CBNS101 Lec. 13 cancer

How does cancer begin?

Cancer begins when a single cell accumulates heritable mutations that give it a selective advantage over its neighbors, founding a mutant clone.

What are the primary tissue origins for Carcinomas, Leukemias/Lymphomas, and Sarcomas?

Carcinomas: Epithelial cells (breast, prostate, lung, colon; most common).

Leukemias / Lymphomas: White blood cells and their precursors.

Sarcomas: Mesenchymal / connective tissues (muscle, bone).

How do Benign and Malignant tumors differ?

Benign: Clustered in a single mass, non-invasive.

Malignant: Invades surrounding tissue, enters blood/lymphatic vessels, and forms metastases at distant sites.

What are the key steps involved in Metastasis?

Cancer cells breach the basal lamina, enter circulation, exit into foreign tissue, and establish secondary growth.

What are Autonomous Growth and Evasion of Apoptosis?

Autonomous Growth: Cells reproduce without restraint and ignore anti-proliferative signals.

Evasion of Apoptosis: Cells bypass standard cell death pathways when damaged.

How do cancer cells bypass Replicative Senescence(2 mechanisms)?

By preventing telomere shortening via two mechanisms:

1. Re-activating telomerase to maintain telomeres.

2. Bypassing cell cycle checkpoints despite uncapped/short telomeres.

How do cancer cells manipulate their microenvironment?

They recruit supporting stromal cells (like tumor-associated fibroblasts) and alter the extracellular matrix using proteolytic enzymes to foster survival and dodge the immune system.

What metabolic and genetic hallmarks are characteristic of cancer cells?

Metabolism: Shifts in nutrient usage, including elevated glucose uptake.

Genetics: Genetic instability, increased mutation rates, uncorrected replication errors, and abnormal karyotypes.

How does a mutated Ras protein contribute to cancer?

Normal Ras hydrolyzes GTP to turn off growth signaling. Mutated Ras cannot hydrolyze GTP, locking it in a hyperactive state

What are key examples of mutated signaling components that act as proto-oncogenes?

Mutated growth factor receptors (e.g., EGF receptor firing without ligand), downstream kinases (Raf), transcription factors (fos, jun, myc), and G1 phase cyclins (Cyclin D).

What is the function of the Rb (Retinoblastoma) protein and how is it inactivated?

Rb is a universal regulator of the cell cycle at the G1/S restriction point. It is inactivated by direct mutations or inhibited by hyperactive CDK4/Cyclin D complexes.

What is p53, and what happens when it is mutated?

a transcription factor activated by stress and DNA damage. Loss of p53 leads to uncorrected mutations and loss of apoptosis.

What are two key downstream targets of p53?

1. p21: A CKI that arrests the cell cycle before S phase to allow DNA repair.

2. Bax: A pro-apoptotic gene that triggers cell death in hopelessly damaged cells.

What are four primary causes of genetic and expression changes in cancer?

1. Chemical Carcinogens: Nucleotide sequence changes.

2. Ionizing Radiation (X-rays): Double-strand breaks and translocations.

3. Viruses: Insertion of foreign DNA into host genomes.

4. Epigenetic Changes: Persistent alterations in gene expression (e.g., DNA methylation) without changing the sequence.

What is the Philadelphia Chromosome and what disease does it drive?

A translocation between chromosomes 9 and 22 that creates a hyperactive Bcr-Abl fusion tyrosine kinase, driving Chronic Myelogenous Leukemia (CML).

How does the targeted drug Imatinib (Gleevec) work?

It specifically binds to and inhibits the Abl kinase domain, turning off the hyperactive growth signal in CML.

What modern techniques are used to map driver mutations and design targeted therapies?

Whole-genome DNA sequencing, exome/RNA profiling, and CRISPR/RNAi genetic screens.