Pancreatic cancer associated with obesity and diabetes: an alternative approach for its targeting

Pothuraju et al. Journal of Experimental & Clinical Cancer Research https://doi.org/10.1186/s13046-018-0963-4 (2018) 37:319 REVIEW Open Access Pancreatic cancer associated with obesity and diabetes: an alternative approach for its targeting Ramesh Pothuraju1, Satyanarayana Rachagani1, Wade M. Junker1,2, Sanjib Chaudhary1, Viswanathan Saraswathi3, Sukhwinder Kaur1 and Surinder K. Batra1,4,5* Abstract Background: Pancreatic cancer (PC) is among foremost causes of cancer related deaths worldwide due to generic symptoms, lack of effective screening strategies and resistance to chemo- and radiotherapies. The risk factors associated with PC include several metabolic disorders such as obesity, insulin resistance and type 2 diabetes mellitus (T2DM). Studies have shown that obesity and T2DM are associated with PC pathogenesis; however, their role in PC initiation and development remains obscure. Main body: Several biochemical and physiological factors associated with obesity and/or T2DM including adipokines, inflammatory mediators, and altered microbiome are involved in PC progression and metastasis albeit by different molecular mechanisms. Deep understanding of these factors and causal relationship between factors and altered signaling pathways will facilitate deconvolution of disease complexity as well as lead to development of novel therapies. In the present review, we focuses on the interplay between adipocytokines, gut microbiota, adrenomedullin, hyaluronan, vanin and matrix metalloproteinase affected by metabolic alteration and pancreatic tumor progression. Conclusions: Metabolic diseases, such as obesity and T2DM, contribute PC development through altered metabolic pathways. Delineating key players in oncogenic development in pancreas due to metabolic disorder could be a beneficial strategy to combat cancers associated with metabolic diseases in particular, PC. Keywords: Pancreatic cancer, Obesity, Insulin resistance, Diabetes, Adiponectin, Leptin, Gut microbiota, Inflammation Background The pancreas contains exocrine and endocrine cells. The endocrine cells secrete insulin, glucagon, and somatostatin, whereas exocrine cells are involved in the secretion of digestive enzymes. Pancreatic cancer (PC) is lethal malignancy and approximately, 95% of PC has an exocrine cell origin. It is very difficult to diagnose at an early stage due to the lack of symptoms and deep retroperitoneal of pancreas. This PC type is commonly known as pancreatic ductal adenocarcinoma (PDAC), with a 5-year survival rate of ~7.2% in the United States * Correspondence: 1 Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA 4 Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA Full list of author information is available at the end of the article (US) [1]. PC has become the third leading cause of cancer-related deaths with an estimated new cases of 55,440 and deaths of 44,330 in 2018 [2]. The lifetime risk of developing PC in any one person is 1.6% and it is expected to surpass colon cancer in mortality by year 2030 [3]. PC is frequently diagnosed at an advanced stage, when the cancer has metastasized to distant organs like the liver, lung, lymph node and peritoneal cavity [4]. Unfortunately by the clinical presentation, 85% of the tumors are unresectable [5, 6] which translates to poor prognosis and high mortality in the absence of effective chemo- and radiotherapies. Risk factors for PDAC include age (high percentage in elderly), sex (high incidence in men), gene mutations, cigarette smoking (nearly one quarter of all PC cases), obesity, chronic pancreatitis, and diabetes [7, 8]. © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Pothuraju et al. Journal of Experimental & Clinical Cancer Research In PC, pancreatic stellate cells form a dense stromal tissue, which is referred to as a desmoplastic reaction. Stellate cells are responsible for limiting vascularization, which leads to hypoxia, tumor progression, invasion, and metastasis [9–13]. In PC, a compendium of mutations occur in various oncogenes like Kirsten rat sarcoma viral oncogene homolog (KRAS) and tumor suppressor genes (INK4A/p16, Tp53 and SMAD4) [14]. Mutations in the KRAS oncogene, observed in more than 90% of PC tumors, leads to constitutively active Ras protein that results in uncontrolled cell proliferation. Further, inactivating mutations in INK4A/p16 and Tp53 results in the loss of cell cycle and apoptotic regulation [4]. Differential expression of epidermal growth factor receptor (EGFR), mucins (MUC1, MUC6 and MUC5AC) and matrix metalloproteinases (MMPs) occurs during precursor development [15]. Mutations in INK4A/p16 (90%) appear in PanIN-2, whereas Tp53 (85%) and SMAD4 (55%) mutations are found in PanIN-3. Since PanINs represent precancerous ductal lesions, these mutations are considered early molecular biomarkers for PC [15]. A combination of biomarkers (EGFR, ERK, SIAH, Ki67 and HIF-α) can predict survival rates for patients with resectable PC. In fact, a combination of these biomarkers is more strongly associated with pathological features including tumor size, tumor grade, margin and lymph node status compared to a single marker [7, 16, 17]. In a multicenter study, to differentiate PC from chronic pancreatitis and their benign controls, mucin (MUC5AC) alone or in combination with CA19-9 could be a potential diagnostic/prognostic biomarker [18]. Due to generic symptoms (weight loss, fatigue, jaundice, abdominal pain and nausea) common across multiple other pathologies , early identification of PC is difficult [19, 20]. Recent studies suggest that PC develops from a precursor lesion of <5 mm in diameter and may take an average of 20 years to metastasize [20]. Therefore, it provides a window of opportunity to diagnose and treat PC if it is detected at an early stage [21]. To date, efforts are being made in multiple directions to develop early diagnostic test for PC including histopathological tests on fine needle aspirates, serological tests, imaging (computed tomography/magnetic resonance imaging), and analysis of genetic mutation markers [21–23]. Regarding PC treatment, gemcitabine (a nucleotide analogue) is the preferred first-line option but survival is often less than ~5 months. Combination therapy with gemcitabine and erlotinib (an inhibitor of EGFR) increased the 1-year survi (...truncated)