Carcinogenesis

Defense mechanisms of malignant cells

↓ MHC Class I Expression: Prevents tumor antigen presentation to CD8+ cytotoxic T-cells, rendering the cancer cell “invisible.”
Upregulation of Immune Checkpoints:
- PD-L1 (on tumor cell) binds PD-1 (on T-cell) → induces T-cell exhaustion/anergy. (Target of Pembrolizumab, Nivolumab).
- CTLA-4 (on T-cell) outcompetes CD28 for B7 (on APCs) → inhibits T-cell activation. (Target of Ipilimumab).
Immunosuppressive Microenvironment:
- Secretion of TGF-β and IL-10 → inhibit T-cells and NK cells.
- Recruitment of regulatory immune cells: Tregs, Myeloid-Derived Suppressor Cells (MDSCs), and M2 Macrophages.
Antigen Loss: Tumor cells lose expression of recognizable neoantigens through mutation, leading to immune escape.

Increased Drug Efflux:
- Upregulation of P-glycoprotein (MDR1 gene product), an ATP-dependent pump that removes chemo drugs (e.g., Vinca alkaloids, taxanes) from the cell.
Modification of Drug Targets:
- Gene Amplification: e.g., DHFR amplification confers resistance to Methotrexate.
- Mutation: e.g., Kinase domain mutations in CML confer resistance to Imatinib.
Enhanced DNA Repair: Increased capacity to repair damage caused by alkylating agents or radiation.
Inhibition of Apoptosis:
- Upregulation of anti-apoptotic proteins (e.g., Bcl-2).
- Inactivation of pro-apoptotic proteins (e.g., mutations in TP53).
Drug Inactivation: Cancer cells produce enzymes that metabolize and inactivate drugs.

Epithelial-Mesenchymal Transition (EMT): A crucial process where epithelial cancer cells lose their cell-cell adhesion and polarity to gain migratory and invasive mesenchymal properties.
- ↓ E-cadherin (Epithelial): Loss of this key adhesion molecule disrupts tight cell-cell junctions, increasing motility. This is a hallmark of EMT.
- ↑ N-cadherin (Neural): A “cadherin switch” can promote invasion by increasing affinity for stromal cells.
- Transcription Factors: EMT is driven by transcription factors like SNAIL, SLUG, and TWIST.
Extracellular Matrix (ECM) Degradation: Tumor cells secrete proteolytic enzymes to break down the ECM and basement membrane.
- Matrix Metalloproteinases (MMPs): A family of zinc-dependent endopeptidases that degrade collagen and other ECM components. MMPs also release bioactive molecules (e.g., growth factors) from the ECM.
- Cathepsins: These proteases also contribute to ECM degradation and are often highly expressed in invasive tumors.
Mesenchymal-Epithelial Transition (MET): The reverse process of EMT, where metastatic cells at a secondary site regain epithelial characteristics to form a new tumor. This is critical for successful colonization.

A helpful mnemonic for these exceptions is “Four Rare Hematogenous Carcinomas”:

Follicular Thyroid Carcinoma: Invades capsular blood vessels, a key feature distinguishing it from follicular adenoma.
Renal Cell Carcinoma (RCC): Classically invades the renal vein and can extend as a tumor thrombus into the inferior vena cava (IVC) and even the right atrium.
Hepatocellular Carcinoma (HCC): Frequently invades the portal and hepatic veins.
Choriocarcinoma: A highly aggressive tumor of trophoblastic tissue that rapidly invades blood vessels, leading to early hematogenous spread to the lungs.