Insulin Receptor in Pancreatic Cancer—Crown Witness in Cross Examination

SIMPLE SUMMARY: Pancreatic cancer (PDAC) is a highly malignant disease with low survival rates. Due to its close proximity to the insulin producing pancreatic islets, PDAC should be exposed to comparatively higher concentrations of the growth promoting hormone insulin. We wanted to know if PDAC might take advantage of this circumstance. Therefore we cross examined the insulin receptor’s (IR) role in PDAC and precursor lesions and put it into context with the expression of the insulin-like growth factor 1 receptor (IGF1R). Our study of 160 PDAC patient samples showed that IR overexpression is already present at the precursor level. IR overexpression in PDAC was associated with adverse clinical features. The IGF1R was found to play a different role than formerly assigned. We hypothesize that the close proximity to the pancreatic islets is exploited by PDAC up to the point of the islets’ ultimate destruction by local cancer growth. ABSTRACT: Background: The proximity of pancreatic cancer (PDAC) to the physiological source of the growth promoting hormone insulin might be exploited by this highly malignant cancer entity. We investigated if (I) PDACs express the insulin receptor (IR) in cancer cells and cancer vasculature, (II) if IR correlates with clinicopathological patient characteristics, including survival, and hence is involved in PDAC biology, (III) if IR is already expressed in precursor lesions, if (IV) the IGF1 receptor (IGF1R) is associated with clinicopathological patient characteristics and survival and (V) is linked to IR expression. Methods: 160 PDAC samples were examined for IR and IGF1R expression by immunohistochemistry. A modified HistoScore was correlated with clinicopathological characteristics and survival. Results: IR overexpression was already observed in pancreatic intraepithelial neoplasia. Furthermore, it was more frequently observed in advanced disease and associated with distant metastasis, UICC stage, lymphatic invasion and an increased lymph node ratio, but without impacting survival in the end. IGF1R expression was not associated with clinicopathological parameters or survival, in contrast to former paradigms. Conclusions: We hypothesize that the close proximity to the pancreatic islets might be advantageous for cancer growth at first, but it experiences self-limitation due to surgical removal or local destruction following accelerated cancer growth.