25. Cancer 1

The professor introduces cancer as a progressive disease arising from stepwise deregulation of cell and tissue behavior. This process stems from mutations in cells that disrupt the normal regulation of growth and survival, leading to uncontrolled proliferation. Two primary classes of genes are implicated in cancer: oncogenes, which promote cell growth and survival following mutation, and proto-oncogenes, their precursors that function in a regulated manner. The transition from a proto-oncogene to an oncogene occurs through mutations that cause the gene to become unregulated, akin to a car with a stuck accelerator.

The focus shifts to tumor suppressors, genes that inhibit growth or promote cell death, and their role in cancer when they lose function. Another critical class of genes, caretaker genes, are introduced. These genes maintain genomic integrity through DNA repair and stabilization, preventing aneuploidy. Loss of function in caretaker genes, exemplified by the BRCA1 gene associated with breast cancer, facilitates the accumulation of further mutations, driving the cancer phenotype. The recent award of the breakthrough prize to an MIT researcher for contributions to understanding genome integrity underscores the significance of these genetic mechanisms in cancer.

An in-depth analysis of the G1 to S transition in the cell cycle reveals how specific genes and pathways influence cell division and cancer development. Key proteins such as cyclins and cyclin-dependent kinases, and their regulation by growth signals, play pivotal roles in this process. The discussion includes the identification of oncogenes, tumor suppressors, and proto-oncogenes within this pathway, highlighting the complex interplay of genetic and molecular signals that control cell growth and division.

Retinoblastoma, a rare childhood eye tumor, serves as a case study for understanding the role of the Rb gene as a tumor suppressor. The disease can manifest in two forms: sporadic and familial, with different characteristics and implications for cancer risk. The inheritance pattern of retinoblastoma, though resulting from a loss of function at the cellular level, behaves dominantly at the organismal level due to the predisposition it confers to the disease. This distinction highlights the complex relationship between genetic inheritance and cancer susceptibility.

The discussion delves into the genetic basis of retinoblastoma, emphasizing the autosomal dominant inheritance pattern despite its recessive behavior at the cellular level. This paradox is explained by the concept of predisposition, where being heterozygous for the Rb gene increases the risk of developing the disease. This section underscores the nuanced understanding of genetic predisposition to cancer, illustrating how individuals can carry a mutant allele without necessarily manifesting the disease.

Exploring mechanisms of loss of heterozygosity, the professor explains how cells can lose the functional copy of a tumor suppressor gene like Rb, leading to cancer. Various mechanisms, including point mutations, chromosome loss, and epigenetic changes like promoter methylation, can result in the loss of gene function. This part of the lecture emphasizes the diverse genetic and molecular events that contribute to the transformation of normal cells into cancerous cells.

Using colon cancer as an example, the professor illustrates how disruptions in tissue homeostasis and signaling pathways, particularly Wnt signaling regulated by the APC tumor suppressor, can lead to cancer. The formation of polyps in familial adenomatous polyposis is highlighted as an early step in tumorigenesis, leading to potential invasive cancer. This section highlights the importance of signaling pathways in maintaining tissue health and how their disruption can initiate cancer.

The lecture concludes with a discussion on targeted cancer treatments, using chronic myelogenous leukemia (CML) and the success of Gleevec, a small molecule inhibitor of the BCR-ABL kinase, as a case study. This example illustrates the potential for targeted therapies to effectively treat specific cancers by inhibiting the molecular drivers of the disease. The promise of future lectures on additional therapies underscores the evolving landscape of cancer treatment and the importance of understanding cancer at the molecular level.