lecture 7 - cancer stem cells II Flashcards
What are the definitions of angiogenesis and metastasis?
Angiogenesis is the growth of new blood vessels to provide the tumour with oxygen and nutrients - can grow a certain size before the cells in the centre start to become hypoxic
Metastasis is the ability of tumour cells to break away from the primary tumour, travel through the body and recolonise at a distant site
Both processes involve mobility/migration of cells
What are stem cell niches?
There is evidence for stem cells to reside in niches, the function of which is to suppress self-renewal but maintain an undifferentiated state
Changes in niche signals enable cells to self-renew and differentiate to generate cells for repair
Changes in signals between cancer stem cells and niche cells can lead to adaptation to different niches in different tissues, or even niche independence
What are the mechanisms of tumour-mediated immune evasion?
Loss of tumour antigens
Downregulation of MHC that normally present antigens to T-cells
Overexpression of immune checkpoint proteins
Overexpression of anti-apoptotic molecules - pro-survival
Secrete immunosuppressive molecules
Switching of macrophages to M2 (tumour promoting) phenotype
What kind of stem cells are linked to tumour-mediated immune evasion?
Mesenchymal stem cells - could be contributing to the recolonisation and growth of the cancer cells
What are the roles of MSCs?
Implicated in tissue homeostasis and repair - need to be able to move around and get to the right site to allow differentiation into the correct cell type
possible roles:
- providing daughter cells that differentiate and participate in repair
- homing to distant sites of injury
- secretion of factors that support wound repair by recruiting other cell types and modulating the immune response
What is EMT and what are the changes that occur?
Epithelial to mesenchymal transition
Epithelial - cell polarity, cell adhesion, stationary, high level of E-cadherin and low level of N-cadherin
Mesenchymal - no cell polarity, loss of cell adhesion, ability to migrate and invade, low level of E-cadherin, high levels of N-cadherin
What are the mechanisms of EMT?
Initiated by signals from tumour storm/microenvironment
Bind tyrosine kinase receptors on neighbouring tumour cells
Activate signalling pathways (MAPK/PI3K)
TGF-b activates Smad complex
Repress epithelial genes by PcG epigenetic mechanisms
EMT results in acquisition of migratory capabilities - so they can start moving away from the tumour mass
MMPs are enzymes that digest the ECM
What are the additional key factors in regulating metastasis?
Integrins are responsible for tethering cells to ECM - changes in intern extracellular domain conformation enables switching of cell adhesion to different ECM components and migration
Proteases - degradation of ECM - serine proteases and MMPs - tumour cells induce up regulation of MMPs in neighbouring cells
What is the process of recolonisation?
EMT - migration - intravasation - transport - extravasation - colonisation
Could either be first pass organ (trappage in capillaries) vs seed and soil theory (selectin expression)
Disseminated tumour cells (micrometastases) have the ability to recolonise into new growths when they find the right environment
If cancer cells originate from stem cells, what does this mean for the development of therapeutic approaches?
Therapies need to target the small population of tumour-initiating cancer cells in addition to the non-stem cells that make up the bulk of the tumour
Must not affect normal stem cells - differential gene expression and effects
Need to make sure that the therapies we use are targeting the bulk of the proliferative cells, as well as the tumour-initiating cancer stem cells
What are the potential therapeutic approaches for cancer stem cells?
Presence of ABC transporters in cancer - these are multi-drug resistant
Therefore ABC inhibitors as adjuvant therapy can be used
However, WT cells are more susceptible to the agents we are using than the tumour cells
How can inhibitors of self renewal pathways be used?
Wnt pathway - requirement to target downstream of APC/Axin
Inhibitors of PcG proteins - Bmi inhibitors - PTC209
How can EMT and metastasis be targeted?
Relatively recent advancement in knowledge of EMT process and complexity of process has limited the development of therapeutic agents
MMP inhibitors - lack of efficacy, toxicity due to lack of specificity
Restoration of metastatic suppressors (steroid inducers of transcription)
How can recolonisation be targeted?
Inhibit MET, target metastatic niche, and target dormant DTCs
