Abstract
Simple SummaryPancreatic Ductal Adenocarcinoma (PDAC) is a rapidly fatal disease. Diabetes mellitus is a major association of PDAC and is both a cause as well as a consequence of cancer. Notably, at the time of diagnosis of PDAC, more than 80% of patients have abnormal fasting blood glucose levels. Even more intriguing is the observation that a third of patients reports being diagnosed with diabetes within 3 years prior to their cancer diagnosis. This new onset diabetes, also called pancreatic cancer-related diabetes (PCRD) may be a harbinger of asymptomatic PDAC. Elucidating the mechanisms mediating PCRD will enable the identification of biomarkers for early diagnosis and/or novel molecular pathways that can be therapeutically targeted to improve patient outcomes.Pancreatic ductal adenocarcinoma (PDAC) is a devastating condition characterised by vague symptomatology and delayed diagnosis. About 30% of PDAC patients report a history of new onset diabetes, usually diagnosed within 3 years prior to the diagnosis of cancer. Thus, new onset diabetes, which is also known as pancreatic cancer-related diabetes (PCRD), could be a harbinger of PDAC. Diabetes is driven by progressive β cell loss/dysfunction and insulin resistance, two key features that are also found in PCRD. Experimental studies suggest that PDAC cell-derived exosomes carry factors that are detrimental to β cell function and insulin sensitivity. However, the role of stromal cells, particularly pancreatic stellate cells (PSCs), in the pathogenesis of PCRD is not known. PSCs are present around the earliest neoplastic lesions and around islets. Given that PSCs interact closely with cancer cells to drive cancer progression, it is possible that exosomal cargo from both cancer cells and PSCs plays a role in modulating β cell function and peripheral insulin resistance. Identification of such mediators may help elucidate the mechanisms of PCRD and aid early detection of PDAC. This paper discusses the concept of a novel role of PSCs in the pathogenesis of PCRD.
Highlights
One of the major risk factors for Pancreatic Ductal Adenocarcinoma (PDAC) is type 2 diabetes mellitus, with type 2 diabetes patients reported to have a two-fold increased risk for the development of Pancreatic ductal adenocarcinoma (PDAC) compared to the general non-diabetic population [1,2,3,4]
While the literature to date supports the concept that ISCs may play a role in inhibiting β cell function in diabetes, most likely via mediators that affect β cells in a paracrine manner, little is known about the possible effects of pancreatic stellate cells (PSCs) on distant targets relevant to diabetes, namely peripheral cells, such as hepatocytes, adipocytes and skeletal myocytes, that regulate glucose homeostasis via insulin-mediated utilisation of glucose
Early detection of PDAC is vital for improved patient outcomes
Summary
One of the major risk factors for Pancreatic Ductal Adenocarcinoma (PDAC) is type 2 diabetes mellitus, with type 2 diabetes patients reported to have a two-fold increased risk for the development of PDAC compared to the general non-diabetic population [1,2,3,4]. The above observations suggest that PCRD is a paraneoplastic phenomenon caused by a developing tumour and that new onset diabetes may be a harbinger of asymptomatic PDAC [8]. Cancers 2021, 13, 5224 insulin signalling pathways leading to insulin resistance These factor(s), if identified and characterised, could be used as (i) biomarkers, in the case of new onset diabetes to identify patients with PDAC that is early or at a premalignant stage, and (ii) as potential therapeutic targets to prevent progression to overt PDAC. Characterisation of the functions of such exosomal cargo may provide valuable insights for early detection of PDAC, and improved patient outcomes
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