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Cancer-induced inflammation and inflammation-induced cancer in colon: a role for S1P lyase

Abstract

A role of sphingolipids for inflammatory bowel disease and cancer is evident. However, the relative and separate contribution of sphingolipid deterioration in inflammation versus carcinogenesis for the pathophysiology of colitis-associated colon cancer (CAC) was unknown and therefore examined in this study. We performed isogenic bone marrow transplantation of inducible sphingosine-1-phosphate (S1P) lyase knockout mice to specifically modulate sphingolipids and associated genes and proteins in a compartment-specific way in a DSS/AOM mediated CAC model. 3D organoid cultures were used in vitro. S1P lyase (SGPL1) knockout in either immune cells or tissue, caused local sphingolipid accumulation leading to a dichotomic development of CAC: Immune cell SGPL1 knockout (I-SGPL−/−) augmented massive immune cell infiltration initiating colitis with lesions and calprotectin increase. Pathological crypt remodeling plus extracellular S1P-signaling caused delayed tumor formation characterized by S1P receptor 1, STAT3 mRNA increase, as well as programmed cell death ligand 1 expression, accompanied by a putatively counter regulatory STAT1S727 phosphorylation. In contrast, tissue SGPL1 knockout (T-SGPL−/−) provoked immediate occurrence of epithelial-driven tumors with upregulated sphingosine kinase 1, S1P receptor 2 and epidermal growth factor receptor. Here, progressing carcinogenesis was accompanied by an IL-12 to IL-23 shift with a consecutive development of a Th2/GATA3-driven, tumor-favoring microenvironment. Moreover, the knockout models showed distinct lymphopenia and neutrophilia, different from the full SGPL1 knockout. This study shows that depending on the initiating cellular S1P source, the pathophysiology of inflammation-induced cancer versus cancer-induced inflammation develops through separate, discernible molecular steps.

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Fig. 1: Compartment-specific SGPL knockout is decisive for S1P distribution.
Fig. 2: Compartment-specific SGPL knockout is decisive for disease severity in CAC.
Fig. 3: Prominent tumor development in T-SGPL–/–.
Fig. 4: Prominent immune cell infiltration in I-SGPL–/– but less in T-SGPL–/–.
Fig. 5: Tumor microenvironment and immune cell sequestration is dependent on compartment-specific SGPL.
Fig. 6: Western Blot and Organoid culture confirm different regulation of genes in I-SGPL–/– or T-SGPL–/–.
Fig. 7: Graphical summary of compartment-specific SGPL knockout effects in the development of cancer-induced inflammation and inflammation-induced cancer.

References

  1. Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest. 2007;117:1175–83.

    Article  CAS  Google Scholar 

  2. Rizzo A, Pallone F, Monteleone G, Fantini MC. Intestinal inflammation and colorectal cancer: a double-edged sword? World J Gastroenterol. 2011;17:3092–3100.

    PubMed  PubMed Central  Google Scholar 

  3. Shalapour S, Karin M. Immunity, inflammation, and cancer: an eternal fight between good and evil. J Clin Invest. 2015;125:3347–55.

    Article  Google Scholar 

  4. Zhong Z, Sanchez-Lopez E, Karin M. Autophagy, inflammation, and immunity: a Troika governing cancer and its treatment. Cell. 2016;166:288–98.

    Article  CAS  Google Scholar 

  5. Minn AJ, Wherry EJ. Combination cancer therapies with immune checkpoint blockade: convergence on interferon signaling. Cell. 2016;165:272–5.

    Article  CAS  Google Scholar 

  6. Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161:205–14.

    Article  CAS  Google Scholar 

  7. Kroemer G, Galluzzi L, Zitvogel L, Fridman WH. Colorectal cancer: the first neoplasia found to be under immunosurveillance and the last one to respond to immunotherapy? Oncoimmunology. 2015;4:e1058597.

    Article  Google Scholar 

  8. Duan RD, Nilsson A. Metabolism of sphingolipids in the gut and its relation to inflammation and cancer development. Prog Lipid Res. 2009;48:62–72.

    Article  CAS  Google Scholar 

  9. Schwiebs A, et al. Activation-induced cell death of dendritic cells is dependent on sphingosine kinase 1. Front Pharmacol. 2016;7:94.

    Article  Google Scholar 

  10. Arlt O, et al. Sphingosine-1-phosphate modulates dendritic cell function: focus on non-migratory effects in vitro and in vivo. Cell Physiol Biochem. 2014;34:27–44.

    Article  CAS  Google Scholar 

  11. Lee H, et al. STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors. Nat Med. 2010;16:1421–8.

    Article  CAS  Google Scholar 

  12. Patmanathan SN, Wang W, Yap LF, Herr DR, Paterson IC. Mechanisms of sphingosine 1-phosphate receptor signalling in cancer. Cell Signal. 2017;34:66–75.

    Article  CAS  Google Scholar 

  13. Suh JH, Saba JD. Sphingosine-1-phosphate in inflammatory bowel disease and colitis-associated colon cancer: the fat’s in the fire. Transl Cancer Res. 2015;4:469–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Degagne E, Saba JD. S1pping fire: Sphingosine-1-phosphate signaling as an emerging target in inflammatory bowel disease and colitis-associated cancer. Clin Exp Gastroenterol. 2014;7:205–14.

    Article  Google Scholar 

  15. Kawamori T, et al. Role for sphingosine kinase 1 in colon carcinogenesis. FASEB J. 2009;23:405–14.

    Article  CAS  Google Scholar 

  16. Liu SQ, et al. Sphingosine kinase 1 promotes tumor progression and confers malignancy phenotypes of colon cancer by regulating the focal adhesion kinase pathway and adhesion molecules. Int J Oncol. 2013;42:617–26.

    Article  CAS  Google Scholar 

  17. Chumanevich AA, et al. Suppression of colitis-driven colon cancer in mice by a novel small molecule inhibitor of sphingosine kinase. Carcinogenesis. 2010;31:1787–93.

    Article  CAS  Google Scholar 

  18. Brizuela L, et al. First evidence of sphingosine 1-phosphate lyase protein expression and activity downregulation in human neoplasm: implication for resistance to therapeutics in prostate cancer. Mol Cancer Ther. 2012;11:1841–51.

    Article  CAS  Google Scholar 

  19. Oskouian B, et al. Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer. Proc Natl Acad Sci USA. 2006;103:17384–9.

    Article  CAS  Google Scholar 

  20. Hamilton SR, Bosman FT, Boffetta P, et al. Carcinoma of the colon and rectum. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, editors. WHO classification of tumours of the digestive system. 4th ed. Lyon, France: IARC Press; 2010. pp 134–46.

  21. Cyster JG, Schwab SR. Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu Rev Immunol. 2012;30:69–94.

    Article  CAS  Google Scholar 

  22. Allende ML, et al. Sphingosine-1-phosphate lyase deficiency produces a pro-inflammatory response while impairing neutrophil trafficking. J Biol Chem. 2011;286:7348–58.

    Article  CAS  Google Scholar 

  23. Vogel P, et al. Incomplete inhibition of sphingosine 1-phosphate lyase modulates immune system function yet prevents early lethality and non-lymphoid lesions. PLoS ONE. 2009;4:e4112.

    Article  Google Scholar 

  24. Helbling M, et al. Investigation of IL-23 (p19, p40) and IL-23R identifies nuclear expression of IL-23 p19 as a favorable prognostic factor in colorectal cancer: a retrospective multicenter study of 675 patients. Oncotarget. 2014;5:4671–82.

    Article  Google Scholar 

  25. Richter C, et al. Defective IL-23/IL-17 axis protects p47phox−/− mice from colon cancer. Front Immunol. 2017;8:44.

    Article  Google Scholar 

  26. Liang J, et al. Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer. Cancer Cell. 2013;23:107–20.

    Article  CAS  Google Scholar 

  27. Degagne E, et al. Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs. J Clin Invest. 2014;124:5368–84.

    Article  Google Scholar 

  28. Nitulescu II, et al. Mediator kinase phosphorylation of STAT1 S727 promotes growth of neoplasms with JAK-STAT activation. EBioMedicine. 2017;26:112–25.

    Article  Google Scholar 

  29. Timofeeva OA, et al. Serine-phosphorylated STAT1 is a prosurvival factor in Wilms’ tumor pathogenesis. Oncogene. 2006;25:7555–64.

    Article  CAS  Google Scholar 

  30. Uddin S, et al. Protein kinase C-delta (PKC-delta) is activated by type I interferons and mediates phosphorylation of Stat1 on serine 727. J Biol Chem. 2002;277:14408–16.

    Article  CAS  Google Scholar 

  31. Dillmann C, et al. S1PR4 signaling attenuates ILT 7 internalization to limit IFN-alpha production by human plasmacytoid dendritic cells. J Immunol. 2016;196:1579–90.

    Article  CAS  Google Scholar 

  32. Snider AJ, et al. A role for sphingosine kinase 1 in dextran sulfate sodium-induced colitis. FASEB J. 2009;23:143–52.

    Article  CAS  Google Scholar 

  33. Shida D, et al. Sphingosine 1-phosphate transactivates c-Met as well as epidermal growth factor receptor (EGFR) in human gastric cancer cells. FEBS Lett. 2004;577:333–8.

    Article  CAS  Google Scholar 

  34. Daub H, Weiss FU, Wallasch C, Ullrich A. Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature. 1996;379:557–60.

    Article  CAS  Google Scholar 

  35. Jonker DJ, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040–8.

    Article  CAS  Google Scholar 

  36. Orr Gandy KA, et al. Epidermal growth factor-induced cellular invasion requires sphingosine-1-phosphate/sphingosine-1-phosphate 2 receptor-mediated ezrin activation. FASEB J. 2013;27:3155–66.

    Article  Google Scholar 

  37. Doll F, Pfeilschifter J, Huwiler A. The epidermal growth factor stimulates sphingosine kinase-1 expression and activity in the human mammary carcinoma cell line MCF7. Biochim Biophys Acta. 2005;1738:72–81.

    Article  Google Scholar 

  38. Foerster S, et al. Characterization of the EGFR interactome reveals associated protein complex networks and intracellular receptor dynamics. Proteomics. 2013;13:3131–44.

    Article  CAS  Google Scholar 

  39. Gu Y, Forostyan T, Sabbadini R, Rosenblatt J. Epithelial cell extrusion requires the sphingosine-1-phosphate receptor 2 pathway. J Cell Biol. 2011;193:667–76.

    Article  CAS  Google Scholar 

  40. Rosen H, Alfonso C, Surh CD, McHeyzer-Williams MG. Rapid induction of medullary thymocyte phenotypic maturation and egress inhibition by nanomolar sphingosine 1-phosphate receptor agonist. Proc Natl Acad Sci USA. 2003;100:10907–12.

    Article  CAS  Google Scholar 

  41. Schwab SR, Cyster JG. Finding a way out: lymphocyte egress from lymphoid organs. Nat Immunol. 2007;8:1295–301.

    Article  CAS  Google Scholar 

  42. Billich A, et al. Partial deficiency of sphingosine-1-phosphate lyase confers protection in experimental autoimmune encephalomyelitis. PLoS ONE. 2013;8:e59630.

    Article  Google Scholar 

  43. Schwab SR, et al. Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science. 2005;309:1735–9.

    Article  CAS  Google Scholar 

  44. Kumar A, Zamora-Pineda J, Degagne E, Saba JD. S1P lyase regulation of thymic egress and oncogenic inflammatory signaling. Mediat Inflamm. 2017;2017:7685142.

    Article  Google Scholar 

  45. Zamora-Pineda J, Kumar A, Suh JH, Zhang M, Saba JD. Dendritic cell sphingosine-1-phosphate lyase regulates thymic egress. J Exp Med. 2016;213:2773–91.

    Article  CAS  Google Scholar 

  46. Alvarez SE, et al. Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature. 2010;465:1084–8.

    Article  CAS  Google Scholar 

  47. Caini S, et al. Total and cancer mortality in a cohort of ulcerative colitis and Crohn’s disease patients: The Florence inflammatory bowel disease study, 1978-2010. Dig Liver Dis. 2016;48:1162–7.

    Article  Google Scholar 

  48. Bernstein CN, Blanchard JF, Kliewer E, Wajda A. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer. 2001;91:854–62.

    Article  CAS  Google Scholar 

  49. Monteleone G, Pallone F, Stolfi C. The dual role of inflammation in colon carcinogenesis. Int J Mol Sci. 2012;13:11071–84.

    Article  CAS  Google Scholar 

  50. Zhang W, et al. SOCS3 Suppression promoted the recruitment of CD11b( + )Gr-1(−)F4/80(−)MHCII(−) early-stage myeloid-derived suppressor cells and accelerated interleukin-6-related tumor invasion via affecting myeloid differentiation in breast cancer. Front Immunol. 2018;9:1699.

    Article  Google Scholar 

  51. Becker C, et al. TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity. 2004;21:491–501.

    Article  CAS  Google Scholar 

  52. Pathria P, et al. Myeloid STAT3 promotes formation of colitis-associated colorectal cancer in mice. Oncoimmunology. 2015;4:e998529.

    Article  Google Scholar 

  53. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.

    Article  CAS  Google Scholar 

  54. Beswick EJ, et al. Expression of programmed death-ligand 1 by human colonic CD90(+) stromal cells differs between ulcerative colitis and Crohn’s disease and determines their capacity to suppress Th1 cells. Front Immunol. 2018;9:1125.

    Article  Google Scholar 

  55. Daniel C, et al. FTY720 ameliorates oxazolone colitis in mice by directly affecting T helper type 2 functions. Mol Immunol. 2007;44:3305–16.

    Article  CAS  Google Scholar 

  56. Wang K, Karin M. Tumor-elicited inflammation and colorectal cancer. Adv Cancer Res. 2015;128:173–96.

    Article  CAS  Google Scholar 

  57. Tanaka T, et al. A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate. Cancer Sci. 2003;94:965–73.

    Article  CAS  Google Scholar 

  58. Kim JJ, Shajib MS, Manocha MM & Khan WI. Investigating intestinal inflammation in DSS-induced model of IBD. J Vis Exp. 2012;60:3678.

  59. Linke B, et al. Toponomics analysis of drug-induced changes in arachidonic acid-dependent signaling pathways during spinal nociceptive processing. J Proteome Res. 2009;8:4851–9.

    Article  CAS  Google Scholar 

  60. Ottenlinger FM, et al. Interferon-beta increases plasma ceramides of specific chain length in multiple sclerosis patients, unlike fingolimod or natalizumab. Front Pharmacol. 2016;7:412.

    Article  CAS  Google Scholar 

  61. Sato T, et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology. 2011;141:1762–72.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (grant number: SFB1039) to (HHR, AS, KGS, DT, EE, AW, KS, GG, JMP). We also acknowledge the support of the Else-Kröner-Fresenius-Graduiertenkolleg for (FO), the Translational Research Innovation Pharma graduate school for (KGS) funded by the Else-Kröner-Fresenius Foundation both awarded to (HHR), and the LOEWE Cell and Gene Therapy Frankfurt faculty (grant number: III L 4 518/17.004) for EW, awarded to HB.

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AS and HHR designed the study and wrote the manuscript. AS performed experiments, data acquisition and evaluation. MH was substantially involved in animal experiments, performed bright field immunostainings and co-wrote the manuscript. KGS helped with sample preparation, endoscopy scoring. HHR and AS, supported by MH and KGS, revised the manuscript for re-submission. EW and HB helped with transplantations and cytokine arrays. MA evaluated histological samples. EE and AW performed immunofluorescence stainings and discussed data. KS performed MELC studies. FO helped with sample preparation and endoscopy scoring. DT and GG conducted LC-MS/MS analysis. JMP provided basic lab equipment and discussed data. All authors reviewed the relevant intellectual content and approved the final manuscript. The authors thank C. Dreis and K. Zych for technical support, H. Vienken for spiritual support, Novartis for providing the inducible knockout mice, and J. Collins (iCCC Rhein-Main, Frankfurt) for correcting and proofreading the manuscript.

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Correspondence to Anja Schwiebs or Heinfried H. Radeke.

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Schwiebs, A., Herrero San Juan, M., Schmidt, K.G. et al. Cancer-induced inflammation and inflammation-induced cancer in colon: a role for S1P lyase. Oncogene 38, 4788–4803 (2019). https://doi.org/10.1038/s41388-019-0758-x

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