Characteristics, Events, and Stages in Tumorigenesis
Franklyn De Silva, Jane Alcorn in The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Microvesicles are produced from the plasma membrane through direct outward budding (and fission) with subsequent release into the extracellular space [830, 857, 896]. Membrane lipid curvature plays an important role for either inward-budding vesicle formation within the endocytic system (exosomes) or an outward-budding vesicle formation at the plasma membrane (microvesicles) [831]. Some of the biogenetic mechanisms involved include flippase, flippase and scramblase (TMEM16F), amino-phospholipid translocases, ARF6, membrane curvature, cytoskeleton, and asymmetric movement of phosphatidylserine [769, 840, 897–900]. From plasma membranes of prostate and breast cancer cells, the shedding of cancer-derived MVs is attributed to the ADP-ribosylation factor 6 (ARF6) that is enriched in MVs [851, 901]. EVs, (especially exosomes), have been identified as major modes by which cells interact with each other, including stromal cells, within the tumor microenvironment [849].
Molecular Imaging of Apoptosis
Michel M. J. Modo, Jeff W. M. Bulte in Molecular and Cellular MR Imaging, 2007
Exposure of phosphatidylserine (PS) on the cell surface occurs relatively early in the apoptotic process.96 PS is normally resident predominantly on the inner leaflet of the plasma membrane bilayer, and this asymmetry is maintained by an ATP-dependent translocase that transports aminophospholipids from the outer leaflet to the inner leaflet. During apoptosis, PS may be flipped to the outer leaflet, due to inhibition of this translocase and by activation of a Ca2+-dependent scramblase, which transports lipids bidirectionally.97 As a result, the number of surface PS molecules can increase 100- to 1000-fold.98,99 For example, in Jurkat cells, the induction of apoptosis results in the exposure of ~240 μmol of PS/106 cells.100 At the estimated cell densities found in tumors of ~109/ml,101 this corresponds to a local PS concentration of ~200 μM. However, PS exposure can also occur during necrosis due to the leakiness of the plasma membrane under these conditions, and therefore is not specific to apoptosis per se.18
Moving beyond size and phosphatidylserine exposure: evidence for a diversity of apoptotic cell-derived extracellular vesicles in vitro
Published in Journal of Extracellular Vesicles, 2019
Ivan K. H. Poon, Michael A. F. Parkes, Lanzhou Jiang, Georgia K. Atkin-Smith, Rochelle Tixeira, Christopher D. Gregory, Dilara C. Ozkocak, Stephanie F. Rutter, Sarah Caruso, Jascinta P. Santavanond, Stephanie Paone, Bo Shi, Amy L. Hodge, Mark D. Hulett, Jenny D. Y. Chow, Thanh Kha Phan, Amy A. Baxter
The ability of apoptotic cells to expose PtdSer via a caspase-dependent mechanism is a relatively well-described process, in particular through the activation of the scramblase Xkr8 [65] and inhibition of flippases ATP11A and ATP11C [66]. Since the formation of ApoBDs is a somewhat late event during the progression of apoptosis, at a stage that PtdSer is already exposed on the dying cell, it is not surprising that PtdSer can be found on the surface of ApoBDs [36,39]. Despite the fact that PtdSer can also be detected on smaller EVs like [2,67–69], PtdSer is often used as a positive marker for ApoBDs [39]. Notably, when we monitored the exposure of PtdSer on ApoBDs generated from THP-1 and LIM1215 cells treated with UV to induce apoptosis, ApoBDs were found to be either PtdSerIntermediate or PtdSerLow based on A5 (a PtdSer-binding protein) staining as monitored by confocal microscopy (Figure 2(a,b)), indicating PtdSer exposure alone may not be a suitable marker to either include or exclude a certain vesicle population to be classified as ApoBDs. It should be noted that it is possible for PtdSerLow ApoBD-like vesicles to be released from non-apoptotic cells. To address this, we performed live time-lapse microscopy and did not observe ApoBD-like vesicles being released from viable cells (cells that exhibited no apoptotic morphologies like cell detachment, cell rounding, membrane blebbing and thin membrane protrusion formation) (Supplementary Video 4 and 5).
Potential mechanism of thymosin-α1-membrane interactions leading to pleiotropy: experimental evidence and hypotheses
Published in Expert Opinion on Biological Therapy, 2018
Walter Mandaliti, Ridvan Nepravishta, Francesca Pica, Paola Sinibaldi Vallebona, Enrico Garaci, Maurizio Paci
This also reveals a defect in a protein-catalyzed scrambling of membrane phospholipids as in pathological states such as chronic ethanol administration [43] and post-oxidative stress [49]. Such evidence has been reviewed [50], the conclusions being that the engulfment due to the apoptotic process exhibits a unique pharmacological profile, where the sensitivity to blockers correlates with the occurrence of PS exposure on the phagocytic prey [46]. In particular, PS exposure occurs on both the prey and the phagocyte. While the phospholipid scrambling exposes phosphatidylserine on the dying cells, lipid randomization is required on the phagocyte. The specificity of PS exposure is a biologically important response, its appearance on the cell surface during apoptosis in thymocytes and cytotoxic T lymphocyte cell lines provoking PS-dependent recognition by activated macrophages [47]. Activating a translocase and a nonspecific lipid scramblase is responsible for PS reaching the surface from its intracellular location before DNA degradation, meiosis, and cell lysis in the apoptotic pathway [47]. The finding that Tα1 interacts with regions of the membrane surface where an exposure of PS assuming partial helical conformation(s) occurs prior to the interaction with receptors may indicate the possible action pathway for its pharmacological action.
Bacteria-induced intracellular signalling in platelets
Published in Platelets, 2015
Bacillus anthracis-derived peptidoglycan activates platelets by binding IgG and subsequently engaging the FcγRIIA pathway, as outlined above, leading to aggregation, αIIbβ3 integrin expression and exposure of the phosphatidylserine-enriched procoaggulant surface [86]. However, although blockade of FcγRIIA inhibited aggregation and αIIbβ3 integrin expression, there was no significant effect on the procoaggulant surface exposure [86]. Furthermore, the B. anthracis-derived peptidoglycan-induced expression of the procoaggulant surface was a consequence of complement binding [86]. Interestingly, complement does not bind to quiescent platelets. Taken together, this suggests that B. anthracis-derived peptidoglycan activates the IgG/FcγRIIA pathway which in turn up-regulates gC1q-R expression, as suggested for S. sanguinis, leading to complement binding [86]. The pathway distal to gC1q-R leading to the exposure of the procoaggulant surface has not been addressed. However, under in vitro conditions, procoaggulant surface expression requires a huge increase in the cytosolic calcium level (as induced by a combination of thrombin and collagen) to induce the activation of scramblase and the expression of the phosphatidylserine-enriched pro-coagulant surface [87]. The precise mechanism has not been elucidated but the calcium store-operated Orai 1 [88] channel and the STIM1 calcium sensors [89] have been implicated, although these are unlikely to be the only processes involved [89]. Thus, it is possible that engagement of gC1q-R leads to an elevation of cytosolic calcium to a level which stimulates scramblase.