The Molecular Basis of Cancer

Fundamental Principles of Cancer

• Cancer is a multi-step process that involves multiple genetic events (mutations) in tumors.
• Nonlethal genetic damage (mutation) is a crucial step in carcinogenesis, which can be acquired through environmental agents or inherited in the germ line.
• The genetic hypothesis of cancer states that a tumor mass results from the clonal expansion of a single progenitor cell that has sustained genetic damage.

Targets of Genetic Damage

• Growth-promoting proto-oncogenes can be targets of genetic damage.
• Growth-inhibiting tumor suppressor genes can be targets of genetic damage.
• Apoptosis-regulating genes can be targets of genetic damage.
• DNA repair genes can be targets of genetic damage.

Proto-oncogenes and Oncogenes

• Proto-oncogenes are normal cellular counterparts of oncogenes, regulating cell proliferation and differentiation.
• Oncogenes are mutant alleles of proto-oncogenes, promoting autonomous cell growth in cancer.
• Oncogenes are dominant because a single allele mutation can lead to neoplastic transformation.
• Oncoproteins are products of oncogenes, lacking important regulatory elements.

Tumor Suppressor Genes

• Tumor suppressor genes normally prevent uncontrolled growth and mutation leads to transformation.
• Both normal alleles must be damaged for transformation to occur (recessive oncogenes).
• Examples of tumor suppressor genes include P53 and Retinoblastoma genes (RB).

Genes that Regulate Apoptosis

• Genes that regulate apoptosis can be dominant or recessive.
• These genes enhance cell survival, rather than stimulating proliferation.
• Genes that protect against apoptosis are often overexpressed in cancer cells, while those that promote apoptosis are underexpressed or functionally inactivated.

DNA Repair Genes

• DNA repair genes affect cell proliferation or survival indirectly by influencing the ability to repair nonlethal damage in other genes.
• A disability in DNA repair genes can predispose to mutations in the genome and hence to neoplastic transformation.

Tumor Progression

• Carcinogenesis is a multistep process resulting from the accumulation of multiple mutations.
• Increasing malignancy is often acquired step by step.
• Tumor progression results from multiple mutations that accumulate independently in different cells, generating subclones with different characteristics.

Hallmarks of Cancer

• Self-sufficiency in growth signals: Tumors have the capacity to proliferate without external stimuli.
• Insensitivity to growth-inhibitory signals: Tumors are resistant to growth-inhibitory signals.
• Evasion of apoptosis: Tumors may be resistant to programmed cell death.
• Altered cellular metabolism: Tumors have altered cellular metabolism.
• Limitless replicative potential: Tumor cells have unrestricted proliferative capacity.
• Sustained angiogenesis: Tumors have the ability to sustain angiogenesis.