Signaling pathways involved in pancreatic stellate cells activity and interaction with pancreatic cancer cells

Authors

DOI:

https://doi.org/10.26641/1997-9665.2021.2.7-15

Keywords:

stellate pancreatocytes, pancreatic tumor cells, tumor microenvironment, signaling pathways, chemoresistance

Abstract

Background. The activation, proliferation and migration capabilities of stellate pancreatocytes are guaranteed by a number of signaling molecular mechanisms that support the interaction of tumor cells with the PSC and determine the neoplastic process. Objective The review is a continuation of aт articles series devoted to the modern understanding of the role and functions of stellate pancreatocytes, namely, their involvement in interaction with cancer cells and signaling molecular pathways that provide synergism of the stellate pancreatocyte-cancer cell system. Methods. Data processing was carried out by the method of complex material analysis. Results. The Нedgehog signaling pathway provides interaction between PSC and tumor cells, which involves the leading mediator of this pathway - sHH (sonic hedgehog), the overexpression of which is recorded in the tumor tissue of the pancreas and ensures the formation of the tumor stroma. Stellate pancreatocytes also trigger the HGF / c-Met / survivin signaling pathway for invasion and metastasis. The activation of the PSCs themselves may be mediated by serotonin via the RhoA / ROCK signaling pathway. While the proliferation and migration of these cells, activated by alcohol, HNE (human neutrophil elastase), PDGF, IL-33 PSC are regulated by the MAP kinase and PI3K pathways. The Wnt signaling pathway promotes collagen accumulation. Through the AMPK / mTOR pathway, factor FTY720 induces apoptosis and inhibits the autophagy of stellate pancreatocytes. The interaction of PSC and tumor cells is also mediated through Notch and TGF-β, and through the Hippo signaling pathway with the participation of YAP / TAZ factors, it is possible to suppress the fibrotic activity of PSC. The interaction of stellate pancreatocytes and tumor cells is reflected in a direct correlation between a decrease in autophagy and apoptosis of stellate pancreatocytes and suppression of invasion and migration of tumor cells. This interaction can be mediated by ERK1 / 2 kinase. Among the factors secreted by tumor cells and causing PSC activation are: growth factor β1 (TGF-β1), PAI-1 protein, translation initiation factor 4E (eIF4E), sHH (involving PSC in pain deployment), Exo-Pan and Exo-Mia exosomes (engaging PSCs in carcinogenesis). Deactivation is mediated by colony stimulating factor 1 (CSF1R, cytokine). In turn, stellate pancreatocytes secrete the chemokine CXCL1, which stimulates the migration and invasion of tumor cells, exosomes with multiple miRNAs, which stimulate the proliferation and migration of cancer cells. Сonclusion. The activation of stellate pancreatocytes, which is necessary for the implementation of their fibrotic functions, is mediated through the RhoA / ROCK signaling pathway via serotonin. The Hippo pathway (activation) and AMPK / mTOR (suppression of autophagy and activation of apoptosis) are also involved in the regulation of the activity of stellate pancreatocytes. The interaction between the tumor cell and stellate pancreatocyte occurs through the Hedgehog, Notch, and TGF-β signaling pathways; regulation of invasion and metastasis of cancer cells provides the HGF / c-Met / survivin signaling pathway.

References

  1. Masamune A, Shimosegawa T. Pancreatic stellate cells: A dynamic player of the intercellular communication in pancreatic cancer. Clin Res Hepatol Gastroenterol. 2015; 39(1):S98–S103.
  2. Xue R, Jia K, Wang J, Yang L, Wang Y, Gao L, Hao J. A Rising Star in Pancreatic Diseases: Pancreatic Stellate Cells. Front Physiol. 2018, Jun 18; 9:754.
  3. Thomas D, Radhakrishnan P. Pancreatic Stellate Cells: The Key Orchestrator of the Pancreatic Tumor Microenvironment. Adv Exp Med Biol. 2020; 1234:57–70.
  4. Cortes E, Lachowski D, Robinson B, Sarper M, Teppo JS, Thorpe SD, Lieberthal TJ, Iwamoto K, Lee DA, Okada-Hatakeyama M, Varjosalo MT, Del Río Hernández AE. Tamoxifen mechanically reprograms the tumor microenvironment via HIF-1A and reduces cancer cell survival. EMBO Rep. 2019 Jan; 20(1):e46557.
  5. Papalazarou V, Salmeron-Sanchez M, Machesky LM. Tissue engineering the cancer microenvironment-challenges and opportunities. Biophys Rev. 2018 Dec; 10(6):1695–1711.
  6. Han L, Ma J, Duan W, Zhang L, Yu S, Xu Q, Lei J, Li X, Wang Z, Wu Z, Huang JH, Wu E, Ma Q, Ma Z. Pancreatic stellate cells contribute pancreatic cancer pain via activation of sHH signaling pathway. Oncotarget. 2016 Apr 5; 7(14):18146–18158.
  7. 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 Jun 16; 25(6):735–47.
  8. Jakubowska MA, Ferdek PE, Gerasimenko OV, Gerasimenko JV, Petersen OH. Nitric oxide signals are interlinked with calcium signals in normal pancreatic stellate cells upon oxidative stress and inflammation. Open Biol. 2016 Aug; 6(8):160149.
  9. Yang XP, Liu SL, Xu JF, Cao SG, Li Y, Zhou YB. Pancreatic stellate cells increase pancreatic cancer cells invasion through the hepatocyte growth factor /c-Met/survivin regulated by P53/P21. Exp Cell Res. 2017 Aug 1; 357(1):79–87.
  10. Tao X, Chen Q, Li N, Xiang H, Pan Y, Qu Y, Shang D, Go VLW, Xue J, Sun Y, Zhang Z, Guo J, Xiao GG. Serotonin-RhoA/ROCK axis promotes acinar-to-ductal metaplasia in caerulein-induced chronic pancreatitis. Biomed Pharmacother. 2020 May; 125:109999.
  11. Leal AS, Misek SA, Lisabeth EM, Neubig RR, Liby KT. The Rho/MRTF pathway inhibitor CCG-222740 reduces stellate cell activation and modulates immune cell populations in KrasG12D; Pdx1-Cre (KC) mice. Sci Rep. 2019 May 8; 9(1):7072.
  12. Bynigeri RR, Jakkampudi A, Jangala R, Subramanyam C, Sasikala M, Rao GV, Reddy DN, Talukdar R. Pancreatic stellate cell: Pandora's box for pancreatic disease biology. World J Gastroenterol. 2017 Jan 21; 23(3):382–405.
  13. Li X, Wang Z, Ma Q, Xu Q, Liu H, Duan W, Lei J, Ma J, Wang X, Lv S, Han L, Li W, Guo J, Guo K, Zhang D, Wu E, Xie K. Sonic hedgehog paracrine signaling activates stromal cells to promote perineural invasion in pancreatic cancer. Clin Cancer Res. 2014 Aug 15; 20(16):4326–4338.
  14. Khan MA, Srivastava SK, Zubair H, Patel GK, Arora S, Khushman M, Carter JE, Gorman GS, Singh S, Singh AP. Co-targeting of CXCR4 and hedgehog pathways disrupts tumor-stromal crosstalk and improves chemotherapeutic efficacy in pancreatic cancer. J Biol Chem. 2020 Jun 19; 295(25):8413–8424.
  15. Cui L, Li C, Gao G, Zhuo Y, Yang L, Cui N, Zhang S. FTY720 inhibits the activation of pancreatic stellate cells by promoting apoptosis and suppressing autophagy via the AMPK/mTOR pathway. Life Sci. 2019 Jan 15; 217:243–250.
  16. Bailey JM, Leach SD. Signaling pathways mediating epithelial- mesenchymal crosstalk in pancreatic cancer: Hedgehog, Notch and TGFβ. In: Grippo PJ, Munshi HG, editors. Pancreatic Cancer and Tumor Microenvironment. Trivandrum (India): Transworld Research Network. 2012. Chapter 7; PMID: 22876389.
  17. Martinez B, Yang Y, Harker DMR, Farrar C, Mukundan H, Nath P, Mascareñas D. YAP/TAZ Related BioMechano Signal Transduction and Cancer Metastasis. Front Cell Dev Biol. 2019 Oct 4; 7:199.
  18. Pothula SP, Pirola RC, Wilson JS, Apte MV. Pancreatic stellate cells: Aiding and abetting pancreatic cancer progression. Pancreatology. 2020 Apr; 20(3):409–418.
  19. Wang L, Bi R, Li L, Zhou K, Liu H. Functional characteristics of autophagy in pancreatic cancer induced by glutamate metabolism in pancreatic stellate cells. J Int Med Res. 2020 Apr; 48(4):300060519865368.
  20. Li C, Cui L, Yang L, Wang B, Zhuo Y, Zhang L, Wang X, Zhang Q, Zhang S. Pancreatic Stellate Cells Promote Tumor Progression by Promoting an Immunosuppressive Microenvironment in Murine Models of Pancreatic Cancer. Pancreas. 2020 Jan; 49(1):120–127.
  21. Wen Z, Liu Q, Wu J, Xu B, Wang J, Liang L, Guo Y, Peng M, Zhao Y, Liao Q. Fibroblast activation protein α-positive pancreatic stellate cells promote the migration and invasion of pancreatic cancer by CXCL1-mediated Akt phosphorylation. Ann Transl Med. 2019 Oct; 7(20):532.
  22. Wang HC, Lin YL, Hsu CC, Chao YJ, Hou YC, Chiu TJ, Huang PH, Tang MJ, Chen LT, Shan YS. Pancreatic stellate cells activated by mutant KRAS-mediated PAI-1 upregulation foster pancreatic cancer progression via IL-8. Theranostics. 2019 Sep 23; 9(24):7168–7183.
  23. Qian B, Wei L, Yang Z, He Q, Chen H, Wang A, Yang D, Li Q, Li J, Zheng S, Fu W. Hic-5 in pancreatic stellate cells affects proliferation, apoptosis, migration, invasion of pancreatic cancer cells and postoperative survival time of pancreatic cancer. Biomed Pharmacother. 2020 Jan; 121:109355.
  24. Van Loenhout J, Flieswasser T, Freire Boullosa L, De Waele J, Van Audenaerde J, Marcq E, Jacobs J, Lin A, Lion E, Dewitte H, Peeters M, Dewilde S, Lardon F, Bogaerts A, Deben C, Smits E. Cold Atmospheric Plasma-Treated PBS Eliminates Immunosuppressive Pancreatic Stellate Cells and Induces Immunogenic Cell Death of Pancreatic Cancer Cells. Cancers (Basel). 2019 Oct 19; 11(10):1597.
  25. Nam S, Khawar IA, Park JK, Chang S, Kuh HJ. Cellular context-dependent interaction between cancer and stellate cells in hetero-type multicellular spheroids of pancreatic tumor. Biochem Biophys Res Commun. 2019 Jul 12; 515(1):183–189.
  26. Yan Z, Ohuchida K, Fei S, Zheng B, Guan W, Feng H, Kibe S, Ando Y, Koikawa K, Abe T, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Mizumoto K, Hashizume M, Nakamura M. Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer-stromal interaction and metastasis. J Exp Clin Cancer Res. 2019 May 27; 38(1):221.
  27. Chen YT, Chen FW, Chang TH, Wang TW, Hsu TP, Chi JY, Hsiao YW, Li CF, Wang JM. Hepatoma-derived growth factor supports the antiapoptosis and profibrosis of pancreatic stellate cells. Cancer Lett. 2019 Aug 10; 457:180–190.
  28. Marzoq AJ, Mustafa SA, Heidrich L, Hoheisel JD, Alhamdani MSS. Impact of the secretome of activated pancreatic stellate cells on growth and differentiation of pancreatic tumour cells. Sci Rep. 2019 Mar 28; 9(1):5303.
  29. Zhang YF, Zhou YZ, Zhang B, Huang SF, Li PP, He XM, Cao GD, Kang MX, Dong X, Wu YL. Pancreatic cancer-derived exosomes promoted pancreatic stellate cells recruitment by pancreatic cancer. J Cancer. 2019 Jul 23; 10(18):4397–4407.
  30. Takikawa T, Masamune A, Yoshida N, Hamada S, Kogure T, Shimosegawa T. Exosomes Derived From Pancreatic Stellate Cells: MicroRNA Signature and Effects on Pancreatic Cancer Cells. Pancreas. 2017 Jan; 46(1):19–27.
  31. Masamune A, Yoshida N, Hamada S, Takikawa T, Nabeshima T, Shimosegawa T. Exosomes derived from pancreatic cancer cells induce activation and profibrogenic activities in pancreatic stellate cells. Biochem Biophys Res Commun. 2018 Jan 1; 495(1):71–77.
  32. Steins A, van Mackelenbergh MG, van der Zalm AP, Klaassen R, Serrels B, Goris SG, Kocher HM, Waasdorp C, de Jong JH, Tekin C, Besselink MG, Busch OR, van de Vijver MJ, Verheij J, Dijk F, van Tienhoven G, Wilmink JW, Medema JP, van Laarhoven HW, Bijlsma MF. High-grade mesenchymal pancreatic ductal adenocarcinoma drives stromal deactivation through CSF-1. EMBO Rep. 2020 May 6; 21(5):e48780.
  33. Yu L, Li JJ, Liang XL, Wu H, Liang Z. PSME3 Promotes TGFB1 Secretion by Pancreatic Cancer Cells to Induce Pancreatic Stellate Cell Proliferation. J Cancer. 2019 May 16; 10(9):2128–2138.
  34. Shao C, Tu C, Cheng X, Xu Z, Wang X, Shen J, Chai K, Chen W. Inflammatory and Senescent Phenotype of Pancreatic Stellate Cells Induced by Sqstm1 Downregulation Facilitates Pancreatic Cancer Progression. Int J Biol Sci. 2019 Apr 21; 15(5):1020–1029.
  35. Liu SL, Cao SG, Li Y, Sun B, Chen D, Wang DS, Zhou YB. Pancreatic stellate cells facilitate pancreatic cancer cell viability and invasion. Oncol Lett. 2019 Feb; 17(2):2057–2062.
  36. Schnittert J, Bansal R, Prakash J. Targeting Pancreatic Stellate Cells in Cancer. Trends Cancer. 2019 Feb; 5(2):128–142.
  37. Bynigeri RR, Jakkampudi A, Jangala R, Subramanyam C, Sasikala M, Rao GV, Reddy DN, Talukdar R. Pancreatic stellate cell: Pandora's box for pancreatic disease biology. World J Gastroenterol. 2017 Jan 21; 23(3):382–405.
  38. Ramakrishnan P, Loh WM, Gopinath SCB, Bonam SR, Fareez IM, Mac Guad R, Sim MS, Wu YS. Selective phytochemicals targeting pancreatic stellate cells as new anti-fibrotic agents for chronic pancreatitis and pancreatic cancer. Acta Pharm Sin B. 2020 Mar; 10(3):399–413.
  39. Masamune A, Shimosegawa T. Signal transduction in pancreatic stellate cells. J Gastroenterol. 2009; 44(4):249–260.
  40. Cui LH, Li CX, Zhuo YZ, Yang L, Cui NQ, Zhang SK. Saikosaponin d ameliorates pancreatic fibrosis by inhibiting autophagy of pancreatic stellate cells via PI3K/Akt/mTOR pathway. Chem Biol Interact. 2019 Feb 25; 300:18–26.
  41. Cortes E, Sarper M, Robinson B, Lachowski D, Chronopoulos A, Thorpe SD, Lee DA, Del Río Hernández AE. GPER is a mechanoregulator of pancreatic stellate cells and the tumor microenvironment. EMBO Rep. 2019 Jan; 20(1):e46556.
  42. Tozzi M, Sørensen CE, Magni L, Christensen NM, Bouazzi R, Buch CM, Stefanini M, Duranti C, Arcangeli A, Novak I. Proton Pump Inhibitors Reduce Pancreatic Adenocarcinoma Progression by Selectively Targeting H+, K+-ATPases in Pancreatic Cancer and Stellate Cells. Cancers (Basel). 2020 Mar 10; 12(3):640.
  43. Lee SC, Hong TH, Kim OH, Cho SJ, Kim KH, Song JS, Hwang KS, Jung JK, Hong HE, Seo H, Choi HJ, Ahn J, Lee TY, Rim E, Jung KY, Kim SJ. A Novel Way of Preventing Postoperative Pancreatic Fistula by Directly Injecting Profibrogenic Materials into the Pancreatic Parenchyma. Int J Mol Sci. 2020 Mar 4; 21(5):1759.
  44. Han H, Hou Y, Chen X, Zhang P, Kang M, Jin Q, Ji J, Gao M. Metformin-Induced Stromal Depletion to Enhance the Penetration of Gemcitabine-Loaded Magnetic Nanoparticles for Pancreatic Cancer Targeted Therapy. J Am Chem Soc. 2020 Mar 11; 142(10):4944–4954.
  45. Yang Y, Kim JW, Park HS, Lee EY, Yoon KH. Pancreatic stellate cells in the islets as a novel target to preserve the pancreatic β-cell mass and function. J Diabetes Investig. 2020 Mar; 11(2):268–280.
  46. Zhao H, Jiang X, Duan L, Yang L, Wang W, Ren Z. Liraglutide suppresses the metastasis of PANC-1 co-cultured with pancreatic stellate cells through modulating intracellular calcium content. Endocr J. 2019 Dec 25; 66(12):1053–1062.
  47. Amrutkar M, Aasrum M, Verbeke CS, Gladhaug IP. Secretion of fibronectin by human pancreatic stellate cells promotes chemoresistance to gemcitabine in pancreatic cancer cells. BMC Cancer. 2019 Jun 17; 19(1):596.
  48. Dalin S, Sullivan MR, Lau AN, Grauman-Boss B, Mueller HS, Kreidl E, Fenoglio S, Luengo A, Lees JA, Vander Heiden MG, Lauffenburger DA, Hemann MT. Deoxycytidine Release from Pancreatic Stellate Cells Promotes Gemcitabine Resistance. Cancer Res. 2019 Nov 15; 79(22):5723–5733.

Downloads

Published

2021-12-21

How to Cite

Signaling pathways involved in pancreatic stellate cells activity and interaction with pancreatic cancer cells. (2021). Морфологія / Morphologia / Morfologìâ, 15(2), 7–15. https://doi.org/10.26641/1997-9665.2021.2.7-15

Issue

Vol. 15 No. 2 (2021)

Section

Статті

License

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

 The authors reserve the right to authorship of their work and transfer to the Journal the right to the first publication of this work under the terms of a license Creative commons Attribution 4.0 International (CC BY 4.0), which allows other people to freely distribute the published work with a mandatory reference to the authors of the original work and the first publication of the work in this journal.
        By submitting a manuscript to the editorial office of the Journal ‘Morphologia’ authors agree to transfer the rights to protect and use the manuscript (all supplemental materials, particularly protected objects such as photos, drawings, diagrams, tables, etc.), including the reproduction in the press and distribution via the Internet; translation of the manuscript into any language; export and import of journal copies with the Authors’ article in order to make it available for public. Authors convey the rights mentioned above to the editorial office without any temporal or territorial limitation all over the world. 
        The Authors guarantee that they have the exclusive rights to use the material transferred to editorial office. Editors are not responsible to third parties for contraventions of warranty given by the Authors. The considered rights are transferred to the editorial office since the moment when the current issue is signed for publishing. Reproduction of materials published in the Journal by other individuals and legal entities is possible only with the consent of Editorial office, with the obligatory indication of the full bibliographic reference of the primary publication. The Authors reserve the right to use the published material, its fragments and parts for teaching materials, oral presentations, dissertation thesis prepararion with obligatory bibliographic citation of the original paper. Electron copy of the published article, downloaded from official journal web-site in .pdf format may be put by authors on the official web-site of their institutions, any other official resources with open access.