Tumor Biology

, Volume 35, Issue 5, pp 4285–4293 | Cite as

The mannose-sensitive hemagglutination pilus strain of Pseudomonas aeruginosa shift peritoneal milky spot macrophages towards an M1 phenotype to dampen peritoneal dissemination

  • Zhi-Feng Miao
  • Ting-Ting Zhao
  • Feng Miao
  • Zhen-Ning Wang
  • Ying-Ying Xu
  • Xiao-Yun Mao
  • Jian Gao
  • Jian-Hua Wu
  • Xing-Yu Liu
  • Yi You
  • Hao Xu
  • Hui-Mian Xu
Research Article


Peritoneal dissemination (PD) of tumor cells is the most frequent pattern of gastric cancer recurrence and the leading cause of death. Peritoneal milky spots are deemed as the site of origin of gastric cancer PD wherein the main cellular components are macrophages. A vaccine derived from the mannose-sensitive hemagglutination pilus strain of Pseudomonas aeruginosa (PA-MSHA) has exhibit strong immune modulatory properties. In the present study, we tested the hypothesis whether the PA-MSHA vaccine activated peritoneal milky spot macrophages (PMSM) in a manner that would attenuate PD. It was observed that PA-MSHA activated PMSM towards a classical activation phenotype via a toll-like receptor4/9-dependent mechanism, which increased interleukin-12 levels and promoted the expression of co-stimulatory and antigen-presenting molecules like CD80, CD86, and MHC-II (P < 0.05). In addition, PA-MSHA-treated PMSM exhibited strong nonspecific antitumor effects in both contact-dependent and contact-independent modes of action (P < 0.05). In mice treated with PA-MSHA before inoculating gastric cancer cells, we noted alleviated PD toward the untreated mice. In conclusion, our findings demonstrated that PA-MSHA can stimulate PMSM towards an M1 phenotype and that activated PMSM inhibit gastric cancer growth and PD both in vitro and in vivo. The results of the current study provide a mechanistic insight that is relevant to the potential application of PA-MSHA in the treatment of gastric cancer-mediated PD.


Peritoneal carcinomatosis Stomach cancer Peritoneal macrophage Immunotherapy PA-MSHA Inflammatory cytokines 


Conflicts of interest



  1. 1.
    Catalano V, Labianca R, Beretta GD, et al. Gastric cancer. Crit Rev Oncol Hematol. 2009;71:127–64.CrossRefPubMedGoogle Scholar
  2. 2.
    Ferrone C, Dranoff G. Dual roles for immunity in gastrointestinal cancers. J Clin Oncol. 2010;28:4045–51.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Jackson C, Cunningham D, Oliveira J, et al. Gastric cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20:34–6.CrossRefPubMedGoogle Scholar
  4. 4.
    Buzzoni R, Bajetta E, Di Bartolomeo M, et al. Pathological features as predictors of recurrence after radical resection of gastric cancer. Br J Surg. 2006;93:205–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Sun P, Xiang JB, Chen ZY. Meta-analysis of adjuvant chemotherapy after radical surgery for advanced gastric cancer. Br J Surg. 2009;96:26–33.CrossRefPubMedGoogle Scholar
  6. 6.
    Gill RS, Al-Adra DP, Nagendran J, et al. Treatment of gastric cancer with peritoneal carcinomatosis by cytoreductive surgery and HIPEC: a systematic review of survival, mortality, and morbidity. J Surg Oncol. 2011;104:692–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Sugarbaker PH, Yu W, Yonemura Y. Gastrectomy, peritonectomy, and perioperative intraperitoneal chemotherapy: the evolution of treatment strategies for advanced gastric cancer. Semin Surg Oncol. 2003;21:233–48.CrossRefPubMedGoogle Scholar
  8. 8.
    Matharu G, Tucker O, Alderson D. Systematic review of intraperitoneal chemotherapy for gastric cancer. Br J Surg. 2011;98:1225–35.CrossRefPubMedGoogle Scholar
  9. 9.
    Mebius RE. Lymphoid organs for peritoneal cavity immune response: milky spots. Immunity. 2009;30:670–2.CrossRefPubMedGoogle Scholar
  10. 10.
    Krist LF, Kerremans M, Broekhuis-Fluitsma DM, et al. Milky spots in the greater omentum are predominant sites of local tumour cell proliferation and accumulation in the peritoneal cavity. Cancer Immunol Immunother. 1998;47:205–12.CrossRefPubMedGoogle Scholar
  11. 11.
    Khan SM, Funk HM, Thiolloy S, et al. In vitro metastatic colonization of human ovarian cancer cells to the omentum. Clin Exp Metastasis. 2010;27:185–96.CrossRefPubMedGoogle Scholar
  12. 12.
    Cao L, Hu X, Zhang Y, et al. Omental milky spots in screening gastric cancer stem cells. Neoplasma. 2011;58:20–6.CrossRefPubMedGoogle Scholar
  13. 13.
    Sorensen EW, Gerber SA, Sedlacek AL, et al. Omental immune aggregates and tumor metastasis within the peritoneal cavity. Immunol Res. 2009;45:185–94.CrossRefPubMedGoogle Scholar
  14. 14.
    Oosterling SJ, van der Bij GJ, Bögels M, et al. Insufficient ability of omental milky spots to prevent peritoneal tumor outgrowth supports omentectomy in minimal residual disease. Cancer Immunol Immunother. 2006;55:1043–51.CrossRefPubMedGoogle Scholar
  15. 15.
    Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11:889–96.CrossRefPubMedGoogle Scholar
  16. 16.
    Koido S, Homma S, Okamoto M. Combined TLR2/4-activated dendritic/tumor cell fusions induce augmented cytotoxic T lymphocytes. PLoS One. 2013;8:e59280.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Liu W, O'Donnell MA, Chen X, et al. Recombinant bacillus Calmette-Guérin (BCG) expressing interferon-alpha 2B enhances human mononuclear cell cytotoxicity against bladder cancer cell lines in vitro. Cancer Immunol Immunother. 2009;58:1647–55.CrossRefPubMedGoogle Scholar
  18. 18.
    Byeon SE, Lee J, Kim JH et al. Molecular mechanism of macrophage activation by red ginseng acidic polysaccharide from Korean red ginseng. Mediators Inflamm 2012:732860.Google Scholar
  19. 19.
    Moschos SJ, Edington HD, Land SR, et al. Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses. J Clin Oncol. 2006;24:3164–71.CrossRefPubMedGoogle Scholar
  20. 20.
    Zhang J, Tang Q, Zhou C, et al. GLIS, a bioactive proteoglycan fraction from Ganoderma lucidum, displays anti-tumour activity by increasing both humoral and cellular immune response. Life Sci. 2010;87:628–37.CrossRefPubMedGoogle Scholar
  21. 21.
    Cao Z, Shi L, Li Y, et al. Pseudomonas aeruginosa: mannose sensitive hemagglutinin inhibits the growth of human hepatocarcinoma cells via mannose-mediated apoptosis. Dig Dis Sci. 2009;54:2118–27.CrossRefPubMedGoogle Scholar
  22. 22.
    Liu ZB, Hou YF, Zhu J, et al. Inhibition of EGFR pathway signaling and the metastatic potential of breast cancer cells by PA-MSHA mediated by type 1 fimbriae via a mannose-dependent manner. Oncogene. 2010;29:2996–3009.CrossRefPubMedGoogle Scholar
  23. 23.
    Liu ZB, Hou YF, Min-Dong, et al. PA-MSHA inhibits proliferation and induces apoptosis through the up-regulation and activation of caspases in the human breast cancer cell lines. J Cell Biochem. 2009;108:195–206.CrossRefPubMedGoogle Scholar
  24. 24.
    Zhu YP, Bian XJ, Ye DW, et al. Pseudomonas aeruginosa-mannose-sensitive hemagglutinin inhibits proliferation and induces apoptosis in a caspase-dependent manner in human bladder cancer cell lines. Oncol Lett. 2013;5:1357–62.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Hou J, Liu Y, Liu Y, Shao Y. The MSHA strain of Pseudomonas aeruginosa activated TLR pathway and enhanced HIV-1 DNA vaccine immunoreactivity. PLoS One. 2012;7:e47724.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Soudi S, Zavaran-Hosseini A, Muhammad Hassan Z, et al. Comparative study of the effect of LPS on the function of BALB/c and C57BL/6 peritoneal macrophages. Cell J. 2013;15:45–54.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Allavena P, Mantovani A. Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment. Clin Exp Immunol. 2012;167:195–205.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Curiel TJ. Tregs and rethinking cancer immunotherapy. J Clin Invest. 2007;117:1167–74.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hallam S, Escorcio-Correia M, Soper R, et al. Activated macrophages in the tumour microenvironment-dancing to the tune of TLR and NF-kappaB. J Pathol. 2009;219:143–52.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Dumitru CD, Antonysamy MA, Gorski KS, et al. NK1.1+ cells mediate the antitumor effects of a dual Toll-like receptor 7/8 agonist in the disseminated B16-F10 melanoma model. Cancer Immunol Immunother. 2009;58:575–87.CrossRefPubMedGoogle Scholar
  31. 31.
    Hu X, Chakravarty SD, Ivashkiv LB. Regulation of interferon and Toll-like receptor signaling during macrophage activation by opposing feedforward and feedback inhibition mechanisms. Immunol Rev. 2008;226:41–56.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Pinto A, Morello S, Sorrentino R. Lung cancer and Toll-like receptors. Cancer Immunol Immunother. 2011;60:1211–20.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Zhi-Feng Miao
    • 1
  • Ting-Ting Zhao
    • 2
  • Feng Miao
    • 3
  • Zhen-Ning Wang
    • 1
  • Ying-Ying Xu
    • 2
  • Xiao-Yun Mao
    • 2
  • Jian Gao
    • 4
  • Jian-Hua Wu
    • 1
  • Xing-Yu Liu
    • 1
  • Yi You
    • 1
  • Hao Xu
    • 1
  • Hui-Mian Xu
    • 1
  1. 1.Department of Surgical OncologyThe First Affiliated Hospital of China Medical UniversityShenyangChina
  2. 2.Department of Breast SurgeryThe First Affiliated Hospital of China Medical UniversityShenyangChina
  3. 3.Department of DigestionThe Fourth Affiliated Hospital of China Medical UniversityShenyangChina
  4. 4.Center of Laboratory Technology and Experimental MedicineChina Medical UniversityShenyangChina

Personalised recommendations