Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2019

Open Access 01-12-2019 | Metastasis | Review

Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis

Authors: Divya Thomas, Prakash Radhakrishnan

Published in: Molecular Cancer | Issue 1/2019

Login to get access

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with high morbidity and mortality worldwide. To date, limited therapeutic achievements targeting cell proliferation and related mechanisms has led researchers to focus on the microenvironment where pancreatic cancers develop. The anomalous proliferation of stromal cells, such as pancreatic stellate cells, and an increased deposition of altered matrix proteins create an environment that facilitates tumor growth, metastasis and drug resistance. Here, we summarize our understanding of recent advances in research about the role of fibrosis in pancreatic cancer progression, with particular emphasize on the involvement of fibrotic machineries such as wound healing, extra cellular matrix degradation, and epithelial-to-mesenchymal transition. The precise influence of these mechanisms on the biological behaviors and growth of cancer cells has great impact on clinical therapy and therefore deserves more attention. We also discuss the role of various stromal components in conferring drug resistance to PDAC which further worsening the pessimistic disease prognosis. A more in depth understanding of cancer-stroma crosstalk within the tumor microenvironment and stroma based clinical and translational therapies may provide new therapeutic strategies for the prevention of pancreatic cancer progression.
Literature
1.
Noone AM, Howlader N, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin(eds) KA. SEER Cancer Statistics Review. 1975–2015, National Cancer Institute. https://​seer.​cancer.​gov/​csr/​1975_​2015/​, based on November 2017 SEER data submission, posted to the SEER web site, April 2018. Accessed 10 Sept 20108.
2.
Sidaway P. Pancreatic cancer: TCGA data reveal a highly heterogeneous disease. Nat Rev Clin Oncol. 2017;14(11):648.PubMed
3.
Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913–21.CrossRefPubMed
4.
Winter JM, Brennan MF, Tang LH, D'Angelica MI, Dematteo RP, Fong Y, Klimstra DS, Jarnagin WR, Allen PJ. Survival after resection of pancreatic adenocarcinoma: results from a single institution over three decades. Ann Surg Oncol. 2012;19(1):169–75.PubMedCrossRef
5.
Castellanos E, Berlin J, Cardin DB. Current treatment options for pancreatic carcinoma. Curr Oncol Rep. 2011;13(3):195–205.PubMedCrossRef
6.
Collins MA, Bednar F, Zhang Y, Brisset JC, Galbán S, Galbán CJ, Rakshit S, Flannagan KS, Adsay NV, Pasca di Magliano M. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest. 2012;122(2):639–53.PubMedPubMedCentralCrossRef
7.
Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, Locasale JW, Son J, Zhang H, Coloff JL, Yan H, Wang W, Chen S, Viale A, Zheng H, Paik JH, Lim C, Guimaraes AR, Martin ES, Chang J, Hezel AF, Perry SR, Hu J, Gan B, Xiao Y, Asara JM, Weissleder R, Wang YA, Chin L, Cantley LC, DePinho RA. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell. 2012;149(3):656–70.PubMedPubMedCentralCrossRef
8.
Redston MS, Caldas C, Seymour AB, Hruban RH, da Costa L, Yeo CJ, Kern SE. p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res. 1994;54(11):3025–33.PubMed
9.
Carnevale J, Ashworth A. Assessing the significance of BRCA1 and BRCA2 mutations in pancreatic Cancer. J Clin Oncol. 2015;33(28):3080–1.PubMedCrossRef
10.
D M, Pierreux CE, Howell M, Wilentz RE, Owen MJ, Hill CSD. Loss of Smad4 function in pancreatic tumors: C-terminal truncation leads to decreased stability. J Biol Chem. 2001;276(46):43175–81.CrossRef
11.
Desmeules, Giroux M, Beaulieu M, Richard P. Neoplastic aspect of a case of interstitial pulmonary fibrosis. Laval Med. 1955;20(10):1315–25.PubMed
12.
Themel KG, Luders CJ. The role of tuberculous scars in the pathogenesis of peripheral lung carcinoma; a contribution to the symptomatology of cancer of the pulmonary scars. Dtsch Med Wochenschr. 1955;80(37):1360–3.PubMedCrossRef
13.
14.
matrix MKE. Preconditioning the ECM for fibrosis. Nat Rev Mol Cell Biol. 2014;15(12):766–7.
15.
16.
17.
18.
19.
Kopfstein L, Christofori G. Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment. Cell Mol Life Sci. 2006;63(4):449–68.PubMedCrossRef
20.
21.
Takeuchi S, Doi M, Ikari N, Yamamoto M, Furukawa T. Mutations in BRCA1, BRCA2, and PALB2, and a panel of 50 cancer-associated genes in pancreatic ductal adenocarcinoma. Sci Rep. 2018;8(1):8105.PubMedPubMedCentralCrossRef
22.
23.
24.
Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. J Cell Sci. 2012;125(Pt 23):5591–6.PubMedCrossRef
25.
Bidard FC, Pierga JY, Vincent-Salomon A, Poupon MF. “Class action” against the microenvironment: do cancer cells cooperate in metastasis? Cancer Metastasis Rev. 2008;27(1):5–10.PubMedPubMedCentralCrossRef
26.
27.
J H, LM H, G G, MS M, WP S, AR D. Pancreatic stellate cells and pancreas cancer: current perspectives and future strategies. Eur J Cancer. 2014;50(15):2570–82.CrossRef
28.
Kayed H, Kleeff J, Osman T, Keleg S, Buchler MW, Friess H. Hedgehog signaling in the normal and diseased pancreas. Pancreas. 2006;32(2):119–29.PubMedCrossRef
29.
Maitra A. Tracking down the hedgehog's lair in the pancreas. Gastroenterology. 2010;138(3):823–5.PubMedCrossRef
30.
Menke A, Yamaguchi H, Gress TM, Adler G. Extracellular matrix is reduced by inhibition of transforming growth factor beta1 in pancreatitis in the rat. Gastroenterology. 1997;113(1):295–303.PubMedCrossRef
31.
Masamune A, Watanabe T, Kikuta K, Shimosegawa T. Roles of pancreatic stellate cells in pancreatic inflammation and fibrosis, Clin. Gastroenterol Clin Gastroenterol Hepatol. 2009;7(11 Suppl):S48–54.PubMedCrossRef
32.
Chen S, Chen X, Shan T, Ma J, Lin W, Li W, Kang Y. MiR-21-mediated metabolic alteration of Cancer-associated fibroblasts and its effect on pancreatic Cancer cell behavior. Int J Biol Sci. 2018;14(1):100–10.PubMedPubMedCentralCrossRef
33.
Takahashi K, Ehata S, Koinuma D, Morishita Y, Soda M, Mano H, Miyazono K. Pancreatic tumor microenvironment confers highly malignant properties on pancreatic cancer cells. Oncogene. 2018;37(21):2757–72.PubMedPubMedCentralCrossRef
34.
Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV, De Jesus-Acosta A, Sharma P, Heidari P, Mahmood U, Chin L, Moses HL, Weaver VM, Maitra A, Allison JP, LeBleu VS, Kalluri R. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014;25(6):719–34.PubMedPubMedCentralCrossRef
35.
Erkan M, Michalski CW, Rieder S, Reiser-Erkan C, Abiatari I, Kolb A, Giese NA, Esposito I, Friess H, Kleeff J. The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin Gastroenterol Hepatol. 2008;6(10):1155–61.PubMedCrossRef
36.
Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321(5897):1801–6.PubMedPubMedCentralCrossRef
37.
Vogelmann R, Ruf D, Wagner M, Adler G, Menke A. Effects of fibrogenic mediators on the development of pancreatic fibrosis in a TGF-beta1 transgenic mouse model. Am J Physiol Gastrointest Liver Physiol. 2001;280(1):G164–72.PubMedCrossRef
38.
Ostapoff KT, Cenik BK, Wang M, Ye R, Xu X, Nugent D, Hagopian MM, Topalovski M, Rivera LB, Carroll KD, Brekken BRA. Neutralizing murine TGFβR2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis. Cancer Res. 2014;74(18):4996–5007.PubMedPubMedCentralCrossRef
39.
Principe DR, DeCant B, Mascarinas E, Wayne EA, Diaz AM, Akagi N, Hwang R, Pasche B, Dawson DW, Fang D, Bentrem DJ, Munshi HG, Jung B, Grippo PJ. TGFβ signaling in the pancreatic tumor Microenvironment promotes fibrosis and immune evasion to facilitate tumorigenesis. Cancer Res. 2016;76(9):2525–39.PubMedPubMedCentralCrossRef
40.
41.
Vonlaufen A, Phillips PA, Xu Z, Goldstein D, Pirola RC, Wilson JS, Apte MV. Pancreatic stellate cells and pancreatic cancer cells: an unholy alliance. Cancer Res. 2008;68(19):7707–10.PubMedCrossRef
42.
43.
Menke A, Adler G. TGFbeta-induced fibrogenesis of the pancreas. Int J Gastrointest Cancer. 2002;31(1–3):41–6.PubMedCrossRef
44.
TCY P, Wilson JS, Apte MV. Pancreatic stellate cells: what's new? Curr Opin Gastroenterol. 2017;33(5):366–73.CrossRef
45.
Olivares MJR, Gouirand V, Torrence ME, Gicquel T, Borge L, Lac S, Roques J, Lavaut MN, Berthezene P, Rubis M, Secq V, Garcia S, Moutardier V, Lombardo D, Iovanna JL, Tomasini R, Guillaumond F, Vander Heiden MG, Vasseur S. Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. Nat Commun. 2017;8:16031.PubMedPubMedCentralCrossRef
46.
Jaster R, Sparmann G, Emmrich J, Liebe S. Extracellular signal regulated kinases are key mediators of mitogenic signals in rat pancreatic stellate cells. Gut. 2002;51(4):579–84.PubMedPubMedCentralCrossRef
47.
Angelescu R, Burada F, Angelescu C, Gheonea DI, Iordache S, Mixich F, Ioana M, Săftoiu A. Expression of vascular endothelial growth factor and epidermal growth factor receptor in pancreatic ductal adenocarcinomas, neuroendocrine tumours and chronic pancreatitis. Endosc Ultrasound. 2013;2(2):86–91.PubMedPubMedCentralCrossRef
48.
Kikuta K, Masamune A, Watanabe T, Ariga H, Itoh H, Hamada S, Satoh K, Egawa S, Unno M, Shimosegawa T. Pancreatic stellate cells promote epithelial-mesenchymal transition in pancreatic cancer cells. Biochem Biophys Res Commun. 2010;403(3–4):380–4.PubMedCrossRef
49.
Pothula SP, Xu Z, Goldstein D, Pirola RC, Wilson JS, Apte MV. Key role of pancreatic stellate cells in pancreatic cancer. Cancer Lett. 2016;381(1):194–200.PubMedCrossRef
50.
Aterman K. The parasinusoidal cells of the liver: a historical account. Histochem J. 1986;18(6):279–305.PubMedCrossRef
51.
Watari N, Hotta Y, Mabuchi Y. Morphological studies on a vitamin A-storing cell and its complex with macrophage observed in mouse pancreatic tissues following excess vitamin a administration. Okajimas Folia Anat Jpn. 1982;58(4–6):837–58.PubMedCrossRef
52.
Erkan M, Adler G, Apte MV, Bachem MG, Buchholz M, Detlefsen S, Esposito I, Friess H, Gress TM, Habisch HJ, Hwang RF, Jaster R, Kleeff J, Kloppel G, Kordes C, Logsdon CD, Masamune A, Michalski CW, Oh J, Phillips PA, Pinzani M, Reiser-Erkan C, Tsukamoto H, Wilson J, Stella TUM. Current consensus and discussion on pancreatic stellate cell research. Gut. 2012;61(2):172–8.PubMedCrossRef
53.
Mews P, Phillips P, Fahmy R, Korsten M, Pirola R, Wilson J, Apte M. Pancreatic stellate cells respond to inflammatory cytokines: potential role in chronic pancreatitis. Gut. 2002;50(4):535–41.PubMedPubMedCentralCrossRef
54.
MJ B, Seiz O, Nast JF, Benten D, Bläker M, Koch J, Lohse AW, Pace A. CCK1 and CCK2 receptors are expressed on pancreatic stellate cells and induce collagen production. J Biol Chem. 2010;285(50):38905–14.CrossRef
55.
Mato E, Lucas M, Petriz J, Gomis R, Novials A. Identification of a pancreatic stellate cell population with properties of progenitor cells: new role for stellate cells in the pancreas. Biochem J. 2009;421(2):181–91.PubMedCrossRef
56.
Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, Menke A, Siech M, Beger H, Grünert A, Adler G. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology. 1998;115(2):421–32.PubMedCrossRef
57.
Xu Z, Vonlaufen A, Phillips PA, Fiala-Beer E, Zhang X, Yang L, Biankin AV, Goldstein D, Pirola RC, Wilson JS, Apte MV. Role of pancreatic stellate cells in pancreatic cancer metastasis. Am J Pathol. 2010;177(5):2585–96.PubMedPubMedCentralCrossRef
58.
Eguchi D, Ikenaga N, Ohuchida K, Kozono S, Cui L, Fujiwara K, Fujino M, Ohtsuka T, Mizumoto K, Tanaka M. Hypoxia enhances the interaction between pancreatic stellate cells and cancer cells via increased secretion of connective tissue growth factor. J Surg Res. 2013;181(2):225–33.PubMedCrossRef
59.
Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986;315(26):1650–9.PubMedCrossRef
60.
Barcellos-Hoff MH, Lyden D, Wang TC. The evolution of the cancer niche during multistage carcinogenesis. Nat Rev Cancer. 2013;13(7):511–8.PubMedCrossRef
61.
62.
Schneider A, Whitcomb DC. Hereditary pancreatitis: a model for inflammatory diseases of the pancreas. Best Pract Res Clin Gastroenterol. 2002;16(3):347–63.PubMedCrossRef
63.
Chambers RC, Scotton CJ. Coagulation cascade proteinases in lung injury and fibrosis. Proc Am Thorac Soc. 2012;9(3):96–101.PubMedCrossRef
64.
Midwood KS, Williams LV, Schwarzbauer JE. Tissue repair and the dynamics of the extracellular matrix. Int J Biochem Cell Biol. 2004;36(6):1031–7.PubMedCrossRef
65.
DiGiacomo JW, Gilkes DM. Tumor hypoxia as an enhancer of inflammation-mediated metastasis: emerging therapeutic strategies. Target Oncol. 2018;13(2):157–73.PubMedCrossRef
66.
Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003;3(4):347–61.PubMedCrossRef
67.
Zhang X, Liu L, Wei X, Tan YS, Tong L, Chang R, Ghanamah MS, Reinblatt M, Marti GP, Harmon JW, Semenza GL. Impaired angiogenesis and mobilization of circulating angiogenic cells in HIF-1alpha heterozygous-null mice after burn wounding. Wound Repair Regen. 2010;18(2):193–201.PubMedPubMedCentralCrossRef
68.
Li N, Li Y, Li Z, Huang C, Yang Y, Lang M, Cao J, Jiang W, Xu Y, Dong J, Ren H. Hypoxia Inducible Factor 1 (HIF-1) Recruits Macrophage to Activate Pancreatic Stellate Cells in Pancreatic Ductal Adenocarcinoma. Int J Mol Sci. 2016;17(6).
69.
Masamune A, Kikuta K, Watanabe T, Satoh K, Hirota M, Shimosegawa T. Hypoxia stimulates pancreatic stellate cells to induce fibrosis and angiogenesis in pancreatic cancer. Am J Physiol Gastrointest Liver Physiol. 2008;295(4):G709–17.PubMedCrossRef
70.
Bosco MC, Puppo M, Pastorino S, Mi Z, Melillo G, Massazza S, Rapisarda A, Varesio L. Hypoxia selectively inhibits monocyte chemoattractant protein-1 production by macrophages. J Immunol. 2004;172(3):1681–90.PubMedCrossRef
71.
Mojsilovic-Petrovic J, Callaghan D, Cui H, Dean C, Stanimirovic DB, Zhang W. Hypoxia-inducible factor-1 (HIF-1) is involved in the regulation of hypoxia-stimulated expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and MCP-5 (Ccl12) in astrocytes. J Neuroinflammation. 2007;4:12.PubMedPubMedCentralCrossRef
72.
Ishida Y, Kimura A, Kuninaka Y, Inui M, Matsushima K, Mukaida N, Kondo T. Pivotal role of the CCL5/CCR5 interaction for recruitment of endothelial progenitor cells in mouse wound healing. J Clin Invest. 2012;122(2):711–21. https://​doi.​org/​10.​1172/​JCI43027.
73.
Zhang W, Smith C, Shapiro A, Monette R, Hutchison J, Stanimirovic D. Increased expression of bioactive chemokines in human cerebromicrovascular endothelial cells and astrocytes subjected to simulated ischemia in vitro. J Neuroimmunol. 1999;101(2):148–60.PubMedCrossRef
74.
Low QE, Drugea IA, Duffner LA, Quinn DG, Cook DN, Rollins BJ, Kovacs EJ, DiPietro LA. Wound healing in MIP-1alpha(−/−) and MCP-1(−/−) mice. Am J Pathol. 2001;159(2):457–63.PubMedPubMedCentralCrossRef
75.
C G, Collado M, Navas C, Schuhmacher AJ, Hernández-Porras I, Cañamero M, Rodriguez-Justo M, Serrano M, Barbacid M. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell. 2011;19(6):728–39.CrossRef
76.
Erkan M, Hausmann S, Michalski CW, Fingerle AA, Dobritz M, Kleeff J, Friess H. The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol Hepatol. 2012;9(8):454–67.PubMedCrossRef
77.
Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357(9255):539–45.PubMedCrossRef
78.
Baumgart S, Ellenrieder V, Fernandez-Zapico ME. Oncogenic transcription factors: cornerstones of inflammation-linked pancreatic carcinogenesis. Gut. 2013;62(2):310–6.PubMedCrossRef
79.
Hiraoka N, Yamazaki-Itoh R, Ino Y, Mizuguchi Y, Yamada T, Hirohashi S, Kanai Y. CXCL17 and ICAM2 are associated with a potential anti-tumor immune response in early intraepithelial stages of human pancreatic carcinogenesis. Gastroenterology. 2011;140(1):310–21.PubMedCrossRef
80.
McCawley LJ, Matrisian LM. Tumor progression: defining the soil round the tumor seed. Curr Biol. 2001;11(1):R25–7.PubMedCrossRef
81.
Bauer C, Kuhnemuth B, Duewell P, Ormanns S, Gress T, Schnurr M. Prevailing over T cell exhaustion: new developments in the immunotherapy of pancreatic cancer. Cancer Lett. 2016;381(1):259–68.PubMedCrossRef
82.
Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 2007;67(19):9518–27.PubMedCrossRef
83.
Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Andersen JR, Dimagno EP, Andrén-Sandberg A, Domellof L. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med. 1993;328(20):1433–7.PubMedCrossRef
84.
Ochi A, Graffeo CS, Zambirinis CP, Rehman A, Hackman M, Fallon N, Barilla RM, Henning JR, Jamal M, Rao R, Greco S, Deutsch M, Medina-Zea MV, Bin Saeed U, Ego-Osuala MO, Hajdu C, Miller G. Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans. J Clin Invest. 2012;122(11):4118–29.PubMedPubMedCentralCrossRef
85.
Hurwitz H, Van Cutsem E, Bendell J, Hidalgo M, Li CP, Salvo MG, Macarulla T, Sahai V, Sama A, Greeno E, Yu KH, Verslype C, Dawkins F, Walker C, Clark J, O'Reilly EM. Ruxolitinib + capecitabine in advanced/metastatic pancreatic cancer after disease progression/intolerance to first-line therapy: JANUS 1 and 2 randomized phase III studies. Investig New Drugs. 2018;36(4):683–95.CrossRef
86.
Aoyagi Y, Oda T, Kinoshita T, Nakahashi C, Hasebe T, Ohkohchi N, Ochiai A. Overexpression of TGF-beta by infiltrated granulocytes correlates with the expression of collagen mRNA in pancreatic cancer. Br J Cancer. 2004;91(7):1316–26.PubMedPubMedCentralCrossRef
87.
88.
89.
90.
Hwang RF, Moore T, Arumugam T, Ramachandran V, Amos KD, Rivera A, Ji B, Evans DB, Logsdon CD. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 2008;68(3):918–26.PubMedPubMedCentralCrossRef
91.
Kamphorst JJ, Nofal M, Commisso C, Hackett SR, Lu W, Grabocka E, Vander Heiden MG, Miller G, Drebin JA, Bar-Sagi D, Thompson CB, Rabinowitz JD. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 2015;75(3):544–53.PubMedPubMedCentralCrossRef
92.
Davidson SM, Jonas O, Keibler MA, Hou HW, Luengo A, Mayers JR, Wyckoff J, Del Rosario AM, Whitman M, Chin CR, Condon KJ, Lammers A, Kellersberger KA, Stall BK, Stephanopoulos G, Bar-Sagi D, Han J, Rabinowitz JD, Cima MJ, Langer R, Vander Heiden MG. Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors. Nat Med. 2017;23(2):235–41.PubMedCrossRef
93.
94.
95.
96.
Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–90.PubMedCrossRef
97.
Ma Y, Zhang H, Xiong C, Liu Z, Xu Q, Feng J, Zhang J, Wang Z, Yan X. CD146 mediates an E-cadherin-to-N-cadherin switch during TGF-β signaling-induced epithelial-mesenchymal transition. Cancer Lett. 2018;430:201–14.PubMedCrossRef
98.
99.
Wang H, Wu J, Zhang Y, Xue X, Tang D, Yuan Z, Chen M, Wei J, Zhang J, Miao Y. Transforming growth factor β-induced epithelial-mesenchymal transition increases cancer stem-like cells in the PANC-1 cell line. Oncol Lett. 2012;3(1):229–33.PubMedCrossRef
100.
Rice AJ, Cortes E, Lachowski D, Cheung BCH, Karim SA, Morton JP, Del Río Hernandez A. Matrix stiffness induces epithelial-mesenchymal transition and promotes chemoresistance in pancreatic cancer cells. Oncogene. 2017;6(7):e352.CrossRef
101.
102.
Chen S, Chen X, Li W, Shan T, Lin WR, Ma J, Cui X, Yang W, Cao G, Li Y, Wang L, Kang Y. Conversion of epithelial-to-mesenchymal transition to mesenchymal-to-epithelial transition is mediated by oxygen concentration in pancreatic cancer cells. Oncol Lett. 2018;15(5):7144–52.PubMedPubMedCentral
103.
Katoch A, Suklabaidya S, Chakraborty S, Nayak D, Rasool RU, Sharma D, Mukherjee D, Faheem MM, Kumar A, Sharma PR, Senapati S, Kumar LD, Goswami A. Dual role of Par-4 in abrogation of EMT and switching on mesenchymal to epithelial transition (MET) in metastatic pancreatic cancer cells. Mol Carcinog. 2018. https://​doi.​org/​10.​1002/​mc.​22828 [Epub ahead of print].
104.
Izumiya M, Kabashima A, Higuchi H, Igarashi T, Sakai G, Iizuka H, Nakamura S, Adachi M, Hamamoto Y, Funakoshi S, Takaishi H, Hibi T. Chemoresistance is associated with cancer stem cell-like properties and epithelial-to-mesenchymal transition in pancreatic cancer cells. Anticancer Res. 2012;32(9):3847–53.PubMed
105.
K Q, Tonigold M, Di Fazio P, Montalbano R, Lingelbach S, Ruckert F, Alinger B, Ocker M, Neureiter D. Pancreatic cancer cells surviving gemcitabine treatment express markers of stem cell differentiation and epithelial-mesenchymal transition. Int J Oncol. 2012;41(6):2093–102. https://​doi.​org/​10.​3892/​ijo.​2012.​1648.CrossRef
106.
107.
Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, Sarkar S. Drug resistance in Cancer: an overview. Cancers (Basel). 2014;6(3):1769–92.CrossRef
108.
109.
Van Cutsem E, Hidalgo M, Canon JL, Macarulla T, Bazin I, Poddubskaya E, Manojlovic N, Radenkovic D, Verslype C, Raymond E, Cubillo A, Schueler A, Zhao C, Hammel P. Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer. Int J Cancer. 2018;143(8):2053–64.PubMedCrossRef
110.
Marchegiani G, Todaro V, Boninsegna E, Negrelli R, Sureka B, Bonamini D, Salvia R, Manfredi R, Pozzi Mucelli R, Bassi C. Surgery after FOLFIRINOX treatment for locally advanced and borderline resectable pancreatic cancer: increase in tumour attenuation on CT correlates with R0 resection. Eur Radiol. 2018. https://​doi.​org/​10.​1007/​s00330-018-5410-6 [Epub ahead of print].
111.
Shabason JE, Chen J, Apisarnthanarax S, Damjanov N, Giantonio B, Loaiza-Bonilla A, O'Dwyer PJ, O'Hara M, Reiss KA, Teitelbaum U, Wissel P, Drebin JA, Vollmer C, Kochman M, Mick R, Vergara N, Jhala N, Doucette A, Lukens JN, Plastaras JP, Metz JM, Ben-Josef E. A phase I dose escalation trial of nab-paclitaxel and fixed dose radiation in patients with unresectable or borderline resectable pancreatic cancer. Cancer Chemother Pharmacol. 2018;81(3):609–14.PubMedCrossRef
112.
Grasso C, Jansen G, Giovannetti E. Drug resistance in pancreatic cancer: impact of altered energy metabolism. Crit Rev Oncol Hematol. 2017;114:139–52.PubMedCrossRef
113.
114.
Al Shemaili J, Mensah-Brown E, Parekh K, Thomas SA, Attoub S, Hellman B, Nyberg F, Adem A, Collin P, Adrian TE. Frondoside a enhances the antiproliferative effects of gemcitabine in pancreatic cancer. Eur J Cancer. 2014;50(7):1391–8.PubMedCrossRef
115.
Gregoire V, Rosier JF, De Bast M, Bruniaux M, De Coster B, Octave-Prignot M, Scalliet P. Role of deoxycytidine kinase (dCK) activity in gemcitabine's radioenhancement in mice and human cell lines in vitro. Radiother Oncol. 2002;63(3):329–38.PubMedCrossRef
116.
Giovannetti E, Del Tacca M, Mey V, Funel N, Nannizzi S, Ricci S, Orlandini C, Boggi U, Campani D, Del Chiaro M, Iannopollo M, Bevilacqua G, Mosca F, Danesi R. Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res. 2006;66(7):3928–35.PubMedCrossRef
117.
Coppola S, Carnevale I, Danen EHJ, Peters GJ, Schmidt T, Assaraf YG, Giovannetti E. A mechanopharmacology approach to overcome chemoresistance in pancreatic cancer. Drug Resist Updat. 2017;31:43–51.PubMedCrossRef
118.
119.
Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21(3):418–29.PubMedPubMedCentralCrossRef
120.
Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, Dekleva EN, Saunders T, Becerra CP, Tattersall IW, Westphalen CB, Kitajewski J, Fernandez-Barrena MG, Fernandez-Zapico ME, Iacobuzio-Donahue C, Olive KP, Stanger BZ. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014;25(6):735–47.PubMedPubMedCentralCrossRef
121.
Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, Frese KK, Feig C, Nakagawa T, Caldwell ME, Zecchini HI, Lolkema MP, Jiang P, Kultti A, Thompson CB, Maneval DC, Jodrell DI, Frost GI, Shepard HM, Skepper JN, Tuveson DA. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut. 2013;62(1):112–20.PubMedCrossRef
122.
Kozono S, Ohuchida K, Eguchi D, Ikenaga N, Fujiwara K, Cui L, Mizumoto K, Tanaka M. Pirfenidone inhibits pancreatic cancer desmoplasia by regulating stellate cells. Cancer Res. 2013;73(7):2345–56.PubMedCrossRef
123.
Khan S, Ebeling MC, Chauhan N, Thompson PA, Gara RK, Ganju A, Yallapu MM, Behrman SW, Zhao H, Zafar N, Singh MM, Jaggi M, Chauhan SC. Ormeloxifene suppresses desmoplasia and enhances sensitivity of gemcitabine in pancreatic cancer. Cancer Res. 2015;75(11):2292–304.PubMedPubMedCentralCrossRef
124.
ClinicalTrials.gov identifier (NCT number): NCT01839487.
125.
Masamune A, Satoh M, Kikuta K, Suzuki N, Satoh K, Shimosegawa T. Ellagic acid blocks activation of pancreatic stellate cells. Biochem Pharmacol. 2005;70(6):869–78.PubMedCrossRef
126.
Yallapu MM, Ebeling MC, Khan S, Sundram V, Chauhan N, Gupta BK, Puumala SE, Jaggi M, Chauhan SC. Novel curcumin-loaded magnetic nanoparticles for pancreatic cancer treatment. Mol Cancer Ther. 2013;12(8):1471–80.PubMedPubMedCentralCrossRef
127.
Notta F, Chan-Seng-Yue M, Lemire M, Li Y, Wilson GW, Connor AA, Denroche RE, Liang SB, Brown AM, Kim JC, Wang T, Simpson JT, Beck T, Borgida A, Buchner N, Chadwick D, Hafezi-Bakhtiari S, Dick JE, Heisler L, Hollingsworth MA, Ibrahimov E, Jang GH, Johns J, Jorgensen LG, Law C, Ludkovski O, Lungu I, Ng K, Pasternack D, Petersen GM, Shlush LI, Timms L, Tsao MS, Wilson JM, Yung CK, Zogopoulos G, Bartlett JM, Alexandrov LB, Real FX, Cleary SP, Roehrl MH, McPherson JD, Stein LD, Hudson TJ, Campbell PJ, Gallinger S. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature. 2016;538(7625):378–82.PubMedPubMedCentralCrossRef
128.
Makareeva E, Han S, Vera JC, Sackett DL, Holmbeck K, Phillips CL, Visse R, Nagase H, Leikin S. Carcinomas contain a matrix metalloproteinase-resistant isoform of type I collagen exerting selective support to invasion. Cancer Res. 2010;70(11):4366–74.PubMedPubMedCentralCrossRef
129.
Shields MA, Dangi-Garimella S, Redig AJ, Munshi HG. Biochemical role of the collagen-rich tumour microenvironment in pancreatic cancer progression. Biochem J. 2012;441(2):541–52.PubMedCrossRef
130.
Misra S, Hascall VC, Markwald RR, Ghatak S. Interactions between Hyaluronan and its receptors (CD44, RHAMM) regulate the activities of inflammation and Cancer. Front Immunol. 2015;6:201.PubMedPubMedCentralCrossRef
131.
Itano N, Zhuo L, Kimata K. Impact of the hyaluronan-rich tumor microenvironment on cancer initiation and progression. Cancer Sci. 2008;99(9):1720–5.PubMedCrossRef
132.
Bourdoulous S, Orend G, MacKenna DA, Pasqualini R, Ruoslahti E. Fibronectin matrix regulates activation of RHO and CDC42 GTPases and cell cycle progression. J Cell Biol. 1998;143(1):267–76.PubMedPubMedCentralCrossRef
133.
Topalovski M, Brekken RA. Matrix control of pancreatic cancer: new insights into fibronectin signaling. Cancer Lett. 2016;381(1):252–8.PubMedCrossRef
134.
van der Zee JA, van Eijck CH, Hop WC, Biermann K, Dicheva BM, Seynhaeve AL, Koning GA, Eggermont AM, Ten Hagen TL. Tumour basement membrane laminin expression predicts outcome following curative resection of pancreatic head cancer. Br J Cancer. 2012;107(7):1153–8.PubMedPubMedCentralCrossRef
135.
136.
Rotty JD, Hart GW, Coulombe PA. Stressing the role of O-GlcNAc: linking cell survival to keratin modification. Nat Cell Biol. 2010;12(9):847–9.PubMedCrossRef
137.
Yang MC, Wang HC, Hou YC, Tung HL, Chiu TJ, Shan YS. Blockade of autophagy reduces pancreatic cancer stem cell activity and potentiates the tumoricidal effect of gemcitabine. Mol Cancer. 2015;14:179.PubMedPubMedCentralCrossRef
138.
Qian X, Rothman VL, Nicosia RF, Tuszynski GP. Expression of thrombospondin-1 in human pancreatic adenocarcinomas: role in matrix metalloproteinase-9 production. Pathol Oncol Res. 2001;7(4):251–9.PubMedCrossRef
139.
Liu Y, Li F, Gao F, Xing L, Qin P, Liang X, Zhang J, Qiao X, Lin L, Zhao Q, Du L. Role of microenvironmental periostin in pancreatic cancer progression. Oncotarget. 2016;8(52):89552–65.PubMedPubMedCentral
140.
Asano K, Nelson CM, Nandadasa S, Aramaki-Hattori N, Lindner DJ, Alban T, Inagaki J, Ohtsuki T, Oohashi T, Apte SS, Hirohata S. Stromal Versican regulates tumor growth by promoting angiogenesis. Sci Rep. 2017;7(1):17225.PubMedPubMedCentralCrossRef
141.
Paron I, Berchtold S, Voros J, Shamarla M, Erkan M, Hofler H, Esposito I. Tenascin-C enhances pancreatic cancer cell growth and motility and affects cell adhesion through activation of the integrin pathway. PLoS One. 2011;6(6):e21684.PubMedPubMedCentralCrossRef
142.
Saha S, Xiong X, Chakraborty PK, K S, Arvizo RR, Kudgus RA, Dwivedi SK, Hossen MN, Gillies EM, JD R, JT D, Urrutia RA, Postier RG, Bhattacharya R, Mukherjee P. Gold nanoparticle reprograms pancreatic tumor Microenvironment and inhibits tumor growth. ACS Nano. 2016;10(12):10636–51.PubMedCrossRefPubMedCentral
143.
Wang L, Liu X, Zhou Q, Sui M, Lu Z, Zhou Z, Tang J, Miao Y, Zheng M, Wang W, Shen Y. Terminating the criminal collaboration in pancreatic cancer: nanoparticle-based synergistic therapy for overcoming fibroblast-induced drug resistance. Biomaterials. 2017;144:105–18.PubMedCrossRef
144.
Joubert F, Martin L, Perrier S, Pasparakis G. Development of a gemcitabine-polymer conjugate with prolonged cytotoxicity against a pancreatic Cancer cell line. ACS Macro Lett. 2017;6(5):535–40.CrossRef
145.
Kesharwani P, Banerjee S, Padhye S, Sarkar FH, Iyer AK. Parenterally administrable nano-micelles of 3,4-difluorobenzylidene curcumin for treating pancreatic cancer. Colloids Surf B Biointerfaces. 2015;132:138–45.PubMedCrossRef
146.
Hoskins C, Ouaissi M, Lima SC, Cheng WP, Loureirio I, Mas E, Lombardo D, Cordeiro-da-Silva A, Ouaissi A, Kong Thoo Lin P. In vitro and in vivo anticancer activity of a novel nano-sized formulation based on self-assembling polymers against pancreatic cancer. Pharm Res. 2010;27(12):2694–703.PubMedCrossRef
147.
Oluwasanmi A, Al-Shakarchi W, Manzur A, Aldebasi MH, Elsini RS, Albusair MK, Haxton KJ, Curtis ADM, Hoskins C. Diels Alder-mediated release of gemcitabine from hybrid nanoparticles for enhanced pancreatic cancer therapy. J Control Release. 2017;266:355–64.PubMedCrossRef
148.
Malekigorji M, Alfahad M, Kong Thoo Lin P, Jones S, Curtis A, Hoskins C. Thermally triggered theranostics for pancreatic cancer therapy. Nanoscale. 2017;9(34):12735–45.PubMedCrossRef
149.
Rapoport NY, Kennedy AM, Shea JE, Scaife CL, Nam KH. Controlled and targeted tumor chemotherapy by ultrasound-activated nanoemulsions/microbubbles. J Control Release. 2009;138(3):268–76.PubMedPubMedCentralCrossRef
150.
ClinicalTrials.gov identifier (NCT number): NCT01064622.
151.
Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, Marsh R, Wallace J, Kozloff M, Rajdev L, Cohen D, Wade J, Sleckman B, Lenz HJ, Stiff P, Kumar P, Xu P, Henderson L, Takebe N, Salgia R, Wang X, Stadler WM, de Sauvage FJ, Kindler HL. 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(36):4284–92.PubMedPubMedCentralCrossRef
152.
ClinicalTrials.gov identifier (NCT number): NCT02052492.
153.
ClinicalTrials.gov identifier (NCT number): NCT02030860.
154.
ClinicalTrials.gov identifier (NCT number): NCT02583477.
155.
ClinicalTrials.gov identifier (NCT number): NCT02758587.
156.
ClinicalTrials.gov identifier (NCT number): NCT02428270.
157.
ClinicalTrials.gov identifier (NCT number): NCT03307148.
158.
ClinicalTrials.gov identifier (NCT number): NCT02923921.
159.
ClinicalTrials.gov identifier (NCT number): NCT02930902.
160.
ClinicalTrials.gov identifier (NCT number): NCT02526017.
161.
ClinicalTrials.gov identifier (NCT number): 2013-002370-51.
Metadata
Title
Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis
Authors
Divya Thomas
Prakash Radhakrishnan
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2019
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-018-0927-5

Other articles of this Issue 1/2019

Molecular Cancer 1/2019 Go to the issue

Correction

Correction to: A novel tumor suppressor protein encoded by circular AKT3 RNA inhibits glioblastoma tumorigenicity by competing with active phosphoinositide-dependent Kinase-1

Correction

Correction to: Role of Bruton’s tyrosine kinase in B cells and malignancies

Research

Nuclear lncRNA HOXD-AS1 suppresses colorectal carcinoma growth and metastasis via inhibiting HOXD3-induced integrin β3 transcriptional activating and MAPK/AKT signalling

Review

Targeting Tyro3, Axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment

Research

Loss of the transcriptional repressor TGIF1 results in enhanced Kras-driven development of pancreatic cancer

Research

Small Molecule KRAS Agonist for Mutant KRAS Cancer Therapy
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits