أسئلة_الـ_18_باثو_PPPM_قبل_التعديل_

Definition

• Neoplastic changes result from non-lethal genetic changes passed to new cells within the neoplasm.

Steps of Carcinogenesis

• Carcinogenesis is a multistep process involving three stages: initiation, promotion, and progression.
• Tumor growth becomes autonomous in the progression step.

Initiation

• The first step induces an irreversible, non-lethal change in the genetic material of the affected cell.
• This mutation can be inherited in germ cells or acquired through carcinogens.
• Multiple mutations are required.
• The genetic change is induced by irreversible, non-lethal genetic material change (gene mutation).
• Mutations affect growth regulatory genes including:
  • Growth-promoting proto-oncogenes
  • Growth-inhibiting tumor suppressor genes
  • Genes regulating programmed cell death (apoptosis)
  • Genes involved in DNA repair

Oncogenes

• Proto-oncogenes in normal cells control growth and proliferation.
• Mutated proto-oncogenes are called oncogenes.
• Dominant genes: alterations are usually acquired.
• Single tumors often show multiple oncogene abnormalities.
• Example: Epidermal Growth Factor Receptor (EGFR) in breast carcinoma.

Tumor Suppressor Genes

• These genes produce proteins that inhibit cell proliferation.
• Gene damage inactivates these genes.
• Tumor suppressor genes are recessive; transformation requires the absence of both copies.
• Mutations may be inherited or acquired
• Examples include P53 in most tumors and BRCA-1 & 2 in breast and ovary carcinoma.

P53 Gene

• (Guardian of the genome) is mutated in over 50% of malignant tumors.
• DNA damage causes P53 to induce cell cycle arrest at G1, allowing time for DNA repair and then the cell can re-enter the cell cycle.
• If DNA repair fails, P53 activates BAX (pro-apoptotic gene), causing cell death via apoptosis.

Mitochondrial Genes

• There are two types:
  • Pro-apoptotic (e.g., Bax)
  • Anti-apoptotic (e.g., bcl2)
• Activation of anti-apoptotic genes extends the lifespan of genetically mutated cells promoting malignant tumor development.
• bcl2 is found in Follicular B-cell lymphoma.

DNA Mismatch Repair Genes

• Normal DNA sustains minor daily damage from body heat and UV rays, repaired by DNA ligases.
• Mutations in genes controlling DNA ligase expression can lead to tumor development.
• Xeroderma Pigmentosa leads to frequent skin malignancies.

Promotion

• Initiated cells proliferate, expanding monoclonally from a single progenitor cell, leading to tumor mass formation.
• Depends on two factors: intrinsic factor (kinetics of tumor cell growth) and host factor (angiogenesis).

Cell Production/Cell Loss Ratio

• Increase proliferation.
• Increase telomerase activity.
• Decreased apoptosis.

Telomeres

• They consist of repeated sequences at chromosome ends.
• They shorten with cell division, eventually halting division in aging cells.
• Tumor cells reactivate telomerase, lengthening telomeres.

Host Factor (Angiogenesis)

• Solid tumors require angiogenesis (new vessel formation) to grow beyond 1-2 mm in diameter.

Tumor-Associated Angiogenic Factors

• Produced by tumor cells, e.g., Fibroblastic Growth Factor (FGF), Vascular Endothelial Growth Factor (VEGF).
• Derived from inflammatory cells (macrophages) as TGF-α, TNF.

Tumor Progression & Heterogeneity

• Aggressiveness of tumors increases over time, acquiring malignant characteristics.
• Tumors, while initially monoclonal, become heterogeneous due to multiple mutations in constituent cells.