Lecture 16 - Angiogenesis Flashcards
Why, in many tumors, are many of the surrounding cells normal: in some cases up to 90-99% normal?
Cancer cells are in constant communication with the normal cells around them and rely on them for nutrient supply etc…
In Hodgkins Lymphoma, over 99% of tumor cells are normal.
The stroma of epithelial cancers may contain many different cell types. Name five.
1 - Fibroblasts 2 - Myofibroblasts 3 - Smooth muscle cells 4 - Endothelial cells 5 - Mast cells
What is heterotypic signalling and what are the three kinds? Give one example for each.
What provides the necessary microenvironment for the proliferation of cancer cells?
Heterotypic signalling is communication between two different cell types.
1 - Mitogenic growth factors: TGF-alpha
2 - Growth inhibitory signals: TGF-beta
3 - Trophic factors: IGF-1/2
Stroma cells provide a facilitative microenvironment for the proliferation of cancer cells.
What is the basement membrane?
The basement membrane is a specialized ECM that seperates epithelial and stromal cells. Properties dependent on factors released in surrounding environment.
During microvessel formation, who sets up the ECM? How does microvessel formation occur?
During microvessel formation, stromal and epithelial cells set up the ECM. These recruite endothelial cells.
What follows is that recruited endothelial cells release PDGF and HB-EGF. This further attracts pericytes and smooth muscle cells to finish the formation.
Why are tumors so similar to wound healing? What are the differences between them? Define both options for Stroma and Epithelium.
Tumors are similar to wounds that do not heal.
In the Stroma:
Following PDGF release, macrophages are recruited and myofibroblasts form. The difference is that the pathway is turned off automatically by several sensors including density dependent sensors. In cancer, these shut-offs are typically inhibited or have been deleted.
In the Epithelium:
Epithelial cells receive TGF-beta1, MMPs signals from stroma and then morph into mesenchymal cells (EMT). These mesenchymal cells move into the wound site, proliferate, and cover the wound. To finish, they morph back into epithelial cells (MET) and reconstruct the epithelium. In cancer, this pathway is usually overexpressed via signalling and EMT’s continously gather to a location where no wound exists.
What are MMPs and what do they do?
[say in an “Arnie” voice]
Matrix Metalloproteinases, or MMPs, are released by fibroblasts and macrophages. They function by remodelling the ECM, making room for new cells and releasing sequestered growth factors.
What happens to cell attachments during wound healing?
During wound healing, cell attachments are severed. This includes the connections to the basement membrane.
Give a brief summary of the relationship between wound healing and tumorigenesis. Include the 3 main points.
1 - Cancer cells release PDGF, a mitogen and attractant for mesenchymal cells.
2 - Formation of Myofibroblasts occurs (CAFs = carcinoma associated fibroblasts). TGF-beta signalling.
3 - Desmoplastic stroma occurs. Hard tumors form in remodelled and extensive ECM.
What is the relationship between tumors showing similar gene expression patterns as healing wounds and mortality rates.
Tumors showing the same gene expression patterns as healing wounds show much much much higher mortality rates. The body is less likely to respond negatively as the tumor grows since it is being tricked into believing in the presence of a “ghost wound”.
What do epithelial cancer cells like to release? [In relation to macrophages and tumorigenesis]
Epithelial cancer cells like to release monocyte chemotactic proteins called “Chemokines” which attract monocytes that differentiate into macrophages and stimulate angiogenesis.
How do macrophages stimulate angiogenesis?
Macrophages stimulate angiogenesis by releasing angiogenic factors such as VEGF and IL-8. They also disrupt and reshape the ECM, making room for growth.
Of what importance are immature myeloid cells (iMCs)? What role do they play?
Tumor cells like to release CCL9 which recruits immature myeloid cells from bone marrow to release MMPs that digest the ECM.
Why is angiogenesis so important to tumor growth? What determines the vascular structure? Of what quality is the overall vascular structure and why?
Angiogenesis is so important because cells need to be within 0.2 mm of blood in order to grow. Furthermore, tumor/cancerous cells grow so incredibly compact to each other that it is difficult to access them and feed the central tumor cells the nutrients they require. Therefore, an intricate vascular network is required to feed the tumor cells.
However, angiogenesis and the routing of individual capillaries is determined by heterotypic interactions. It is not a genetically determined process. This means, cancerous cells with destabilized genomes will do a poor job of directing angiogenesis and the resulting vascular network is poorly constructed… at best.
This shoddy construction is typically don in balance of VEGF and angioprotein 1 & 2 signals.
What is the Rip-Tag model of tumor progression?
The Rip-Tag model of tumor progression is where tumor progression can be categorized into distinct stages, during which many cells die of hypoxia through p53 mediated apoptosis.
Stages are: 1 - Normal Islets 2 - Hyperplastic Islets 3 - Angiogenic Islets 4 - Tumors
