Biomarker And Therapeutic Target

Discuss the importance of the P2X7 purinergic receptor in cancer

The purinergic receptors are a family of plasma membrane molecules which are usually found in all mammalian tissuesand are seen to be specifically involved in migration and proliferation of cells, cytokine secretion, vascular reactivity and apoptosis (Burnstock, 2017).The different classes of purinergic receptor include P1 receptors, P2Y receptors and P2X receptors. P2X7 is a type of purinergic receptor which has presently attracted attention in the cancer research as it is being regarded as a biomarker for cancer detection or a target for executing pharmacological intervention (Adinolfi et al. 2017). Thus, in this essay the importance of P2X7 purinergic receptor (P2X7R) in cancer studies will be discussed to develop a clear concept regarding itsimportant role and function in cancer.

The P2X7 purinergic receptor is often found in the peripheral and central nervous systemin macrophages, microglia, uterine endometrium and in the retina of the eye (Sperlágh and Illes, 2014). It also acts as a patternrecognition receptor for regulation of receptor trafficking, extracellular ATP-mediatedapoptotic cell death, mast cell degranulation, and inflammation (Takaiet al. 2014). The receptor is responsible for triggering release of proinflammatory cytokines (e.g.interleukin-1α) andpromotes the activation of inflammasome along with production of reactive oxygen species (McLarnon, 2017). The P2X7R is referred as a trimeric ligand-gated ion channel which is activated by extracellular ATP also plays a significant role in promoting inflammationof cancer cells (Avanzatoet al. 2016).

In human neuroblastoma, P2X7 purinergic receptor is seen to be important as it supports the release of substance P (an undecapeptide which is a member of tachykinin neuropeptide family) that acts as a growth factor for the cancer development in immature nerve cells (Di Virgilio et al. 2009). Moreover, in human thyroid papillary carcinoma, it is reported to trigger the release of IL-6 that is a growth factor for thyreocytes (Amoroso et al. 2015). The receptor helps in promoting the growth of cancer cells in the body. Therefore, the receptor is important to be considered as it may act as a potential expression to be considered in cancer detection mechanism among humans. Furthermore, the P2X7R in the neuroblastoma cells executes a death escape mechanism which resultsto form faulty coupling of caspase with the neuroblastoma cells due to which the cancerous growth remains undetected by the body’s immune system to get destroyed (Di Virgilio et al. 2009). Thus, the P2X7 purinergic receptor is important to be considered because if the receptor can be targeted in the pharmacological intervention to be inhibited then it may lead to resolving cancer development in humans. This is because through pharmacological intervention by targeting the receptor the death escapes mechanism is to be inhibited which is going to help in the death of cancerous proliferation of cells in the body thus resolving cancer development.

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In most cells types where P2X7 is heterogeneously or endogenously expressed, its pharmacological activation by using higher concentration of agonist such as BzATP or ATP was seen to be usually associated with considerable cellular events like cell swelling, loss of asymmetry in distribution of phosphatidyl, membrane blebbing and permeabilization, loss of potential of mitochondria and increase of internal calcium ion (Giannuzzoet al. 2016).This event is seen to be reversible when the agonists were applied for a shorter period of timeand are associated with the process that is called pseudoptosis. However, the events were seen to lead to cell death of the cancerous growth after a prolonged stimulation of the receptor. This information led to initially formulating the hypothesis regarding the P2X7 receptor is that its overexpression could create a deleteriouseffect for the cancerous cells. Thus,the study of the effect of stimulating its activity is important for the development of new clinical therapies for cancer treatment.

The P2X7R is important to be considered in cancer studies because its presence in the body may result to help in early detection of cancerous growth in the body. This can be proved from the cohort study conducted of 100 biopsies for prostate cancer that are obtained from men who are aged 47-91 years who indicating confirmed presence of cancerous growth. It was found that all the biopsies of cancer showed positive indicator for the presence of P2X7 receptor without any correlation with age of the participant. The P2X7 was also found in the non-cancerous epithelial cells that are present adjacent to the tumour in the individuals. However, the labelling was seemed as distinct depending on the vicinity or stage of the tumour cells. The presence of P2X7 receptors was found on the nucleus of the non-cancerous cells and then on the cytoplasm and then on the apical membrane of the cells which are later progressing to cancerous stage among individuals who are assumed to be having prostate cancer. However, there was no expression of P2X7 receptors on the prostate tissues which came from the patients who have no evidence of cancer development (Solini et al. 2015).This informs that presence of P2X7 purinergic receptor is a potential factor to be considered for early detection of cancer among patients because it was seen not at all present entirely for the individuals who are unaffected by cancer.

In another study, the expressions of P2X7 receptors were compared with the level of prostate-specific antigen presence in prostate cancer biopsies from 174 patients. In this study, a direct positive correlation was found between P2X7 receptor expressions with increased level of prostate-specific antigen in patients who showed positive result for diagnosis of cancerous growth in the prostate region (Roger et al. 2015). Thus, the similarity between the studies by Roger et al. and Solinin et al. is that they both proved through their experimentation that presence of P2X7 receptor is an early aspect in individuals which informs they are going to develop cancer. In the study of Xia et al. (2015), it is examined whether ATP could be able to stimulate the activation of AKT pathway involved in the breast cancer cell development. This is because AKT acts as a key kinase in the cell signalling pathway which participates in tumour development and metastasis leading to cancer. The examination performed through ATP time-dependent stimulation informed that a marked increase in the phosphorylation level of AKT in the T47D cells was seen. The western blot analysis in the experiment informed that the ATP-induced activation of the AKT pathway was highly inhibited when the P2X7 receptor was knocked down. This suggests that P2X7 receptor have a great contribution to the ATP-induced activation of the AKT pathway involved in breast cancer development. Thus, the P2X7 purinergic receptor is important aspect in controlling cancerous growth among individuals as its inhibition leads to inactivate the pathways which are responsible for tumour metastasis and cancer development. The difference between the above two studies with the study by Xia et al. is that those studies focused on to ensure whether or not P2X7 can act as a potential aspect for early diagnosis to identify cancer development. However, the study Xia et al. focused on whether or not P2X7 receptor inhibition can avoid cancer development and metastasis.

In the study of Franceschini and Adinolfi (2014), P2X7 receptor is assumed to be an interesting target for developing pain easing and anti-cancer therapies. In the current researches, different P2X7 antagonists such as A-74003, A-438079, AZ-10606120 and others are seen to be undergoing clinical trials to reduce inflammatory and neuropathic pain and its role in the pain regulating pathway is being confirmed by the P2X7 receptor which is expressed in spinal microglia in inducing morphine tolerance. Further, the study showed that P2X7R has a growth inducer in the case of cancer development because its expression is found to affect increased tumour engraftment, increase tumour growth rate and angiogenesis.

In order to further detect the efficiency of P2X7R in drug therapy, Giannuzzoet al. (2015) tried to found expression of P2X7 receptor in the human pancreatic ductal adenocarcinoma cell lines (PDAC) in comparison to the normal human pancreatic duct epithelial cell line along with characterisation of function of P2X7 receptor in migration, proliferation and invasion. The results are found to show higher expression of P2X7 protein in the PDAC than in the HPDE cells and notable disparate impact is seen on the survival of PDAC as a result of P2X7. Further, the results informed that high concentration ATP (Adenosine Triphosphate) or the specific P2X7 agonist (BzATP- benzoyl ATP) has cytotoxic impact in the cell lines and cell death was seen to be medicated through necrosis.The P2X7 pore antagonist that is A4370879 was seen to prevent ATP-induced formation of cell pores and cell death. In basal conditions, with lower concentration of ATP or BzATP, the P2X7 allosteric inhibitor lowers proliferation in the PDAC cell lines thus helping to control the spread of cancerous cell lines.This led to the conclusion that reduced expression of P2X7 receptor in the PDAC cell lines has a crucial role to play and drugs targeting the P2X7R could be used to exploit effective therapeutic measures for pancreatic cancer.

Thus, the above evaluation informs that the P2X7 purinergic receptor has wider important activities in cancer studies. Firstly, it is able to act as an anti-tumour receptor which acts to induce cancer cell death resulting in improves therapeutic opportunity for cancer patients. Secondly, it acts a precancer receptor because it supports the cancerous cell proliferation, invasion and migration both in ex-vivo and in-vivo conditions. Thus, it can be a potential factor of detection for early diagnosis of cancer.Thirdly, the P2X7 receptor is involved in immune system modulation and inflammation that has the potential to affect progression of tumour growth which mentions that it has the efficiency to induce cancerous growth in individuals.

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References

  • Adinolfi, E., Giuliani, A.L., De Marchi, E., Pegoraro, A., Orioli, E. and Di Virgilio, F., 2017. The P2X7 receptor: a main player in inflammation. Biochemical pharmacology.pp.90-122.
  • Amoroso, F., Capece, M., Rotondo, A., Cangelosi, D., Ferracin, M., Franceschini, A., Raffaghello, L., Pistoia, V., Varesio, L. and Adinolfi, E., 2015. The P2X7 receptor is a key modulator of the PI3K/GSK3β/VEGF signaling network: evidence in experimental neuroblastoma. Oncogene, 34(41), p.5240.
  • Avanzato, D., Genova, T., Pla, A.F., Bernardini, M., Bianco, S., Bussolati, B., Mancardi, D., Giraudo, E., Maione, F., Cassoni, P. and Castellano, I., 2016. Activation of P2X7 and P2Y11 purinergic receptors inhibits migration and normalizes tumor-derived endothelial cells via cAMP signaling. Scientific reports, 6, p.32602.
  • Burnstock, G., 2017. Introduction to the special issue on purinergic receptors. In Protein Reviews (pp. 1-6). Springer, Singapore.
  • Di Virgilio, F., Ferrari, D. and Adinolfi, E., 2009. P2X 7: a growth-promoting receptor—implications for cancer. Purinergic signalling, 5(2), pp.251-256.
  • Franceschini, A. and Adinolfi, E., 2014. P2X receptors: new players in cancer pain. World journal of biological chemistry, 5(4), p.429
  • Giannuzzo, A., Saccomano, M., Napp, J., Ellegaard, M., Alves, F. and Novak, I., 2016. Targeting of the P2X7 receptor in pancreatic cancer and stellate cells. International journal of cancer, 139(11), pp.2540-2552.
  • Giannuzzo, A., Pedersen, S.F. and Novak, I., 2015. The P2X7 receptor regulates cell survival, migration and invasion of pancreatic ductal adenocarcinoma cells. Molecular cancer, 14(1), p.203.
  • McLarnon, J.G., 2017. Roles of purinergic P2X7 receptor in glioma and microglia in brain tumors. Cancer letters, 402, pp.93-99.
  • Roger, S., Jelassi, B., Couillin, I., Pelegrin, P., Besson, P. and Jiang, L.H., 2015. Understanding the roles of the P2X7 receptor in solid tumour progression and therapeutic perspectives. Biochimica et Biophysica Acta (BBA)-Biomembranes, 1848(10), pp.2584-2602.
  • Solini, A., Simeon, V., Derosa, L., Orlandi, P., Rossi, C., Fontana, A., Galli, L., Di Desidero, T., Fioravanti, A., Lucchesi, S. and Coltelli, L., 2015. Genetic interaction of P2X7 receptor and VEGFR-2 polymorphisms identifies a favorable prognostic profile in prostate cancer patients. Oncotarget, 6(30), p.28743.
  • Sperlágh, B. and Illes, P., 2014. P2X7 receptor: an emerging target in central nervous system diseases. Trends in pharmacological sciences, 35(10), pp.537-547.
  • Takai, E., Tsukimoto, M., Harada, H. and Kojima, S., 2014. Autocrine signaling via release of ATP and activation of P2X7 receptor influences motile activity of human lung cancer cells. Purinergic signalling, 10(3), pp.487-497.

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