🧬 Carcinogens & Cancer Causes

Ultraviolet (UV) Light

• Source: Sunlight (UV-B is carcinogenic)
• Cancers: BCC, SCC, Melanoma
• Mechanism: Forms pyrimidine dimers in DNA

Ionizing Radiation (X-ray, α-ray, β-ray)

• Cancers: All leukemias (except CLL), AML, ALL, CML, Thyroid tumors
• Mechanism: Reactive free radical formation

3 Stages of Carcinogenesis

1. Initiation

• Direct-acting carcinogens act directly on DNA
• Indirect-acting (procarcinogens) need metabolic activation (in liver via CYP450)
• Smoking → inactive chemicals → converted to active form by CYP450
• Active compound goes to cytoplasm of target organ → damages DNA → loss of tumor suppressor genes → electrophile (cave charges)
• Key steps:
  • a) Metabolic activation
  • b) Reactive electrophiles formed
  • c) Target molecule (DNA) mutations
  • d) Initiated cell formed

2. Promotion

• Promoter carcinogens involved
• Do NOT damage DNA themselves (not mutagenic)
• Enhance effect of initiators
• Cause clonal proliferation and expansion of initiated (mutated) cells
• To produce a tumor: Initiator must be followed by promoter

3. Progression

• Clonal proliferation of altered cells
• Leads to cancer phenotype → Malignant Tumor

Sequence of Initiator & Promoter (Diagram Summary)

Simple Flow

Carcinogen → DNA Damage (Initiated Cell)
     ↓
Promoter → Clonal Proliferation
     ↓
Progression → Malignant Tumor
```## 3) Progression of Carcinogenesis

- Stage where mutated proliferated cell shows **phenotypic features of malignancy**

---

## Ames Test (Chemical Carcinogenicity Test)

- Tests if a chemical can **induce mutation** in a mutant strain of *Salmonella typhimurium* that cannot synthesize histidine
- Normal bacteria = synthesize histidine → if chemical causes mutation → bacteria survive on histidine-free medium → **chemical is carcinogenic**

---

## Chemical Carcinogens & Associated Cancers

| Chemical | Cancer |
|----------|--------|
| Alkylating agents | AML, Bladder cancer |
| Androgens | Prostate cancer |
| Aromatic amines / aniline dyes | Bladder cancer |
| Arsenic | Lung, skin cancer |
| Asbestos | Mesothelioma, Lung, Pleura, Peritoneum |
| Estrogen | Endometrium, Liver, Breast cancer |
| Ethyl alcohol | Liver, Esophagus, Head & Neck cancer |
| Tobacco (smokeless) | Upper aerodigestive tract, Bladder |
| Vinyl chloride | Liver cancer (angiosarcoma) |
| Chromium & Nickel | Lung cancer |
| Benzene | Leukemia, Hodgkin's lymphoma |
| Nitrates | Gastric cancer |
| Aflatoxin | Liver cancer |

---

## Biologic Carcinogens

### Infectious Agents & Tumors

| Agent | Tumor |
|-------|-------|
| **HPV** | Cervical, vulvar, penile cancers (SCC) |
| **EBV** | Nasopharyngeal carcinoma, Burkitt's lymphoma, Hodgkin's lymphoma |
| **HBV, HCV** | Hepatocellular carcinoma (HCC) |
| **HTLV-1** | Adult T-cell leukemia |
| **HHV-8** | Kaposi sarcoma, primary effusion lymphoma |
| **H. pylori** (bacteria) | Gastric cancer |
| **Schistosomiasis** (parasite) | Bladder cancer (SCC) |
| **Clonorchis sinensis** | Liver cancer (HCC), bile duct carcinoma, Pancreatic cancer |
| **Opisthorchis viverrine** | Bile duct carcinoma (cholangiocarcinoma) |
| **Fasciola hepatica** | Bile duct carcinoma (cholangiocarcinoma) |

---

## Carcinogenic Viruses

### RNA Viruses
- HTLV-1 → Human T-cell leukemia
- HCV → Hepatocellular carcinoma

### DNA Viruses
- HBV, HHV-8, HPV, EBV

---

## HPV (Human Papillomavirus)

- **Low risk** (types 6, 11) → benign squamous papilloma (warts)
- **High risk** (16, 18, 31, 33, 45) → SCC of cervix, penis, anogenital region
- Mechanism: HPV E6 inhibits **p53**, HPV E7 inhibits **p21 & RB-E2F** → increased CDK4/cyclin D → **immortalization, increased cell proliferation, genomic instability**

---

## EBV (Epstein-Barr Virus)

**Cancers caused:**
- Burkitt lymphoma
- Nasopharyngeal carcinoma
- T-cell lymphoma
- Hodgkin lymphoma (lymphocyte depleted)
- NK cell lymphoma

**Mechanism (simple flow):**

---

## Carcinogenic Bacteria

- **H. pylori** = first bacterium classified as carcinogen
- Causes:
  1. Gastric adenocarcinoma
  2. Gastric lymphoma