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Exposure to Blood Components and Inflammation Contribute to Pancreatic Cancer Progression

  • Pancreatic Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Pancreatectomy is a highly invasive procedure with extensive intraoperative blood loss (IBL) and high risk of postoperative pancreatic fistula (POPF). We conducted an experimental and retrospective clinical study to determine whether the malignant behaviors of pancreatic cancer cells were enhanced by exposure to blood components in vitro and to evaluate the oncological significance of high IBL and POPF in pancreatic cancer.

Methods

This study included 107 patients undergoing radical pancreatectomy in the University of Yamanashi Hospital between 2011 and 2017, classified into high (n = 29) and low (n = 78) IBL groups. In vitro experiments included functional analyses of Panc-1 pancreatic cancer and normal mesothelial cells exposed to patient blood components, and clinical data were used to assess the contribution of IBL and POPF to patient outcomes.

Results

The migration (p = 0.007), invasion (p < 0.001), and proliferation (p < 0.01) of Panc-1 cells were enhanced with platelet coculture. The ability of Panc-1 cells to adhere mesothelial cells was enhanced by plasma coincubation, especially in the presence of inflammation (p < 0.001). High IBL was associated with worse overall survival (p = 0.007) and increased locoregional recurrence (p = 0.003) in patients. POPF enhanced the negative prognostic significance of high IBL (p < 0.001 for overall survival, p = 0.001 for locoregional recurrence), indicating the oncological negative effects of high IBL and POPF.

Conclusions

Blood components, especially platelets, and inflammation enhance the malignant behaviors of pancreatic cancer cells, potentially contributing to poor prognosis for pancreatic cancer patients.

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References

  1. Kimura W, Miyata H, Gotoh M, et al. A pancreaticoduodenectomy risk model derived from 8575 cases from a national single-race population (Japanese) using a web-based data entry system: the 30-day and in-hospital mortality rates for pancreaticoduodenectomy. Ann Surg. 2014;259(4):773–80. https://doi.org/10.1097/sla.0000000000000263.

    Article  PubMed  Google Scholar 

  2. Raut CP, Tseng JF, Sun CC, et al. Impact of resection status on pattern of failure and survival after pancreaticoduodenectomy for pancreatic adenocarcinoma. Ann Surg. 2007;246(1):52–60. https://doi.org/10.1097/01.sla.0000259391.84304.2b.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hartwig W, Gluth A, Hinz U, et al. Outcomes after extended pancreatectomy in patients with borderline resectable and locally advanced pancreatic cancer. Br J Surg. 2016;103(12):1683–94. https://doi.org/10.1002/bjs.10221.

    Article  CAS  PubMed  Google Scholar 

  4. Hackert T, Hinz U, Pausch T, et al. Postoperative pancreatic fistula: we need to redefine grades B and C. Surgery. 2016;159(3):872–7. https://doi.org/10.1016/j.surg.2015.09.014.

    Article  PubMed  Google Scholar 

  5. Kamei T, Kitayama J, Yamashita H, Nagawa H. Intraoperative blood loss is a critical risk factor for peritoneal recurrence after curative resection of advanced gastric cancer. World J Surg. 2009;33(6):1240–6. https://doi.org/10.1007/s00268-009-9979-4.

    Article  PubMed  Google Scholar 

  6. Ito Y, Kanda M, Ito S, et al. Intraoperative blood loss is associated with shortened postoperative survival of patients with stage ii/iii gastric cancer: analysis of a multi-institutional dataset. World J Surg. 2019;43(3):870–87. https://doi.org/10.1007/s00268-018-4834-0.

    Article  PubMed  Google Scholar 

  7. Nakanishi K, Kanda M, Kodera Y. Long-lasting discussion: adverse effects of intraoperative blood loss and allogeneic transfusion on prognosis of patients with gastric cancer. World J Gastroenterol. 2019;25(22):2743–51. https://doi.org/10.3748/wjg.v25.i22.2743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Arima K, Hashimoto D, Okabe H, et al. Intraoperative blood loss is not a predictor of prognosis for pancreatic cancer. Surg Today. 2016;46(7):792–7. https://doi.org/10.1007/s00595-015-1238-8.

    Article  CAS  PubMed  Google Scholar 

  9. Saito R, Shoda K, Maruyama S, et al. Platelets enhance malignant behaviours of gastric cancer cells via direct contacts. Br J Cancer. 2021;124(3):570–3. https://doi.org/10.1038/s41416-020-01134-7.

    Article  CAS  PubMed  Google Scholar 

  10. McSorley ST, Watt DG, Horgan PG, McMillan DC. Postoperative systemic inflammatory response, complication severity, and survival following surgery for colorectal cancer. Ann Surg Oncol. 2016;23(9):2832–40. https://doi.org/10.1245/s10434-016-5204-5.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Powell DR, Huttenlocher A. Neutrophils in the tumor microenvironment. Trends Immunol. 2016;37(1):41–52. https://doi.org/10.1016/j.it.2015.11.008.

    Article  CAS  PubMed  Google Scholar 

  12. Arita T, Ichikawa D, Konishi H, et al. Increase in peritoneal recurrence induced by intraoperative hemorrhage in gastrectomy. Ann Surg Oncol. 2015;22(3):758–64. https://doi.org/10.1245/s10434-014-4060-4.

    Article  PubMed  Google Scholar 

  13. Nojiri T, Hamasaki T, Inoue M, et al. Long-term impact of postoperative complications on cancer recurrence following lung cancer surgery. Ann Surg Oncol. 2017;24(4):1135–42. https://doi.org/10.1245/s10434-016-5655-8.

    Article  PubMed  Google Scholar 

  14. Watt DG, McSorley ST, Park JH, Horgan PG, McMillan DC. A Postoperative systemic inflammation score predicts short- and long-term outcomes in patients undergoing surgery for colorectal cancer. Ann Surg Oncol. 2017;24(4):1100–9. https://doi.org/10.1245/s10434-016-5659-4.

    Article  PubMed  Google Scholar 

  15. Nagai S, Fujii T, Kodera Y, et al. Recurrence pattern and prognosis of pancreatic cancer after pancreatic fistula. Ann Surg Oncol. 2011;18(8):2329–37. https://doi.org/10.1245/s10434-011-1604-8.

    Article  PubMed  Google Scholar 

  16. UICC. TNM classification of malignant tumours. 8th edn. New York: Wiley; 2017.

    Google Scholar 

  17. Satoh K, Fukasawa I, Kanemaru K, et al. Platelet aggregometry in the presence of PGE(1) provides a reliable method for cilostazol monitoring. Thromb Res. 2012;130(4):616–21. https://doi.org/10.1016/j.thromres.2012.05.030.

    Article  CAS  PubMed  Google Scholar 

  18. Suzuki-Inoue K, Inoue O, Frampton J, Watson SP. Murine GPVI stimulates weak integrin activation in PLCgamma2−/− platelets: involvement of PLCgamma1 and PI3-kinase. Blood. 2003;102(4):1367–73. https://doi.org/10.1182/blood-2003-01-0029.

    Article  CAS  PubMed  Google Scholar 

  19. Ranieri D, Raffa S, Parente A, Rossi Del Monte S, Ziparo V, Torrisi MR. High adhesion of tumor cells to mesothelial monolayers derived from peritoneal wash of disseminated gastrointestinal cancers. PLoS One. 2013;8(2):e57659. https://doi.org/10.1371/journal.pone.0057659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kimura R, Yoneshige A, Hagiyama M, et al. Expression of cell adhesion molecule 1 in gastric neck and base glandular cells: Possible involvement in peritoneal dissemination of signet ring cells. Life Sci. 2018;213:206–13. https://doi.org/10.1016/j.lfs.2018.10.017.

    Article  CAS  PubMed  Google Scholar 

  21. Bassi C, Marchegiani G, Dervenis C, et al. The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 years after. Surgery. 2017;161(3):584–91. https://doi.org/10.1016/j.surg.2016.11.014.

    Article  PubMed  Google Scholar 

  22. Kanda Y. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant. 2013;48(3):452–8. https://doi.org/10.1038/bmt.2012.244.

    Article  CAS  PubMed  Google Scholar 

  23. Xu XR, Yousef GM, Ni H. Cancer and platelet crosstalk: opportunities and challenges for aspirin and other antiplatelet agents. Blood. 2018;131(16):1777–89. https://doi.org/10.1182/blood-2017-05-743187.

    Article  CAS  PubMed  Google Scholar 

  24. Lambert AW, Pattabiraman DR, Weinberg RA. Emerging biological principles of metastasis. Cell. 2017;168(4):670–91. https://doi.org/10.1016/j.cell.2016.11.037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Menter DG, Kopetz S, Hawk E, et al. Platelet “first responders” in wound response, cancer, and metastasis. Cancer Metastasis Rev. 2017;36(2):199–213. https://doi.org/10.1007/s10555-017-9682-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nagai S, Fujii T, Kodera Y, et al. Impact of operative blood loss on survival in invasive ductal adenocarcinoma of the pancreas. Pancreas. 2011;40(1):3–9. https://doi.org/10.1097/MPA.0b013e3181f7147a.

    Article  PubMed  Google Scholar 

  27. Goubran H, Sheridan D, Radosevic J, Burnouf T, Seghatchian J. Transfusion-related immunomodulation and cancer. Transfus Apher Sci. 2017;56(3):336–40. https://doi.org/10.1016/j.transci.2017.05.019.

    Article  PubMed  Google Scholar 

  28. Nathan H, Yin H, Wong SL. Postoperative complications and long-term survival after complex cancer resection. Ann Surg Oncol. 2017;24(3):638–44. https://doi.org/10.1245/s10434-016-5569-5.

    Article  PubMed  Google Scholar 

  29. Mammadova-Bach E, Zigrino P, Brucker C, et al. Platelet integrin alpha6beta1 controls lung metastasis through direct binding to cancer cell-derived ADAM9. JCI insight. 2016;1(14):e88245. https://doi.org/10.1172/jci.insight.88245.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Lavergne M, Janus-Bell E, Schaff M, Gachet C, Mangin PH. Platelet integrins in tumor metastasis: do they represent a therapeutic target? Cancers. 2017. https://doi.org/10.3390/cancers9100133.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was performed mainly with expenses grants of University of Yamanashi, and partially supported by JSPS KAKENHI (20K17642). The data sets used and analyzed in this study are collected at the University of Yamanashi, and they are available from the corresponding author on reasonable request. Most of them are included in this paper. The authors are grateful to Ms. Arisa Ogihara (University of Yamanashi, Yamanashi, Japan) for their expert technical assistance. The authors thank Editage for the English language reviews.

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Correspondence to Daisuke Ichikawa MD, PhD.

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Saito, R., Kawaida, H., Hosomura, N. et al. Exposure to Blood Components and Inflammation Contribute to Pancreatic Cancer Progression. Ann Surg Oncol 28, 8263–8272 (2021). https://doi.org/10.1245/s10434-021-10250-4

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  • DOI: https://doi.org/10.1245/s10434-021-10250-4

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