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.
Highlights
Neoplasms that grow slowly and lack the ability to form metastases are usually termed benign
IL-6, IL-8, MCP-1 and MIP-1α reached high levels, and IL-6, IL-8 and MCP-1 were consistently among the cytokines with the highest expression levels in CP tissue, cultured CP cells and the supernatant of these cultured cells (Fig. 1B–D). These results suggested that pro-inflammatory cytokines are elevated locally around the tumor and in plasma and that tumor cells themselves may be a source for these elevated levels
The suggestion that locally elevated adenosine triphosphate (ATP) levels may participate in cytokine upregulation through activation of P2X7R prompted us to determine whether this ion channel is expressed in CP tissue in vivo and http://erc.endocrinology-journals.org
Summary
Neoplasms that grow slowly and lack the ability to form metastases are usually termed benign. Some of them are locally invasive and damage the surrounding tissue. 2008, Larkin & Ansorge 2013). They are characterized by indistinct margins, adherence to neighboring brain tissue and association with reactive gliosis, all of which render a distinction between tumor and healthy tissue difficult during surgical resection. Morbidity and mortality associated with these tumors are usually high (Garnett et al 2007, Muller 2011, 2013). Radical resection may severely damage critical local structures (Banna 1976, Miller 1994), including the pituitary stalk, cranial and optic nerves and the hypothalamus. Conservative resection is frequently associated with tumor recurrence. Of paramount importance to determine the pathogenetic mechanisms that control local tumor invasion
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