Pancreatic cancer stroma: controversies and current insights

References

• Ansari D, Tingstedt B, Andersson B, et al. Pancreatic cancer: yesterday, today and tomorrow. Future Oncol. 2016;12:1929–1946.
   PubMed Web of Science ®Google Scholar
• Bailey P, Chang DK, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531:47–52.
   PubMed Web of Science ®Google Scholar
• Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801–1806.
   PubMed Web of Science ®Google Scholar
• Notta F, Chan-Seng-Yue M, Lemire M, et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature. 2016;538:378–382.
   PubMed Web of Science ®Google Scholar
• Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467:1114–1117.
   PubMed Web of Science ®Google Scholar
• Kong X, Li L, Li Z, et al. Targeted destruction of the orchestration of the pancreatic stroma and tumor cells in pancreatic cancer cases: molecular basis for therapeutic implications. Cytokine Growth Factor Rev. 2012;23:343–356.
   PubMed Web of Science ®Google Scholar
• Nielsen MF, Mortensen MB, Detlefsen S. Key players in pancreatic cancer-stroma interaction: cancer-associated fibroblasts, endothelial and inflammatory cells. WJG. 2016;22:2678–2700.
   PubMed Web of Science ®Google Scholar
• Rhim AD, Oberstein PE, Thomas DH, et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014;25:735–747.
   PubMed Web of Science ®Google Scholar
• Wang Z, Li J, Chen X, et al. Disrupting the balance between tumor epithelia and stroma is a possible therapeutic approach for pancreatic cancer. Med Sci Monit. 2014;20:2002–2006.
   PubMed Web of Science ®Google Scholar
• Duner S, Lopatko Lindman J, Ansari D, et al. Pancreatic cancer: the role of pancreatic stellate cells in tumor progression. Pancreatology. 2010;10:673–681.
   PubMed Web of Science ®Google Scholar
• Korc M. Pancreatic cancer-associated stroma production. Am J Surg. 2007;194:S84–S86.
   PubMed Web of Science ®Google Scholar
• Rath N, Olson MF. Regulation of pancreatic cancer aggressiveness by stromal stiffening. Nat Med. 2016;22:462–463.
   PubMed Web of Science ®Google Scholar
• Spivak-Kroizman TR, Hostetter G, Posner R, et al. Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer. Cancer Res. 2013;73:3235–3247.
   PubMed Web of Science ®Google Scholar
• Pothula SP, Xu Z, Goldstein D, et al. Key role of pancreatic stellate cells in pancreatic cancer. Cancer Lett. 2016;381:194–200.
   PubMed Web of Science ®Google Scholar
• Masamune A, Watanabe T, Kikuta K, et al. Roles of pancreatic stellate cells in pancreatic inflammation and fibrosis. Clin Gastroenterol Hepatol. 2009;7:S48–S54.
   PubMed Web of Science ®Google Scholar
• Hwang RF, Moore T, Arumugam T, et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 2008;68:918–926.
   PubMed Web of Science ®Google Scholar
• Vonlaufen A, Phillips PA, Xu Z, et al. Pancreatic stellate cells and pancreatic cancer cells: an unholy alliance. Cancer Res. 2008;68:7707–7710.
   PubMed Web of Science ®Google Scholar
• Xu Y, Li H, Huang C, et al. Wnt2 protein plays a role in the progression of pancreatic cancer promoted by pancreatic stellate cells. Med Oncol. 2015;32:97.
   PubMed Web of Science ®Google Scholar
• Hamada S, Masamune A, Yoshida N, et al. IL-6/STAT3 plays a regulatory role in the interaction between pancreatic stellate cells and cancer cells. Dig Dis Sci. 2016;61:1561–1571.
   PubMed Web of Science ®Google Scholar
• Pothula SP, Xu Z, Goldstein D, et al. Hepatocyte growth factor inhibition: a novel therapeutic approach in pancreatic cancer. Br J Cancer. 2016;114:269–280.
   PubMed Web of Science ®Google Scholar
• Takikawa T, Masamune A, Hamada S, et al. miR-210 regulates the interaction between pancreatic cancer cells and stellate cells. Biochem Biophys Res Commun. 2013;437:433–439.
   PubMed Web of Science ®Google Scholar
• Kwon JJ, Nabinger SC, Vega Z, et al. Pathophysiological role of microRNA-29 in pancreatic cancer stroma. Sci Rep. 2015;5:11450.
   PubMed Web of Science ®Google Scholar
• Lonardo E, Frias-Aldeguer J, Hermann PC, et al. Pancreatic stellate cells form a niche for cancer stem cells and promote their self-renewal and invasiveness. Cell Cycle. 2012;11:1282–1290.
   PubMed Web of Science ®Google Scholar
• Hamada S, Masamune A, Takikawa T, et al. Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells. Biochem Biophys Res Commun. 2012;421:349–354.
   PubMed Web of Science ®Google Scholar
• Farrow B, Albo D, Berger DH. The role of the tumor microenvironment in the progression of pancreatic cancer. J Surg Res. 2008;149:319–328.
   PubMed Web of Science ®Google Scholar
• Zhou Z, Lu J, Dou J, et al. FHL1 and Smad4 synergistically inhibit vascular endothelial growth factor expression. Mol Med Rep. 2013;7:649–653.
   PubMed Web of Science ®Google Scholar
• Schwarte-Waldhoff I, Schmiegel W. Smad4 transcriptional pathways and angiogenesis. Int J Gastrointest Cancer. 2002;31:47–59.
   PubMedGoogle Scholar
• Guo X, Zhai L, Xue R, et al. Mast cell tryptase contributes to pancreatic cancer growth through promoting angiogenesis via activation of angiopoietin-1. Int J Mol Sci. 2016;17:834.
   PubMed Web of Science ®Google Scholar
• Topalovski M, Brekken RA. Matrix control of pancreatic cancer: new insights into fibronectin signaling. Cancer Lett. 2016;381:252–258.
   PubMed Web of Science ®Google Scholar
• Liu Y, Li F, Gao F, et al. Periostin promotes tumor angiogenesis in pancreatic cancer via Erk/VEGF signaling. Oncotarget. 2016;7:40148–40159.
   PubMed Web of Science ®Google Scholar
• Heinemann V, Reni M, Ychou M, et al. Tumour-stroma interactions in pancreatic ductal adenocarcinoma: rationale and current evidence for new therapeutic strategies. Cancer Treat Rev. 2014;40:118–128.
   PubMed Web of Science ®Google Scholar
• Sada M, Ohuchida K, Horioka K, et al. Hypoxic stellate cells of pancreatic cancer stroma regulate extracellular matrix fiber organization and cancer cell motility. Cancer Lett. 2016;372:210–218.
   PubMed Web of Science ®Google Scholar
• Eguchi D, Ikenaga N, Ohuchida K, et al. Hypoxia enhances the interaction between pancreatic stellate cells and cancer cells via increased secretion of connective tissue growth factor. J Surg Res. 2013;181:225–233.
   PubMed Web of Science ®Google Scholar
• Inman KS, Francis AA, Murray NR. Complex role for the immune system in initiation and progression of pancreatic cancer. World J Gastroenterol. 2014;20:11160–11181.
   PubMed Web of Science ®Google Scholar
• Helm O, Held-Feindt J, Grage-Griebenow E, et al. Tumor-associated macrophages exhibit pro- and anti-inflammatory properties by which they impact on pancreatic tumorigenesis. Int J Cancer. 2014;135:843–861.
   PubMed Web of Science ®Google Scholar
• Grage-Griebenow E, Jerg E, Gorys A, et al. L1CAM promotes enrichment of immunosuppressive T cells in human pancreatic cancer correlating with malignant progression. Mol Oncol. 2014;8:982–997.
   PubMed Web of Science ®Google Scholar
• Gunderson AJ, Kaneda MM, Tsujikawa T, et al. Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. Cancer Discov. 2016;6:270–285.
   PubMed Web of Science ®Google Scholar
• Lunardi S, Jamieson NB, Lim SY, et al. IP-10/CXCL10 induction in human pancreatic cancer stroma influences lymphocytes recruitment and correlates with poor survival. Oncotarget.2014;5:11064–11080.
   PubMed Web of Science ®Google Scholar
• Ene-Obong A, Clear AJ, Watt J, et al. Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology. 2013;145:1121–1132.
   PubMed Web of Science ®Google Scholar
• Demir IE, Friess H, Ceyhan GO. Nerve-cancer interactions in the stromal biology of pancreatic cancer. Front Physiol. 2012;3:97.
   PubMed Web of Science ®Google Scholar
• Ceyhan GO, Schafer KH, Kerscher AG, et al. Nerve growth factor and artemin are paracrine mediators of pancreatic neuropathy in pancreatic adenocarcinoma. Ann Surg. 2010;251:923–931.
   PubMed Web of Science ®Google Scholar
• Zhu Z, Kleeff J, Kayed H, et al. Nerve growth factor and enhancement of proliferation, invasion, and tumorigenicity of pancreatic cancer cells. Mol Carcinog. 2002;35:138–147.
   PubMed Web of Science ®Google Scholar
• Xu Q, Wang Z, Chen X, et al. Stromal-derived factor-1alpha/CXCL12-CXCR4 chemotactic pathway promotes perineural invasion in pancreatic cancer. Oncotarget. 2015;6:4717–4732.
   PubMed Web of Science ®Google Scholar
• Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004;10:858–864.
   PubMed Web of Science ®Google Scholar
• Zagzag D, Lukyanov Y, Lan L, et al. Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Lab Invest. 2006;86:1221–1232.
   PubMed Web of Science ®Google Scholar
• Li X, Wang Z, Ma Q, et al. Sonic hedgehog paracrine signaling activates stromal cells to promote perineural invasion in pancreatic cancer. Clin Cancer Res. 2014;20:4326–4338.
   PubMed Web of Science ®Google Scholar
• Martinez-Bosch N, Fernandez-Barrena MG, Moreno M, et al. Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and Hedgehog signaling activation. Cancer Res. 2014;74:3512–3524.
   PubMed Web of Science ®Google Scholar
• Tang D, Gao J, Wang S, et al. Apoptosis and anergy of T cell induced by pancreatic stellate cells-derived galectin-1 in pancreatic cancer. Tumour Biol. 2015;36:5617–5626.
   PubMed Web of Science ®Google Scholar
• Lim MJ, Ahn J, Yi JY, et al. Induction of galectin-1 by TGF-beta1 accelerates fibrosis through enhancing nuclear retention of Smad2. Exp Cell Res. 2014;326:125–135.
   PubMed Web of Science ®Google Scholar
• Kaleagasioglu F, Berger MR. SIBLINGs and SPARC families: their emerging roles in pancreatic cancer. World J Gastroenterol. 2014;20:14747–14759.
   PubMed Web of Science ®Google Scholar
• Neuzillet C, Tijeras-Raballand A, Cros J, et al. Stromal expression of SPARC in pancreatic adenocarcinoma. Cancer Metastasis Rev. 2013;32:585–602.
   PubMed Web of Science ®Google Scholar
• Von Hoff DD, Ramanathan RK, Borad MJ, et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011;29:4548–4554.
   PubMed Web of Science ®Google Scholar
• Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–1703.
   PubMed Web of Science ®Google Scholar
• Neesse A, Algul H, Tuveson DA, et al. Stromal biology and therapy in pancreatic cancer: a changing paradigm. Gut. 2015;64:1476–1484.
   PubMed Web of Science ®Google Scholar
• Berchtold S, Grunwald B, Kruger A, et al. Collagen type V promotes the malignant phenotype of pancreatic ductal adenocarcinoma. Cancer Lett. 2015;356:721–732.
   PubMed Web of Science ®Google Scholar
• Sato N, Kohi S, Hirata K, et al. Role of hyaluronan in pancreatic cancer biology and therapy: once again in the spotlight. Cancer Sci. 2016;107:569–575.
   PubMed Web of Science ®Google Scholar
• Kaukonen R, Mai A, Georgiadou M, et al. Normal stroma suppresses cancer cell proliferation via mechanosensitive regulation of JMJD1a-mediated transcription. Nat Comms. 2016;7:12237.
   PubMed Web of Science ®Google Scholar
• Laklai H, Miroshnikova YA, Pickup MW, et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat Med. 2016;22:497–505.
   PubMed Web of Science ®Google Scholar
• Lee J, Condello S, Yakubov B, et al. Tissue transglutaminase mediated tumor-stroma interaction promotes pancreatic cancer progression. Clin Cancer Res. 2015;21:4482–4493.
   PubMed Web of Science ®Google Scholar
• Kahlert C, Fiala M, Musso G, et al. Prognostic impact of a compartment-specific angiogenic marker profile in patients with pancreatic cancer. Oncotarget. 2014;5:12978–12989.
   PubMed Web of Science ®Google Scholar
• Franklin O, Ohlund D, Lundin C, et al. Combining conventional and stroma-derived tumour markers in pancreatic ductal adenocarcinoma. CBM. 2015;15:1–10.
   PubMed Web of Science ®Google Scholar
• Ohlund D, Lundin C, Ardnor B, et al. Type IV collagen is a tumour stroma-derived biomarker for pancreas cancer. Br J Cancer. 2009;101:91–97.
   PubMed Web of Science ®Google Scholar
• Erkan M, Michalski CW, Rieder S, et al. The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin Gastroenterol Hepatol. 2008;6:1155–1161.
   PubMed Web of Science ®Google Scholar
• Marechal R, Bachet JB, Calomme A, et al. Sonic hedgehog and Gli1 expression predict outcome in resected pancreatic adenocarcinoma. Clin Cancer Res. 2015;21:1215–1224.
   PubMed Web of Science ®Google Scholar
• Damhofer H, Medema JP, Veenstra VL, et al. Assessment of the stromal contribution to Sonic Hedgehog-dependent pancreatic adenocarcinoma. Mol Oncol. 2013;7:1031–1042.
   PubMed Web of Science ®Google Scholar
• Gundewar C, Sasor A, Hilmersson KS, et al. The role of SPARC expression in pancreatic cancer progression and patient survival. Scand J Gastroenterol. 2015;50:1170–1174.
   PubMed Web of Science ®Google Scholar
• Scaife CL, Shea J, Emerson L, et al. Prognostic significance of PINCH signalling in human pancreatic ductal adenocarcinoma. HPB (Oxford). 2010;12:352–358.
   PubMed Web of Science ®Google Scholar
• Yuzawa S, Kano MR, Einama T, et al. PDGFRbeta expression in tumor stroma of pancreatic adenocarcinoma as a reliable prognostic marker. Med Oncol. 2012;29:2824–2830.
   PubMed Web of Science ®Google Scholar
• Ikenaga N, Ohuchida K, Mizumoto K, et al. CD10+ pancreatic stellate cells enhance the progression of pancreatic cancer. Gastroenterology. 2010;139:1041–1051.
   PubMed Web of Science ®Google Scholar
• Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324:1457–1461.
   PubMed Web of Science ®Google Scholar
• Catenacci DV, Junttila MR, Karrison T, et al. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a Hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015;33:4284–4292.
   PubMed Web of Science ®Google Scholar
• Gore J, Korc M. Pancreatic cancer stroma: friend or foe?. Cancer Cell. 2014;25:711–712.
   PubMed Web of Science ®Google Scholar
• Lee JJ, Perera RM, Wang H, et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc Natl Acad Sci USA. 2014;111:E3091–E3100.
   PubMed Web of Science ®Google Scholar
• Rimkus TK, Carpenter RL, Qasem S, et al. Targeting the sonic Hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancers (Basel). 2016;8:22.
   PubMed Web of Science ®Google Scholar
• Sherman MH, Yu RT, Engle DD, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell. 2014;159:80–93.
   PubMed Web of Science ®Google Scholar
• Guan J, Zhang H, Wen Z, et al. Retinoic acid inhibits pancreatic cancer cell migration and EMT through the downregulation of IL-6 in cancer associated fibroblast cells. Cancer Lett. 2014;345:132–139.
   PubMed Web of Science ®Google Scholar
• Froeling FE, Feig C, Chelala C, et al. Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-beta-catenin signaling to slow tumor progression. Gastroenterology. 2011;141:1486–1497.
   PubMed Web of Science ®Google Scholar
• Chiorean EG, Coveler AL. Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies. Drug Des Devel Ther. 2015;9:3529–3545.
   PubMed Web of Science ®Google Scholar
• Horioka K, Ohuchida K, Sada M, et al. Suppression of CD51 in pancreatic stellate cells inhibits tumor growth by reducing stroma and altering tumor-stromal interaction in pancreatic cancer. Int J Oncol. 2016;48:1499–1508.
   PubMed Web of Science ®Google Scholar