Lecture #18 Flashcards
what channels are generally expressed in the excitable cells of the nervous system but have recently been discovered to be expressed in som tumor cells?
ASICS (protons sensing ion channels)
what are ASICS?
channels from monomers that form trimers, which construct a pore almost exclusively permeable for Na
react when we have an acidification in the pH range 6.5-7
are ASICS always active?
no - they can be desensitized: after the opening of the channel due to the presence of protons after a certain period it will close and stay closed even if there are protons still present
how can ASICS be detrimental?
they can be activated causing depolarization of the neuron upon tissue acidification which can happen in any anti-inflammatory condition
how is acidification induced to activate ASICS?
on the vesicles that contain neurotransmitters, there are pumps for the acidification of the vesicle, but this means that when we have high frequencies of innervation we can have a high release of protons in the synapse correlating with the high release of neurotransmitters
due to the very small volume of the synapse it is easy to induce acidification
what cancer cell behaviors do ASICS play a role in?
proliferation, apoptosis, invasion, migration
what type of tumors undergo tissue acidification?
solid tumors
although most types of tumors undergo tissue acidification, which type of timor has a niche that is characterized by an acidic pH?
glioblastoma
describe the tumor niche of a glioblastoma cell:
characterized by some alterations with respect to the healthy tissue which is hypo=oxygenation and undergo acidification
consequently, you have a change in the cell metabolism consisting in the switch from oxidative glycolysis to fermentative glycolysis, with the production of lactic acid and protons causing acidification
what are cancer stem cells responsible for?
drug resistance
what are the three main types of glioblastoma?
polyclonal, classical, mesenchymal (most aggressive)
what is one of the most well-characterized biomarkers used for the isolation of cancer stem cells?
CD133
it was observed that by down regulating the expression of ASICS 3 in the cells of patients the tumor grows much less - what does this tell us?
the presence on the membrane of these proton-sensitive channels may give the cells the ability to proliferate more
what is a relevant biophysical signal also in non-excitable cells modulating important cellular activities such as proliferation, differentiation, and migration?
membrane potential
what is one potential way to treat GBM?
we know that GBM cancer stem cells express ASICS3 (a Na permeable channel) so the idea is to open the channels and see if it blocks proliferation
