Fas ligand expression and tumour immune evasion; the role of prostaglandin E2 and the EP1 receptor

Background and Aim: During carcinogenesis, tumours develop multiple mechanisms to evade the immune system and suppress the anti-tumour immune response. Upregulation of Fas Ligand (FasL/CD95L) expression may represent one such mechanism. FasL is a member of the tumour necrosis factor superfamily that triggers apoptotic cell death following ligation to its receptor Fas. Numerous studies have demonstrated upregulated FasL expression in tumor cells, with FasL expression associated with numerous pro-tumorigenic effects. However, little is known about the mechanisms that regulate FasL expression in tumours. The cyclooxgenase (COX) signalling pathway may play an important role in colon carcinogenesis, via the production of prostaglandins, in particular PGE2. PGE2 signals through four different receptor subtypes, EP1 – EP4. Thus, the aim of this study was to investigate the effect of targeting the PGE2-FasL signaling pathway. Results: (i) PGE2 induces FasL expression via the EP1 receptor in colon cancer cells. (ii) Suppression of FasL expression in colon tumour cells in vivo significantly delays and reduces tumour growth. (iii) Blocking EP1 receptor signaling, or suppression of the EP1 receptor in colon tumour cells, reduces tumour growth in vivo. Suppression of tumour growth correlates in part with suppression of FasL expression. (iv) The reduction in tumour growth is associated with an improved anti-tumour immune response. Tumour infiltration by Treg cells and macrophages was reduced, and the cytotoxic activity of CTL generated from splenocytes isolated from these mice increased. Conclusion: 1) Targeting FasL expression by blocking PGE2-EP1 receptor signalling reduces tumour development in vivo. 2) The mechanism is indirect but is associated with an increased anti-tumour immune response. Thus, unraveling the mechanisms regulating FasL expression and the pro-tumorigenic effects of the EP1 receptor may aid in the search for new therapeutic targets against colon cancer.

Parents' experiences of child growth and development concerns: an interpretative phenomenological analysis

Background: Assessing child growth and development is complex. Delayed identification of growth or developmental problems until school entry has health, educational and social consequences for children and families. Health care professionals (HCPs), including Public Health Nurses work with parents to elicit and attend to their growth and development concerns. It is known that parents have concerns about their children’s growth and development which are not expressed in a timely manner. Measuring parental concern has not been fully effective to date and little is known about parents’ experiences of expressing concerns. Aim: To understand how parents make sense of child growth or development concerns. Method: The study was qualitative using Interpretative Phenomenological Analysis (IPA). A purposeful sample of 15 parents of pre-school children referred by their PHN to second tier services was used. Data were collected by semi-structured interviews. NVivo version 10 was used for data management purposes and IPA for analysis. Findings: Findings yielded two contextual themes which captured how parents described The Concern – ‘telling it as it is’ and their experiences of being Referred on. Four superordinate themes were found which encapsulated the Uncertainty – ‘a little bit not sure’ of parents as they made sense of the child’s growth and development problems. They were influenced by Parental Knowledge – ‘being and getting in the know’ which aided their sense-making before being prompted by Triggers to action. Parents then described Getting the child’s problem checked out as they went to express their concerns to HCPs. Conclusion and Implications: Parental expression of concerns about their child is a complex process that may not be readily understood by HCPs. A key implication of findings is to reappraise how parental concern is elicited and attended to in order to promote early referral and intervention of children who may have growth and development problems.