Lecture 21

Resisting Cell Death (Apoptosis)

• BCL-2 controls apoptosis by balancing pro-apoptotic (BAX, BAK) and anti-apoptotic molecules
• Apoptosis can be activated by intrinsic (mitochondrial) and extrinsic pathways, leading to caspase activation
• Mitochondrial membrane permeability is regulated by BCL2
• In 85% of follicular lymphoma cases, the anti-apoptotic BCL2 gene protects tumor cells from apoptosis
• TP53 is a pro-apoptotic gene that induces apoptosis in cells with irreparable DNA damage

Activating Invasion and Metastasis

• Divided into three steps: invasion of extracellular matrix, vascular dissemination, and homing of tumor cells
• Invasion involves detachment of tumor cells from each other, degradation of basement membrane and interstitial matrix, and attachment to new binding sites
• Vascular dissemination and homing of tumor cells involve adhesion to vascular endothelium and entrance into other organ parenchyma
• Metastatic site prediction is influenced by primary tumor location and vascular and lymphatic drainage
• Organ tropism is exhibited by some tumors, possibly due to activation of adhesion or chemokine receptors

Inducing Angiogenesis

• Vascularization of tumor cells is essential for growth and metastasis
• Hypoxia activates HIF1α, leading to transcription of VEGF genes and subsequent angiogenesis
• VEGF secreted by tumor cells leads to new vessel formation
• HIF1α is inactivated by VHL gene (tumor suppressor gene)
• VEGF antibody is approved for treatment of some cancers

Enabling Replicative Immortality

• Cells lose capacity to divide and enter senescence after 60-70 cell doublings due to telomere shortening
• Short telomeres are recognized as DNA damage, leading to cell cycle arrest mediated by P53 and RB
• Cancer cells can reactivate telomerase, achieving immortality
• Cells with mutation in P53 and RB genes cannot recognize DNA damage and continue to divide

The Molecular Basis of Cancer

• Carcinogenesis is a multistep process resulting from multiple genetic alterations
• Tumor progression and heterogeneity result from multiple mutations accumulating independently in different cells
• New subclones arise from the descendants of the original transformed cell by multiple mutations
• Environmental hazards, inherited mutations, and DNA damage contribute to carcinogenesis

Genomic Instability

• Normal cells are able to repair DNA damage
• Individuals with inherited defects in DNA repair genes are at greater risk for cancer development
• Examples include Hereditary non-polyposis colon cancer syndrome, Xeroderma pigmentosum, and BRCA1 and BRCA2 in familial breast cancers

Karyotopic Changes in Tumors

• Genetic damage during carcinogenesis can result in small (point mutations) or large chromosomal changes
• Common types of structural abnormalities in tumor cells include balanced translocations, deletions, gene amplification, and aneuploidy
• Examples of balanced translocations include the Philadelphia (Ph) chromosome in chronic myelogenous leukemia and t(8;14) in Burkitt’s leukemia/lymphoma