Pancreatic Cancer Chemoprevention by Metformin in a High Fat Diet
Creators: name: Castellanos, Karla Josephine
Publisher: name: University of Illinois at Chicago
Year: 2021
Subjects: Uncategorized

description: Risk of developing pancreatic cancer (PC) is increased in obesity and Type 2 Diabetes Mellitus (T2DM), yet the frequency of people with these comorbidities is dramatically rising every year (McAuliffe and Christein, 2013). These indeed serve as modifiable risk factors that may synergistically hasten the development of PC. Several epidemiological studies have shown that T2DM is positively associated with increased risk for developing PC and worse clinical outcome (Pannala et al., 2008). Metformin (MET), a first line drug for the treatment of T2DM, improves glucose control by reducing hepatic gluconeogenesis (Klip and Leiter, 1990). In addition, promising studies have indicated that MET can potentially be used as an anti-cancer drug (McAuliffe and Christein, 2013). PC soon will be the second leading cause of cancer death in the US (Hezel et al., 2006). Therefore, investigating the chemoprotective effects of MET may be relevant therapeutic for patients at high risk of developing PC. The evolution of PC is characterized by the emergence of neoplastic lesions long before detection or diagnosis of PC is made (Wang et al., 2019). Mutations in oncogene Kras arise in over 90% of all PCs and are known to influence the development of PC in humans and mouse models (Hingorani et al., 2003). Kras mutations are believed to be a primary initiating event that lead to the development of PC, though requirement of additional genetic variants is likely necessary (Wei et al., 2016). Various environmental and internal influences fuel the development of overt cancer (Rawla et al., 2019). In this study we will look at the influence obesity has on the development of pancreatic lesions. The road to PC requires repeated insult to pancreatic acinar and ductal cells which may eventually lead to pancreatic dysplasia and acinar cell dedifferentiation typically called acinar-to-ductal metaplasia (ADM). MET activates Adenosine monophosphate-activated protein kinase (AMPK), which is an important enzyme in cellular energy homeostasis. Low intracellular energy leads to the activation of AMPK and induces ATP production by increasing glucose uptake into cells and/or regulating the biosynthesis of fatty acid production and/or its uptake (Hardie et al., 2016). Also, AMPK can induce downstream activation of cellular autophagy, which aids in maintenance of cellular health by removing degraded cytoplasmic organelles, misfolded proteins and other deleterious cellular products that may become toxic to the cell (Chen et al., 2010; Mihaylova and Shaw, 2011). We aimed to investigate the role of MET and subsequently probe if it is able to influence autophagy signaling in the pancreas and liver of mice. To achieve these goals, we utilized a western style high fat diet, which is a well-established model for inducing obesity in mice. Also, we proposed the use of the EL-Kras (EK) neoplastic PC mouse model. It has repeatedly been shown that HFD in mice induces metabolic disease similar to that observed in overweight/obese humans including elevated levels of circulating insulin, fatty liver and increased peri-pancreatic and intrapancreatic fat. The milieu of downstream effects on the pancreas from fat in humans and mice is known to increase metabolic-related disease. However, the precise mechanism by which obesity and diabetes exacerbates disease and fuels the initiation of cancer in the pancreatic parenchyma is still unknown. We aimed to investigate the direct effect of diet-induced obesity in EK and wild type (WT) mice in the presence and absence of MET. We also set out to investigate how MET can ameliorate damage believed to occur in the pancreas due to a HFD. We sought to better understand the function of MET and to incorporate it as an eventual chemopreventive agent and/or adjuvant therapy for patients at high risk for developing PC and patients with PC respectively, to aid in blocking the initiation, progression and severity of this deadly disease.