Chapter 10 Flashcards
(38 cards)
BRAC 1/2 loss of function is associated with loss of which cellular function?
Ability to repair DSB
What is the main cause of cancer progression?
A series of selected genetic and epigenetic changes
What is ECM and why is important in cancer metastasis?
Interaction between the cell and ECM is essential for cell growth and survival, in transformed cells production of ECM is normally impaired and ability to survive despite lack of ECM contact is a feature of malignancy. Disruption of BM and collagen degradation em breakdown of ECM integrity is one of the rate limiting steps in tumour progression and metastasis.
How can cancer cells disrupt ECM?
By aberrant expression of cellular proteases such as MMPs, cathepsins and their inhibitors.
Why are the metalloproteinase family ADAMs important in cancer development?
They are important for release of growth factors and cytokines on the cell surface, and they are critical for the activation of NOTCH pathway and EFGR.
The biomarker prostate specific antigen is used to evaluate disease progression in people, what kind of proteinase is it?
Kallikrein-
Which group of proteinases are responsible for direct digestion of the ECM and activation of other proteases such as urokinase (a plasminogen)
Cathepsins
What are integrins and why are they important for cellular function?
Transmembrane receptor proteins of the ECM which are involved in the regulation of wound healing, inflammation, homeostasis, bone resorption, apoptosis, cell proliferation, tumour growth and metastasis. They also form a structural bridge between actin and the ECM
How does integrins signalling pathways work?
An outside ligand will be bound to the inegrin, which is transmemiranous and bound to intracellular structures. The contact point with actin contains multiple TKs, such s FAK which can activate downstream pathways such as IP3K and ERK
What are cadherins?
Intercellular adhesion receptors that play an important role in assembling adherens junctions and desmosomes.
What is the consequence of e-cadherin loss?
It has been associated with increased cellular invasiveness and with EMT
Which microenvironmental factors can influence the metastatic potential of a tumour?
Hypoxia, hypoglycemia, low pH, increased interstitial pressure
Is tumour metastasis an organ specific process?
The development of distant metastasis tend tooccur in specific organs, it is therefore considered likely that organ-specific adhesive interactions between endothelial cells and the tumour cells, or between tumour cells and growth factors in that organ can influence successful metastatic establishment.
Which other, non tumour cells specific factor is likely to influence the pattern of metastasis?
Blood flow
How can intravasation (shedding of tumour cells into the vasculature?
- Invasion of the tumour into the vessel
- Abnormal vasculature of tumour may permit passage of cells into circulation
- Induced vascular remodelling by VEGF and FGF may facilitate intravasation
What is cross-seeding and how is it facilitated?
When circulating tumour cells are allowed back to the primary tumour, due to the abnormal vasculature of tumours. May be enhanced by IL-6 and IL-8
How can tumour cells detach from the primary tumour?
Either by decreased expression of adhesion molecules, increased expression of motility factors, disruption of E-cadherin, EMT, increased production of proteases including MMPs to break down the ECM and basement membrane.
What are the major steps of metastasis?
intravasation,, survival in the blood stream, extravasation, initiation of new growth
How does cancer cells promote survival in the blood stream?
They can travel with platelets to evade immune surveillance- may also promote cell growth as the platelets contain growth factors such as EGF; VEGF, HGF, and TGF-beta
However, the majority of cells in circulation will arrest in first pass capillary beds such as liver and lung
What is important factors for tumour cells to successfully extravate in a new organ+
Multiple proteases are needed, including MMPs, they modify the integrity of the endothelia and provide entry ponits
How can tumour cells initiate metastatic growth at a new site?
They can modify the target organ and make the environment more favourable for themselves, example is in bone where metastasis disrupt bone homeostasis
- release PRHrP, IL-6, TNF-alpha secreted by the tumour cells stimulate release of RANCL by osteblasts which stimulate development of more osteoclasts which digest the none and create space for metastasis.
Which molecular factors and processes are important for the tumour cells to achieve intravasation?
- Proteolysis is achieved by activating plasmin (with urokinase) and metalloproteinases creating pericellular zones of proteolysis, has been documented to facilitate metastasis, break down of BM membrane. The process in a complex coordination with adhesion molecules such as integrins which are responsible of activation of the MMPs - the result is digestion of ECM at the tumour edge.
How does the MMPs and proteinase inhibitors affect cell growth, angiogenesis and inflammation in the tumour microenvironment?
MMPs and proteinase inhibitors such as TIMPs alter the release of potent growth factors, such as VEGF, TGF-beta, IGF-2. This result in altered bioavailability of growth signals to the cancer cells and impact proliferation. They can also increase expression of ligands activation EGFR or mediate NOTCH activation.
How can MMPs impact EFGR activation?
The subgroup of MMPs called ADAMS, release EGF ligands such as TGF-alpha- result in over expression in many cancers.
