Chapter 11 Flashcards
Genetic instability in tumor cells can result from both genetic and epigenetic changes.
List at least 3 examples or mechanisms of each of these processes.
Epigenetic: methylation, acetylation, phosphorylation
Genetic: point mutations, translocations, deletions, gene amplification
Genetic instability of increased frequency of mutation occurs dt both deficiency of DNA repair and decreased activation of apoptosis.
List 2 examples of decreased repair of apoptosis that have been shown to promote genetic instability.
BRCA1/2 genes are linked w/ repair of DNA strand breaks.
MMR abnormalities leading to replication error repair can result in 1000 fold increase in mutation frequency.
P53 defects lead to decreased apoptosis and t/f survival of abnormal cell clones and perpetuation of mutations. This occurs by mutations in the p53 DNA binding domain which prevents DNA binding and t/f action as a transcription factor.
T/F
Most tumors appear to have few functional lymphatics.
Lymphatics are predominantly located at the center of a tumor.
True
False - at periphery
Explain Paget’s seed and soil hypothesis for mets AND the alternate hypothesis based on hemodynamics.
This hypothesis postulates that different tumor-cell/host-organ interactions occur which are more or less favorable for metastatic development.
The alternate hypothesis states that the #s of mets depends on how many tumor cells are delivered to a particular organ by the blood and the # that are arrested in capillaries.
Some combo of the 2 is thought to be correct as cells must lodge in small vessels or in the organ but then, in order to thrive, the organ must provide a suitable growth environment for the particular tumor cells.
Also - chemokines - molecules used by leukocytes to home to specific organs, may play nb role in organ specificity of metastasis.
Name and describe the steps of metastasis
1) Detachment from the primary tumor.
Involves increased motility factors, decreased cell adhesion mols, increased proteinases (and/or metalloproteinases) and intravasation into blood vessel or lymphatics
2) Tumor cell arrest at new site.
Involves cell lodging in capilary bed and increasing cell adhesion molecules.
3) Survival against host defense mechanisms.
Cells must avoid the immune system, avoid NO from the endothelium which would induce apoptosis, and down regulate apoptosis signals. Immunes system would normally recognize tumor associated antigens, however in cells that are successful at metastasis the immune system has developed tolerance or state of anergy to avoid being killed by the immune system.
4) Extravasation of tumor cells out of the vessel and into the new organ.
Involves extending into endothelial cell junctions allowing access to basement membrane. BM is degraded and cell moves into ECM with new cell-matrix interactions. Includes increased MMP 2 and 9, decreased TIMPS.
5) Establishment of new cell growth.
Requires specific growth factors (may be made by tumor cells - autocrine) or loss of dependence on growth factors, ECM matrix interactions also nb. Increased protease activity can release GFs from binding proteins in the blood such as IGF, or in the ECM such as FGF and VEGF
6) Angiogenesis.
Growth of new BV required for continued growth of the metastatic lesion. FGF and VEGF are angiogenic and stimulate EC growth. w/o this step, tumor cannot exceed 1mm dt limited diffusion.
Explain the concept of metastatic inefficiency
Despite shedding of many cells into blood, relatively few mets are seen. This may be dt the fact that only a very small subpopulation of tumor cells express the properties that allow metastases to grow in a new site.
Epithelial cells interact w/ the basement membrane which is composed of collagen type __, laminin, and heparin sulfate proteoglycan. This is compared to mesenchymal cells which do NOT interact w/ a basement membrane, are not attached to e/o, and are surrounded by collagen types ___, elastin, fibronectin, and vitronectin.
Depriving cells of their interactions w/ these ECM components induces a specific type of apoptosis called _____.
IV
I-III
Anoikis
Cell Adhesion Mols - CAMS - are transmembrane proteins w/ extracellular and intracellular domains. What is their function?
They signal from o/s to inside the cell and vice versa.
Integrins - are transmembrane receptors for ______. They have ___ subunits. Which subunit is responsible for interaction w/ the actin cytoskeleton of the cell? Integrins are also nb mediators of PI3K pathway and angiogenesis
the ECM and other plasma proteins
2
Beta subunit
Cadherins mediate interaction bt what two things?
Name 2 examples:
They are most nb in what group of cells? (mesench, epith, or round)
Adhesion by cadherins is dependent on what?
Catenins link cadherins to what (2 things)?
Decreased expression of ___ has been found in poorly differentiated, invasive tumors
They are INTERcellular adhesion receptors
Adherent junctions and desmosomes
Epithelial
Calcium dependent
Actin cytoskeleton and to signal-transduction components
E-cadherin
Immunoglobulin superfamily receptors are also involved in cell-cell adhesion.
T/F - these interactions are calcium dependent?
List 2 examples of members of this superfamily.
False - not Ca dependent Ig superfamily: *I-CAMs intercellular *V-CAM vascular *N-CAM *contractin *CEA (carcinoembryonic antigen)
Selectins are nb to aid adherence of ___ to endothelial cells and platelets
Leukocytes
CD44 is a cell surface receptor glycoprotein that is a major receptor for interactions w/ ____, a glycosaminoglycan in the ECM. Its principal fxns are aggregation, migration and activation of cells. CD44 is overexpressed by many tumors.
hyaluronate
Gap junctions are nb for communicating bt cells. How can gap junctions contribute to mets?
by mediating transfer of metabolites between interacting cells
Name the 4 classes of naturally occurring proteinases and their inhibitors
Serine (PAIs - plasminogen activator inhibitor)
Cysteine (kininogens, cystatins)
Aspartic (not known!)
MMPs (TIMPs)
