Chapter 16: Cancer: Cellular Mechanisms

The chapter presents a comprehensive overview of cancer, establishing it as a genetic disorder resulting mainly from alterations in somatic cell DNA during an individual's lifetime. Core malignant properties include uncontrolled cell proliferation, resulting in malignant tumors that invade surrounding tissue and metastasize, along with a fundamental loss of growth control, evidenced in culture by the failure of contact inhibition and the formation of multilayered clumps called foci. Cancer cells often achieve indefinite division through the activity of telomerase, display genetic instability leading to aneuploidy, and evade programmed cell death (apoptosis). The historic study of cancer is rooted in the use of the immortal HeLa cell line, established from Henrietta Lacks’ tumor tissue in 1951, which prompted ongoing ethical debates regarding patient consent. The underlying causes of cancer include exposure to carcinogens like chemicals, radiation, and viruses, with evidence suggesting that chronic inflammation also increases risk. Pioneering work involving RNA tumor viruses (retroviruses) led to the discovery of reverse transcriptase and proved that viral oncogenes, such as src, are actually derived from normal cellular genes called proto-oncogenes. Tumor development is a multistep process requiring multiple genetic hits, governed by a balance between two crucial gene categories: tumor-suppressor genes (acting as the cell's brakes, requiring inactivation of both alleles, as demonstrated by Knudson's two-hit hypothesis for retinoblastoma) and oncogenes (acting as accelerators, requiring activation of a single allele). Key tumor suppressors include pRB, which regulates the G1 to S phase transition by controlling the E2F transcription factor, and p53, dubbed the "guardian of the genome," which orchestrates cell cycle arrest, apoptosis, or senescence following DNA damage, and is the most frequently mutated gene in human cancers. Proto-oncogenes, encoding proteins such as growth factors (PDGF), receptors (EGFR), and signaling molecules (RAS, MYC), are activated through mutation, amplification, or rearrangement. Genome sequencing reveals a complex mutational landscape, highlighting highly frequent mutations ("mountains," like APC, KRAS, and TP53) and confirming that cancer is fundamentally a disease of deregulated cellular pathways. Treatment strategies include conventional methods like therapeutic radiation, which induces lethal DNA damage, and chemotherapy agents, often plant-derived, that target cellular processes like microtubule assembly or DNA topoisomerases. Modern, targeted therapies focus on proteins critical for tumor survival, leveraging oncogene addiction. Examples include small-molecule inhibitors like Gleevec (targeting BCR-ABL) and Zelboraf (targeting mutant BRAF), and immunotherapies, which utilize monoclonal antibodies (passive, e.g., Herceptin) or genetically engineered T cells (active/adoptive, e.g., CAR T-cell therapy). Other targets include inhibiting angiogenesis (new blood vessel formation) via anti-VEGF antibodies and selectively destroying cancer stem cells responsible for tumor propagation.