The purine receptor P2X7R regulates the release of pro-inflammatory cytokines in human craniopharyngioma

Abstract

Craniopharyngiomas (CPs) are usually benign, non-metastasizing embryonic malformations originating from the sellar area. They are, however, locally invasive and generate adherent interfaces with the surrounding brain parenchyma. Previous studies have shown the tumor microenvironment is characterized by a local abundance of adenosine triphosphate (ATP), infiltration of leukocytes and elevated levels of pro-inflammatory cytokines that are thought to be responsible, at least in part, for the local invasion. Here, we examine whether ATP, via the P2X7R, participates in the regulation of cytokine expression in CPs. The expression of P2X7R and pro-inflammatory cytokines were measured at the RNA and protein levels both in tumor samples and in primary cultured tumor cells. Furthermore, cytokine modulation was measured after manipulating P2X7R in cultured tumor cells by siRNA-mediated knockdown, as well as pharmacologically by using selective agonists and antagonists. The following results were observed. A number of cytokines, in particular IL-6, IL-8 and MCP-1, were elevated in patient plasma, tumor tissue and cultured tumor cells. P2X7R was expressed in tumor tissue as well as in cultured tumor cells. RNA expression as measured in 48 resected tumors was positively correlated with the RNA levels of IL-6, IL-8 and MCP-1 in tumors. Furthermore, knockdown of P2X7R in primary tumor cultures reduced, and stimulation of P2XR7 by a specific agonist enhanced the expression of these cytokines. This latter stimulation involved a Ca2+-dependent mechanism and could be counteracted by the addition of an antagonist. In conclusion, the results suggest that P2X7R may promote IL-6, IL-8 and MCP-1 production and secretion and contribute to the invasion and adhesion of CPs to the surrounding tissue.

ATP-mediated Events in Peritubular Cells Contribute to Sterile Testicular Inflammation

“…Recently, functional Toll-like receptors were identified in HTPCs and a danger signal from the ECM, biglycan, was implicated in their activation, entailing secretion of the chemo-/cytokines CCL2 and IL6 11 . ATP was also able to induce CCL2 and IL6 production and secretion in HTPCs, similar to results from other cell types 42 – 45 . However, IL6 and CCL2 levels were only mildly elevated.…”

Chemokines modulate the tumour microenvironment in pituitary neuroendocrine tumours

“…IL-8, CCL2, CCL3 and CCL4 were highly secreted by the majority of PitNETs. Cytokine array data from human craniopharyngiomas identified CCL2 and IL-8 as the most secreted cytokines in plasma, primary culture supernatants, cell and tissue lysates [57]. There are no previous data on CCL2, CCL3 or CCL4 in PitNETs, but these chemokines are involved in tumour growth and invasion in other tumours [5, 41], as well as in immune cell chemotaxis in cancer [5, 12, 16, 41, 43, 63, 72, 92].…”

Prevalence of Endocrine and Metabolic Comorbidities in a National Cohort of Patients with Craniopharyngioma

“…Because of the nature of aCP (not well-circumscribed, adheres to the surroundings with finger-like tumor protrusion not visible on MRI scans), complete resection is often not feasible and causes more damage to the adjacent structures while attempting it [22,43]. Another feature of aCP is its secretion of proinflammatory cytokines from the tumor cells and cytokine infiltration of the brain tissue close to the tumor [44,45]. Inflammation is likely to produce greater tumor adherence to and infiltration of the adjacent brain.…”