IJCM  Vol.11 No.10 , October 2020
Manifestation of Pathological States of Numerous Diseases in the Largest Organ of the Human Body: (II) From Pancreatitis to Pancreatic Cancer Invasion, Formation of Stroma around the Primary Tumor in the Fascia, to Early Detection of Non-Coding microRNAs in Body Fluids and Development of Drugs to Treat Different Stages of Pancreatic Cancer
Abstract: Patients suffering from pancreatic ductal adenocarcinoma (PDAC) have an average survival time of 4 - 6 months after confirmed diagnosis. The primary tumor is surrounded by a thick interstitial fluid with high pressure and dense distribution of collagen, forming a huge stroma, rendering the tumor resistant to chemo- and radiotherapy. From the genetic point of view, pancreatic carcinogenesis is driven by mutations, resulting in common activation of the oncogene KRAS, and/or inactivation of one or more of the tumor suppressor genes CDKN2A, TP53, SMAD4 [1]. The pancreas is a mixed exocrine and autocrine organ, with different cell types building up the organ. The pathogenesis involves more than 13 signaling pathways at different stages. Off-balance of the function of the proteins in these pathways due to the stated 4 plus other mutations could readily lead to carcinogenesis. We first present the basic mechanism of these 13 relevant pathways. We then provide a detailed analysis of the progression of this disease, from pancreatitis to tumor formation and metastasis, with special attention on the roles played by the newly discover calcium channel Piezo, stellate cells, stem-cell-like cells, and the concept invadopodium. Thirty potential drugs, based on in vitro and xenograft experiments from different groups, are discussed, including vitamins A, Tocotrienols-E, and D, chemical compounds, non-coding micro RNAs, circular RNA, piwi-interacting RNAs. The recent detection of exosomes enclosing many of these RNAs in body fluids gives us hope of developing early detection methodology because these RNAs carry messages for cell-cell communication at a distance. Delivery of potent drugs by nanoparticles gives us chance to send drugs through the stroma to target the tumor. Since body fluids form a circulating system, together with the connective tissues (where the tumor is associated) form the largest organ—the fascia, we conclude that manifestation of successive pathological states of pancreatic carcinogenesis can be found in compartments of the fascia. We present 17 figures, hoping to ease off the complexity of the pathogenesis of this most lethal cancer disease.
Cite this paper: Fung, P. and Kong, R. (2020) Manifestation of Pathological States of Numerous Diseases in the Largest Organ of the Human Body: (II) From Pancreatitis to Pancreatic Cancer Invasion, Formation of Stroma around the Primary Tumor in the Fascia, to Early Detection of Non-Coding microRNAs in Body Fluids and Development of Drugs to Treat Different Stages of Pancreatic Cancer. International Journal of Clinical Medicine, 11, 618-718. doi: 10.4236/ijcm.2020.1110052.

[1]   Cicenas, J., Kvederaviciute, K., Meskinyte, I., Meskinte-Kausilien, E., Skeberdyte, A. and Cicenas Jr., J. (2018) KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 Mutations in Pancreatic Cancer. Cancers, 9(5), Article 42, 1-8.

[2]   Fung, P.C.W. and Kong, R.K.C. (2019) Manifestation of Pathological States of Numerous Diseases in the Largest Organ of the Human Body: (I) Basics and the Diseases of Tendon. International Journal of Clinical Medicine, 10, 183-249.

[3]   Fung, P.C.W. and Kong, R.K.C. (2017) The Heat Shock Protein Story-From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines. Journal of Cancer Therapy, 8, Article ID: 80657.

[4]   Siegel, R.L., Miller, K.D., Fedewa, S.A., Ahnen, D.J., Meester, R.G.S., Afsaneh Barzi, A. and Jemal, A. (2017) Colorectal Cancer Statistics. Cancer Journal for Clinicians, 67, 7-30.

[5]   Rahib, L., Smith, B.D., Aizenberg, R., Rosenzweig, A.B., Fleshman, J.M. and Matrisian, L.M. (2014) Projecting Cancer Incidence and Deaths to 2030: The Unexpected Burden of Thyroid, Liver, and Pancreas Cancers in the United States. Cancer Research, 74, 2913-2921.

[6]   La Pak, K.M. and Burd, C.E. (2014) The Molecular Balancing Act of p16INK4a in Cancer and Aging. Molecular Cancer Research, 12, 167-183.

[7]   Pallagi, P., Hegyi, P. and Rakonczay Jr., Z. (2015) The Physiology and Pathophysiology of Pancreatic Ductal Secretion. Pancreas, 44, 1211-1233.

[8]   Romac, J.M.J., Shahid, R.A., Swain, S.M., Vigna, S.R. and Liddle, R.A. (2018) Piezo1 Is a Mechanically Activated Ion Channel and Mediates Pressure Pancreatitis. Nature Communications, 9, Article 1715, 1-10.

[9]   Mrkonjic, S., Destaing, O. and Albigès-Rizo, C. (2017) Mechanotransduction Pulls the Strings of Matrix Degradation at Invadosome. Matrix Biology, 57/58, 190-203.

[10]   Kuntze, A., Goetsch, O., Fels, B., Najder, K., Unger, A., Wilhelmi, M., Sargin, S., Schimmelpfennig, S., Neumann, I., Schwab, A. and Pethö, Z. (2020) Protonation of Piezo1 Impairs Cell-Matrix Interactions of Pancreatic Stellate Cells. Frontiers in Physiology, 11, 89.

[11]   Blodgett, D.M., Nowosielska, A., Afik, S., Pechhold, S., Cura, A.J., Kennedy, N.J., Kim, S., Kucukura, A., Davis, R.J., Kent, S.C., Greiner, D.L., Garber, M.G., Harlan, D.M. and Diiorio, P. (2015) Novel Observations from Next-Generation RNA Sequencing of Highly Purified Human Adult and Fetal Islet Cell Subsets. Diabetes, 64, 3172-3181.

[12]   Beger, H.G., Buchler, M.W., Kozarek, R., Lerch, M.M., Neoptolemos, J.P., Warshaw, A.L., Whitcomb, D.C. and Shiratori, K. (2009) The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery. 2nd Edition, John Wiley & Sons, Hoboken, Chapters 1-5, 1-62.

[13]   Clemente, C.D. (2007) Anatomy—A Regional Atlas of the Human Body. 5th Edition, Plate 19, Lippincott Williams & Wilkins, Los Angeles.

[14]   Murtaugh, L.C. and Keefe, M.D. (2015) Regeneration and Repair of the Exocrine Pancreas. Annual Review of Physiology, 77, 229-249.

[15]   Ferdek, P.E. and Jakubowska, M.A. (2017) Biology of Pancreatic Stellate Cells—More than Just Pancreatic Cancer. Pflügers Archiv—European Journal of Physiology, 469, 1039-1050.

[16]   Li, W., Zhou, Y., Wang, X., Cai, M., Gao, F., Per-Ola Carlsson, P.O. and Sun, Z. (2019) A Modified in Vitro Tool for Isolation and Characterization of Rat Quiescent Islet Stellate Cells. Experimental Cell Research, 384, Article ID: 111617.

[17]   Vadlakonda, L., Dash, A., Pasupuleti, M., Kumar, K.A. and Reddanna, P. (2013) The Paradox of Akt-mTOR Interactions. Frontiers in Oncology, 3, Article 165.

[18]   Bader, A.G., Kang, S., Zhao, L. and Vogt, P.K. (2005) Oncogenic PI3K Deregulates Transcription and Translation. Nature Reviews Cancer, 5, 921-929.

[19]   Fu, Z. and Tindall, D.J. (2008) FOXOs, Cancer and Regulation of Apoptosis. Oncogene, 27, 2312-2319.

[20]   Karar, J. and Maity, A. (2011) PI3K/AKT/mTOR Pathway in Angiogenesis. Frontiers in Molecular Neuroscience, 4, 51.

[21]   Simpson, L. and Parsons, R. (2001) PTEN: Life as a Tumor Suppressor. Experimental Cell Research, 264, 29-41.

[22]   NCBI EIF4EBP1 Eukaryotic Translation Initiation Factor 4E Binding Protein 1 [Homo sapiens (Human)], Full Report. Gene ID: 1978, Updated on 18 August, 2020.

[23]   Qin, X., Jiang, B. and Zhang, Y. (2016) 4E-BP1, a Multifactor Regulated Multifunctional Protein. Cell Cycle, 15, 781-786.

[24]   Huang, J., Dibble, C.C., Matsuzaki, M. and Manning, B.D. (2008) The TSC1-TSC2 Complex Is Required for Proper Activation of mTOR Complex 2. Molecular and Cellular Biology, 28, 4104-4115.

[25]   Deivasikamani, V., Dhayalan, S., Abudushalamu, Y., Mughal, R., Visnagri, A., Cuthbertson, K., Scragg, J.L., Munsey, T.S., Viswambharan, H., Muraki, K., Foster, R., Sivaprasadarao, A., Kearney, M.T., Beech, D.J. and Piruthivi Sukumar, P. (2019) Piezo1 Channel Activation Mimics High Glucose as a Stimulator of Insulin Release. Scientific Reports, 9, Article ID: 16876.

[26]   Sheu, F.S., Zhu, W. and Fung, P.C.W. (2000) Direct Observation of Trapping and Release of Nitric Oxide by Glutathione and Cysteine with Electron Paramagnetic Resonance Spectroscopy. Biophysical Journal, 78, 1216-1226.

[27]   Hanahan, D. and Folkman, J. (1996) Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis. Cell, 86, 353-364.

[28]   Bostrom, P., Wu, J., Jedrychowski, M.P., Korde, A., Li, Y., Lo, J.C., Rasbach, K.A., Boström, E.A., Choi, J.H., Long, J.Z., Kajimura, S., Zingaretti, M.C., Vind, B.F., Hua, T., Cinti, S., Højlund, K., Gygi, S.P. and Spiegelman, B.M. (2012) A PGC1-Alpha-Dependent Myokine That Drives Brown-Fat-Like Development of White Fat and Thermogenesis. Nature, 481, 463-468.

[29]   Liu, J., Song, N., Huang, Y. and Chen, Y. (2018) Irisin Inhibits Pancreatic Cancer Cell Growth via the AMPK-mTOR Pathway. Scientific Reports, 8, Article ID: 15247.

[30]   Zhang, D., Zhang, P., Li, L., Tang, N., Huang, F., Kong, X., Tan, X. and Shi, G. (2019) Irisin Functions to Inhibit Malignant Growth of Human Pancreatic Cancer Cells via Downregulation of the PI3K/AKT Signaling Pathway. OncoTargets and Therapy, 12, 7243-7249.

[31]   Zhang, D., Tan, X., Tang, N., Huang, F., Chen, Z. and Shi, G. (2020) Review of Research on the Role of Irisin in Tumors. OncoTargets and Therapy, 13, 4423-4430.

[32]   Wucherpfennig, T.G., Muller, S., Wolfrum, C. and Bode, J.W. (2016) Chemical Synthesis of the 12 kDa Human Myokine Irisin by α-Ketoacid-Hydroxylamine (KAHA) Ligation. Helvetica Chimica Acta, 99, 897-907.

[33]   Lad, Y., McHugh, B., Hodkinson, P.S., MacKinnon, A.C., Haslett, C., Ginsberg, M.H. and Sethi, T. (2006) PLCε Suppresses Integrin Activation. The Journal of Biological Chemistry, 281, 29501-29512.

[34]   Cullen, P.J. and Lockyer, P.J. (2002) Integration of Calcium and Ras Signalling. Nature Reviews Molecular Cell Biology, 3, 339-348.

[35]   Mebratu, Y. and Tesfaigzi, Y. (2009) How ERK1/2 Activation Controls Cell Proliferation and Cell Death: Is Subcellular Localization the Answer? Cell Cycle, 8, 1168-1175.

[36]   Yuan, P., He, X.H., Rong, Y.F., Cao, J., Li, Y., Hu, Y.P., Liu, Y., Li, D., Lou, W. and Liu, M.F. (2017) KRAS/NF-kB/YY1/miR-489 Signaling Axis Controls Pancreatic Cancer Metastasis. Cancer Research, 77, 100-111.

[37]   Fung, P.C.W. (2013) Chapter 5. Plausible Biomedical Consequences of Acupuncture Applied at Sites Characteristic of Acupoints in the Connective-Tissue-Interstitial-Fluid System. In: Chen, L.L. and Cheng, T.O., Eds., Acupuncture in Modern Medicine, InTech Open, Rijeka, 95-131.

[38]   Liu, C.Y., Lin, H.H., Tang, M.J. and Wang, Y.K. (2015) Vimentin Contributes to Epithelial-Mesenchymal Transition Cancer Cell Mechanics by Mediating Cytoskeletal Organization and Focal Adhesion Maturation. Oncotarget, 6, 15966-15983.

[39]   Coste, B., Mathur, J., Schmidt, M., Earley, T.J., Ranade, S., Petrus, M.J., Dubin, A.E. and Patapoutian, A. (2010) Piezo1 and Piezo2 Are Essential Components of Distinct Mechanically-Activated Cation Channels. Science, 330, 55-60.

[40]   Ellefsen, K.L., Holt, J.R., Chang, A.C., Nourse, J.L., Arulmoli, J., Mekhdjian, A.H., Abuwarda, H., Tombola, F., Flanagan, L.A., Dunn, A.R., Parker, I., Medha, M. and Pathak, M.M. (2019) Myosin-II Mediated Traction Forces Evoke Localized Piezo1-Dependent Ca2+ Flickers. Scientific Report. Communications Biology, 2, 298.

[41]   DuFort, C.C., DelGiorno, K.E., Carlson, M.A., Osgood, R.J., Zhao, C., Huang, Z., Thompson, C.B., Connor, R.J., Thanos, C.D., Brockenbrough, J.S., Provenzano, P.P., Frost, G.I., Shepard, H.M. and Hingorani, S.R. (2016) Interstitial Pressure in Pancreatic Ductal Adenocarcinoma Is Dominated by a Gel-Fluid Phase. Biophysical Journal, 110, 2106-2119.

[42]   Pedersen, S.F., Novak, I., Alves, F., Schwab, A. and Pardo, L.A. (2017) Alternating pH Landscapes Shape Epithelial Cancer Initiation and Progression: Focus on Pancreatic Cancer. Bioessays, 39, Article ID: 1600253.

[43]   Fels, B., Nielsen, N. and Schwab, A. (2016) Role of TRPC1 Channels in Pressure-Mediated Activation of Murine Pancreatic Stellate Cells. European Biophysics Journal, 2016, 1-14.

[44]   Lau, K.S. and Haigis, K.M. (2009) Non-Redundancy within the RAS Oncogene Family: Insights into Mutational Disparities in Cancer. Molecules and Cells, 28, 315-320.

[45]   Sun, Q., Burke, J.P., Phan, J., Burns, M.C., Olejniczak, E.T., Waterson, A.G., Lee, T., Rossanese, O.W. and Fesik, S.W. (2012) Discovery of Small Molecules that Bind to K-Ras and Inhibit Sos-Mediated Activation. Angewandte Chemie International Edition in English, 51, 6140-6143.

[46]   Schultheis, B., Reuter, D., Ebert, M.P., Siveke, J., Kerkhoff, A., Berdel, W.E., Hofheinz, R., Behringer, D.M., Schmidt, W.E., Goker, E., Dosso, S.D., Kneba, M., Yalcin, S., Overkamp, F., Schlegel, F., Dommach, M., Rohrberg, R., Steinmetz, T. and Strumberg, D. (2017) Gemcitabine Combined with the Monoclonal Antibody Nimotuzumab Is an Active First-Line Regimen in KRAS Wildtype Patients with Locally Advanced or Metastatic Pancreatic Cancer: A Multicenter, Randomized Phase IIb Study. Annals of Oncology, 28, 2429-2435.

[47]   Schutte, M., Hruban, R.H., Geradts, J., Maynard, R., Hilgers, W., Rabindran, S.K., Moskaluk, C.A., Hahn, S.A., Schwarte-Waldhoff, I., Schmiegel, W., Baylin, S.B., Kern, S.E. and Herman, J.G. (1997) Abrogation of the RB/p16 Tumor-Suppressive Pathway in Virtually All Pancreatic Carcinomas. Cancer Research, 57, 3126-3130.

[48]   Wood, L.D. and Hruban, R.H. (2012) Pathology and Molecular Genetics of Pancreatic Neoplasms. Journal of Cancer, 18, 492-501.

[49]   LaPak, K.M. and Burd, C.E. (2014) The Molecular Balancing Act of p16INK4a in Cancer and Aging. Molecular Cancer Research, 12, 167-183.

[50]   Xiong, Y., Hannon, G., Zhang, H., Casso, D. and Beach, D. (1993) p21 Is a Universal Inhibitor of Cyclin Kinases. Nature, 366, 701-704.

[51]   Duronio, R.J. and Xiong, Y. (2013) Signaling Pathways that Control Cell Proliferation. Cold Spring Harbor Perspectives in Biology, 5, Article ID: a008904.

[52]   Tang, B., Li, Y., Yuan, S., Wang, Z., Yu, S., Li, B. and He, S. (2015) Clinicopathological Significance of CDKN2A Promoter Hypermethylation Frequency with Pancreatic Cancer. Scientific Reports, I5, Article ID: 13563I.

[53]   Kim, E.S. (2017) Abemaciclib: First Global Approval. Drugs, 77, 2063-2070.

[54]   Schettini, F., De Santo, I., Rea, C.G., De Placido, P., Formisano, L., Giuliano, M., Arpino, G., De Laurentiis, M., Puglisi, F., De Placido, S. and Del Mastro, L. (2018) CDK 4/6 Inhibitors as Single Agent in Advanced Solid Tumors. Frontiers in Oncology, 8, Article 608, 1-12.

[55]   Le, N.T. and Richardson, D.R. (2004) Iron Chelators with High Antiproliferative Activity Up-Regulate the Expression of Growth Inhibitory and Metastasis Suppressor Gene: A Link between Iron Metabolism and Proliferation. Blood, 104, 2967-2975.

[56]   Zhang, S., Yu, C., Yang, X., Lu, J., Hu, W., Hao, X., Li, S., Aikemu, B., Yang, G., He, Z., Zhang, L., Xue, P., Cai, Z., Ma, J., Zang, L., Feng, B., Yuan, F., Sun, J. and Zheng, M. (2019) N-myc Downstream-Regulated Gene 1 Inhibits the Proliferation of Colorectal Cancer through Emulative Antagonizing NEDD4-Mediated Ubiquitylation of p21. Journal of Experimental & Clinical Cancer Research, 38, 490.

[57]   Kurdistani, S.K., Arizti, P., Reimer, C.L., Sugrue, M.M., Aaronson, S.A. and Lee, S.W. (1998) Inhibition of Tumor Cell Growth by RTP/rit42 and Its Responsiveness to p53 and DNA Damage. Cancer Research, 58, 4439-4444.

[58]   Stein, S., Thomas, E.K., Herzog, B., Westfall, M.D., Rocheleau, J.V., Jackson, R.S., Wang, M. and Liang, P. (2004) NDRG1 Is Necessary for p53-Dependent Apoptosis. The Journal of Biological Chemistry, 279, 48930-48940.

[59]   Maruyama, Y., Ono, M., Kawahara, A., Yokoyama, T., Basaki, Y., Kage, M., Aoyagi, S., Kinoshita, H. and Kuwano, M. (2006) Tumor Growth Suppression in Pancreatic Cancer by a Putative Metastasis Suppressor Gene Cap43/NDRG1/Drg-1 through Modulation of Angiogenesis. Cancer Research, 66, 6232-6242.

[60]   Whitnall, M., Howard, J., Ponka, P. and Richardson, D.R. (2006) A Class of Iron Chelators with a Wide Spectrum of Potent Antitumor Activity that Overcomes Resistance to Chemotherapeutics. Proceedings of the National Academy of Sciences of the United States of America, 103, 14901-14906.

[61]   Kovacevic, Z., Chikhani, S., Lovejoy, D.B. and Richardson, D.R. (2011) Novel Thiosemicarbazone Iron Chelators Induce Up-Regulation and Phosphorylation of the Metastasis Suppressor, NDRG1: A New Strategy for the Treatment of Pancreatic Cancer. Molecular Pharmacology, 80, 598-609.

[62]   Varelas, X. (2014) The Hippo Pathway Effectors TAZ and YAP in Development, Homeostasis, and Diseases. Development, 141, 1614-1626.

[63]   Zhao, B., Ye, X., Yu, J.D., Li, L., Li, W.Q., Li, S.M., Yu, J.J., Lin, J., Wang, C.Y., Chinnaiyan, A.M., Lai, Z.C. and Guan, K.L. (2008) TEAD Mediates YAP-Dependent Gene Induction and Growth Control. Genes & Development, 22, 1962-1971.

[64]   Jiao, S., Wang, H.Z., Shi, Z.B., Zhang, W.J., Song, X.M., He, F., Wang, Y.C., Zhang, Z.Z., Wang, X., Guo, T., Li, P.X., Zhao, Y., Ji, H.B., Zhang, L. and Zhou, Z.C. (2014) A Peptide Mimicking VGLL4 Function Acts as a YAP Antagonist Therapy against Gastric Cancer. Cancer Cell, 25, 166-180.

[65]   Wu, D.M., Shan Wang, S., Wen, X., Han, X.H., Wang, Y.J., Shen, M., Fan, S.H., Zhang, Z.F., Shan, Q., Li, M.Q., Hu, B., Lu, J., Chen, G.Q. and Zheng, Y.L. (2018) LncRNA SNHG15 Acts as a ceRNA to Regulate YAP1-Hippo Signaling Pathway by Sponging miR-200a-3p in Papillary Thyroid Carcinoma. Cell Death and Disease, 9, 947.

[66]   PTPN14 Protein Tyrosine Phosphatase Non-Receptor Type 14 [Homo sapiens (Human)], Gene ID: 5784, NCBI Full Report, Updated on 5-Jul-2020.

[67]   Raj, N. and Attardi, L.D. (2017) The Transactivation Domains of the p53 Protein. Cold Spring Harbor Perspectives in Biology, 7, Article ID: a026047.

[68]   Mello, S.S., Valente, L.J., Raj, N., Seoane, J.A., Flowers, B.M., McClendon, J., Bieging-Rolett, K.T., Lee, J., Ivanochko, D., Kozak, M.M., Chang, D.T., Longacre, T.A., Koong, A.C., Arrowsmith, C.H., Kim, S.K., Vogel, H., Wood, L.D., Hruban, R.H., Curtis, C. and Attardi, L.D. (2017) A p53 Super-Tumor Suppressor Reveals a Tumor Suppressive p53-Otpn14-Yap Axis in Pancreatic Cancer. Cancer Cell, 32, 460-473.

[69]   Brady, C.A., Jiang, D., Mello, S.S., Johnson, T.M., Jarvis, L.A., Kozak, M.M., Broz, D.K., Basak, S., Park, E.J., McLaughlin, M.E., Karnezis, A.N. and Attardi, L.D. (2011) Distinct p53 Transcriptional Programs Dictate Acute DNA-damage Response and Tumor Suppression. Cell, 145, 571-583.

[70]   Bruan, E. and Sauter, D. (2019) Furin-Mediated Protein Processing in Infectious Diseases and Cancer. Clinical & Translational Immunology, 2019, Article ID: e1073.

[71]   Zhang, Y., Zhou, M., Wei, H., Zhou, H., He, J., Lu, Y., Wang, D., Chen, B. Zeng, J., Peng, W., Du, F., Gong, A. and Xu, M. (2017) Furin Promotes Epithelial-Mesenchymal Transition in Pancreatic Cancer Cells in Hippo-Yap Pathway. International Journal of Oncology, 50, 1352-1362.

[72]   Meng, Z., Moroishi, T. and Guan, K.L. (2016) Mechanisms of Hippo Pathway Regulation. Genes & Development, 30, 1-17.

[73]   UniProtKB-Q8IX03 (KIBRA_HUMAN).

[74]   Becker, G.L., Hardes, K. and Steinmetzer, T. (2011) New Substrate Analogue Furin Inhibitors Derived from 4-Amidinobenzylamide. Bioorganic & Medicinal Chemistry Letters, 21, 4695-4697.

[75]   Lanuza-Masdeu, J., Arévalo, M.I., Vila, C., Albert Barberà, A., Gomis, R. and Caelles, C. (2013) In Vivo JNK Activation in Pancreatic b-Cells Leads to Glucose Intolerance Caused by Insulin Resistance in Pancreas. Diabetes, 62, 2308-2317.

[76]   Codelia, V.A., Sun, G. and Irvine, K.D. (2014) Regulation of YAP by Mechanical Strain through Jnk and Hippo Signaling. Current Biology, 24, 2012-2017.

[77]   Wang, Y., Solt, L.A., Kojetin, D.J. and Burris, T.P. (2012) Regulation of p53 Stability and Apoptosis by a ROR Agonist. PLoS ONE, 7, e34921.

[78]   Su, J., Bo Su, B., Xia, H., Liu, F., Zhao, X.H., Li, J., Zhang, J.Z., Shi, Y., Zeng, Y., Zeng, X., Ling, H., Wu, Y.H. and Su, Q. (2019) RORα Suppresses Epithelial-to-Mesenchymal Transition and Invasion in Human Gastric Cancer Cells via the Wnt/β-Catenin Pathway. Frontiers in Oncology, 9, 1344.

[79]   Yu, F.X., Zhao, B., Panupinthu, N., Jewell, J.L., Lian, I., Wang, L.H., Zhao, J.G., Yuan, H.X., Tumaneng, K., Li, H., Fu, X.D., Mills, G.M. and Guan, K.L. (2012) Regulation of the Hippo-YAP Pathway by G-Protein-Coupled Receptor Signaling. Cell, 150, 669-670.

[80]   Philippe, C., Pinson, B., Dompierre, J., Pantesco, V., Viollet, B., Daignan-Fornier, B. and Moenner, M. (2018) AICAR Antiproliferative Properties Involve the AMPK-Independent Activation of the Tumor Suppressors LATS 1 and 2. Neoplasia, 6, 555-562.

[81]   Corton, J.M., Gillespie, J.G., Hawley, S.A. and Hardie, D.G. (1995) 5-Aminoimidazole-4-Carboxamide Ribonucleoside. A Specific Method for Activating AMP-Activated Protein Kinase in Intact Cells? European Journal of Biochemistry, 229, 558-565.

[82]   Zucker, S., Cao, J. and Chen, W.T. (2000). Critical Appraisal of the Use of Matrix Metalloproteinase Inhibitors in Cancer Treatment. Oncogene, 19, 6642-6650.

[83]   Coppola, J.M., Mahaveer, S., Bhojani, M.S., Ross, B.D. and Rehemtulla, A. (2008) A Small-Molecule Furin Inhibitor Inhibits Cancer Cell Motility and Invasiveness. Neoplasia, 10, 363-370.

[84]   Massagué, J. (1998) TGF-β Signal Transduction. Annual Review of Biochemistry, 67, 753-791.

[85]   Shi, Y. and Massagué, J. (2003) Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus. Cell, 113, 685-700.

[86]   Tang, W.B., Ling, G.H., Lin Sun, L. and Liu, F.Y. (2010) Smad Anchor for Receptor Activation (SARA) in TGF-Beta Signaling. Frontiers in Bioscience, 2, 857-860.

[87]   SMAD2 SMAD Family Member 2 [Homo sapiens (Human)], Gene ID: 4087, NCBI Full Report, Updated on 6-Sep-2020.

[88]   Levy, L. and Hill, C.S. (2005) Smad4 Dependency Defines Two Classes of Transforming Growth Factor β (TGF-β) Target Genes and Distinguishes TGF-β-Induced Epithelial Mesenchymal Transition from Antiproliferative and Migratory Responses. Molecular and Cellular Biology, 25, 8108-8125.

[89]   Inoue, M., Sawada, T., Uchima, Y. and Kimura, K. (2006) Plasminogen Activator Inhibitor-1 (PAI-1) gene Transfection Inhibits the Liver Metastasis of Pancreatic Cancer by Preventing Angiogenesis. Oncology Reports, 14, 1445-1451.

[90]   UniProtKB Q02952 (AKA12_HUMAN).

[91]   Hayashi, M., Nomoto, S., Kanda, M., Okamura, Y., Nishikawa, Y., Yamada, S., Fujii, T., Sugimoto, H., Takeda, S. and Kodera, Y. (2012) Identification of the A Kinase Anchor Protein 12 (AKAP12) Gene as a Candidate Tumor Suppressor of Hepatocellular Carcinoma. Journal of Surgical Oncology, 105, 381-386.

[92]   Xia, W., Ni, J., Zhuang, J.H., Qiana, L.X., Wang, P. and Wang, J.N. (2016) MiR-103 Regulates Hepatocellular Carcinoma Growth by Targeting AKAP12. The International Journal of Biochemistry & Cell Biology, 7, 1-11.

[93]   UniProtKB-P18564 (ITB6_HUMAN).

[94]   Blackford, A., Serrano, O.K., Wolfgang, C.L., Parmigiani, G., Jones, S., Zhang, X.S., Parsons, D.W., Cheng, J.H.L., Leary, R.J., Eshleman, J.R., Goggins, M., Jaffee, E.M., Iacobuzio-Donahue, C.A., Maitra, A., Cameron, J.L., Olino, K., Schulick, R., Winter, J., Herman, J.M., Laheru, D., Klein, A.P., Vogelstein, B., Kinzler, K.W., Velculescu, V.E. and Hruban, R.H. (2009) SMAD4 Gene Mutations Are Aassociated with Poor Prognosis in Pancreatic Cancer. Clinical Cancer Research, 15, 4674-4679.

[95]   Hoshino, Y., Nishida, J., Katsuno, Y., Koinuma, D., Aoki, T., Kokudo, N., Miyazono, K. and Ehata, S. (2015) Smad4 Decreases the Population of Pancreatic Cancer-Initiating Cells through Transcriptional Repression of ALDH1A1. The American Journal of Pathology, 185, 1457-1470.

[96]   Marcato, P., Dean, C.A., Giacomantonio, C.A. and Lee, P.W. (2011) Aldehyde Dehydrogenase: Its Role as a Can Stem Cell Marker Comes Down to the Specific Isoform. Cell Cycle, 10, 1378-1384.

[97]   Henson, E.S. and Gibson, S.B. (2006) Surviving Cell Death through Epidermal Growth Factor (EGF) Signal Transduction Pathways: Implications for Cancer Therapy. Cellular Signalling, 18, 2089-2097.

[98]   Du, Y., Shen, J., Hsu, J.L., Han, Z., Hsu, M.C., Yang, C.C., Kuo, H.P., Wang, Y.N., Yamaguchi, H., Miller, S.A. and Hung, M.C. (2014) Syntaxin 6-Mediated Golgi Translocation Plays an Important Role in Nuclear Functions of EGFR through Microtubule-Dependent Trafficking. Oncogene, 33, 756-770.

[99]   Veigel, C. and Schmidt, C.F. (2011) Moving into the Cell: Single-Molecule Studies of Molecular Motors in Complex Environments. Nature Reviews Molecular Cell Biology, 12, 163-176.

[100]   Hirokawa, N. (1998) Kinesin and Dynein Superfamily Proteins and the Mechanism of Organelle Transport. Science, 279, 519-526.

[101]   Wendler, F. and Tooze, S.A. (2001) Syntaxin6: The Promiscuous Behavior of SNARE Protein. Traffic, 2, 606-611.

[102]   Springer, S., Spang, A. and Schekman, R. (1999) A Primer on Vesicle Budding. Cell, 97, 145-148.

[103]   Wang, Y.N., Wang, H., Yamaguchi, H., Lee, H.J., Lee, H.H. and Hung, M.C. (2010) COPI-Mediated Retrograde Trafficking from the Golgi to the ER Regulates EGFR Nuclear Transport. Biochemical and Biophysical Research Communications, 399, 498-504.

[104]   Gogala, M., Becker, T., Beatrix, B., Armache, J.P., Barrio-Garcia, C., Berninghausen, O. and Beckmann, R. (2014) Structures of the Sec61 Complex Engaged in Nascent Peptide Translocation or Membrane Insertion. Nature, 506, 107-110.

[105]   Y.N., Lee, H.H., Lee, H.J., Du, Y., Yamaguchi, H. and Hung, M.C. (2012) Membrane-Bound Trafficking Regulates Nuclear Transport of Integral Epidermal Growth Factor Receptor (EGFR) and ErbB-2. The Journal of Biological Chemistry, 287, 16869-16879.

[106]   Xiong, H.Q. and Abbruzzese, J.L. (2002) Epidermal Growth Factor Receptor-Targeted Therapy for Pancreatic Cancer. Seminars in Oncology, 29, 31-37.

[107]   Brand, T.M., Iida, M., Luthar, N., Star, M.M., Huppert, E.J. and Wheeler, D.L. (2013) Nuclear EGFR as a Molecular Target in Cancer. Radiotherapy & Oncology, 108, 370-377.

[108]   Rafiq, N.B.M., Nishimura, Y., Plotnikov, S.V., Thiagarajan, V., Zhang, Z., Shi, S.D., Natarajan, M., Viasnoff, V., Kanchanawong, P., Jones, G.E. and Bershadsky, A.D. (2019) A Mechano-Signalling Network Linking Microtubules, Myosin IIA Filaments and Integrin-Based Adhesions. Nature Materials, 18, 638-649.

[109]   Lin, S.Y., Makino, K., Xia, W., Matin, A., Wen, Y., Kwong, K.Y., Bourguignon, L. and Hung, M.C. (2001) Nuclear Localization of EGF Receptor and Its Potential New Role as a Transcription Factor. Nature Cell Biology, 3, 802-808.

[110]   Cunningham, D., Humblet, Y., Siena, S., Khayat, D., Bleiberg, H., Santoro, A., Bets, D., Mueser, M., Harstrick, A., Verslype, C., Chau, I. and van Cutsem, E. (2004) Cetuximab Monotherapy and Cetuximab Plus Irinotecan in Irinotecan Refractory Metastatic Colorectal Cancer. New England Journal of Medicine, 351, 337-345.

[111]   Wu, M., Rivkin, A. and Pham, T. (2008) Panitumumab: Human Monoclonal Antibody against Epidermal Growth Factor for the Treatment of Metastatic Colorectal Cancer. Clinical Therapeutics, 30, 14-30.

[112]   Thatcher, N., Hirsch, F.R., Luft, A.V., Szczesna, A., Ciuleanu, T.E., Dediu, M., Ramlau, R., Galiulin, R.K., Bálint, B., Losonczy, G., Kazarnowicz, A., Park, K., Schumann, C., Reck, M., Depenbrock, H., Nanda, S., Kruljac-Letunic, A., Kurek, R., Paz-Ares, L. and Socinski, M.A. (2015) Necitumumab Plus Gemcitabine and Cisplatin versus Gemcitabine and Cisplatin Alone as First-Line Therapy in Patients with Stage IV Squamous Non-Small-Cell Lung Cancer (SQUIRE): An Openlabel, Randomised, Controlled Phase 3 Trial. The Lancet Oncology, 16, 763-774.

[113]   Lu, M., Wang, X.C., Shen, L., Jia, J., Gong, J.F., Li, J., Li, J., Li, Y., Zhang, X.T., Lu, Z.H., Zhou, J. and Zhang, X.Z. (2016) Nimotuzumab Plus Paclitaxel and Cisplatin as the First Line Treatment for Advanced Esophageal Squamous Cell Cancer: A Single Centre Prospective Phase II Trial. Cancer Science, 170, 486-490.

[114]   Li, Z., Wang, M., Yao, X., Luo, W., Qu, Y., Yu, D., Li, X., Fang, J. and Huang, C. (2019) Development of a Novel EGFR-Targeting Antibody-Drug Conjugate for Pancreatic Cancer Therapy. Targeted Oncology, 14, 93-105.

[115]   Oeckinghaus, A. and Ghosh, S. (2009) The NF-kB Family of Transcription Factors and Its Regulation. Cold Spring Harbor Perspectives in Biology, 1, Article ID: a000034.

[116]   Liu, T., Zhang, L., Joo, D. and Sun, S.C. (2017) NF-κB Signaling in Inflammation. Signal Transduction and Targeted Therapy, 2, Article ID: e17023.

[117]   Crowe, P.D., VanArsdale, T.L., Walter, B.N., Ware, C.F., Hession, C., Ehrenfels, B., Browning, J.L., Din, W.S., Goodwin, R.G. and Smith, C.A. (1994) A Lymphotoxin-Beta-Specific Receptor. Science, 264, 707-710.

[118]   Nedwin, G.E., Naylor, S.L., Sakaguchi, A.Y., Smith, D., Jarrett-Nedwin, J., Pennica, D., Goeddel, D.V. and Gray, P.W. (1985) Human Lymphotoxin and Tumor Necrosis Factor Genes: Structure, Homology and Chromosomal Localization. Nucleic Acids Research, 13, 6361-6373.

[119]   Taniguchi, K. and Karin, M. (2018) NF-κB, Inflammation, Immunity and Cancer: Coming of Age. Nature Reviews Immunology, 18, 309-324.

[120]   Frank, P.G. and Lisanti, M.P. (2008) ICAM-1: Role in Inflammation and in the Regulation of Vascular Permeability. American Journal of Physiology-Heart and Circulatory Physiology, 295, H926-H927.

[121]   Cook-Mills, J.M., Marchese, M.E. and Abdala-Valencia, H. (2011) Vascular Cell Adhesion Molecule-1 Expression and Signaling During Disease: Regulation by Reactive Oxygen Species and Antioxidants. Antioxidants & Redox Signaling, 15, 1607-1638.

[122]   Meulmeester, E. and Ten Dijke, P. (2011) The Dynamic Roles of TGF-β in Cancer. The Journal of Pathology, 223, 205-218.

[123]   O’Reilly, D.A., Roberts, J.R., Cartmell, M.T., Demaine, A.G. and Kingsnorth, A.N. (2006) Heat Shock Factor-1 and Nuclear Factor-kappaB Are Systemically Activated in Human Acute Pancreatitis. JOP Journal of the Pancreas, 7, 174-184.

[124]   Ling, J., Kang, Y.A., Zhao, R.Y., Xia, Q.H., Lee, D.F., Chang, Z., Li, J., Peng, B.L., Fleming, J.B., Wang, H.M., Liu, J.S., Lemischka, I.R., Hung, M.C. and Chiao, P.J. (2012) KrasG12D-Induced Ikk2/ β/NF-κB Activation By IL-1α and p62 Feedforward Loops Is Required for Development of Pancreatic Ductal Adenocarcinoma. Cancer Cell, 21, 105-120.

[125]   Voronov, E., Dotan, S., Krelin, Y., Song, X.P., Elkabets, M., Carmi, Y., Rider, P., Cohen, I., Romzova, M., Kaplanov, I. and Apte, R.N. (2013) Unique versus Redundant Functions of IL-1α and IL-1β in the Tumor Microenvironment. Frontiers in Immunology, 4, 177.

[126]   Hruban, R.H., Goggins, M., Parsons, J. and Kern, S.E. (2000) Progression Model for Pancreatic Cancer. Clinical Cancer Research, 6, 2969-2972.

[127]   Matsuo, Y., Sawai, H., Ochi, N., Yasuda, A., Takahashi, H., Funahashi, H., Takeyama, H. and Guha, S. (2009) Interleukin-1 α Secreted by Pancreatic Cancer Cells Promotes Angiogenesis and Its Therapeutic Implications. Journal of Surgical Research, 153, 274-281.

[128]   Cheng, Z.X., Sun, B., Wang, S.J., Gao, Y., Zhang, Y.M., Zhou, H.X., Jia, G., Wang, Y.W., Kong, R., Pan, S.H., Xue, D.B., Jiang, H.C. and Bai, X.W. (2011) Nuclear Factor-κB-Dependent Epithelial to Mesenchymal Transition Induced by HIF-1α Activation in Pancreatic Cancer Cells under Hypoxic Conditions. PLoS ONE, 6, e23752.

[129]   McIntyre, A., Patiar, S., Wigfield, S., Li, J.L., Ledaki, I., Turley, H., Leek, R., Snell, C., Gatter, K., Sly, W.S., Vaughan-Jones, R.D., Swietach, P. and Harris, A.L. (2012) Carbonic Anhydrase IX Promotes Tumor Growth and Necrosis in vivo and Inhibition Enhances Anti-VEGF Therapy. Clinical Cancer Research, 18, 3100-3111.

[130]   Supuran, C.T. (2017) Carbonic Anhydrase Inhibition and the Management of Hypoxic Tumors. Metabolites, 7, 48.

[131]   Fishel, M.L., Jiang, Y.L., Rajeshkumar, N.V., Scandura, G., Sinn, A.L., He, Y., Shen, C.Y., Jones, D.R., Pollok, K.E., Ivan, M., Maitra, A. and Kelley, M.R. (2011) Impact of APE1/Ref-1 Redox Inhibition on Pancreatic Tumor Growth. Molecular Cancer Therapeutics, 10, 1698-1708.

[132]   Shah, F., Logsdon, D., Messmann, R.A., Fehrenbacher, J.C., Fishel, M.L. and Kelley, M.R. (2017) Exploiting the Ref-1-APE1 Node in Cancer Signaling and Other Diseases: From Bench to Clinic. npj Precision Oncology, 1, Article ID: 19.

[133]   Logsdon, D.P., Shah, F., Carta, F., Supuran, C.T., Kamocka, M., Jacobsen, M.H., Sandusky, G.E., Kelley, M.R. and Fishel, M.K. (2018) Blocking HIF Signaling Via Novel Inhibitors of CA9 and APE1/Ref-1 Dramatically Affects Pancreatic Cancer Cell Survival. Scientific Reports, 8, Article ID: 13759.

[134]   Osman, M.O., Jacobsen, N.O., Kristensen, J.U., Deleuran, B., Christian, B.G., Larsen, G. and Jensen, S.L. (1998) IT 9302, a Synthetic Interleukin-10 Agonist, Diminishes Acute Lung Injury in Rabbits with Acute Necrotizing Pancreatitis. Surgery, 124, 584-592.

[135]   UniProtKB-P08151 (GLI1_HUMAN), as of 20200603.

[136]   Walter, K., Omura, N., Hong, S.M., Griffith, M., Vincent, A., Borges, M. and Goggins, M. (2012) Overexpression of Smoothened Activates the Sonic Hedgehog Signaling Pathway in Pancreatic Cancer Associated Fibroblasts. Clinical Cancer Research, 16, 1781-1789.

[137]   Lee, D.H., Lee, S.Y. and Oh, S.C. (2017) Hedgehog Signaling Pathway as a Potential Target in the Treatment of Advanced Gastric Cancer. Tumor Biology, 2017, 1-10.

[138]   Dahmane, N., Lee, J., Robins, P., Heller, P. and Altaba, A.R.I. (1997) Activation of the Transcription Factor Gli1 and the Sonic Hedgehog Signalling Pathway in Skin Tumours. Nature, 389, 876-881.

[139]   Karhadkar, S.S., Bova, G.S., Abdallah, N., Dhara, S., Gardner, D., Maitra, A., Isaacs, J.T., Berman, D.M. and Beachy P.A. (2004) Hedgehog Signalling in Prostate Regeneration, Neoplasia and Metastasis. Nature, 431, 707-712.

[140]   Slade, I., Murray, A., Hanks, S., Kumar, A., Walker, L., Hargrave, D., Douglas, J., Stiller, C., Izatt, L. and Rahman, N. (2011) Heterogeneity of Familial Medulloblastoma and Contribution of Germline PTCH1 and SUFU Mutations to Sporadic Medulloblastoma. Familial Cancer, 10, Article ID: 337342.

[141]   Berlin, J., Bendel, J.C., Hart, L.L., Firdaus, I., Gore, I., Hermann, R.C., Mulcahy, M.F., Zalupski, M.M., Mackey, H.M., Yauch, R.L., Graham, R.A., Bray, G.L. and Low, J.A. (2013) A Randomized Phase II Trial of Vismodegib versus Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer. Clinical Cancer Research, 19, 258-267.

[142]   Kaye, S.B., Fehrenbacher, L., Holloway, R., Amit, A., Karlan, B., Slomovitz, B., Sabbatini, P., Fu, L., Yauch, R.L., Chang, I. and Reddy, J.C. (2012) A Phase II, Randomized, Placebo-Controlled Study of Vismodegib as Maintenance Therapy in Patients with Ovarian Cancer in Second or Third Complete Remission. Clinical Cancer Research, 18, 6509-6518.

[143]   Morton, J.P., Mongeau, M.E., Klimstra, D.S., Morris, J.P., Lee, Y.C., Kawaguchi, Y., Wright, C.V.E., Hebro, M. and Lewis, B.C. (2007) Sonic Hedgehog Acts at Multiple Stages during Pancreatic Tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America, 104, 5103-5108.

[144]   Lee, K.M., Nguyen, C., Ulrich, A.B., Pour, P.M. and Ouellette, M.M. (2003) Immortalization with Telomerase of the Nestin-Positive Cells of the Human Pancreas. Biochemical and Biophysical Research Communications, 301, 1038-1044.

[145]   Infante, J.R., Matsubayashi, H., Sato, N., Tonascia, J., Klein, A.P., Riall, T.A., Yeo, C., Iacobuzio-Donahue, C. and Goggins, M. (2007) Peritumoral Fibroblast SPARC Expression and Patient Outcome with Resectable Pancreatic Adenocarcinoma. Journal of Clinical Oncology, 25, 319-325.

[146]   Feig, C., Gopinathan, A., Neesse, A., Chan, D.S., Cook, N. and Tuveson, D.A. (2012) The Pancreas Cancer Microenvironment. Clinical Cancer Research, 18, 4266-4276.

[147]   Zhao, J., Wang, H., Hsiao, C.H., Chow, D.S-L., Koay, E.J., Kang, Y., Wen, X., Huang, Q., Ma, Y., Bankson, J.A., Ullrich, S.E., Overwijk, W., Maitra, A., Piwnica-Worms, D., Fleming, J.B. and Li, C. (2018) Simultaneous Inhibition of Hedgehog Signaling and Tumor Proliferation Remodels Stroma and Enhances Pancreatic Cancer Therapy. Biomaterials, 159, 215-228.

[148]   Hidelgo, M., Amant, F., Biankin, A.V., Budinská, E., Byrne, A.T., Caldas, C., Clarke, R.B., Jong, S.D., Jonkers, J., Mælandsmo, G.M., Roman-Roman, S., Seoane, J., Trusolino, L. and Villanueva, A. (2014) Patient-Derived Xenograft Models in as an Emerging Platform for Translational Cancer Research. Cancer Discovery, 4, 998-1013.

[149]   Lee, J.W., Komar, C.A., Bengsch, F., Graham, K. and Beatty, G.L. (2016) Genetically Engineered Mouse Models of Pancreatic Cancer: The KPC Model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre), Its Variants and Their Application in Immuno-Oncology Drug Discovery. Current Protocols in Pharmacology, 73, 14.39.1-14.39.20.

[150]   Rosler, A., Vandermeulen, G.W. and Klok, H.A. (2001) Advanced Drug Delivery Devices via Self-Assembly of Amphiphilic Block Copolymers. Advanced Drug Delivery Reviews, 53, 95-108.

[151]   Aster, J.C. (2014) In Brief: Notch Signalling in Health and Disease. The Journal of Pathology, 232, 1-3.

[152]   Li, X.Y., Zhai, W.J. and Teng, C.B. (2016) Notch Signaling in Pancreatic Development. International Journal of Molecular Sciences, 17, 48.

[153]   Bray, S.J. (2006) Notch Signalling: A Simple Pathway Becomes Complex. Nature Reviews Molecular Cell Biology, 7, 678-689.

[154]   Dikic, I. and Schimidt, M.H. (2010) Notch: Implications of Endogenous Inhibitors for Therapy. BioEssays, 32, 481-487.

[155]   Akanuma, T., Chen, C., Sato, T., Merks, R.M. and Sato T.N. (2016) Memory of Cell Shape Biases Stochastic Fate Decision-Making despite Mitotic Rounding. Nature Communications, 7, Article ID: 11963.

[156]   Kopan, R. and Ilagan, M.X. (2009) The Canonical Notch Signalling Pathway: Unfolding the Activation Mechanism. Cell, 137, 216-233.

[157]   Gao, J., Long, B. and Wang, Z. (2017) Role of Notch Signaling Pathway in Pancreatic Cancer. American Journal of Cancer Research, 7, 173-186.

[158]   Kageyama, R., Ohtsuka, T. and Kobayashi, T. (2007) The Hes Gene Family: Repressors and Oscillators that Orchestrate Embryogenesis. Development, 134, 1243-1251.

[159]   HEY1 Hes Related Family bHLH Transcription Factor with YRPW Motif 1 [Homo sapiens (Human)], NCBI, Full Report, Gene ID: 23462, Updated on 24-Mar-2020.

[160]   Chillakuri, C.R., Sheppard, D., Lea, S.M. and Handford, P.A. (2012) Notch Receptor-Ligand Binding and Activation: Insights from Molecular Studies. Seminars in Cell & Developmental Biology, 23, 421-428.

[161]   Joussineau, C.D., Soulé, J., Martin, M., Anguille, C., Montcourrier, P. and Alexandre, D. (2003) Delta-Promoted Filopodia Mediate Long-Range Lateral Inhibition in Drosophila. Nature, 426, 555-559.

[162]   Abel, E.V., Kim, E.J., Wu, J., Hynes, M., Bednar, F., Proctor, E., Wang, L., Dziubinski, M.L. and Simeone, D.M. (2014) The Notch Pathway Is Important in Maintaining the Cancer Stem Cell Population in Pancreatic Cancer. PLoS One, 9, e91983.

[163]   Li, C., Heidt, D.G., Dalerba, P., Burant, C.F., Zhang, L., Adsay, V., Wicha, M., Clarke, M.F. and Simeone, D.M. (2007) Identification of Pancreatic Cancer Stem Cells. Cancer Research, 67, 1030-1037.

[164]   Richter, S., Mcwhirter, E., Chen, E.X. and Tran, B. (2012) A Phase I Study of R04929097, an Oral Gamma Secretase Inhibitor, in Combination with Gemcitabine in Patients with Advanced Solid Tumors (PHL-078/CTEP 8575). Journal of Clinical Oncology, 30, 3082-3082.

[165]   Jesus-Acosta, A., Laheru, D., Maitra, A., Arcaroli, J., Rudek, M.A., Dasari, A., Blatchford, P.J., Quackenbush, K. and Messersmith, W. (2014) A Phase II Study of the Gamma Secretase Inhibitor R04929097 in Patients Previously Treated Metastatic Pancreatic Adenocarcinoma. Investigational New Drugs, 32, 739-745.

[166]   Fung, P.C.W. and Kong, R.K.C. (2016) The Integrative Five-Fluid Circulation System in the Human Body. Open Journal of Molecular and Integrative Physiology, 6, 45-97.

[167]   Zha, M., Li, F., Xu, W., Chen, B. and Sun, Z. (2014) Isolation and Characterization of Islet Stellate Cells in Rat. Islets, 4, Article ID: e28701.

[168]   Apte, M.V., Pirola, R.C. and Wilson, J.S. (211) Pancreatic Stellate Cells: A Starring Role in Normal and Diseased Pancreas. Frontiers in Physiology, 3, 344.

[169]   McCarroll, J.A., Phillips, P.A., Santucci, N., Pirola, R.C., Wilson, J.S. and Apte, M.V. (2006) Vitamin A Inhibits Pancreatic Stellate Cell Activation: Implication for Treatment of Pancreatic Fibrosis. Gut, 55, 79-89.

[170]   Erkan, M., Kleeff, J., Gorbachevski, A., Reiser, C., Mitkus, T., Esposito, I., Giese, T., Büchler, M.W., Giese, N.A. and Friess, H. (2007) Periostin Creates a Tumor-Supportive Microenvironment in the Pancreas by Sustaining Fibrogenic Stellate Cell Activity. Gastroenterology, 132, 1447-1464.

[171]   Zilberberg, L., Vesna Todorovic, V., Dabovic, B., Horiguchi, M., Couroussé, T., Sakai, l.Y. and Rifkin, D.B. (2012) Specificity of Latent TGF-ß Binding Protein (LTBP) Incorporation into Matrix: Role of Fibrillins and Fibronectin. Journal of Cellular Physiology, 227, 3828-3836.

[172]   Fung, P.C.W. (2009) Probing the Mystery of Chinese Medicine Meridian Channels with Special Emphasis on the Connective Tissue Interstitial Fluid System, Mechanotransduction, Cells Durotaxis and Mast Cell Degranulation. Chinese Medicine, 4, 10.

[173]   Munger, J.S. and Sheppard, D. (2011) Cross Talk among TGF-Beta Signal Pathways, Integrins and the ECM. Cold Spring Harbor Perspectives in Biology, 3, Article ID: a005017.

[174]   Han, X., Xu, Y., Zhao, X., Zhang, Y., Yang, X., Wang, Y., Zhao, R., Anderson, G.J., Zhao, Y. and Nie, G. (2018) Reversal of Pancreatic Desmoplasia by Re-Educating Stellate Cells with a Tumour Microenvironment-Activated Nanosystem. Nature Communications, 9, Article ID: 3390.

[175]   Ren, B., Cui, M., Yang, G., Wang, H., Feng, M., You, L. and Zhao, Y. (2018) Tumor Microenvironment Participates in Metastasis of Pancreatic Cancer. Molecular Cancer, 17, Article 108, 1-15.

[176]   Haber, P.S., Keogh, G.W., Apte, M.V., Moran, C.S., Stewart, N.L., Crawford, D.H., Pirola, R.C., McCaughan, G.W., Ramm, G.A. and Wilson, J.S. (1999) Activation of Pancreatic Stellate Cells in Human and Experimental Pancreatic Fibrosis. The American Journal of Pathology, 155, 1087-1095.

[177]   Jun, J.I. and Lau, L.F. (2011) Taking Aim at the Extracellular Matrix: CCN Proteins as Emerging Therapeutic Targets. Nature Reviews Drug Discovery, 10, 945-963.

[178]   Charrier, A.L. and Brigstock, D.R. (2010) Connective Tissue Growth Factor Production by Activated Pancreatic Stellate Cells in Mouse Alcoholic Chronic Pancreatitis. Laboratory Investigation, 90, 1179-1188.

[179]   Jin, G., Hong, W., Guo, Y., Bai, Y. and Chen, B. (2020) Molecular Mechanism of Pancreatic Cell Activation in Chronic Pancreatitis and Pancreatic Cancer. Journal of Cancer, 11, 1505-1515.

[180]   Luttenberger, T., Schmid-Kotsas, A., Menke, A., Siech, M., Beger, H., Adler, G., Grünert, A. and Bachem, M.G. (2000) Platlet-Derived Growth Factors Stimulate Prolin and Extracellular Matrix Synthesis of Pancreatic Stellate Cells: Implication in Pathogenesis of Pancreas Fibrous. Laboratory Investigation, 80, 47-55.

[181]   Masamune, A. (2013) Connexins Regulate Cell Functions in Pancreatic Stellate Cells. Pancreas, 42, 308-316.

[182]   Delmos, A., Van Laethem, J.L., Quertinmont, E., Degraef, C., Delhaye, M., Geerts, A. and Deviere, J. (2002) Endogenous Interleukin-10 Modulates Fibrosis and Regeneration in Experimental Chronic Pancreatitis. American Journal of Physiology-Gastrointestinal and Liver Physiology, 282, G1105-G1112.

[183]   Driessler, F., Venstrom, K., Sabat, R., Asadullah, K. and Schottelius, A.J. (2004) Molecular Mechanisms of Interleukin-10-Mediated Inhibition of NF-kB Activity: A Role for p50 F. Clinical & Experimental Immunology, 135, 64-73.

[184]   Carey, A.J., Tan, C.K. and Ulett, G.C. (2012) Infection-Induced IL-10 and JAK-STAT a Review of the Molecular Circuitry Controlling Immune Hyperactivity in Response to Pathogenic Microbes. JAK-STAT, 3, 159-167.

[185]   Asaumi, H., Watanabe, S., Taguchi, M., Tashiro, M. and Otsuki, M. (2007) Externally Applied Pressure Activates Pancreatic Stellate Cells through the Generation of Intracellular Reactive Oxygen Species. American Journal of Physiology-Gastrointestinal and Liver Physiology, 293, G972-G978.

[186]   McGavran, M.H., Unger, R.H., Recant, L., Polk, H.C., Kilo, C. and Levin, M.E. (1966) A Glucagon-Secreting Alpha-Cell Carcinoma of the Pancreas. New England Journal of Medicine, 274, 1408-1413.

[187]   Kim, S.K., Kim, H., Lee, D.-H., Kim, T.-S., Kim, T., Chung, C., Koh, G.Y., Kim, H. and Lim. D.S. (2013) Reversing the Intractable Nature of Pancreatic Cancer by Selectively Targeting ALDH-High, Therapy-Resistant Cancer Cells. PLoS ONE, 8, e78130.

[188]   Ginestier, C., Hur, M.H., Charafe-Jauffret, E., Monville, F., Dutcher, J., Brown, M., Jacquemier, J., Viens, P., Kleer, C.G., Liu, S., Schott, A., Hayes, D., Birnbaum, D., Wicha, M.S. and Dontu, G. (2007) ALDH1 Is a Marker of Normal and Malignant Human Mammary Stem Cells and a Predictor of Poor Clinical Outcome. Cell, Stem Cell, 1, 555-567.

[189]   CD24 CD24 Molecule [Homo sapiens (Human)], Gene ID: 100133941, NCBI Full Report Updated on 20-Sep-2020.

[190]   Wei, H.J., Yin, T., Zhu, Z., Shi, P.F., Tian, Y. and Wang, C.Y. (2011) Expression of CD44, CD24 and ESA in Pancreatic Adenocarcinoma Cell Lines Varies with Local Microenvironment. Hepatobiliary & Pancreatic Diseases International, 10, 428-434.

[191]   Lin, L., Jou, D., Wang, Y., Ma, H., Lin, T., Fuchs, J., Li, P.K., Lu, J., Li, C. and Lin, J. (2016) Stats3 as a Potential Therapeutic Target in ALDH+ and CD44+/CD24+ Stem Cell-Like Pancreatic Cancer Cells. International Journal of Oncology, 49, 2265-2274.

[192]   Perez, A., Neskey, D.M., Wen, J., Pereira, L., Reategui, E.P., Goodwin, W.J., Carraway, K.L. and Franzmann, E.J. (2013) CD44 Interacts with EGFR and Promotes Head and Neck Squamous Cell Carcinoma Initiation and Progression. Oral Oncology, 49, 306-313.

[193]   Yin, J., Zhang, H., Wu, X., Zhang, Y., Li, J., Shen, J., Zhao, Y., Xiao, Z., Lu, L., Huang, C., Zhang, Z., Du, F., Wu, Y., Kaboli, P.J., Cho, C.H., Yuan, D. and Li, M. (2020) CD44 Inhibition Attenuates EGFR Signaling and Enhances Cisplatin Sensitivity in Human EGFR Wild-Type Non-Small-Cell Lung Cancer Cells. International Journal of Molecular Medicine, 45, 1783-1792.

[194]   Pantel, K., Brakenhoff, R.H. and Brandt, B. (2008) Detection, Clinical Relevance and Specific Biological Properties of Disseminating Tumour Cells. Nature Reviews Cancer, 8, 329-340.

[195]   Greco, F.A. and Hainsworth, J.D. (2009) Introduction: Unknown Primary Cancer. Seminars in Oncology, 36, 6-7.

[196]   Gupta, P.B., Mani, S., Yang, J., Hartwell, K. and Weinberg, R.A. (2005) The Evolving Portrait of Cancer Metastasis. Cold Spring Harbor Perspectives in Biology, 70, 291-297.

[197]   Han, S.P. and Yap, A.S. (2012) The Cytoskeleton and Classical Adhesions. Subcellular Biochemistry, 60, 111-135.

[198]   Brieher, W.M. and Yap, A.S. (2012) Cadherin Junctions and Their Cytoskeleton(s). Current Opinion in Cell Biology, 25, 39-46.

[199]   Ribeiro, A.S. and Paredes, J. (2015) P-Cadherin Linking Breast Can Invasion: A Promising Marker to Identify an “Intermediate/Metastable” EMT State. Frontiers in Oncology, 4, Article ID: 371.

[200]   Storz, P. (2017) Acinar Cell Plasticity and Development of Pancreatic Ductal Adenocarcinoma. Nature Reviews Gastroenterology & Hepatology, 14, 296-304.

[201]   Rhim, A.D., Thege, F.I., Santana, S.M., Lannin, T.B., Saha, T.N., Tsai, S., Maggs, L.R., Kochman, M.L., Ginsberg, G.G., Lieb, J.G., Chandrasekhara, V., Drebin, J.A., Ahmad, N., Yang, Y.X., Kirby, B.J. and Stanger, B.Z. (2014) Detection of Circulating Pancreas Epithelial Cells in Patients with Pancreatic Cystic Lesions. Gastroenterology, 146, 647-651.

[202]   Peć ina-Slaus, N. (2003) Tumor Suppressor Gene E-Cadherin and Its Role in Normal and Malignant Cells. Cancer Cell International, 3, Article 17, 1-7.

[203]   Gu, G., Brown, J.R. and Melton, D.A. (2003) Direct Lineage Tracing Reveals the Ontogeny of Pancreatic Cell Fates during Mouse Embryogenesis. Mechanisms of Development, 120, 35-43.

[204]   Rhim, A.D., Mirek, E.T., Aiello, N.M., Maitra, A., Bailey, J.M., McCallister, F., Reichert, M., Beatty, G.L., Rustgi, A.K., Vonderheide, R.H., Leach, S.D. and Stanger, B.Z. (2012) EMT and Dissemination Precede Pancreatic Tumor Formation. Cell, 148, 349-361.

[205]   Masugi, Y., Yamazak, I.K., Hibi, T., Aiura, K., Kitagawa, Y. and Sakamoto, M. (2010) Solitary Cell Infiltration Is a Novel Indicator of Poor Prognosis and Epithelial-Mesenchymal Transition in Pancreatic Cancer. Human Pathology, 41, 1061-1068.

[206]   Aruffo, A., Stamenkovic, I., Melnick, M., Underhill, C.B. and Seed, B. (1990) CD44 Is the Principal Cell Surface Receptor for Hyaluronate. Cell, 61, 1303-1313.

[207]   Jiang, W., Zhang, Y., Kane, K.T., Collins, M.A., Simeone, D.M., di Magliano, M.P. and Nguyen, K.T. (2015) CD44 Regulates Pancreatic Cancer Invasion through MT1-MMP. Molecular Cancer Research, 13, 9-15.

[208]   Chang, T.T., Thakar, D. and Weaver, V.M. (2017) Force-Dependent Breaching of the Basement Membrane. Matrix Biology, 57/58, 178-189.

[209]   O’Leary, L.E.R., Fallas, J.A., Bakota, E.L, Kang, M.K. and Hartgerink, J.D. (2011) Multi-Hierarchical Self-Assembly of a Collagen Mimetic Peptide from Triple Helix to Nanofibre and Hydrogel. Nature Chemistry, 3, 821-828.

[210]   Monteiro, P., Rosse, C., Castro-Castro, A., Irondellel, M., Lagoutte, E., Paul-Gillotreaux, P., Desnos, C., Formstcher, E., Darchen, F., Perrais, D., Gautreau, A., Hertzog, M. and Chavrier, P. (2013) Endosomal WASH and Exocyst Complexes Control Exocytosis of MT1-MMP at Uinvadopodia. Journal of Cell Biology, 203, 1063-1079.

[211]   Marchesin, V., Castro-Castro, A., Lodillinsky, C., Castagnino, A., Cyrta, J., Bonsang-Kitzis, H., Fuhrmann, L., Irondelle, M., Infante, E., Montagnac, G., Reyal, F., Vincent-Salomon, A. and Chevrier, P. (2015) ARF6-JIP3/4 Regulate Endosomal Tubules for MT1-MMP Exocytosis in Cancer Invasion. Journal of Cell Biology, 211, 339-358.

[212]   Castro-Castro, A., Marchesin, V., Monteiro, P., Lodillinsky, C., Rosse, C. and Chavrier, P. (2016) Cellular and Molecular Mechanisms of MT1-MMP-Dependent Cancer Cell Invasion. Annual Review of Cell and Developmental Biology, 32, 555-576.

[213]   Hoyer, M.J., Chitwood, P.J., Ebmeier, C.C., Striepen, J.F., Qi, R.Z., Old, W.M. and Voeltz, G.K. (2018) A Novel Class of ER Membrane Proteins Regulates ER-Associated Endosome Fission. Cell, 175, 254-265.

[214]   Pedersen, N.M., Wenzel, E.M., Wang, L., Antoine, S., Chavrier, P., Stenmark, H. and Raiborg, C. (2020) Protrudin-Mediated ER-Endosome Contact Sites Promote MT1-MMP Exocytosis and Cell Invasion. Journal of Cell Biology, 219, e2020 03063.

[215]   Fisher, K.E., Sacharidou, A., Stratman, A.N., Mayo, A.M., Fisher, S.B., Mahan, R.D., Davis, M.J. and Davis, G.E. (2009) MT1-MMP- and Cdc42-Dependent Signaling Co-Regulate Cell Invasion and Tunnel Formation in 3D. Collagen Matrices. Journal of Cell Science, 122, 4558-4569.

[216]   Ortenos, C., Ehlert, R. and Gollnick, H. (1987) The Retinoids: A Review of Their Clinical Pharmacologic and Therapeutic Use. Drugs, 34, 459-503.

[217]   Bold, R.J., Ishizuka, J., Townsend Jr., C.M. and Thompson, J.C. (1996) All-Trans-Retinoic Acid Inhibits Growth of Human Pancreatic Cancer Cell Lines. Pancreas, 12, 189-195.

[218]   Chronopoulos, A., Robinson, B., Sarper, M., Cortes, E., Hurnheimar, V., Lachoqwski, D., Attwood, S., Garcia, R., Ghassemi, S., del Rio Fabry, B. and Hernandez, A. (2016) ATRA Mechanically Reprograms Pancreatic Stellar Cells to Supress Matrix Remodeling and Inhibition of Cancer Cell Invasion. Nature Communications, I7, Article ID: 126301I.

[219]   Fairus, S., Nor, R.M., Cheng, H.M. and Sundram, K. (2006) Postprandial Metabolic Fate of Tocotrienol-Rich Vitamin E Differs Significantly from that of Alpha-Tocopherol. The American Journal of Clinical Nutrition, 84, 835-842.

[220]   Fu, J.Y., Che, H.L., Tan, D.M.Y. and Teng, K.T. (2014) Bioavailability of Tocotrienols: Evidence in Human Studies. Nutrition & Metabolism, 11, 5.

[221]   Fu, J.Y., Blatchford, D.R., Tetley, L. and Dufes, C. (2009) Tumor Regression after Systemic Administration of Tocotrienol Entrapped in Tumor-Targeted Vesicles. Journal of Controlled Release, 140, 95-99.

[222]   Miyosh, N., Wakao, Y., Tomono, S., Tatemichi, M., Yano, T. and Ohshima, H. (2011) The Enhancement of the Oral Bioavailability of Gamma-Tocotrienol in Mice by Gamma-Cyclodextrin Inclusion. The Journal of Nutritional Biochemistry, 22, 1121-1126.

[223]   Fu, J.Y., Zhang, W., Blatchford, D.R., Tetley, L., McConnell, G. and Dufes, C. (2011) Novel Tocotrienol-Entrapping Vesicles Can Eradicate Solid Tumors. Journal of Controlled Release, 154, 20-26.

[224]   Husain, K., Francois, R.A., Yamauchi, T., Pereg, M., Sebti, S.M. and Malafa, M.P. (2011) Vitamin E Delta-Tocotrienol Augments the Antitumor Activity of Gemcitabine and Suppresses Constitutive NF-k B Action in Pancreatic Cancer. Molecular Cancer Therapeutics, 10, 2363-2372.

[225]   Husain, K., Centeno, B.A., Coppla, D., Trevisso, J., Sebti, S.M. and Malafa, M.P. (2017) Delta-Tocotrienol, a Natural Form of Vitamin E, Inhibits Pancreatic Cancer Stem-Like Cells and Prevents Pancreatic Cancer Metastasis. Oncotarget, 8, 31554-31567.

[226]   Vitamin D Receptor-Mediated Stromal Reprogramming Supresses Pancreatitis and Enhances Pancreatic Cancer Therapy. Cell, 159, 80-93.

[227]   Hingorani, S.R., Wang, L., Multani, A.S., Combs, C., Therese B Deramaudt, T.B., Hruban, R.H., Rustgi, A.K., Chang, S. and Tuveson, D.A. (2005) Trp53R172H and KrasG12D Cooperate to Promote Chromosomal Instability and Widely Metastatic Pancreatic Adenocarcinoma. Cancer Cell, 7, 469-483.

[228]   Kong, F., Li, L., Wang, G., Deng, X., Li, Z. and Kong, X. (2019) VDR Signaling Inhibits Cancer Associated-Fibroblasts’ Release of Exosomal miR-10a-5p and Limits Their Supportive Effects on Pancreatic Cancer Cells. Gut, 68, 950-951.

[229]   Sato, N., Kohi, S., Hirata, K. and Goggins, M. (2016) Role of Hyaluronan in Pancreatic Cancer Biology and Therapy: Once again in the Spotlight. Cancer Science, 107, 567-575.

[230]   Shepard, H.M. (2015) Breaching the Castle Walls: Hyaluronan Depletion as a Therapeutic Approach to Cancer Therapy. Frontiers in Oncology, 5, 192.

[231]   Thompson, C.B., Shepard, H.M., Kadhim, S., Jiang, P. and Osgood, R.J. (2010) Enzymatic Depletion of Tumor Hyaluronan Induces Antitumor Responses in Preclinical Animal Models. Molecular Cancer Therapeutics, 9, 3052-3064.

[232]   O’Brien, J., Hayder, H., Zayed, Y. and Peng, C. (2018) Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Frontiers in Endocrinology, 9, 402.

[233]   Zhang, H. and Lu, W. (2018) LncRNA SNHG12 Regulates Gastric Cancer Progression by Acting as a Molecular Sponge of miR-320. Molecular Medicine Reports, 17, 2743-2749.

[234]   Yeung, T.L., Leung, C.S., Wong, K.K., Gutierrez-Hartmann, A., Kwong, J., Gershenson, D.M. and Mok, S.C. (2017) ELF3 Is a Negative Regulator of Epithelial-Mesenchymal Transition in Ovarian Cancer Cells. Oncotarget, 8, 16951-16963.

[235]   Zhang, Z.Q., Zhang, J.K., Li, J.M., Geng, H.J., Zhou, B.J., Zhang, B.X. and Chen, H. (2020) miR-320/ELF3 Axis Inhibits the Progression of Breast Cancer via the PI3K/AKT Pathway. Oncology Letters, 19, 3239-3248.

[236]   Almoguera, C., Shibata, D., Forrester, K., Martin, J., Arnheim, N. and Perucho, M. (1988) Most Human Carcinomas of the Exocrine Pancreas Contain Mutant c-K-ras Genes. Cell, 53, 549-554.

[237]   Campbell, P.M., Groehler, A.L., Lee, K.M., Ouellette, M.M., Khazak, V. and Der, C.J. (2007) K-Ras Promotes Growth Transformation and Invasion of Immortalized Human Pancreatic Cells by Raf and Phosphatidylinositol 3-Kinase Signaling. Cancer Research, 67, 2098-2106.

[238]   Kallifatidis, G., Rausch, V., Baumann, B., Apel, A., Beckermann, B.M., Groth, A., Mattern, J., Li, Z., Kolb, A., Moldenhauer, G., Altevogt, P., Wirth, T., Werner, J., Schemmer, P., Büchler, M.W., Salnikov, A.V. and Herr, I. (2009) Sulforaphane Targets Pancreatic Tumour-Initiating Cells by NF-κB-Induced Antiapoptotic Signalling. Gut, 58, 949-963.

[239]   Agbunag, C. and Bar-Sagi, D. (2004) Oncogenic K-Ras Drives Cell Cycle Progression and Phenotypic Conversion of Primary Pancreatic Duct Epithelial Cells. Cancer Research, 64, 5659-5663.

[240]   Yu, S.N., Lu, Z.H., Liu, C.Z., Meng, Y.X., Ma, Y.H., Zhao, W.G., Liu, J.P., Yu, J. and Chen, J. (2010) miRNA-96 Suppresses KRAS and Functions as a Tumor Suppressor Gene in Pancreatic Cancer. Cancer Research, 70, 6015-6025.

[241]   Apelqvist, Å., Li, H., Sommer, L., Beatus, P., Anderson, D.J., Honjo, T., de Angelis, M.H., Lendahl, U. and Edlund, H. (1999) Notch Signalling Controls Pancreatic Cell Differentiation. Nature, 400, 877-881.

[242]   Raver-Shapira, N., Marciano, E., Meiri, E., Spector, Y., Rosenfeld, N., Moskovits, N., Bentwich, Z. and Oren, M. (2007) Transcriptional Activation of miR-34a Contributes to p53-Mediated Apoptosis. Molecular Cell, 26, 731-743.

[243]   Perumalsamy, L.R., Nagala, M. and Sarin, A. (2010) Notch-Activated Signaling Cascade Interacts with Mitochondrial Remodeling Proteins to Regulate Cell Survival. PNAS, 107, 6882-6887.

[244]   Ji, Q., Hao, X., Zhang, M., Tang, W., Yang, M., Li, L., Xiang, D., Desano, J.T., Bommer, G.T., Fan, D., Fearon, E.R., Lawrence, T.S. and Xu, L. (2009) MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells. PLoS ONE, 4, e6816.

[245]   Niess, H., Camaj, P., Renner, A., Ischenko, I., Zhao, Y., Krebs, S., Mysliwietz, J., Jäckel, C., Nelson, P.J., Blum, H., Jauch, K.W., Ellwart, J.W. and Bruns, C.J. (2014) Side Population Cells of Pancreatic Cancer Show Characteristics of Cancer Stem Cells Responsible for Resistance and Metastasis. Targeted Oncology, 10, 215-227.

[246]   Zhao, Y., Zhao, L., Ischenko, I., Bao, Q., Schwarz, B., Nieß, H., Wang, Y., Renner, A., Mysliwietz, J., Jauch, K.W., Nelson, P.J., Ellwart, J.W., Bruns, C.J. and Camaj, P. (2015) Antisense Inhibition of microRNA-21 and microRNA-221 in Tumor-Initiating Stem-Like Cells Modulates Tumorigenesis, Metastatic, and Chemotherapy Resistance in Pancreatic Cancer. Targeted Oncology, 10, 535-548.

[247]   Park, J.K., Lee, E.J., Esau, C. and Schmittgen, T.D. (2009) Antisense Inhibition of miroRNA-21 or -221 Arrests Cell Cycle, Induces Apoptosis, and Sensitizes the Effects of Gemcitabine in Pancreatic Adenocarcinoma. Pancreas, 38, e190-e199.

[248]   Li, Y., Vanderboom, T.G., Wang, Z., Kong, D., Ali, S., Philip, P.A. and Sarkar, F.H. (2010) miR-146a Suppresses Invasion of Pancreatic Cancer Cells. Cancer Research, 70, 1486-1495.

[249]   Si, W., Liu, X., Wei, R., Zhang, Y., Zhao, Y., Cui, L. and Hong, T. (2019) MTA2-Mediated Inhibition of PTEN Leads to Pancreatic Ductal Adenocarcinoma Carcinogenesis. Cell Death & Disease, 10, 206.

[250]   Bahn, J.H., Zhang, Q., Li, F., Chan, T.M., Lin, X.Z., Kim, Y., Wong, D.T.W. and Xiao, X.S. (2015) The Landscape of MicroRNA, Piwi-Interacting RNA, and Circular RNA in Human Saliva. Clinical Chemistry, 61, 221-230.

[251]   Liu, J., Zhang, X., Yan, M.N. and Li, H. (2020) Emerging Role of Circular RNAs in Cancer. Frontiers in Oncology, 10, 663.

[252]   Ma, L.N., Liu, J., Shen, J.J., Liu, L., Wu, J., Li, W., Luo, J.J., Chen, Q. and Qian, C. (2010) Expression of miR-122 Mediated by Adenoviral Vector Induces Apoptosis and Cell Cycle Arrest of Cancer Cells. Cancer Biology & Therapy, 9, 554-561.

[253]   Gui, Y., Liu, H., Zhang, L., Lv, W. and Hu, X. (2015) Altered microRNA Profiles in Cerebrospinal Fluid Exosome in Parkinson Disease and Alzheimer Disease. Oncotarget, 6, 37043-37053.

[254]   Kölling, M., Haddad, G., Wegmann, U., Kistler, A., Bosakova, A., Seeger, H., Hübel, K., Haller, H., Mueller, T., Wüthrich, R.P. and Lorenzen, J.M. (2019) Transplant Patients with Acute T Cell-Mediated Allograft Rejection. Clinical Chemistry, 65, 1287-1294.

[255]   Li, H.M., Hao, X.K., Wang, H.M., Liu, Z.C., He, Y., Pu, M., Zhang, H.T., Yu, H.C., Duan, J.L. and Qu, S.B. (2016) Circular RNA Expression Profile of Pancreatic Ductal Adenocarcinoma Revealed by Microarray. Cell Physiol Biochem, 40, 1334-1344.

[256]   Li, J., Li, Z.H., Jiang, P., Peng, M.J., Zhang, X., Chen, K., Liu, H., Bi, H.Q., Liu, X.D. and Li, X.W. (2018) Circular RNA IARS (circ-IARS) Secreted by Pancreatic Cancer Cells and Located Within Exosomes Regulates Endothelial Monolayer Permeability to Promote Tumor Metastasis. Journal of Experimental & Clinical Cancer Research, 37, Article ID: 177.

[257]   UniProtKB-Q07157 (ZO1_HUMAN).

[258]   Yang, F., Liu, D.Y., Guo, J.T., Ge, N., Zhu, P., Liu, X., Wang, S., Wang, G.X. and Sun, S.Y. (2017) Circular RNA circ-LDLRAD3 as a Biomarker in Diagnosis of Pancreatic Cancer. World Journal of Gastroenterology, 23, 8345-8354.

[259]   Chen, G., Shi, Y., Zhang, Y. and Sun, J. (2017) CircRNA_100782 Regulates Pancreatic Carcinoma Proliferation through the IL6-STAT3 Pathway. OncoTargets and Therapy, 10, 5783-5794.

[260]   Hao, L.G., Rong, W., Bai, L.J., Cui, H.S., Zhang, S.L., Li, Y.C., Chen, D.T. and Meng, X. (2018) Upregulated Circular RNA circ_0007534 Indicates an Unfavorable Prognosis in Pancreatic Ductal Adenocarcinoma and Regulates Cell Proliferation, Apoptosis, and Invasion by Sponging miR-625 and miR-892b. Journal of Cellular Biochemistry, 120, 3780-3789.

[261]   Li, X.L., Wu, Z.Q., Fu, X.B. and Han, W.D. (2014) LncRNA: Insights into Their Function and Mechanics in Underlying Disorders. Mutation Research-Reviews in Mutation Research, 762, 1-21.

[262]   Takagi, T., Moribe, H., Kondoh, H. and Higashi, Y. (1998) DeltaEF1, a Zinc Finger and Homeodomain Transcription Factor, Is Required for Skeleton Patterning in Multiple Lineages. Development, 125, 21-31.

[263]   Gregory, P.A., Bert, A.G., Peterson, E.L., Barry, S.C., Tsykin, A., Farshid, G., Vadas, M.A., Kew-Goodall, Y. and Goodall, G.J. (2008) The miR-200 Family and miR-205 Regulate Epithelial to Mesenchymal Transition by Targeting ZEB1 and SIP1. Nature Cell Biology, 10, 593-601.

[264]   Niu, K., Shen, W.J., Zhang, Y.H., Zhao, Y. and Lu, Y.X. (2015) miR-205 Promotes Motility of Ovarian Cancer Cells via Targeting ZEB1. Genes, 574, 330-336.

[265]   Song, S.Z., Yu, W.H., Lin, S., Zhang, M.B., Wang, T., Guo, S. and Wang, H.B. (2018) LncRNA ADPGK-AS1 Promotes Pancreatic Cancer Progression through Activating ZEB1-Mediated Epithelial-Mesenchymal Transition. Cancer Biology & Therapy, 19, 573-583.

[266]   Sonohara, F., Yamada, S., Takeda, S., Hayashi, M., Suenaga, M., Sunagawa, Y., Tashiro, M., Takami, H., Kanda, M., Tanaka, C., Kobayashi, D., Nakayama, G., Koike, M., Fujiwara, M. and Kodara, Y. (2020) Exploration of Exosomal Micro RNA Biomarkers Related to Epithelial-to-Mesenchymal Transition in Pancreatic Cancer. Anticancer Research, 40, 1843-1853.

[267]   Xie, F., Huang, Q., Wang, C., Chen, S., Liu, C., Lin, X., Lv, X. and Wang, C. (2020) Downregulation of Long Oncoding RNA SNHG14 Suppresses Cell Proliferation and Invasion by Regulating EZH2 in Pancreatic Ductal Adenocarcinoma (PDAC). Cancer Biomarkers, 27, 357-364.

[268]   Heurtier, V., Owens, N., Gonzalez, I., Mueller, F., Proux, C., Mornico, D., Clerc, P., Dubois, A. and Navarro, P. (2019) The Molecular Logic of Nanog-Induced Self-Renewal in Mouse Embryonic Stem Cells. Nature Communications, 10, 1109.

[269]   Veneti, Z., Gkouskou, K.K. and Eliopoulos, A.G. (2017) Polycomb Repressor Complex 2 in Genomic Instability and Cancer. International Journal of Molecular Sciences, 18, Article 1657, 1-16.

[270]   Han, T., Jiao, F., Hu, H., Yuan, C.C., Wang, L., Jin, Z.L., Song, W.F. and Wang, L.W. (2016) EZH2 Promotes Cell Migration and Invasion but Not Alters Cell Proliferation by Suppressing E-Cadherin, Partly through Association with MALAT-1 in Pancreatic Cancer. Oncotarget, 7, 11194-11207.

[271]   Li, S., Li, Y., Chen, B., Zhao, J., Yu, S., Tang, Y., Zheng, Q., Li, Y., Wang, P., He, X. and Huang, S. (2018) exoRBase: A Database of circRNA, lncRNA and mRNA in Human Blood Exosomes. Nucleic Acids Research, 46, D106-D112.

[272]   Wang, Y.H., Ji, J., Wang, B.C., Chen, H., Yang, Z.H., Wang, K., Luo, C.L., Zhang, W.W., Wang, F.B. and Zhang, X.L. (2018) Tumor-Derived Exosomal Long Noncoding RNAs as Promising Diagnostic Biomarkers for Prostate Cancer. Cell Physiol Biochem, 46, 532-545.

[273]   Lau, C., Kim, Y., Chia, D., Spielmann, N., Eibl, G., Elashoff, D., Wei, F., Lin, Y.L., Moro, A., Grogan, T., Chiang, S., Feinstein, E., Schafer, C., Farrell, J. and Wong, D.T.W. (2013) Role of Pancreatic Cancer-Derived Exosomes in Salivary Biomarker. The Journal of Biological Chemistry, 288, 26888-26897.

[274]   Cheng, L., Sun, X., Scicluna, B.J., Coleman, B.M., Andrew, F. and Hill, A.F. (2014) Characterization and Deep Sequencing Analysis of Exosomal and Non-Exosomal miRNA in Human Urine. Kidney International, 86, 433-444.

[275]   Sagredo, A.I., Santiago, A., Sepulveda, S.A., Roa, J.C. and Oróstica, L. (2017) Exosomes in Bile as Potential Pancreatobiliary Tumor Biomarkers. Translational Cancer Research, 6, S1371-S1383.