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What is the role of hyaluronic acid (hyaluronan) in tumor cell metastasis?
Hyaluronic acid binds to CD44 on tumor cells, promoting invasion.
What are the factors that can stimulate EMT?
EGF, FGF, HGF, collagen, MMPs, TGFβ
What cellular factors are lost, altered, or gained in EMT?
- Lost or altered in EMT:
- 1.E- cadherin
- 2.a-catenin, b-catenin frequently translocates to nucleus (Wnt)
- 3.Apico-basal polarity
- 4.Circumferential F-actin fibers
- 5.Epithelial cytokeratins
- Gained in EMT?
- 2.avb6 integrin
- 3.Intermediate filament protein - Vimentin
- 4.Matrix metalloproteinases secreted, produced
- 5.Fibronectin secretion
- 6.a-smooth muscle actin (myofibroblasts)
- 7.Motility, Invasiveness
List the sequence of events leading from normal cells to establishing a successful metastatic focus.
- 1: Detachment from the primary mass (epithelial – mesenchymal transition (EMT))
- 2: Invasion through the basement membrane and migration through the extracellular matrix
- 3: Penetration (intravasion) of blood and/or lymphatic vessels
- 4: Survival within the circulation
- 5: Arrest in the distant organ’s microcirculation (capillaries, sinuses or venules)
- 6: Penetration of vessels at the distant site
- 7: Invasion through the distant site’s parenchyma
What are the two patterns and the possible configuration of tumor cells migrating through the ECM?
- Individual cell migration or collective cell migration.
- Can occur through Intravasation (through veins, accompanied by platelets) and extravasation (involves selectin cell adhesion molecules on the tumor and EC, regulated by the microenvironment).
What are Cell Cycle Specific (CCS) Agents?
Drugs that have activity in specific phases of cell cycle. Examples: vinca alkaloids work in M-phase, antimetabolites work in S-phase
What are Cell Cycle Nonspecific (CCNS) Agents?
Drugs that exert a cytotoxic effect throughout the cell cycle Examples: alkylating agents, anthracyclines
What are Alkylating agents?
- weak carcinogens that don’t require metabolism
- chemotherapy drugs that form DNA adducts are alkyl groups(e.g. CH3-, C2H5-) to DNA’s guanine residues.
What are Polycyclic hydrocarbons?
- potent carcinogens
- P450-dependent mixed function oxidases
- Includes cigarette smoke, broiled animal fat,smoked meats, and chemical (e.g. vinyl chloride)
What is alfatoxin?
- Produced by Aspergillus flavus, P450
- system yields epoxides, TP53gene mutation
- Found on improperly stored grains and peanuts.