Telomere Complexes, DNA Replication, and Cancer Mechanisms: A Detailed Study Guide

What two specific complexes make up the telomere structure, and what is the function of each?

The TRF1 complex is responsible for length control, while the TRF2 complex is responsible for protection and maintaining the normal telomere structure by forming the T-loop.

What is the End-Replication Problem and why does it cause telomere shortening?

DNA polymerase cannot replace RNA primers at the 3' end of the DNA strand because it lacks a free end to attach to, causing the chromosome to get shorter with every replication.

Describe the molecular and physical evidence that indicates a cell is in replicative senescence.

Senescent cells exhibit high Beta galactosidase activity, higher levels of the cell cycle inhibitors p21 and p16, and often display an enlarged, flat, 'fried egg' appearance.

How does a competent p53 pathway determine the outcome of dysfunctional telomeres?

When the p53 pathway is competent, dysfunctional telomeres initiate a DNA damage response that triggers senescence and apoptotic programs to inhibit tumorigenesis.

How does the Alternative Lengthening of Telomeres (ALT) mechanism work?

The ALT mechanism involves the exchange of sequence information between the telomeres of different chromosomes, where a terminal telomeric DNA strand invades another telomeric DNA strand, annexes, and synthesizes new double-stranded DNA.

What are dicentric chromosomes and what instability cycle do they drive?

Dicentric chromosomes have two centromeres and are formed when broken chromosome ends (lacking telomeres) fuse together. They drive the Breakage-Fusion-Bridge (BFB) cycle, which leads to massive genomic rearrangements.

What is the mechanism of action for the three FDA-approved drugs targeting VEGF signaling: Iressa, Avastin, and Sutent?

Iressa blocks the production of VEGF by the tumor cell; Avastin neutralizes VEGF in the extracellular space; and Sutent blocks the VEGF receptor on the endothelial cell.

List two signaling pathways activated by the VEGF Receptor (VEGFR) that promote endothelial cell function.

1. Ras pathway (for cell proliferation) and 2. PI3K pathway (leading to cell survival).

How do Matrix Metalloproteases (MMPs) function in the process of angiogenesis?

MMPs are secreted by activated endothelial cells to digest the surrounding matrix, allowing the endothelial cell to migrate and divide to form a new tube.

What are the four steps in the formation of a new capillary via angiogenesis?

1. A pro-angiogenesis stimulus is released. 2. Endothelial cells break away and migrate. 3. Endothelial cells proliferate and connect to build a new tube. 4. Pericytes stabilize the newly formed vessel.

Name three different categories of drugs used as angiogenesis inhibitors based on their targets.

1. Direct Inhibitors (e.g., Endostatin); 2. Signaling Cascade Blockers (e.g., Anti-VEGF antibody, Interferon-alpha); 3. Extracellular Matrix (ECM) Breakdown Blockers (e.g., Marimistat).

Define MET (Mesenchymal-Epithelial Transition) and explain its role in metastasis.

MET is the reversible process where migrating mesenchymal-like cancer cells reacquire epithelial characteristics (like E-cadherin) to colonize and grow at metastatic sites, enabling micrometastasis to develop into macrometastasis.

What is the Sentinel Node, and how is it clinically identified?

The Sentinel Node is the first lymph node to receive lymphatic drainage from the primary tumor, identified by injecting a blue dye or radioactive tracer and tracking which node lights up first.

List three morphological differences between Epithelial cells and Mesenchymal cells.

Epithelial cells have Apical-basal polarization, maintain contact with neighbors, and have restricted movement. Mesenchymal cells have anterior-posterior polarization, no durable adhesive properties, and are able to migrate as individual cells.

How do Tumor Associated Macrophages (TAMs) support cancer metastasis?

Tumors with high TAM content are more aggressive. TAMs release factors like VEGF and proteases, which promote angiogenesis, remodel the ECM, and suppress T-cell immune responses, enhancing intravasation.

Explain the difference between Pharmacokinetics (PK) and Pharmacodynamics (PD).

PK describes what the body does to the drug (including ADME: Absorption, Distribution, Metabolism, Elimination). PD describes the effects of the drug on the body.

What specific mutation allows the BCR-ABL protein to confer resistance to Gleevec?

A point mutation in the ATP binding site, such as T315I, blocks the ability of Gleevec (Imatinib) to bind and inhibit the tyrosine kinase. Resistance can also occur through BCR-ABL gene amplification.

Why are Cancer Stem Cells (CSCs) highly resistant to chemotherapy?

CSCs have increased resistance due to high expression levels of ABC-drug pumps, high levels of anti-apoptotic molecules, and resistance to oxidative stress and DNA damage.

Name three major Tumor Markers and their corresponding cancers.

PSA for Prostate cancer (95%); CA125 for Ovarian epithelial cancer (80%); CA19-9 for Pancreatic cancer (80%); AFP for Hepatocellular carcinoma (50%);.

What are the key focuses of Clinical Trial Phase II and Phase III?

Phase II focuses on the effectiveness of the drug in the targeted disease. Phase III compares the drug to standard therapy in a large population to evaluate survival benefit and side effects.