胰臟癌病人的五年存活率只有9%，且在化學藥物治療期間或切除腫瘤後常發生復發，復發病人的存活率低於沒復發的病人，並具有更高的癌症轉移率，由此可知胰臟癌是十分惡性與急迫需解決的疾病。已有研究利用帶有四環黴素控制的突變KrasG12D基因的胰臟癌小鼠模型並透過調控KrasG12D基因表達，來探討初級與復發型癌症中病變組織或腫瘤微環境的變化。近年來有文獻發現高果糖玉米糖漿與胰臟癌罹患風險上升有關，且會透過改變細胞代謝促進腫瘤細胞生長。然而高果糖玉米糖漿是否會造成胰臟癌復發與影響機制目前研究尚不清楚，本篇研究假設飲食中高果糖玉米糖漿會促進胰臟癌病變組織生成，進而導致惡性胰臟癌的發生。在我們的模型中發現在KrasG12D表達期間能誘導腫瘤進展，且移除KrasG12D表達後會減輕腫瘤惡性程度，接著在飲食中給予高果糖玉米糖漿用來觀察小鼠胰臟的變化。從結果可得知在胰臟中發現組織結構變化與胰臟癌前體組織生成，然而移除KrasG12D表達與高果糖玉米糖漿都無法回復腫瘤所造成的β細胞凋亡。此外在給予高果糖玉米糖漿期間發現體重下降且與肌肉萎縮有關，也許是經由高血糖症誘導的肌肉萎縮。綜合上述結果可知飲食中的精緻糖可透過胰腺導管化生作用導致胰臟癌前體組織生成，導致治療期間的胰臟惡化。

Pancreatic cancer is the most aggressive malignancy with the 5‐year survival rate only 9%, and it frequently relapses during chemotherapy. Patients with tumor recurrence are associated with lower survival rate and higher risk of metastasis. With the expression of a tetracycline-inducible KrasG12D knock-in mutation, this pancreatic cancer mouse model allows the study of primary and recurrent pancreatic cancer lesions under the influences of Kras mutation. Several studies of refined high-fructose corn syrup (HFCS) show that the composition of 34% glucose and 42% fructose, increases pancreatic cancer incidences and promotes cancer cell growth in mice. However, the mechanism between HFCS and cancer recurrence is not well-defined. We hypothesized that the HFCS promote precancerous lesions of the pancreas leading to recurrent pancreatic cancer. We verified the model on the KrasG12D induced tumor progression in the Kras-on phase and the resulting tumor ablation in the Kras-off phase, and then compared the effects of HFCS upon the mice of the Kras-off phase. Our data showed a disorganized tissue architecture and precancerous lesions in the pancreas. The Kras-off phase and HFCS treatment did not recover pancreatic cancer inducting β cell apoptosis. Decreased body weight and muscle atrophy were enriched in the HFCS treated mice. In summary, high-dose refined dietary HFCS lead to precancerous lesions of the pancreas via acinar-to-ductal metaplasia (ADM).

1.Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA Cancer J Clin 70, 7-30, doi:10.3322/caac.21590 (2020).
2.Jemal, A. et al. Cancer statistics, 2006. CA Cancer J Clin 56, 106-130, doi:10.3322/canjclin.56.2.106 (2006).
3.Klein, A. P. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol, doi:10.1038/s41575-021-00457-x (2021).
4.Mizrahi, J. D., Surana, R., Valle, J. W. & Shroff, R. T. Pancreatic cancer. Lancet 395, 2008-2020, doi:10.1016/s0140-6736(20)30974-0 (2020).
5.Rodriguez-Aznar, E., Wiesmüller, L., Sainz, B., Jr. & Hermann, P. C. EMT and Stemness-Key Players in Pancreatic Cancer Stem Cells. Cancers (Basel) 11, doi:10.3390/cancers11081136 (2019).
6.Chuvin, N. et al. Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRAS(G12D)-driven Pancreatic Tumorigenesis. Cell Mol Gastroenterol Hepatol 4, 263-282, doi:10.1016/j.jcmgh.2017.05.005 (2017).
7.Gopinathan, A., Morton, J. P., Jodrell, D. I. & Sansom, O. J. GEMMs as preclinical models for testing pancreatic cancer therapies. Dis Model Mech 8, 1185-1200, doi:10.1242/dmm.021055 (2015).
8.Hruban, R. H. et al. An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 28, 977-987, doi:10.1097/01.pas.0000126675.59108.80 (2004).
9.Pittman, M. E., Rao, R. & Hruban, R. H. Classification, Morphology, Molecular Pathogenesis, and Outcome of Premalignant Lesions of the Pancreas. Arch Pathol Lab Med 141, 1606-1614, doi:10.5858/arpa.2016-0426-RA (2017).
10.Sener, S. F., Fremgen, A., Menck, H. R. & Winchester, D. P. Pancreatic cancer: a report of treatment and survival trends for 100,313 patients diagnosed from 1985-1995, using the National Cancer Database. J Am Coll Surg 189, 1-7, doi:10.1016/s1072-7515(99)00075-7 (1999).
11.Bardeesy, N., Sharpless, N. E., DePinho, R. A. & Merlino, G. The genetics of pancreatic adenocarcinoma: a roadmap for a mouse model. Semin Cancer Biol 11, 201-218, doi:10.1006/scbi.2000.0371 (2001).
12.Jaffee, E. M., Hruban, R. H., Canto, M. & Kern, S. E. Focus on pancreas cancer. Cancer Cell 2, 25-28, doi:10.1016/s1535-6108(02)00093-4 (2002).
13.Ryan, D. P., Hong, T. S. & Bardeesy, N. Pancreatic adenocarcinoma. N Engl J Med 371, 1039-1049, doi:10.1056/NEJMra1404198 (2014).
14.Schutte, M. et al. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res 57, 3126-3130 (1997).
15.Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469-483, doi:10.1016/j.ccr.2005.04.023 (2005).
16.Ariston Gabriel, A. N. et al. Differences between KC and KPC pancreatic ductal adenocarcinoma mice models, in terms of their modeling biology and their clinical relevance. Pancreatology 20, 79-88, doi:10.1016/j.pan.2019.11.006 (2020).
17.Fischer, R. et al. Early recurrence of pancreatic cancer after resection and during adjuvant chemotherapy. Saudi J Gastroenterol 18, 118-121, doi:10.4103/1319-3767.93815 (2012).
18.Sakamoto, H. et al. The Evolutionary Origins of Recurrent Pancreatic Cancer. Cancer Discov 10, 792-805, doi:10.1158/2159-8290.Cd-19-1508 (2020).
19.Cameron, J. L., Riall, T. S., Coleman, J. & Belcher, K. A. One thousand consecutive pancreaticoduodenectomies. Ann Surg 244, 10-15, doi:10.1097/01.sla.0000217673.04165.ea (2006).
20.Hou, P. et al. Tumor Microenvironment Remodeling Enables Bypass of Oncogenic KRAS Dependency in Pancreatic Cancer. Cancer Discov 10, 1058-1077, doi:10.1158/2159-8290.Cd-19-0597 (2020).
21.Kapoor, A. et al. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell 158, 185-197, doi:10.1016/j.cell.2014.06.003 (2014).
22.Ying, H. et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656-670, doi:10.1016/j.cell.2012.01.058 (2012).
23.Collins, M. A. et al. Metastatic pancreatic cancer is dependent on oncogenic Kras in mice. PLoS One 7, e49707, doi:10.1371/journal.pone.0049707 (2012).
24.Xie, I. Y. & Gallinger, S. The genomic landscape of recurrent pancreatic cancer is modified by treatment. Nat Rev Gastroenterol Hepatol 17, 389-390, doi:10.1038/s41575-020-0321-9 (2020).
25.Moore, A. & Donahue, T. Pancreatic Cancer. Jama 322, 1426, doi:10.1001/jama.2019.14699 (2019).
26.Bray, G. A., Nielsen, S. J. & Popkin, B. M. Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr 79, 537-543, doi:10.1093/ajcn/79.4.537 (2004).
27.Chari, S. T. et al. Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology 134, 95-101, doi:10.1053/j.gastro.2007.10.040 (2008).
28.Aune, D. et al. Dietary fructose, carbohydrates, glycemic indices and pancreatic cancer risk: a systematic review and meta-analysis of cohort studies. Ann Oncol 23, 2536-2546, doi:10.1093/annonc/mds076 (2012).
29.Goncalves, M. D. et al. High-fructose corn syrup enhances intestinal tumor growth in mice. Science 363, 1345-1349, doi:10.1126/science.aat8515 (2019).
30.Sadowska, J. & Bruszkowska, M. Comparing the effects of sucrose and high-fructose corn syrup on lipid metabolism and the risk of cardiovascular disease in male rats. Acta Sci Pol Technol Aliment 16, 231-240, doi:10.17306/j.Afs.0482 (2017).
31.Softic, S., Cohen, D. E. & Kahn, C. R. Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease. Dig Dis Sci 61, 1282-1293, doi:10.1007/s10620-016-4054-0 (2016).
32.Mozaffarian, D. Dietary and Policy Priorities for Cardiovascular Disease, Diabetes, and Obesity: A Comprehensive Review. Circulation 133, 187-225, doi:10.1161/circulationaha.115.018585 (2016).
33.Martinez-Bosch, N., Vinaixa, J. & Navarro, P. Immune Evasion in Pancreatic Cancer: From Mechanisms to Therapy. Cancers (Basel) 10, doi:10.3390/cancers10010006 (2018).
34.Duan, Q. et al. High glucose promotes pancreatic cancer cells to escape from immune surveillance via AMPK-Bmi1-GATA2-MICA/B pathway. J Exp Clin Cancer Res 38, 192, doi:10.1186/s13046-019-1209-9 (2019).
35.Zhou, B. et al. Obesity and pancreatic cancer: An update of epidemiological evidence and molecular mechanisms. Pancreatology 19, 941-950, doi:10.1016/j.pan.2019.08.008 (2019).
36.Liu, H. et al. Fructose induces transketolase flux to promote pancreatic cancer growth. Cancer Res 70, 6368-6376, doi:10.1158/0008-5472.Can-09-4615 (2010).
37.Cole, J. B. & Florez, J. C. Genetics of diabetes mellitus and diabetes complications. Nat Rev Nephrol 16, 377-390, doi:10.1038/s41581-020-0278-5 (2020).
38.Cho, N. H. et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 138, 271-281, doi:10.1016/j.diabres.2018.02.023 (2018).
39.Woodmansey, C. et al. Incidence, Demographics, and Clinical Characteristics of Diabetes of the Exocrine Pancreas (Type 3c): A Retrospective Cohort Study. Diabetes Care 40, 1486-1493, doi:10.2337/dc17-0542 (2017).
40.Zhao, S. et al. Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate. Nature 579, 586-591, doi:10.1038/s41586-020-2101-7 (2020).
41.Shi, G. et al. Maintenance of acinar cell organization is critical to preventing Kras-induced acinar-ductal metaplasia. Oncogene 32, 1950-1958, doi:10.1038/onc.2012.210 (2013).
42.Vessoni, A. T., Filippi-Chiela, E. C., Lenz, G. & Batista, L. F. Z. Tumor propagating cells: drivers of tumor plasticity, heterogeneity, and recurrence. Oncogene 39, 2055-2068, doi:10.1038/s41388-019-1128-4 (2020).
43.Golson, M. L., Misfeldt, A. A., Kopsombut, U. G., Petersen, C. P. & Gannon, M. High Fat Diet Regulation of β-Cell Proliferation and β-Cell Mass. Open Endocrinol J 4, doi:10.2174/1874216501004010066 (2010).
44.Stamateris, R. E. et al. Glucose Induces Mouse β-Cell Proliferation via IRS2, MTOR, and Cyclin D2 but Not the Insulin Receptor. Diabetes 65, 981-995, doi:10.2337/db15-0529 (2016).
45.Chung, K. M. et al. Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma. Cell 181, 832-847.e818, doi:10.1016/j.cell.2020.03.062 (2020).
46.Jamal, A. M. et al. Morphogenetic plasticity of adult human pancreatic islets of Langerhans. Cell Death Differ 12, 702-712, doi:10.1038/sj.cdd.4401617 (2005).
47.Hernández-Díazcouder, A., Romero-Nava, R., Carbó, R., Sánchez-Lozada, L. G. & Sánchez-Muñoz, F. High Fructose Intake and Adipogenesis. Int J Mol Sci 20, doi:10.3390/ijms20112787 (2019).
48.Dumitru, A., Radu, B. M., Radu, M. & Cretoiu, S. M. Muscle Changes During Atrophy. Adv Exp Med Biol 1088, 73-92, doi:10.1007/978-981-13-1435-3_4 (2018).
49.Maughan, R. J. Relationship between muscle strength and muscle cross-sectional area. Implications for training. Sports Med 1, 263-269, doi:10.2165/00007256-198401040-00002 (1984).
50.King, A. J. The use of animal models in diabetes research. Br J Pharmacol 166, 877-894, doi:10.1111/j.1476-5381.2012.01911.x (2012).
51.Cohen, S., Nathan, J. A. & Goldberg, A. L. Muscle wasting in disease: molecular mechanisms and promising therapies. Nat Rev Drug Discov 14, 58-74, doi:10.1038/nrd4467 (2015).
52.De Souza, A., Irfan, K., Masud, F. & Saif, M. W. Diabetes Type 2 and Pancreatic Cancer: A History Unfolding. Jop 17, 144-148 (2016).
53.Parajuli, P. et al. Pancreatic cancer triggers diabetes through TGF-β-mediated selective depletion of islet β-cells. Life Sci Alliance 3, doi:10.26508/lsa.201900573 (2020).
54.Tomita, T. Apoptosis in pancreatic β-islet cells in Type 2 diabetes. Bosn J Basic Med Sci 16, 162-179, doi:10.17305/bjbms.2016.919 (2016).