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Titel:The role of MMP3 and Rac1b during development and progression of pancreatic cancer
Autor:Förster, Juliane
Weitere Beteiligte: Buchholz, Malte (Prof.)
Veröffentlicht:2017
URI:https://archiv.ub.uni-marburg.de/diss/z2017/0608
URN: urn:nbn:de:hebis:04-z2017-06083
DOI: https://doi.org/10.17192/z2017.0608
DDC:610 Medizin
Publikationsdatum:2017-11-01
Lizenz:https://creativecommons.org/licenses/by-nc-sa/4.0

Dokument

Schlagwörter:
MMP3, EMT, pancreatic cancer, Pankreatitis, PanIN, Pankreaskarzinom, EMT, PDAC, Pankreatitis, pancreatitis, Rac1b, EMT, Pankreaskarzinom

Summary:
Chronic pancreatitis is a major risk factor for pancreatic ductal adenocarcinoma (PDAC), one of the deadliest cancer types. During the progression to cancer the inflammatory-harmed tissue undergoes formations such as acinar to ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN) and epithelial mesenchymal transition (EMT). Previously it has been shown that MMP3 and Rac1b play important roles during the progression of lung and mammary cancer and transition in different cell lines. To investigate whether MMP3 and Rac1b have an influence on the development and progression of pancreatic cancer, different cell lines for in vitro and two triple transgenic mouse models (rtTA-Ela1/tet-HA-MMP3/tet-KRAs and rtTA-Ela1/tet-YFP-Rac1b/tet-KRas) for in vivo experiments were examined. The in vitro results were achieved by comparing different cell lines to the amount of endogenous MMP3 and Rac1b and the growth behavior. S2-007, an invasive and epithelial cell line, and MiaPaCa, a more mesenchymal behaving cell line, were the most promising ones and used for further investigations. To examine the effects on EMT, the cells were treated with recombinant protein or adenoviral constructs to overexpress MMP3 and Rac1b and screened for EMT marker proteins by RT-qPCR. The results show an influence of MMP3 and Rac1b on EMT machinery mainly in S2-007 cells and less in MiaPaCa cells. In the same way, a higher migration potential in S2-007 cells after MMP3 overexpression was found by using a wound healing assay performed. The infection with adenoviral constructs showed different effects on EMT marker expression compared to the ectopic expression with recombinant proteins. Additionally, both kinds of treatment resulted in higher Rac1b, E-cadherin, and Vimentin expression levels on Plastic than on Matrigel. For in vivo experiments mice were treated for 5 months either with NaCl or Caerulein to induce chronic pancreatitis. The transgene was activated by using a reverse tetracycline-dependent promotor. The expectation that KRas on the background of chronic pancreatitis drives forward the tissue alterations to pancreatic cancer could not be confirmed, but ADM was found, what is one of the pre-stages of PDAC. All these findings suggested that MMP3 and Rac1b seem not to influence the EMT machinery in pancreatic tissue as much as expected, especially under in vivo conditions. Here additional pathways, such as TGFβ or NFκB signaling, seem to prefer Rac1b as interaction partner to promote EMT.

Bibliographie / References

  1. Brentnall, T.A. et al., 1995. Microsatellite instability and K-ras mutations associated with pancreatic adenocarcinoma and pancreatitis. Cancer Research, 55(19), pp.4264-7. Available at: http://cancerres.aacrjournals.org/content/55/19/4264.short%5Cnhttp://www.ncbi.nlm.n ih.gov/pubmed/7671233.
  2. Tjomsland, V. et al., 2016. Profile of MMP and TIMP Expression in Human Pancreatic Stellate Cells: Regulation by IL-1α and TGFβ and Implications for Migration of Pancreatic Cancer Cells. Neoplasia (United States), 18(7), pp.447-456. Available at: http://dx.doi.org/10.1016/j.neo.2016.06.003.
  3. Fiegen, D. et al., 2004. Alternative Splicing of Rac1 Generates Rac1b, a Self-activating GTPase. Journal of Biological Chemistry, 279(6), pp.4743-4749.
  4. Zeisberg, M., Shah, A.A. & Kalluri, R., 2005. Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. Journal of Biological Chemistry, 280(9), pp.8094-8100.
  5. American Cancer Society, 2013. Cancer Facts & Figures 2013. Cancer Facts & Figures, pp.1-9.
  6. American Cancer Society, 2016. Cancer Facts & Figures 2016. Cancer Facts & Figures, pp.1-9.
  7. Thompson, D. & Easton, D.F., 2002. Cancer Incidence in BRCA1 mutation carriers. Journal of the National Cancer Institute, 94(18), pp.1358-1365.
  8. Streff, H. et al., 2016. Cancer Incidence in First-and Second-Degree Relatives of BRCA1 and BRCA2 Mutation Carriers. The Oncologist, pp.1-6.
  9. Nelson, C.M. et al., 2008. Change in CellShape Is Required for Matrix Metalloproteinase- References induced Epithelia-Mesenchymal transition of Mammary Epithelial Cells. Journal of Cell Biochemistry, 105(1), pp.25-33.
  10. Siveke, J.T. et al., 2007. Concomitant Pancreatic Activation of KrasG12D and Tgfa Results in Cystic Papillary Neoplasms Reminiscent of Human IPMN. Cancer Cell, 12(3), pp.266-279.
  11. Imai, K. et al., 1997. Degradation of decorin by matrix metalloproteinases: identification of the cleavage sites, kinetic analyses and transforming growth factor-beta1 release. The Biochemical Journal, 322 ( Pt 3, pp.809-814.
  12. Ito, A. et al., 1996. Degradation of interleukin 1beta by matrix metalloproteinases. The Journal of Biological Chemistry, 271(25), pp.14657-14660.
  13. Song, J., 2007. EMT or apoptosis: a decision for TGF-β. Cell Research, 1725(17), pp.289-290.
  14. Kataoka, H. et al., 1999. Enhanced Tumor Growth and Invasiveness in Vivo by a Carboxyl- Terminal Fragment of ␣ 1-Proteinase Inhibitor Generated by Matrix Metalloproteinases.
  15. Volkholz, H., Stolte, M. & Becker, V., 1982. Epithelial dysplasias in chronic pancreatitis.
  16. Yang, J. & Weinberg, R.A., 2008. Epithelial-Mesenchymal Transition: At the Crossroads of Development and Tumor Metastasis. Developmental Cell, 14(6), pp.818-829.
  17. Alexander, C.M. et al., 1996. Expression and function of matrix metalloproteinases and their inhibitors at the maternal-embryonic boundary during mouse embryo implantation.
  18. Liu, F. et al., 2010. Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression. Journal of Cell Biology, 190(4), pp.693-706.
  19. Löhr, M. et al., 2005. Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta- analysis. Neoplasia, 7(1), pp.17-23. Available at: /pmc/articles/PMC1490318/?report=abstract.
  20. Fujioka, S. et al., 2003. Function of nuclear factor kappaB in pancreatic cancer metastasis. Clinical Cancer Research, 9(1078-0432 (Print)), pp.346-354.
  21. Ferreras, M. et al., 2000. Generation and degradation of human endostatin proteins by various proteinases. FEBS Letters, 486(3), pp.247-251.
  22. Hanahan, D. & Weinberg, R.A., 2011. Hallmarks of cancer: The next generation. Cell, 144(5), pp.646-674.
  23. Zhao, S. et al., 2008. Inhibition of STAT3Tyr705 phosphorylation by Smad4 suppresses transforming growth factor beta-mediated invasion and metastasis in pancreatic cancer cells. Cancer Research, 68(11), pp.4221-4228.
  24. Stolzenberg-Solomon, R.Z. et al., 2005. Insulin, Glucose, Insulin Resistance and Pancreatic Cancer in Male Smokers. Journal of American Medical Association, 294(22).
  25. De Rooij, J. et al., 2005. Integrin-dependent actomyosin contraction regulates epithelial cell scattering. Journal of Cell Biology, 171(1), pp.153-164.
  26. Heuberger, J. & Birchmeier, W., 2010. Interplay of cadherin-mediated cell adhesion and canonical Wnt signaling. Cold Spring Harbor Perspectives in Biology, 2(2), pp.1-24.
  27. Berx, G. & van Roy, F., 2009. Involvement of members of the cadherin superfamily in cancer. References Cold Spring Harbor Perspectives in Biology, 1(6).
  28. Georgatos, S.D. & Blobel, G., 1987. Lamin B constitutes an intermediate filament attachment site at the nuclear envelope. Journal of Cell Biology, 105(1), pp.117-125.
  29. Suzuki, M. et al., 1997. Matrix metalloproteinase-3 releases active heparin-binding EGF-like growth factor by cleavage at a specific juxtamembrane site. Journal of Biological Chemistry, 272(50), pp.31730-31737.
  30. Radisky, D.C. & Bissell, M.J., 2006. Matrix metalloproteinase-induced genomic instability. Current Opinion in Genetic Development, 16(1), pp.45-50.
  31. Witty, J.P., Wright, J.H. & Matrisian, L.M., 1995. Matrix metalloproteinases are expressed during ductal and alveolar mammary morphogenesis, and misregulation of stromelysin-1 in transgenic mice induces unscheduled alveolar development. Molecular Biology of the Cell, 6(10), pp.1287-1303.
  32. Hashimoto, G. et al., 2002. Matrix metalloproteinases cleave connective tissue growth factor and reactivate angiogenic activity of vascular endothelial growth factor 165. Journal of Biological Chemistry, 277(39), pp.36288-36295.
  33. Vu, T.H. & Werb, Z., 2000. Matrix metalloproteinases: Effectors of development and normal physiology. Genes and Development, 14(17), pp.2123-2133.
  34. Lochter, A. et al., 1997. Matrix Metalloproteinase Stromelysin-1 Triggers a Cascade of Molecular Alterations That Leads to Stable Epithelial-to-Mesenchymal Conversion and a Premalignant Phenotype in Mammary Epithelial Cells. The Journal of Cell Biology, 139(7), pp.1861-1872.
  35. Pöpperl, H. et al., 1997. Misexpression of Cwnt8C in the mouse induces an ectopic embryonic axis and causes a truncation of the anterior neuroectoderm. Development, 124(15), pp.2997-3005.
  36. Maitra, A. et al., 2003. Multicomponent Analysis of the Pancreatic Adenocarcinoma Progression Model Using a Pancreatic Intraepithelial Neoplasia Tissue Microarray. Modern Pathology, 16(9), pp.902-912.
  37. Agnihotri, R. et al., 2001. Osteopontin, a Novel Substrate for Matrix Metalloproteinase-3 (Stromelysin-1) and Matrix Metalloproteinase-7 (Matrilysin). Journal of Biological Chemistry, 276(30), pp.28261-28267.
  38. Mergui, X. et al., 2010. p21Waf1 expression is regulated by nuclear intermediate filament vimentin in neuroblastoma. BMC cancer, 10, p.473.
  39. Maitra, A. & Hruban, R.H., 2008. Pancreatic Cancer. Annual Review of Pathology, 3, pp.157- 188.
  40. Lowenfels, A.B. et al., 1993. Pancreatitis and the risk of pancreatic cancer. New England Journal of Medicine, 328(20), pp.1753-1759.
  41. Lynch, H.T. et al., 2002. Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: The familial atypical multiple mole melanoma-pancreatic carcinoma syndrome. Cancer, 94(1), pp.84-96.
  42. Hingorani, S.R. et al., 2003. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell, 4(6), pp.437-450.
  43. Slater, E.P. et al., 2010. Prevalence of BRCA2 and CDKN2a mutations in German familial pancreatic cancer families. Familial Cancer, 9(3), pp.335-343.
  44. Lee, S. et al., 2005. Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. Journal of Cell Biology, 169(4), pp.681-691.
  45. Waldmann, J. et al., Rac1b and MMP-3 can induce Epithelial-to-Mesenchymal-Transition ( EMT ) in alveolar epihelilal type 2 cells and provoke lungfibrosis upon adenoviral endotracheal delivery. , pp.1-15.
  46. Radisky, D.C. et al., 2005. Rac1b and reactive oxygen species mediate MMP3-induced EMT and genomic instability. Nature, 436(7047), pp.123-127.
  47. Schnelzer, A. et al., 2000. Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene, 19(26), pp.3013-3020.
  48. Logsdon, C.D. & Ji, B., 2009. Ras activity in acinar cells links chronic pancreatitis and pancreatic cancer. Clinical Gastroenterology and Hepatology, 7, pp.40-43.
  49. Ji, B. et al., 2009. Ras Activity Levels Control the Development of Pancreatic Diseases. Gastroenterology, 137(3), pp.1072-1082.
  50. Janda, E. et al., 2002. Ras and TGFβ cooperatively regulate epithelial cell plasticity and metastasis: Dissection of Ras signaling pathways. Journal of Cell Biology, 156(2), pp.299- 313.
  51. Hordijk, P.L., 2006. Regulation of NADPH Oxidases: The Role of Rac proteins. Circulation Research, 98(4), pp.453-462.
  52. Blackford, A. et al., 2009. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clinical Cancer Research, 15(14), pp.4674-4679.
  53. Kalluri, R. & Weinberg, R. a, 2009. The basics of epithelial-mesenchymal transition. Journal of Clinical Investigation, 119(6), pp.1420-1428.
  54. Whitelock, J.M. et al., 1996. The Degradation of Human Endothelial Cell-derived Perlecan and Release of Bound Basic Fibroblast Growth Factor by Stromelysin , Collagenase , Plasmin , and Heparanases *. The Journal of Biological Chemistry, 271(17), pp.10079-10086.
  55. Boettner, B. & Van Aelst, L., 2002. The role of Rho GTPases in disease development. Gene, 286(2), pp.155-174.
  56. Barrallo-Gimeno, A. & Nieto, A.M., 2005. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development, 132(14), pp.3151-3161.
  57. Sternlicht, M.D. et al., 1999. The Stromal Proteinase MMP3 / Stromelysin-1 Promotes Mammary Carcinogenesis. Cell, 98, pp.137-146.
  58. Huth, J. et al., 2011. TimeLapseAnalyzer: Multi-target analysis for live-cell imaging and time- lapse microscopy. Computer Methods and Programs in Biomedicine, 104(2), pp.227-234.
  59. Heyne K, Förster J, Schüle R, Roemer K. Transcriptional repressor NIR interacts with the p53-inhibiting ubiquitin ligase MDM2; Nucleic Acids Res. 2014; 42(6):3565-79
  60. Ellenrieder, V. et al., 2001. Transforming Growth Factor β1 Treatment Leads to an Epithelial- Mesenchymal Transdifferentiation of Pancreatic Cancer Cells Requiring Extracellular Signal-regulated Kinase 2 Activation. Cancer Research, pp.1-8.
  61. Mehner, C. et al., 2014. Tumor Cell-derived MMP-3 Orchestrates Rac1b and Tissue Alterations that Promote Pancreatic Adenocarcinoma. Molecular Cancer Research, 12(10), pp.1430- 1439.
  62. Mehner, C. et al., 2015. Tumor cell expression of MMP3 as a prognostic factor for poor survival in pancreatic, pulmonary, and mammary carcinoma. Genes & Cancer, 6(11-12), pp.480- 489.
  63. Matos, P., Collard, J.G. & Jordan, P., 2003. Tumor-related Alternatively Spliced Rac1b Is Not Regulated by Rho-GDP Dissociation Inhibitors and Exhibits Selective Downstream Signaling. Journal of Biological Chemistry, 278(50), pp.50442-50448.
  64. Phua, D.C., Humbert, P.O. & Hunziker, W., 2009. Vimentin Regulates Scribble Activity by Protecting it from Protesasomal Degradation. Molecular Biology of the Cell, 20(4), pp.2841-2855.
  65. Ungefroren, H. et al., 2014. Rac1b negatively regulates TGF-β1-induced cell motility in pancreatic ductal epithelial cells by suppressing Smad signalling. Oncotarget, 5(1), pp.1- 28. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960208/.
  66. Liu, P. et al., 1999. Requirement for Wnt3 in vertebrate axis formation. Nature Genetics, 22(4), pp.361-5. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10431240 [Accessed May References 22, 2016].
  67. MacCallum, D.E. & Hall, P.A., 1999. Biochemical characterization of pKi67 with the identification of a mitotic-specific form associated with hyperphosphorylation and altered DNA binding. Experimental cell research, 252(1), pp.186-98. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10502411 [Accessed December 1, 2016].
  68. Giehl, K. et al., 2000. TGFbeta1 represses proliferation of pancreatic carcinoma cells which correlates with Smad4-independent inhibition of ERK activation. Oncogene, 19(39), pp.4531-41. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11002426.
  69. Balkwill, F. & Mantovani, A., 2001. Inflammation and cancer: back to Virchow? Lancet, 357(9255), pp.539-45. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11229684 [Accessed February 12, 2015].
  70. Vetter, I.R. & Wittinghofer, A., 2001. The guanine nucleotide-binding switch in three dimensions. Science, 294(5545), pp.1299-304. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11701921 [Accessed August 18, 2016].
  71. Ridley, A.J., 2001. Rho family proteins: coordinating cell responses. Trends in Cell Biology, 11(12), pp.471-7. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11719051 [Accessed August 18, 2016].
  72. Egeblad, M. & Werb, Z., 2002. New functions for the matrix metalloproteinases in cancer progression. Nature Reviews Cancer, 2(3), pp.161-74. Available at: References http://www.ncbi.nlm.nih.gov/pubmed/11990853 [Accessed August 24, 2016].
  73. McQuibban, G.A. et al., 2002. Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti- inflammatory properties in vivo. Blood, 100(4), pp.1160-7. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12149192.
  74. Thiery, J.P., 2002. Epithelial-mesenchymal transitions in tumour progression. Nature Reviews Cancer, 2(6), pp.442-54. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12189386 [Accessed October 19, 2016].
  75. Overall, C.M., 2002. Molecular determinants of metalloproteinase substrate specificity: matrix metalloproteinase substrate binding domains, modules, and exosites. Molecular Biotechnology, 22(1), pp.51-86. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12353914 [Accessed August 24, 2016].
  76. Hahn, S.A. et al., 2003. BRCA2 germline mutations in familial pancreatic carcinoma. Journal of the National Cancer Institute, 95(3), pp.214-21. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12569143.
  77. Sahai, E. & Marshall, C.J., 2002. RHO-GTPases and cancer. Nature Reviews Cancer, 2(2), pp.133-42. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12635176 [Accessed August 18, 2016].
  78. Thun, M.J., Henley, S.J. & Gansler, T., 2004. Inflammation and cancer: an epidemiological perspective. Novartis Foundation Symposium, 256, pp.6-21-8, 49-52, 266-9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15027481 [Accessed August 6, 2016].
  79. Singh, A. et al., 2004. Rac1b, a tumor associated, constitutively active Rac1 splice variant, promotes cellular transformation. Oncogene, 23(58), pp.9369-80. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15516977 [Accessed March 27, 2014].
  80. Matos, P. & Jordan, P., 2005. Expression of Rac1b stimulates NF-kappaB-mediated cell survival and G1/S progression. Experimental Cell Research, 305(2), pp.292-9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15817154 [Accessed August 18, 2016].
  81. Huber, M.A., Kraut, N. & Beug, H., 2005. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Current Opinion in Cell Biology, 17(5), pp.548-58. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16098727 [Accessed May 12, 2016].
  82. Deramaudt, T. & Rustgi, A.K., 2005. Mutant KRAS in the initiation of pancreatic cancer. Biochimica et biophysica acta, 1756(2), pp.97-101. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16169155 [Accessed August 6, 2016].
  83. Bierie, B. & Moses, H.L., 2006. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nature Reviews Cancer, 6(7), pp.506-20. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16794634 [Accessed March 13, 2016].
  84. Perlson, E. et al., 2006. Vimentin binding to phosphorylated Erk sterically hinders enzymatic dephosphorylation of the kinase. Journal of molecular biology, 364(5), pp.938-44. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17046786 [Accessed October 19, 2016].
  85. Couch, F.J. et al., 2007. The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiology, Biomarkers & Prevention, 16(2), pp.342-6. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17301269.
  86. Guerra, C. et al., 2007. Chronic Pancreatitis Is Essential for Induction of Pancreatic Ductal Adenocarcinoma by K-Ras Oncogenes in Adult Mice. Cancer Cell, 11(3), pp.291-302. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17349585 [Accessed January 20, References
  87. Singh, M. & Maitra, A., 2007. Precursor lesions of pancreatic cancer: molecular pathology and clinical implications. Pancreatology, 7(1), pp.9-19. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17449961 [Accessed August 6, 2016].
  88. Peinado, H., Olmeda, D. & Cano, A., 2007. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nature Reviews Cancer, 7(6), pp.415-428. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17508028 [Accessed October 6, 2015].
  89. Orlichenko, L.S. & Radisky, D.C., 2008. Matrix metalloproteinases stimulate epithelial- mesenchymal transition during tumor development. Clinical & Experimental Metastasis, 25(6), pp.593-600. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18286378 [Accessed August 11, 2016].
  90. Thiery, J.P. et al., 2009. Epithelial-mesenchymal transitions in development and disease. Cell, 139(5), pp.871-90. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19945376 [Accessed July 10, 2014].
  91. Nagase, H. & Woessner, F.J.J., 1999. Matrix metalloproteinases. The Journal of Biological Chemistry, 1803(1), pp.1-2. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20159302.
  92. Maier, H.J., Schmidt-Strassburger, U., et al., 2010. NF-kappaB promotes epithelial- mesenchymal transition, migration and invasion of pancreatic carcinoma cells. Cancer Letters, 295(2), pp.214-28. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20350779 [Accessed August 8, 2016].
  93. Ikushima, H. & Miyazono, K., 2010. TGFbeta signalling: a complex web in cancer progression. Nature Reviews Cancer, 10(6), pp.415-24. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20495575 [Accessed October 29, 2015].
  94. Raimondi, S. et al., 2010. Pancreatic cancer in chronic pancreatitis; aetiology, incidence, and early detection. Best Practice & Research Clinical Gastroenterology, 24(3), pp.349-58. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20510834 [Accessed March 23, 2014].
  95. Nieto, A.M., 2011. The ins and outs of the epithelial to mesenchymal transition in health and disease. Annual Review of Cell and Developmental Biology, 27, pp.347-76. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21740232 [Accessed August 8, 2016].
  96. Aune, D. et al., 2012. Body mass index, abdominal fatness and pancreatic cancer risk: a systematic review and non-linear dose-response meta-analysis of prospective studies. Annals of oncology, 23(4), pp.843-52. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21890910 [Accessed March 20, 2014].
  97. Almoguera, C. et al., 1988. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell, 53(4), pp.549-54. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2453289 [Accessed April 6, 2016].
  98. Gerdes, J. et al., 1983. Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. International journal of cancer, 31(1), pp.13-20. Available at: http://www.ncbi.nlm.nih.gov/pubmed/6339421 [Accessed December 1, 2016].
  99. Traub, P. & Shoeman, R.L., 1994. Intermediate filament proteins: cytoskeletal elements with gene-regulatory function? International review of cytology, 154, pp.1-103. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8083030 [Accessed October 19, 2016].
  100. Ekbom, A. et al., 1994. Pancreatitis and pancreatic cancer: a population-based study. Journal of the National Cancer Institute, 86(8), pp.625-7. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8145277 [Accessed August 6, 2016].
  101. Stetler-Stevenson, W.G., Hewitt, R. & Corcoran, M., 1996. Matrix metalloproteinases and tumor invasion: from correlation and causality to the clinic. Seminars in Cancer Biology, 7(3), pp.147-54. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8773300 [Accessed August 16, 2016].
  102. Tanaka, M. et al., 1998. Downregulation of Fas ligand by shedding. Nature Medicine, 4(1), pp.31-6. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9427603 [Accessed August 24, 2016].
  103. Kheradmand, F. et al., 1998. Role of Rac1 and oxygen radicals in collagenase-1 expression induced by cell shape change. Science, 280(5365), pp.898-902. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9572733 [Accessed August 26, 2016].
  104. Bartsch, D.K. et al., 2002. CDKN2A germline mutations in familial pancreatic cancer. Annals of surgery, 236(6), pp.730-7. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1422639&tool=pmcentrez& rendertype=abstract.
  105. Berrington de Gonzalez, A., Sweetland, S. & Spencer, E., 2003. A meta-analysis of obesity and the risk of pancreatic cancer. British Journal of Cancer, 89(3), pp.519-23. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2394383&tool=pmcentrez& rendertype=abstract [Accessed March 26, 2014].
  106. Hassan, M.M. et al., 2008. Association between hepatitis B virus and pancreatic cancer. Journal of Clinical Oncology, 26(28), pp.4557-62. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2562875&tool=pmcentrez& rendertype=abstract [Accessed April 8, 2014].
  107. Koorstra, J.-B.M. et al., 2008. Pancreatic carcinogenesis. Pancreatology, 8(2), pp.110-25. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2663569&tool=pmcentrez& rendertype=abstract [Accessed February 16, 2014].
  108. Lee, K. et al., 2012. Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial-mesenchymal transition. Molecular Biology of the Cell, 23(20), pp.4097- 108. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3469523&tool=pmcentrez& rendertype=abstract.
  109. Stallings-Mann, M.L. et al., 2012. Matrix Metalloproteinase Induction of Rac1b, a Key Effector of Lung Cancer Progression. Science Translational Medicine, 4(142), pp.1-24. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3733503&tool=pmcentrez& rendertype=abstract [Accessed March 9, 2014].
  110. Chen, Q.K. et al., 2013. Extracellular matrix proteins regulate epithelial-mesenchymal transition in mammary epithelial cells. Differentiation; research in biological diversity, 86(3), pp.126-32. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3762919&tool=pmcentrez& rendertype=abstract.
  111. Maier, H.J., Wirth, T. & Beug, H., 2010. Epithelial-mesenchymal transition in pancreatic References carcinoma. Cancers, 2(4), pp.2058-83. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3840444&tool=pmcentrez& rendertype=abstract [Accessed May 13, 2015].


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