Biopeptides involved in glucose and energy homeostasis that are cleaved by DPP4* and/or FAP**.
Abstract
Sporadic pancreatic cancer (SPC) has been frequently associated with impaired glucose homeostasis manifested by prediabetes, Type 2 diabetes or predominantly by T3c diabetes which develops as the first symptom of cancer. Pathogenic mechanisms in the development of T3c diabetes have not been fully elucidated although specific substances originating in the tumor cells are supposed to be the cause of β-cell dysfunction and insulin resistance. New biomarkers evaluated in patients with recent-onset diabetes are necessary for the early diagnosis of this tumor. Actual data characterizing risk factors, early symptoms, pathogenic mechanisms, biomarkers and structured programs in detection of SPC are described. A multidisciplinary team of primary care physicians, gastroenterologists, endoscopists, radiologists and pathologists should improve the prognosis of this malignant disease.
Keywords
- sporadic pancreatic cancer
- risk factors
- early symptoms
- T3c diabetes mellitus
- β-cell dysfunction
- insulin resistance
- biomarkers
- multidisciplinary team approach
1. Introduction
Pancreatic adenocarcinoma is a highly malignant cancer which occurs in three different forms: (1) sporadic pancreatic cancer (SPC) accounting for 90% of all pancreatic cancers, (2) familial pancreatic cancer accounting for 7%, and (3) pancreatic cancer as a part of genetic cancer syndromes, which account for the remaining 3%. A detailed program of long-term tertiary prevention (surveillance) is available for the two smaller groups. In contrast, there has been, up to now, no preventive program for the much larger SPC group.
The clinical diagnostics of SPC starts now much as it did in the middle of the past century, that is, after the appearance of local and/or systemic symptoms. They include abdominal and back pain, fatigue, loss of body weight, painless jaundice, anemia, peripheral phlebitis, and cachexia. These symptoms are nevertheless also harbingers of advanced disease.
High-resolution imaging methods (HRIMs: CT, MRI, MRCP, EUS) and histomorphology provide information suitable for diagnostics; nevertheless, their impact on patient prognosis is limited as they are typically ordered at an advanced disease stage. Radical surgery may only be suitable for 15–20% of patients. The relapses are frequent as well as early, and chemotherapy is basically palliative. This confluence of factors results in very low 5-year survival rates of only 3–6% of patients [1].
We recently recommended a screening program for early SPC detection based on cooperation of primary care physicians with gastroenterologists and other specialists [2].
2. Sporadic pancreatic cancer development
Pancreatic carcinogenesis begins with the transformation of pancreatic cells and evolution of the precancerous lesions (precursors). At present, six precursors with different morphologies and malignant potential are distinguished [serous microcystic adenoma (SMA); intraductal papillary mucinous neoplasm (IPMN); intraductal tubulopapillary neoplasm (ITPN); mucinous cystic neoplasm (MCN); pancreatic intraepithelial neoplasm (PanIN); and solid pseudopapillary neoplasm (SPN)] [3, 4]. The development of SPC based on the gradual accumulation of genetic and epigenetic alterations consists of three stages: (1) time prior to the invasive lesion, (2) time to the development of the metastatic subclone, and (3) time period of metastatic dissemination that leads to patient death. The average duration of the first two time periods is estimated to be about 18 years. Early detection must be concentrated during these two periods, when patients are often without any symptoms [5].
3. Sporadic pancreatic cancer and diabetes mellitus
The association between diabetes mellitus and pancreatic cancer has been repeatedly observed, and several case–control and cohort studies have been analyzed in meta-analyses [6]. The relationship between diabetes and SPC is reciprocal. While long-term diabetes is considered an etiologic/risk factor of SPC, new-onset diabetes may be the first manifestation of SPC [7] as recently summarized by D.K. Andersen [8].
3.1. Type 2 diabetes and obesity: important risk factors
Long-term Type 2 diabetes is frequently associated with
3.2. New-onset T3c diabetes: an early symptom of sporadic pancreatic cancer
Newly developed impairment of glucose homeostasis represented either by prediabetes (impaired fasting glucose or impaired glucose tolerance) or diabetes develops as the sole early symptom of SPC and is called pancreatogenic diabetes Type 3c (T3cDM), which appears up to 24 months (or even 36 months according to some investigators) before the clinical manifestation of SPC [19, 20, 21]. The relative probability of an already existing undiagnosed SPC is the highest in patients who were diagnosed with impairment of glucose homeostasis within the last 12 months (RR 5.4: 95% CI 3.5–8.3) [22]. A causal relationship between SPC and T3c diabetes is supported by the observation that diabetes resolves after surgical removal of the tumor in more than 50% of patients [23]. However, improvement of glucose homeostasis may be linked to the surgical procedure itself since it has also been demonstrated that subtotal pancreatoduodenectomy similarly improved diabetes in patients with or without pancreatic cancer [24].
T3c diabetes, which represents up to 8% of the total number of patients with diabetes mellitus, can occur secondary to other pancreatic disorders like chronic pancreatitis, hemochromatosis, or cystic fibrosis; however, in these cases, clinical manifestation of exocrine insufficiency usually precedes the development of pancreatic endocrine dysfunction [25]. Pancreatic cancers occur in about 9% of patients with T3cDM [26]. Therefore, one case of SPC per roughly 140 patients with new-onset diabetes can be expected. Patients with new-onset diabetes are associated with a 4- to 7-fold increase in risk of pancreatic cancer, such that 1–2% of patients with recent-onset diabetes were suggested to develop pancreatic cancer within 3 years [27].
4. Pathophysiology of T3cDM associated with sporadic pancreatic cancer
The pathophysiological relationship between T3cDM and SPC remains largely unknown. The high proportion of patients who develop T3cDM as the first clinical symptom of SPC (about 74% patients developing diabetes up to 24 months prior to SPC diagnosis) suggests that the tumor is the cause of the diabetes [28]. In addition, the prevalence of diabetes in patients with SPC is much higher (68%) compared to diabetes that develops in association with other cancers (up to 24%) [29].
4.1. β-cell dysfunction and insulin resistance
New-onset diabetes associated with SPC is a paraneoplastic phenomenon that is characterized by impaired insulin secretion and insulin resistance [30]. Impaired glucoregulation develops gradually. Approximately 15–20% SPC patients are normoglycemic with normal β-cell function but increased insulin resistance. Subjects with impaired glucose tolerance have disturbed β-cell function, but the insulin resistance is not significantly different from the preceding group. The changes in β-cells associated with SPC are initially functional as previously supposed in experimental study [31]. In contrast, morphological changes or a decrease of their counts are associated with other diseases of the exocrine pancreas, that is, chronic pancreatitis, cystic fibrosis, tropical pancreatitis, and hemochromatosis [32].
Several findings support the hypothesis that β-cell dysfunction is caused by substances overproduced by the cancer cells [21], which may impair glucose-stimulated insulin release and contribute to glucose dysregulation. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine which affects both inflammation and glucose homeostasis. Its overproduction by pancreatic cancer cells has been observed, and its effect on the inhibition of glucose-stimulated insulin release from β-cells as well as from isolated islets, through regulation of Ca2+ channels, has also been demonstrated [33]. In addition, increased serum levels of MIF have been found in new-onset diabetic patients with pancreatic cancer while no such increase has been seen in patients with pancreatic cancer without diabetes or in non-cancer new-onset Type 2 diabetic patients [33]. Cancer cells have also been shown to upregulate adrenomedullin, a potent inhibitor of insulin secretion (see below) [34, 35].
In addition to β-cell dysfunction, a significant increase in insulin resistance develops in SPC patients with diabetes [36]. Peripheral insulin resistance was confirmed by hyperinsulinemic clamps in patients with pancreatic cancer and was found to be higher in those with diabetes than in nondiabetic subjects [37]. Improved insulin sensitivity was observed after surgical removal of the pancreatic cancer [37]. Insulin resistance was found to be associated with reduced glycogen synthesis in muscles, which was also confirmed
4.1.1. Adrenomedullin
Adrenomedullin secreted by pancreatic cancer cells was found to be an important factor influencing β-cell function. It was first identified in 1993 in a pheochromocytoma as a hypotensive peptide [42]. It binds with three types of specific receptors (ADMR), which belong to the 7-transmembrane superfamily of G-protein-coupled receptors. One of them, the calcitonin receptor-like receptor (CRLR), is modulated by the receptor activity modifying protein (RAMP) [43]. Adrenomedullin is released by pancreatic cancer cells in
Body weight loss is another symptom frequently accompanying new-onset diabetes associated with SPC. It usually starts shortly after the onset of diabetes, precedes the development of other symptoms, and progresses up to the diagnosis of SPC. Weight loss varies extensively among individual patients with an average loss of between 4 and 5 kg. Weight loss may have a similar paraneoplastic origin as T3cDM. The adrenomedullin-containing exosomes secreted from pancreatic cancer cells interact with adipose cells and are internalized by endocytosis. Adrenomedullin via its receptors activates p38 and ERK1/2 MAPKs and promotes lipolysis through phosphorylation of hormone sensitive lipase [45]; thus, the loss of subcutaneous fat observed in SPC may be a paraneoplastic symptom mediated by exosomal adrenomedullin. Exosome induced β-cell dysfunction and lipolysis could be inhibited by adrenomedullin receptor blockade [30, 45], which underscores the role of adrenomedullin in the development of new-onset diabetes and weight loss in SPC. Nevertheless, exosomes are involved in several other aspects of cancer development including angiogenesis, stromal remodeling, chemo-resistance, and genetic intercellular exchange [46]. Cancer-derived exosomes can also enter muscle cells and inhibit insulin and PI3K/Akt signaling, leading to impaired GLUT 4 trafficking [47]. This effect leading to skeletal muscle insulin resistance may be mediated by microRNAs carried by exosomes [47]. This interaction between pancreatic cancer cells and normal cells represents another example of a “metabolic crosstalk” in malignant tumors [47]. In additional to the peripheral insulin resistance expressed in skeletal muscles, impaired insulin action has been found in the liver where similar pathogenic mechanisms may be present [32].
4.1.2. Dipeptidyl peptidase 4 and fibroblast activation protein alpha
The membrane-bound proteases dipeptidyl peptidase 4 (DPP4, EC 3.4.14.5, CD26) and fibroblast activation protein alpha (FAP alpha, EC 3.4.21.B28, seprase) may represent other factors contributing to impaired glucoregulation in SPC [48]. DPP4 is a membrane glycoprotein expressed on the surface of many cell types including endothelial and epithelial cells, fibroblasts, and activated lymphocytes. Its soluble form is also present in the serum and other body fluids. FAP alpha is a close structural homolog of DPP4 with 52% amino acid sequence identity. Under physiological conditions, the expression of FAP alpha is restricted to alpha cells of pancreatic islets and stromal cells in the uterus. During carcinogenesis, FAP alpha is upregulated in the stromal fibroblasts of various malignancies [49]. FAP alpha positive fibroblasts have been found in primary and secondary cancerous lesions, whereas benign epithelial lesions rarely contain FAP alpha positive stromal cells.
DPP4 and FAP alpha are multifunctional proteins that exhibit both enzyme activity dependent and enzyme activity independent biological functions. The catalytic activity of DPP4 and FAP alpha cleaves off the N-terminal dipeptide from peptides and proteins containing proline or alanine in the penultimate position. In addition, FAP alpha also possesses endopeptidase enzymatic activity, with the potential to cleave among others FGF21 [49]. A number of DPP4 and FAP alpha substrates are related to the regulation of glucose metabolism and energy homeostasis (Table 1). The proteolytic cleavage significantly modifies the biological activity of the targets leading to inactivation, modified receptor preference, or increased susceptibility to cleavage by other proteases [50].
Biopeptide | Main physiological functions | References |
---|---|---|
GIP* | Stimulation of insulin and glucagon secretion | [78] |
GLP-1* | Stimulation of glucose-stimulated insulin secretion, inhibition of glucagon secretion | [78] |
PYY*,** NPY*,** |
Regulation of food intake, adipogenesis, energy homeostasis, glucose-stimulated insulin secretion, lipolysis and blood pressure. Involved in stress reaction and pain perception | [78, 79, 80, 81] |
Glucagon* | Increase of glycemia and ketogenesis | [79, 82, 83] |
FGF21*,** | Stimulation of glucose uptake in adipocytes, increase of energy expenditure | [84, 85, 86] |
VIP*, PACAP* | Regulation of insulin and glucagon secretion, regulation of body weight, energy and lipid metabolism. Gastrointestinal motility. Immunomodulation | [87, 88] |
The role of DPP4 and FAP alpha has been studied in the context of various malignancies, including pancreatic cancer. Expression of both proteases is increased in SPC tissues and SPC patients with recent onset diabetes or prediabetes have increased plasma DPP4 enzymatic activity [51]. Increased expression and activity of these proteases may thus lead to decreased bioavailability of their substrates and thus contribute to impaired glucose homeostasis in SPC.
In summary, pancreatic cancer cells dysregulate the production of various substances with hormonal or enzymatic activities, which lead to impaired functioning of both the endocrine pancreas and other organs. New-onset T3cDM is therefore a consequence of impaired glucose homeostasis caused by the cancer cells.
5. Diagnosis of T3cDM
Early diagnosis of impaired glucose homeostasis is the first important step in the proper diagnosis of T3cDM associated with SPC. At this stage, the patient is usually without any clinical symptoms and a small decrease in body weight is frequently overlooked or considered unrelated. Determination of blood glucose every 2 years in patients over 50 years is highly recommended as a part of regular preventive examinations by general practitioners. A finding of impaired fasting glucose (IFG) or increased random blood glucose should initiate the next level of examination (i.e., oral glucose tolerance test or HbA1c), which can confirm a diagnosis of prediabetes or diabetes.
The main task for physicians is to distinguish T3c diabetes from the more common Type 2 or Type 1 diabetes, since in general practice only the latter two types are usually considered without any suspicion of T3c. Several indicators can be used for a better evaluation. Firstly, changes in body weight differ in subjects with T2DM vs. T3cDM after the appearance of diabetes. A decrease in body weight at the diagnosis of prediabetes or diabetes is significantly more frequent in patients with T3cDM than with T2DM, likely due to the tumor induced loss of subcutaneous fat tissue [45]. In SPC, the decrease in body weight usually precedes other systemic and local symptoms. T2DM frequently begins with increased body weight associated with insulin resistance and hyperinsulinemia and BMI is often higher compared to T3cDM [8]. A family history of diabetes is common in T2DM but not in T3cDM associated with SPC. The absence of markers of autoimmune disease may help exclude Type 1 diabetes. Therefore, an association of newly diagnosed prediabetes or diabetes with progressive weight loss should lead to the suspicion of T3cDM. Basic laboratory and clinical data that differentiates T2DM and T3cDM are presented in Table 2.
Indicator | Type 2 DM | Type 3c DM |
---|---|---|
Body weight | Increase | Decrease |
Family history of DM | Positive | Frequently negative |
Fasting plasma concentration | ||
Insulin | High or normal | Low or normal |
PP | High or normal | Low or normal |
GIP | Normal | Low or normal |
Poststimulation levels | ||
Insulin | High or normal | Low |
PP | High or normal | Low |
GIP | Normal | Low |
The plasma pancreatic polypeptide (PP) concentration in the fasting state and after meal-stimulation may also help discriminate between T2DM and T3cDM [8, 52]. The test is based on increased PP secretion after 30 min of nutritional stimulation in healthy controls and T2DM patients (usually by more than 100% of the baseline value); this increase is missing in T3cDM patients. The discriminative value of this test was found to be higher in cancer of the pancreatic head than in the other regions of the gland [53], since PP-cells are predominantly located within the head of the pancreas.
6. Diagnosis of sporadic pancreatic cancer
Failure to diagnose SPC at an early stage is the main impediment to improving the prognosis of patients with this malignant disease. Currently, more than 80% of cases are diagnosed in advanced stages (T3 and T4), which generally excludes radical surgery, the only possibly curative treatment. The prerequisite for early diagnosis of SPC is the timely use of high-resolution imaging methods (HRIMs), which will lead to the identification of patients with early stage, effectively curable disease. The specificity and sensitivity of the classical tumor biomarkers currently used in the clinical practice is low. Therefore, novel biomarkers are critically needed to identify patients in whom HRIMs should be used. Recently, we have proposed a structured diagnostic strategy for individuals with newly diagnosed diabetes, who represent a significant risk group for SPC, involving primary care physicians (both general practitioners and diabetologists) [2].
6.1. Biomarkers
T3cDM with weight loss are alarming signs of a paraneoplastic origin and patients presenting with these signs require further examination. Recent reviews have summarized the present knowledge of biomarkers for the diagnosis of SPC [54, 55, 56]. A widely used biomarker,
Another area of investigation provides new data from
T3cDM caused by pancreatic cancer is characterized by
It appears that an early diagnosis is increasingly dependent on a combination of biomarkers with sufficient sensitivity to disclose localized tumors or, better still, their precursors.
6.2. Imaging methods
Diagnosis based on visualization of the tumor and classification of its stage is necessary for clinical decisions regarding treatment and the use of high-resolution imaging methods (HRIMs) is therefore immediately recommended in patients suspected of having SPC. The results of different methods were compared using a large database [73]. Effective screening procedures for early detection of pancreatic cancer were described by Hanada et al. [74, 75]. A review of the advances in various imaging methods, as well as their proper selection is beyond the scope of this review.
7. Risk groups of diabetic patients suggested for screening of sporadic pancreatic cancer
Early diagnosis and subsequent successful treatment of SPC associated with diabetes depends on proper evaluation of the
Patients with new-onset prediabetes or diabetes:
With decreasing body weight (>2 kg) and anorexia as the only clinical symptom
With failure of introductory antidiabetic drug therapy during the first 3 months and stagnation or a decrease in body weight (>2 kg)
With persistent impairment of glucose homeostasis despite the additional of a second antidiabetic drug during the next 3 months or a decrease in body weight (>2 kg)
Patients with long-term diabetes and obesity when there is a failure of antidiabetic drug therapy that developed during the preceding 6 months combined with a decreasing body weight (>2 kg).
In patients from the first group, the new-onset diabetes and the loss of body weight may be
8. Protocol for early sporadic pancreatic cancer detection
The program of early SPC detection has three steps [2]:
A clinical suspicion of SPC in the risk groups evaluated by general practitioners (GPs) or diabetologists,
A determination of biomarkers (oncomarkers, microRNAs, etc.) and hormones (GIP, PP, GLP-1) after nutritional stimulation as prescribed by a gastroenterologist,
An endoscopic examination of the patient and use of high-resolution imaging methods (HRIMs) as prescribed by an endoscopist/radiologist in collaboration with a pathologist.
A multidisciplinary team approach should improve the prognosis of this malignant disease. The early symptoms (new-onset T3cDM and weight loss), the effect of the initial antidiabetic drug therapy, as well as the failure of antidiabetic therapy in long-term diabetes control, with newly developing weight loss, should be properly evaluated by a GP or a diabetologist.
We suggested an algorithm for the examination of patients with new-onset diabetes (Figure 1) [2]. Regular screening of blood glucose in the general population above 50 years of age may disclose abnormalities in glucose homeostasis. Additionally, the evaluation of body weight and any changes during the months prior to the visit is critical. A decrease in body weight > 2 kg in a patient with newly confirmed prediabetes or diabetes should arouse suspicion of its paraneoplastic origin. In this case, a gastroenterologist should be consulted.
A patient with new-onset diabetes should be treated with the first line antidiabetic drug according to the guidelines for Type 2 diabetes. If the diabetes control is not satisfactory during the first 3 months and body weight remains stable or increases, then a second antidiabetic drug should be added. An inadequate response to intensified treatment or unintentional weight loss should lead to a suspicion of T3cDM. In this situation, the collaboration with a gastroenterologist, preferably in a tertiary center, is necessary. The patient should be tested for PP and GIP secretion after nutritional stimulation. A response by PP and GIP that is diminished or absent confirms the pancreatogenic origin of the diabetes (T3cDM). A gastroenterologist should arrange the next steps involving an endoscopic examination and HRIMs.
A patient with long-term diabetes with failing antidiabetic drug treatment combined with decreasing body weight should be included in the same multistep screening program as described for T3cDM patients.
9. Conclusion
The association of SPC with diabetes mellitus offers an opportunity for early detection of this malignant disease. While long-term Type 2 diabetes is an important risk factor of SPC, new-onset T3cDM represents an early symptom as well as a pathogenetic feature of SPC. Thus, proper assessment of new-onset diabetes with a focus on the analysis of early symptoms, that is, failure of antidiabetic drug treatment including unstable diabetes requiring insulin administration, represents a promising step in shifting the diagnosis of SPC to an earlier stage. New biomarkers and high-resolution imaging methods may help discriminate between different pathologies with better accuracy, including identification of the earlier stages of pancreatic cancer. A multistep and multidisciplinary preventive program based on collaboration between GPs, diabetologists and gastroenterologists offers an opportunity for timely SPC diagnosis. This approach may improve the prognosis for these patients.
Acknowledgments
This manuscript was supported by the Research Project of Charles University, PROGRES Q25 and Q28.
Conflict of interest
The authors have no conflict of interest.
References
- 1.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: a Cancer Journal for Clinicians. 2016; 66 :7-30. DOI: 10.3322/caac.21387 - 2.
Frič P, Šedo A, Škrha J, Bušek P, Laclav M, Škrha P, Zavoral M. Early detection of sporadic pancreatic cancer: Time for change. European Journal of Gastroenterology & Hepatology. 2017; 29 :885-891. DOI: 10.1097/MEG.0000000000000904 - 3.
Pittman ME, Rao R, Hruban RH. Classification, morphology, molecular pathogenesis, and outcome of premalignant lesions of the pancreas. Archives of Pathology & Laboratory Medicine. 2017; 141 :1606-1614. DOI: 10.5858/arpa.2016-0426-RA - 4.
Frič P, Škrha J, Šedo A, Bušek P, Laclav M, Bunganič B, Zavoral M. Precursors of pancreatic cancer. European Journal of Gastroenterology & Hepatology. 2017; 29 :E13-E18. DOI: 10.1097/MEG.0000000000000810 - 5.
Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu BJ, Kamiyama M, Hruban RH, Eshleman JR, Nowak MA, Velculescu VE, Kinzler KW, Vogelstein B, Iacobuzio-Donahue CA. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010; 467 :1114-1117. DOI: 10.1038/nature09515 - 6.
Tan JX, You Y, Guo F, Xu JH, Dai HS, Bie P. Association of elevated risk of pancreatic cancer in diabetic patients: A systematic review and meta-analysis. Oncology Letters. 2017; 13 :1247-1255. DOI: 10.3892/ol.2017.5586 - 7.
Salvatore T, Marfella R, Rizzo MR, Sasso FC. Pancreatic cancer and diabetes: A two-way relationship in the perspective of diabetologist. International Journal of Surgery. 2015; 21 :S72-S77. DOI: 10.1016/j.ijsu.2015.06.063 - 8.
Andersen DK, Korc M, Petersen GM, Eibl G, Li D, Rickels MR, Chari ST, Abbruzzess JL. Diabetes, Pancreatogenic diabetes, and pancreatic Cancer. Diabetes. 2017; 66 :1103-1110. DOI: 10.2337/db16-1477 - 9.
Stevens RJ, Roddam AW, Beral W. Pancreatic cancer in type 1 and young-onset diabetes. British Journal of Cancer. 2007; 96 :507-509. DOI: 10.1038/sj.bjc.6603571 - 10.
Huxley R, Ansary-Moghaddam A, de Gonzalez AB, Barzi F, Woodward M. Type II-diabetes and pancreatic cancer: A meta-analysis of 36 studies. British Journal of Cancer. 2005; 92 :2076-2083. DOI: 10.1038/sj.bjc.6602619 - 11.
Han L, Ma Q, Li J, Liu H, Li W, Ma GD, Xu QH, Zhou S, Wu EX. High glucose promotes pancreatic cancer cell proliferation via the induction of EGF expression and transactivation of EGFR. PLoS One. 2011; 6 :e27074. DOI: 10.1371/journal.pone.0027074 - 12.
Kang R, Loux T, Tang D, Schapiro NE, Vernon P, Livesey KM, Krasinskas A, Lotze MT, Zeh HJ. The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia. Proceedings of the National Academy of Sciences of the United States of America. 2012; 109 :7031-7036. DOI: 10.1073/pnas.1113865109 - 13.
Arumugam T, Ramachandran V, Gomez SB, Schmidt AM, Logsdon CD. S100P-derived RAGE antagonistic peptide reduces tumor growth and metastasis. Clinical Cancer Research. 2012; 18 :4356-4364. DOI: 10.1158/1078-0432.CCR-12-0221 - 14.
Rozengurt E. Mechanistic target of rapamycin (mTOR): A point of convergence in the action of insulin/IGF-1 and G protein-coupled receptor agonists in pancreatic cancer cells. Frontiers in Physiology. 2014; 5 :Art.357. DOI: 10.3389/fphys.2014.00357 - 15.
Vucenik I, Stains JP. Obesity and cancer risk: Incidence, mechanisms, recommendations. Annals of the New York Academy of Sciences. 2012; 1271 :37-43. DOI: 10.1111/j.1749-6632.2012.06750.x - 16.
Chen J. Multiple signal pathways in obesity-associated cancer. Obesity Reviews. 2011; 12 :1063-1070. DOI: 10.1111/j.1467-789X.2011.00917.x - 17.
Dalamaga M, Diakopoulos KN, Mantzoros CS. The role of adiponectin in cancer: A review of current evidence. Endocrine Reviews. 2012; 33 :547-594. DOI: 10.1210/er.2011-1015 - 18.
Azizan N, Suter MA, Liu Y, Logsdon CD. RAGE maintains high levels of NF kappa B and oncogenic Kras activity in pancreatic cancer. Biochemical and Biophysical Research Communications. 2017; 493 :592-597. DOI: 10.1016/j.bbrc.2017.08.147 - 19.
Andersen DK. The practical importance of recognizing pancreatogenic or type 3c diabetes. Diabetes/Metabolism Research and Reviews. 2012; 28 :326-328. DOI: 10.1002/dmrr.2285 - 20.
Chari ST, Leibson CL, Rabe KG, Timmons LJ, Ransom J, De Andreade M, Petersen GM.Pancreatic cancer-associated diabetes mellitus: Prevalence and temporal association with diagnosis of cancer. Gastroenterology. 2008; 134 :95-101. DOI: 10.1053/j.gastro.2007.10.040 - 21.
Sah RP, Nagpal SJ, Mukhopadhyay D, Chari ST. New insights into pancreatic cancer-induced paraneoplastic diabetes. Nature Reviews. Gastroenterology & Hepatology. 2013; 10 :423-433. DOI: 10.1038/nrgastro.2013.49 - 22.
Ben Q, Xu M, Ning X, Liu J, Hong SY, Huang W, Zhang HG, Li ZS. Diabetes mellitus and risk of pancreatic cancer: A meta-analysis of cohort studies. European Journal of Cancer. 2011; 47 :1928-1937. DOI: 10.1016/j.ejca.2011.03.003 - 23.
Permert J, Ihse I, Jorfeldt L, Arnquist HJ, Larsson J. Improved glucose metabolism after subtotal pancreatectomy for pancreatic cancer. The British Journal of Surgery. 1993; 80 :1047-1050. DOI: 10.1002/bjs.1800800841 - 24.
Wu JM, Kuo TC, Yang CY, Chiang PY, Jeng YM, Huang PH, Tien YW. Resolution of diabetes after pancreaticoduodenectomy in patients with and without pancreatic ductal cell adenocarcinoma. Annals of Surgical Oncology. 2013; 20 :242-249. DOI: 10.1245/s10434-012-2577-y - 25.
Rickels MR, Bellin M, Toledo FGS, Robertson RP, Andersen DK, Chari ST, Brand R, Frulloni L, Anderson MA, Whitcomb DC, PancreasFest Recommendation Conference Participants. Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: Recommendations from PancreasFest 2012. Pancreatology. 2013; 13 :336-342. DOI: 10.1016/j.pan.2013.05.002 - 26.
Ewald N, Kaufmann C, Raspe A, Kloer HU, Bretzel RG, Hardt PD. Prevalence of diabetes mellitus secondary to pancreatic diseases (type 3c). Diabetes/Metabolism Research and Reviews. 2012; 28 :338-342. DOI: 10.1002/dmrr.2260 - 27.
Magruder JT, Elahi D, Andersen DK. Diabetes and pancreatic cancer: Chicken or egg? Pancreas. 2011; 40 :339-351. DOI: 10.1097/MPA.0b013e318209e05d - 28.
Pelaez-Luna M, Takahashi N, Fletscher JG, Chari ST. Resectability of presymptomatic pancreatic cancer and its relationship to onset of diabetes: A retrospective review of CT scans and fasting glucose values prior to diagnosis. The American Journal of Gastroenterology. 2007; 102 :2157-2163. DOI: 10.1111/j.1572-0241.2007.01480.x - 29.
Aggarwal G, Kamada P, Chari ST. Prevalence of diabetes mellitus in pancreatic cancer compared to common cancers. Pancreas. 2013; 42 :198-201. DOI: 10.1097/MPA.0b013e3182592c96 - 30.
Javeed N, Sagar G, Dutta SK, Smyrk TC, Lau JS, Bhattacharya S, Truty M, Petersen GM, Kaufman RJ, Chari ST, Mukhopadhyay D. Pancreatic cancer-derived exosomes cause paraneoplastic β-cell dysfunction. Clinical Cancer Research. 2015; 21 :1722-1733. DOI: 10.1158/1078-0432.CCR-15-1524 - 31.
Wang F, Larsson J, Adrian TE, Gasslander T, Permert J. InVitro influences between pancreatic carcinoma cells and pancreatic islets. The Journal of Surgical Research. 1998;79 :13-19. DOI: 10.1006/jsre.1998.5393 - 32.
Cui YF, Andersen DK. Diabetes and pancreatic cancer. Endocrine-Related Cancer. 2012; 19 :F9-F26. DOI: 10.1530/ERC-12-0105 - 33.
Tan L, Ye X, Zhou Y, Yu M, Fu Z, Chen R, Zhuang B, Zeng B, Ye H, Gao W, Lin Q, Li Z, Zhou Q, Chen R. Macrophage migration inhibitory factor is overexpressed in pancreatic cancer tissues and impairs insulin secretion functionof β-cell. Journal of Translational Medicine. 2014; 12 :art.92. DOI: 10.1186/1479-5876-12-92 - 34.
Martinez A, Weaver C, Lopez J, Bhathena SJ, Elsasser TH, Miller MJ, Moody TW, Unsworth EJ, Cuttitta F. Regulation of insulin secretion and blood glucose metabolism by adrenomedullin. Endocrinology. 1996; 137 :2626-2632. DOI: 10.1210/en.137.6.2626 - 35.
Sekine N, Takano K, Kimata-Hayashi N, Kadowaki T, Fujita T. Adrenomedullin inhibits insulinexocytosis via pertussis toxin-sensitive G protein-coupled mechanism. American Journal of Physiology. Endocrinology and Metabolism. 2006; 291 :E9-E14. DOI: 10.1152/ajpendo.00213.2005 - 36.
Chari ST, Zapiach M, Yadav D, Rizza R. Beta-cell function and insulin resistence evaluated by HOMA in pancreatic cancer subjects with varying decrease of glucose intolerance. Pancreatology. 2005; 5 :229-233. DOI: 10.1159/000085276 - 37.
Permert J, Adrian TE, Jacobsson P, Jorfelt L, Fruin B, Larsson J. Is profound insulin resistance in patients with pancreatic cancer caused by a tumor-associated factor? American Journal of Surgery. 1993; 165 :61-67. DOI: 10.1016/S0002-9610(05)80405-2 - 38.
Liu J, Knezetic JA, Strőmmer L, Permert J, Larsson J, Adrian TE. The intracellular mechanism of insulin resistance in pancreatic cancer patients. The Journal of Clinical Endocrinology and Metabolism. 2000; 85 :1232-1238. DOI: 10.1210/jc.85.3.1232 - 39.
Agustsson T, MA D’s, Nowak G, Isaksson B. Mechanisms for skeletal muscle insulin resistance in patients with pancreatic ductal adenocarcinoma. Nutrition. 2011; 27 :796-801. DOI: 10.1016/j.nut.2010.08.022 - 40.
Cui Y, Andersen DK. Pancreatogenic diabetes: Special considerations for management. Pancreatology. 2011; 11 :279-294 - 41.
Rabiee A, Galiatsatos P, Salas-Carrillo R. Pancreatic polypeptide infusion increases insulin sensitivity and reduces insulin requirement of patients on insulin pump therapy. Journal of Diabetes Science and Technology. 2011; 5 :1521-1528 - 42.
Ishimitsu T, Nishikimi T, Saito Y, Kitamura K, Eto T, Kangawa K, Matsuo H, Omae T, Matsuoka H. Plasma levels of adrenomedullin, a newly identified hypotensive peptide, in patients with hypertension and renal failure. The Journal of Clinical Investigation. 1994; 94 :2158-2161. DOI: 10.1172/JCI117573 - 43.
Smith DM, Coppock HA, Withers DJ, Owji AA, Hay DL, Choksi TP, Chakravarty P, Legon S, Poyner DR. Adrenomedullin : Receptor and signal transduction. Biochemical Society Transactions. 2002; 30 :432-437. DOI: 10.1042/bst0300432 - 44.
Korc M. Pancreatic cancer-associated diabetes is an “Exosomopathy”. Clinical Cancer Research. 2015; 21 :1508-1510. DOI: 10.1158/1078-0432.CCR-14-2990 - 45.
Sagar G, Sah RP, Javeed N, Dutta SK, Smyrk TC, Lau JS, Giorgadze N, Tchkonia T, Kirkland J, Chari ST, Mukhopadhyay D. Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue. Gut. 2016; 65 :1165-1174. DOI: 10.1136/gutjnl-2014-308350 - 46.
Taylor DD, Gercel-Taylor C. Exosomes/microvesicles: Mediators of cancer-associated immunosuppresive microenvironments. Seminars in Immunopathology. 2011; 33 :441-454. DOI: 10.1007/s00281-010-0234-8 - 47.
Wang L, Zhang B, Zheng W, Kang M, Chen Q, Qin W, Lin C, Zhang Y, Shao Y, Wu Y. Exosomes derived from pancreatic cancer cells induce insulin resistance in C2C12 myotube cells through the PI3K/ASkt/FoxO1 pathway. Scientific Reports. 2017; 7 :Art 5384 - 48.
Frič P, Zavoral M. Early diagnosis of pancreatic adenocarcinoma: Role of stroma, surface proteases, and glucose-homeostatic agents. Pancreas. 2012; 41 :663-670. DOI: 10.1097/MPA.0b013e31823b5827 - 49.
Bušek P, Mateu R, Zubal M, Kotačková L, Šedo A. Targeting fibroblast activation protein in cancer; prospects and caveats. Frontiers in Bioscience. 2018; accepted - 50.
Bušek P, Malik R, Šedo A. Dipeptidyl peptidase IV activity and/or structure homologues (DASH) and their substrates in cancer. The International Journal of Biochemistry & Cell Biology. 2004; 36 :408-421. DOI: 10.1016/S1357-2725(03)00262-0 - 51.
Bušek P, Vaníčková Z, Hrabal P, Brabec M, Frič P, Zavoral M, Škrha J, Kmochová K, Laclav M, Bunganič B, Augustyns A, Van der Veken P, Šedo A. Increased tissue and circulating levels of dipeptidyl-peptidase-IV enzymatic activity in patients with pancreatic ductal adenocarcinoma. Pancreatology. 2016; 16 :829-838. DOI: 10.1016/j.pan.2016.06.001 - 52.
Al-Modaris FI, Taylor IC, McConnell JG, Power MJP, Armstrong E, Buchanan KD. Pancreatic polypeptide and exocrine pancreatic function in the elderly. The Ulster Medical Journal. 1993; 62 :44-49 - 53.
Hart PA, Baichoo E, Bi Y, Hinton A, Kudva YC, Chari ST. Pancreatic polypeptide response to a mixed meal in blunted in pancreatic head cancer associated with diabetes mellitus. Pancreatology. 2015; 15 :162-166. DOI: 10.1016/j.pan.2015.02.006 - 54.
Zhou B, Xu JW, Cheng YG, Gao JY, Hu SY, Wang L, Zhan HX. Early detection of pancreatic cancer: Where are we now and where are we going? International Journal of Cancer. 2017; 141 :231-241. DOI: 10.1002/ijc.30670 - 55.
Gallego J, Lópéz C, Pazo-Cid R, López-Ríos F, Carrato A. Biomarkers in pancreatic ductal adenocarcinoma. Clinical & Translational Oncology. 2017; 19 (12):1430-1437. DOI: 10.1007/s12094-017-1691-5 - 56.
Frič P, Škrha J, Šedo A, Zima T, Bušek P, Kmochová K, Laclav M, Bunganič B, Solař S, Hrabal P, Bělina F, Záruba P, Škrha P, Zavoral M. Early detection of pancreatic cancer: Impact of high-resolution imaging methods and biomarkers. European Journal of Gastroenterology & Hepatology. 2016; 28 :e33-e43. DOI: 10.1097/MEG.0000000000000727 - 57.
Goonetilleke KS, Siriwardena AK. Systematic review of carbohydrate antigen (CA 19-9) as a biochemical marker in the diagnosis of pancreatic cancer. European Journal of Surgical Oncology. 2007; 33 :266-270. DOI: 10.1016/j.ejso.2006.10.004 - 58.
Jawad ZAR, Theodorou IG, Jiao LR, Xie F. Highly sensitive plasmonic detection of the pancreatic cancer biomarker CA 19-9. Scientific Reports. 2017; 7 :Art.14309. DOI: 10.1038/s41598-017-14688-z - 59.
Balasenthil S, Huang Y, Liu S, Marsh T, Chen J, Stass SA, KuKuruga D, Brand R, Chen N, Frazier ML, Lee JJ, Srivastava S, Sen S, McNeill Killary A. A Plasma biomarker panel to identify surgically resectable early-stage pancreatic cancer. Journal of the National Cancer Institute. 2017; 109 :djw341. DOI: 10.1093/jnci/djw341 - 60.
Banaei N, Foley A, Houghton JM, Sun Y, Kim B. Multiplex detection of pancreatic cancer biomarkers using a SERS-based immunoassay. Nanotechnology. 2017; 28 :455101. DOI: 10.1088/1361-6528/aa8e8c - 61.
Huang J, Liu J, Chen-Xiao K, Zhang X, Lee WNP, Liang V, Go W, Xiao GG. Advance in microRNA as a potential biomarker for early detection of pancreatic cancer. Biomarker Research. 2016; 4 :20. DOI: 10.1186/s40364-016-0074-3 - 62.
Yuan W, Tang W, Xie Y, Wang S, Chen Y, Qi J, Qiao Y, Ma J. New combined microRNA and protein plasmatic biomarker panel for pancreatic cancer. Oncotarget. 2016; 7 :80033-80045. DOI: 10.18632/oncotarget.12406 - 63.
Dai X, Pang WJ, Zhou YF, Yao WY, Xia L, Wang C, Chen X, Zen K, Zhang CY, Yuan YZ. Altered profile of serum microRNAs in pancreatic cancer-associated new-onset diabetes mellitus. Journal of Diabetes. 2016; 8 :422-433 - 64.
Škrha P, Hořínek A, Pazourková E, Hajer J, Frič P, Škrha J, Anděl M. Serum microRNA-196 and microRNA-200 in pancreatic ductal adenocarcinoma of patients with diabetes mellitus. Pancreatology. 2016; 16 :839-843. DOI: 10.1016/j.pan.2016.05.005 - 65.
Giulietti M, Occhipinti G, Principato G, Piva F. Identification of candidate miRNA biomarkers for pancreatic ductal adenocarcinoma by weighted gene co-expression network analysis. Cellular Oncology. 2017; 40 :181-192. DOI: 10.1007/s13402-017-0315-y - 66.
Franklin O, Jonsson P, Billing O, Lundberg E, Őhlund D, Nystrőm H, Lundin C, Antti H, Sund M. Plasma micro-RNA alterations appear late in pancreatic cancer. Annals of Surgery. 2017;Jan 3. DOI: 10.1097/SLA0000000000002124 - 67.
He X, Zhong J, Wang S, Zhou Y, Wang L, Zhang Y, Yuan Y. Serum metabolomics differentiating pancreatic cancer from new-onset diabetes. Oncotarget. 2017; 8 :29116-29124. DOI: 10.18632/oncotarget.16249 - 68.
DiGangi IM, Mazza T, Fontana A, Copetti M, Fusilli C, Ippolito A, Mattivi F, Latiano A, Adriulli A, Vrhovsek U, Pazienza V. Metabolomic profile in pancreatic cancer patients: A consensus-based approach to identify highly discriminating metabolites. Oncotarget. 2016; 7 :5815-5829 - 69.
Mirzaei H, Sahebkar A, Jaafari MR, Goodarzi M, Mirzaei MR. Diagnostic and therapeutic potential of exosomes in cancer: The beginning of a new tale? Journal of Cellular Physiology. 2017; 232 :3251-3260. DOI: 10.1002/jcp.25739 - 70.
Jin H, Wu Y, Tan X. The role of pancreatic cancer-derived exosomes in cancer progress and their potential application as biomarkers. Clinical & Translational Oncology. 2017; 19 :921-930. DOI: 10.1007/s12094-017-1625-2 - 71.
Xu YF, Hannafon BN, Zhao YD, Postier RG, Ding WQ. Plasma exosome miR-196a and miR-1246 are potential indicators of localized pancreatic cancer. Oncotarget. 2017; 8 :77028-77040. DOI: 10.18632/oncotarget.20332 - 72.
Nuzhat Z, Palma C, Rice GE, Joshi V, Salomon C. Exosomes in pancreatic juice as valuable source of biomarkers for early diagnosis of pancreatic cancer. Translational Cancer Research. 2017; 6 (Suppl 8):S1339-S1351. DOI: 10.21037/tcr.2017.10.21 - 73.
Tamburrino D, Riviere D, Yaghoobi M, Davidson BR, Gurusamy KS. Diagnostic accuracy of different imaging modalities following computed tomography (CT) scanning for assessing the resectability with curative intent in pancreatic and periampullary cancer. Cochrane Database of Systematic Reviews. 2016;(9: Art. No.: CD011515). DOI: 10.1002/14651858.CD011515.pub2 - 74.
Hanada K, Okazaki A, Hirano N, Izumi Y, Teraoka Y, Ikemoto J, Kanemitsu K, Hino F, Fukuda T, Yonehara S. Diagnostic strategies for early pancreatic cancer. Journal of Gastroenterology. 2015; 50 :147-154. DOI: 10.1007/s00535-014-1026-z - 75.
Hanada K, Okazaki A, Hirano N, Izumi Y, Minami T, Ikemoto J, Kanemitsu K, Hino F. Effective screening for early diagnosis of pancreatic cancer. Best Practice & Research. Clinical Gastroenterology. 2015; 29 :929-939. DOI: 10.1016/j.bpg.2015.09.017 - 76.
Frič P, Škrha J, Šedo A, Bušek P, Kmochova K, Laclav M, Solař S, Bunganič B, Zavoral M. Early pancreatic carcinogenesis – Risk factors, early symptoms, and the impact of antidiabetic drugs. European Journal of Gastroenterology & Hepatology. 2016; 28 :E19-E25. DOI: 10.1097/MEG.0000000000000646 - 77.
Sadr-Azodi O, Gudbjőrnsdottir S, Ljung R. Pattern of increasing HbA1c levels in patients with diabetes mellitus before clinical detection of pancreatic cancer – A population-based nationwide case-control study. Acta Oncologica. 2015; 54 :986-992. DOI: 10.3109/0284186X.2015.1006402 - 78.
Lambeir AM, Durinx C, Scharpe S, De Meester I. Dipeptidyl-peptidase IV from bench to bedside: An update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Critical Reviews in Clinical Laboratory Sciences. 2003; 40 :209-294. DOI: 10.1080/713609354 - 79.
Keane FM, Nadvi NA, Yao TW, Gorrell MD, Neuropeptide Y. B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-alpha. The FEBS Journal. 2011; 278 :1316-1332. DOI: 10.1111/j.1742-4658.2011.08051.x - 80.
Manning S, Batterham RL. The role of gut hormone peptide YY in energy and glucose homeostasis: Twelve years on. Annual Review of Physiology. 2014; 76 :585-608. DOI: 10.1146/annurev-physiol-021113-170404 - 81.
Loh K, Herzog H, Shi YC. Regulation of energy homeostasis by the NPY system. Trends in Endocrinology and Metabolism. 2015; 26 :125-135. DOI: 10.1016/j.tem.2015.01.003 - 82.
Hinke SA, Pospisilik JA, Demuth HU, Mannhart S, Kuhn-Wache K, Hoffmann T, Nishimura T, Pederson RA, McIntosh CH. Dipeptidyl peptidase IV (DPIV/CD26) degradation of glucagon. Characterization of glucagon degradation products and DPIV-resistant analogs. The Journal of Biological Chemistry. 2000; 275 :3827-3834. DOI: 10.1074/jbc.275.6.3827 - 83.
Pospisilik JA, Hinke SA, Pederson RA, Hoffmann T, Rosche F, Schlenzig D, Glund K, Heiser U, McIntosh CH, Demuth H. Metabolism of glucagon by dipeptidyl peptidase IV (CD26). Regulatory Peptides. 2001; 96 :133-141. DOI: 10.1016/S0167-0115(00)00170-1 - 84.
Zhen EY, Jin Z, Ackermann BL, Thomas MK, Gutierrez JA. Circulating FGF21 proteolytic processing mediated by fibroblast activation protein. The Biochemical Journal. 2016; 473 :605-614. DOI: 10.1042/BJ20151085 - 85.
Dunshee DR, Bainbridge TW, Kljavin NM, Zavala-Solorio J, Schroeder AC, Chan R, Corpuz R, Wong M, Zhou W, Deshmukh G, Ly J, Sutherlin DP, Ernst JA, Sonoda J. Fibroblast activation protein cleaves and inactivates fibroblast growth factor 21. The Journal of Biological Chemistry. 2016; 291 :5986-5996. DOI: 10.1074/jbc.M115.710582 - 86.
Coppage AL, Heard KR, DiMare MT, Liu Y, Wu W, Lai JH, Bachovchin WW. Human FGF-21 is a substrate of fibroblast activation protein. PLoS One. 2016; 11 :e0151269. DOI: 10.1371/journal.pone.0151269 - 87.
Winzell MS, Ahren B. Role of VIP and PACAP in islet function. Peptides. 2007; 28 :1805-1813. DOI: 10.1016/j.peptides.2007.04.024 - 88.
Moody TW, Ito T, Osefo N, Jensen RT. VIP and PACAP: Recent insights into their functions/roles in physiology and disease from molecular and genetic studies. Current Opinion in Endocrinology, Diabetes, and Obesity. 2011; 18 :61-67. DOI: 10.1097/MED.0b013e328342568a