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Methylprednisolone Inhibits Tumor Growth and Peritoneal Seeding Induced by Surgical Stress and Postoperative Complications

  • Yoshiki Taniguchi
  • Yukinori KurokawaEmail author
  • Takaomi Hagi
  • Tsuyoshi Takahashi
  • Yasuhiro Miyazaki
  • Koji Tanaka
  • Tomoki Makino
  • Makoto Yamasaki
  • Kiyokazu Nakajima
  • Masaki Mori
  • Yuichiro Doki
Translational Research and Biomarkers
  • 25 Downloads

Abstract

Background

Surgery often introduce inflammatory response, which may promote tumor growth and metastasis of residual cancer cells. We investigated the impacts of methylprednisolone on the tumor growth and peritoneal seedings in mice treated with lipopolysaccharide (LPS), which mimics systemic inflammation induced by surgical stress and postoperative complications.

Methods

The serum interleukin-6 (IL-6) levels, tumor volume, tumor weight, and the number of peritoneal nodules were investigated in tumor growth model and peritoneal seeding model using BALB/c mice and murine CT26 cancer cell lines in vivo. We conducted functional analyses of IL-6 in Western blotting and proliferation assays in vitro. We also investigated whether preoperative administration of methylprednisolone decreased postoperative serum IL-6 levels in cancer patients in a randomized clinical study.

Results

In the in vivo study, methylprednisolone inhibited the LPS-induced increase of serum IL-6 levels (mean, 33,756 pg/ml vs. 5917 pg/ml; P < 0.001), tumor volume (mean, 397 mm3 vs. 274 mm3; P = 0.019), tumor weight (mean, 0.38 g vs. 0.15 g; P = 0.020), and the number of peritoneal nodules (mean, 112 vs. 47; P = 0.002). In the in vitro study, IL-6 enhanced JAK/STAT signaling and increased the cell proliferation, and IL-6R-neutralizing antibody attenuated these effects. In the clinical study, serum IL-6 levels were significantly decreased by methylprednisolone (median, 97.5 pg/ml vs. 18.0 pg/ml; P = 0.030).

Conclusions

Surgical stress and postoperative complications may enhance tumor growth due to the increase of IL-6. However, methylprednisolone can decrease serum IL-6 levels, thus inhibiting tumor growth and peritoneal seeding.

Notes

Disclosure

There are no conflicts of interest.

Supplementary material

10434_2019_7585_MOESM1_ESM.tif (11.7 mb)
Supplementary Figure S1 Representative images in tumor growth experiment. a Photographs of resected tumor specimens from the backs of mice. b Representative images of tumor specimens stained with Ki67 antibody. Scale bar, 100 μm. LPS lipopolysaccharide, MP methylprednisolone (TIFF 11968 kb)
10434_2019_7585_MOESM2_ESM.tif (7.2 mb)
Supplementary Figure S2 Representative images in tumor seeding experiment. Photographs of resected tumor specimens from the peritoneum of mice. LPS lipopolysaccharide, MP methylprednisolone (TIFF 7421 kb)

References

  1. 1.
    Artinyan A, Orcutt ST, Anaya DA, et al. Infectious postoperative complications decrease long-term survival in patients undergoing curative surgery for colorectal cancer: a study of 12,075 patients. Ann Surg. 2015;261:497–505.CrossRefGoogle Scholar
  2. 2.
    Lerut T, Moons J, Coosemans W, et al. Postoperative complications after transthoracic esophagectomy for cancer of the esophagus and gastroesophageal junction are correlated with early cancer recurrence: role of systematic grading of complications using the modified Clavien classification. Ann Surg. 2009;250:798–807.CrossRefGoogle Scholar
  3. 3.
    Saito T, Kurokawa Y, Miyazaki Y, et al. Which is a more reliable indicator of survival after gastric cancer surgery: postoperative complication occurrence or C-reactive protein elevation? J Surg Oncol. 2015;112:894–9.CrossRefGoogle Scholar
  4. 4.
    Goumas FA, Holmer R, Egberts JH, et al. Inhibition of IL-6 signaling significantly reduces primary tumor growth and recurrences in orthotopic xenograft models of pancreatic cancer. Int J Cancer. 2015;137:1035–46.CrossRefGoogle Scholar
  5. 5.
    Suchi K, Fujiwara H, Okamura S, et al. Overexpression of Interleukin-6 suppresses cisplatin-induced cytotoxicity in esophageal squamous cell carcinoma cells. Anticancer Res. 2011;31:67–75.Google Scholar
  6. 6.
    Lin MT, Lin BR, Chang CC, et al. IL-6 induces AGS gastric cancer cell invasion via activation of the c-Src/RhoA/ROCK signaling pathway. Int J Cancer. 2007;120:2600–8.CrossRefGoogle Scholar
  7. 7.
    Nakayama T, Yoshizaki A, Izumida S, et al. Expression of interleukin-11 (IL-11) and IL-11 receptor alpha in human gastric carcinoma and IL-11 upregulates the invasive activity of human gastric carcinoma cells. Int J Oncol. 2007;30:825–33.Google Scholar
  8. 8.
    Foran E, Garrity-Park MM, Mureau C, et al. Upregulation of DNA methyltransferase- mediated gene silencing, anchorage-independent growth, and migration of colon cancer cells by interleukin-6. Mol Cancer Res. 2010;8:471–81.CrossRefGoogle Scholar
  9. 9.
    Nojiri T, Hosoda H, Tokudome T, et al. Atrial natriuretic peptide prevents cancer metastasis through vascular endothelial cells. Proc Natl Acad Sci USA. 2015;112:4086–91.CrossRefGoogle Scholar
  10. 10.
    Shimada H, Ochiai T, Okazumi S, et al. Clinical benefits of steroid therapy on surgical stress in patients with esophageal cancer. Surgery. 2000;128(5):791–8.CrossRefGoogle Scholar
  11. 11.
    Sato N, Koeda K, Ikeda K, et al. Randomized study of the benefits of preoperative corticosteroid administration on the postoperative morbidity and cytokine response in patients undergoing surgery for esophageal cancer. Ann Surg. 2002;236(2):184–90.CrossRefGoogle Scholar
  12. 12.
    Szczepanik AM, Scislo L, Scully T, et al. IL-6 serum levels predict postoperative morbidity in gastric cancer patients. Gastric Cancer. 2011;14(3):266–73.CrossRefGoogle Scholar
  13. 13.
    Wen XH, Kong HY, Zhu SM, et al. Plasma levels of tumor necrotic factor-alpha and interleukin-6, -8 during orthotopic liver transplantation and their relations to postoperative pulmonary complications. Hepatobil Pancreat Dis Int. 2004;3(1):38–41.Google Scholar
  14. 14.
    Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 2005;41:2502–12.CrossRefGoogle Scholar
  15. 15.
    Blechacz B, Gores GJ. Cholangiocarcinoma: advances in pathogenesis, diagnosis, and treatment. Hepatology. 2008;48(1):308–21.CrossRefGoogle Scholar
  16. 16.
    Garbers C, Hermanns HM, Schaper F, et al. Plasticity and cross-talk of interleukin 6-type cytokines. Cytokine Growth Factor Rev. 2012;23:85–97.CrossRefGoogle Scholar
  17. 17.
    Kishimoto T. IL-6: from its discovery to clinical applications. Int Immunol. 2010;22:347–52.CrossRefGoogle Scholar
  18. 18.
    Leu CM, Wong FH, Chang C, et al. Interleukin-6 acts as an antiapoptotic factor in human esophageal carcinoma cells through the activation of both STAT3 and mitogen-activated protein kinase pathways. Oncogene. 2003;22:7809–18.CrossRefGoogle Scholar
  19. 19.
    Sansone P, Storci G, Tavolari S, et al. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest. 2007;117:3988–4002.CrossRefGoogle Scholar
  20. 20.
    Salvans S, Mayol X, Alonso S, et al. Postoperative peritoneal infection enhances migration and invasion capacities of tumor cells in vitro: An insight into the association between anastomotic leak and recurrence after surgery for colorectal cancer. Ann Surg. 2014;260:939–44.CrossRefGoogle Scholar
  21. 21.
    Wu FP, Sietses C, von Blomberg BM, Van Leeuwen PA, Meijer S, Cuesta MA. Systemic and peritoneal inflammatory response after laparoscopic or conventional colon resection in cancer patients: a prospective, randomized trial. Dis Colon Rectum. 2003;46:147–55.CrossRefGoogle Scholar
  22. 22.
    Pascual M, Alonso S, Pares D, et al. Randomized clinical trial comparing inflammatory and angiogenic response after open versus laparoscopic curative resection for colonic cancer. Br J Surg. 2011;98:50–9.CrossRefGoogle Scholar
  23. 23.
    Okamoto M, Lee C, Oyasu R. Autocrine effect of androgen on proliferation of an androgen responsive prostatic carcinoma cell line, LNCAP: role of interleukin-6. Endocrinology. 1997;138:5071–4.CrossRefGoogle Scholar
  24. 24.
    Eustace D, Han X, Gooding R, Rowbottom A, Riches P, Heyderman E. Interleukin-6 (IL-6) functions as an autocrine growth factor in cervical carcinomas in vitro. Gynecol Oncol. 1993;50:15–9.CrossRefGoogle Scholar
  25. 25.
    Ashizawa T, Okada R, Suzuki Y, et al. Clinical significance of interleukin-6 (IL-6) in the spread of gastric cancer: role of IL-6 as a prognostic factor. Gastric Cancer. 2005;8(2):124–31.CrossRefGoogle Scholar
  26. 26.
    Lee SW, Southall J, Allendorf J, Bessler M, Whelan RL. Traumatic handling of the tumor independent of pneumoperitoneum increases port site implantation rate of colon cancer in a murine model. Surg Endosc. 1998;12(6):828–34.CrossRefGoogle Scholar
  27. 27.
    Sugarbaker PH. Strategies for the prevention and treatment of peritoneal carcinomatosis from gastrointestinal cancer. Cancer Invest. 2005;23(2):155–72.CrossRefGoogle Scholar
  28. 28.
    Xiao J, Gong Y, Chen Y, et al. IL-6 promotes epithelial-to-mesenchymal transition of human peritoneal mesothelial cells possibly through the JAK2/STAT3 signaling pathway. Am J Physiol Renal Physiol. 2017;313(2):F310–8.CrossRefGoogle Scholar
  29. 29.
    Mochizuki Y, Nakanishi H, Kodera Y, et al. TNF-alpha promotes progression of peritoneal metastasis as demonstrated using a green fluorescence protein (GFP)-tagged human gastric cancer cell line. Clin Exp Metastasis. 2004;21:39–47.CrossRefGoogle Scholar
  30. 30.
    Matsutani T, Onda M, Sasajima K, Miyashita M. Glucocorticoid attenuates a decrease of antithrombin III following major surgery. J Surg Res. 1998;79(2):158–63.CrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2019

Authors and Affiliations

  • Yoshiki Taniguchi
    • 1
  • Yukinori Kurokawa
    • 1
    Email author
  • Takaomi Hagi
    • 1
  • Tsuyoshi Takahashi
    • 1
  • Yasuhiro Miyazaki
    • 1
  • Koji Tanaka
    • 1
  • Tomoki Makino
    • 1
  • Makoto Yamasaki
    • 1
  • Kiyokazu Nakajima
    • 1
  • Masaki Mori
    • 1
  • Yuichiro Doki
    • 1
  1. 1.Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineSuitaJapan

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