Denley, Simon M.
The role of the systemic inflammatory response, the JAK STAT pathway and the MAPK pathway in the prognosis of resectable pancreatic cancer.
MD thesis, University of Glasgow.
Full text available as:
Pancreatic cancer is a devastating disease with a five year survival of only 2-3%. Only 10-15% of patients have resectable disease at presentation and the only potential cure is major surgery with adjuvant chemotherapy. The outcomes of surgery are disappointing with a median survival of only15-17 months and operative mortality and morbidity figures of 5-10% and 40% respectively. This abysmal prognosis is likely due to the highly aggressive nature of the tumour, its resistance to adjuvant therapy, its late presentation and the likely presence of micro-metastases not detectable at staging or surgery.
A pre-operative systemic inflammatory response (as measured by CRP) is known to be associated with a poor prognosis in a number of cancers including pancreatic cancer. The reasons behind this poor prognosis are not yet known. The main driver of plasma CRP levels is the cytokine IL-6, known to be elevated in the plasma of patients with pancreatic cancer. This thesis hypothesises that upregulation of two IL-6-dependent pathways, the JAK STAT and MAPK pathways is responsible for the poor prognosis associated with an inflammatory response in pancreatic cancer. Both of these pathways are known to be involved in cellular growth, differentiation and apoptosis and when activated they may confer a growth or survival advantage to tumour cells. The aims of this thesis were to establish the prognostic role of a systemic inflammatory response in resectable pancreatic cancer in both a retrospective and prospective cohort and establish whether increased protein expression in either the JAK STAT or MAPK pathways is associated with a poor prognosis in the same retrospective cohort.
A retrospective database of 148 patients who had undergone Whipple resection for either pancreatic cancer (PC) or non-pancreatic peri-ampullary cancer (NPPC) was created with pre-operative CRP values and survival data. The author then created tissue micro-arrays (TMA’s) with both tumour and normal pancreatic duct tissue from each of the 148 patients in the retrospective cohort and carried out immunohistochemistry on 12 antibodies known to be crucial in IL-6 signalling (6 in the JAK STAT and 6 in the MAPK pathways). Following staining the author scored each of the antibodies using the weighted histoscore to allow analysis of antigen expression. During the period of research the author also created a prospective database of 36 patients who underwent surgery for either PC or NPPC. Plasma was stored pre-operatively from each of the patients and this was later thawed and using an ELISA kit another research fellow (JL) was able to establish plasma levels of IL-6 in the prospective cohort.
On univariate analysis a raised pre-operative CRP was associated with poorer survival, 374 days versus 618 days (p=0.0001) in the retrospective PC group only. On multivariate analysis, only pre-operative CRP retained statistical significance amongst those factors shown to be significant on univariate analysis (P=0.009). In the prospective group, patients with low levels of IL-6 had a median survival of 799 days, against a median survival of 537 days in those with high plasma IL-6 levels (P=0.002) when all 36 patients were analysed together. On analysis of protein expression, no significant relationship between increased expression and poor survival was seen for any of the 12 proteins analysed.
The results from this thesis confirm that a pre-operative inflammatory response is associated with poor survival in patients with resectable pancreatic cancer. Raised plasma levels of IL-6 are also associated with poorer survival in similar patients. However, the poor prognosis appears to be via a JAK STAT/ MAPK independent mechanism. Other possible explanations for this poor prognosis including the connection between inflammation and cachexia and other important inflammatory proteins such as NF-κB and SOCS are explored in the discussion of this thesis.
Actions (login required)