenocarcinomas and (3) gastric lymphomas.

1. Gastric adenocarcinomas Mechanism: It is similar to that of HBV and HCV induced hepatocellular carcinoma.

• Chronic inflammation:

H. pylori causes chronic inflammation (chronic gastritis) → followed by gastric atrophy → intestinal metaplasia →
dysplasia → cancer.

• Genes:

H. pylori causing gastric adenocarcinoma contains cytotoxin-associated A (CagA) gene can penetrate into gastric
epithelial cells → initiation of signals → unregulated growth factor stimulation

2. Gastric lymphoma: H. pylori produces lymphoma of B-cell origin and are called as lymphomas of
mucosaassociated lymphoid tissue, or MALTomas.

Fungi Aspergillus flavus produces aflatoxin B: Hepatocellular carcinoma.

Parasites
Two parasites which can causes tumor are:

• Schistosoma is strongly implicated in carcinoma of urinary bladder (usually of squamous cell type). The ova of the
parasite can be found in the affected tissue.

• Clonorchis sinensis (Chinese liver fluke) lodges in the bile ducts → produces an inflammatory reaction, epithelial
hyperplasia and sometimes adenocarcinoma of the bile ducts (cholangiocarcinoma).
Hormones
act as cofactors in carcinogenesis.

Estrogen
• Endometrial carcinoma: It may develop in females with estrogen-secreting granulosa cell tumor of ovary or those
receiving exogenous estrogen.

• Adenocarcinoma of vagina: Increased frequency of adenocarcinoma of vagina is observed in daughters of mothers

who received estrogen during pregnancy.

• Abnormal vascularity of tumor: Estrogens can make existing tumors abnormally vascular (e.g. adenomas and focal
nodular hyperplasia).

Androgenic and anabolic steroids: They may cause hepatocellular tumors.

Hormone-dependent Tumors

• Prostatic carcinoma usually responds to administration of estrogens or castration.

• Breast carcinomas regress following oophorectomy.

Radiation Carcinogenesis
 Extremely long latent period
 it has a cumulative effect
 additive or synergistic effects with other potential carcinogenic agents

UV rays causes skin cancer:

1. Squamous cell carcinoma

2. Basal cell carcinoma

3. Malignant melanoma.

Types of radiation:

(1) ultraviolet (UV) rays of sunlight and (2) ionizing electromagnetic and particulate radiation

Ultraviolet Rays
Skin cancer, namely (1) squamous cell carcinoma, (2) basal cell carcinoma and (3) malignant melanoma.

Lymphoid tissue: Most sensitive to radiation.

Bone: Least sensitive to radiation.

The amount of damage incurred depends on:
• Type of UV rays

• Intensity of exposure

• Protective mantle of melanin – Melanin absorbs UV radiation and has a protective effect.

– Skin cancers are more common in fair-skinned people and those living in geographic location receiving a
greater amount of sunlight (e.g. Queensland, Australia, close to the equator).

Pathogenesis
• UV radiation leads to → formation of pyrimidine dimers in DNA, which is a type of DNA damage which is
responsible for carcinogenicity.

• DNA damage is repaired by the nucleotide excision repair pathway.

• With excessive sun exposure, the DNA damage exceeds the capacity of the nucleotide excision repair pathway
and genomic injury becomes mutagenic and carcinogenic.

• Xeroderma pigmentosum:

It is a rare hereditary autosomal recessive disorder characterized by congenital deficiency of nucleotide

excision repair DNA.

These individuals develop skin cancers (basal cell carcinoma, squamous cell carcinoma and melanoma)
due to impairment in the excision of UV-damaged DNA.
Ionizing Radiation
Electromagnetic (X-rays, γ rays) and particulate (α particles, β particles, protons, neutrons) radiations are all
carcinogenic.

Ionizing radiation:

 Damages DNA.
 Ionizing radiation: Causes genetic damage by— 1. Chromosomal breakage 2. Translocations 3. Point mutations.

Neoplasms associated with therapeutic radiation

1. Papillary carcinoma of thyroid 2. Angiosarcoma of liver. CLL: Not associated with ionizing radiation.

Cancers Produced
• Medical or occupational exposure, e.g. leukemia and skin cancers

• Nuclear plant accidents: Risk of lung cancers.

• Atomic bomb explosion: Survivors atomic bomb explosion (dropped on Hiroshima and Nagasaki) → increased
incidence of leukemias → mainly acute and chronic myelogenous leukemia after about 7 years.

Subsequently, increased mortality due to solid tumors (e.g. breast, colon, thyroid and lung).

• Therapeutic radiation:

(1) papillary carcinoma of the thyroid follows irradiation of head and neck and

(2) angiosarcoma of liver due to radioactive thorium dioxide used to visualize the arterial tree.

Mechanism: Hydroxyl free radical injury to DNA.

Tissues which are relatively resistant to radiation-induced neoplasia: Skin, bone and the gastrointestinal tract.