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Frontiers in Medical Science Research, 2023, 5(8); doi: 10.25236/FMSR.2023.050804.

OK-432 suppresses lymphorrhea after urological tumorectomy by regulating Akt/NFκB mediated VEGFC/VEGFR-3 signaling

Author(s)

Peng Zhang1, Xing Huang1,2, Weibing Zhang1, Hang Zheng1

Corresponding Author:
Xing Huang
Affiliation(s)

1Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China

2Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China

Abstract

Lymphorrhea following retroperitoneal surgery is a challenging complication. This study aimed at exploring the efficiency, mechanisms of immunotherapeutic agent OK-432 in urological cancer-associated lymphorrhea. Intracavitary administration of OK-432 suppressed lymphorrhea after urological tumorectomy. In malignancy-related lymphorrhea, researches on OK-432 was in high-profile. Expressions of VEGFC increased in infiltrating urothelial cancer compared to superficial tumor and was correlated to immune cell infiltration. OK-432 impaired T24 cells viability and anchorage-independent growth by inhibiting Akt/NFκB-mediated VEGFC expression, while facilitated migration and tube formation of lymphatic endothelial cells by enhancing Akt/NFκB-mediated VEGFR-3 expression. OK-432 is an alternative for the lymphorrhea after urological tumorectomy by promoting VEGFR-3 mediated-lymphatic endothelial cells migration and impairing viability of cancer cells through down-regulating expression of VEGFC, and both of which were Akt/NFκB signaling dependent.

Keywords

Picibanil, Urothelial Carcinoma, Lymphorrhagia, Vascular Endothelial Growth Factor, Immunotherapy

Cite This Paper

Peng Zhang, Xing Huang, Weibing Zhang, Hang Zheng. OK-432 suppresses lymphorrhea after urological tumorectomy by regulating Akt/NFκB mediated VEGFC/VEGFR-3 signaling. Frontiers in Medical Science Research (2023) Vol. 5, Issue 8: 26-35. https://doi.org/10.25236/FMSR.2023.050804.

References

[1] K. Tanaka, Y. Ohmori, Y. Mohri, H. Tonouchi, M. Suematsu, Y. Taguchi, Y. Adachi, M. Kusunoki, Successful treatment of refractory hepatic lymphorrhea after gastrectomy for early gastric cancer, using surgical ligation and subsequent OK-432 (Picibanil) sclerotherapy, Gastric Cancer, 7 (2004) 117-121.

[2] A. Bachmann, R. Ruszat, M. Dickenmann, O. Giannini, M. Mayr, J. Steiger, T.C. Gasser, T. Sulser, Chyloretroperitoneum with secondary chylothorax after retroperitoneoscopic donor nephrectomy, Urology, 66 (2005) 881.

[3] A. Cardenas, S. Chopra, Chylous ascites, Am J Gastroenterol, 97 (2002) 1896-1900.

[4] H. Minami, N. Mukohara, T. Shida, Postoperative chylothorax in patients with a thoracic aortic aneurysm, Ann Thorac Cardiovasc Surg, 12 (2006) 116-120.

[5] J. I. Ulibarri, Y. Sanz, C. Fuentes, A. Mancha, M. Aramendia, S. Sanchez, Reduction of lymphorrhagia from ruptured thoracic duct by somatostatin, Lancet, 336 (1990) 258.

[6] B. D. Carr, C.N. Grant, R.E. Overman, S.K. Gadepalli, J.D. Geiger, Retroperitoneal exploration with Vicryl mesh and fibrin tissue sealant for refractory chylous ascites, J Pediatr Surg, 54 (2019) 604-607.

[7] Y. Yang, E. Gao, X. Liu, Z. Ye, Y. Chen, Q. Li, J. Qu, X. Dai, O. Wang, Y. Pan, X. Zhang, Effectiveness of OK-432 (Sapylin) to reduce seroma formation after axillary lymphadenectomy for breast cancer, Ann Surg Oncol, 20 (2013) 1500-1504.

[8] S. Schwager, M. Detmar, Inflammation and Lymphatic Function, Front Immunol, 10 (2019) 308.

[9] C. Ma, J. Xie, C. Luo, H. Yin, R. Li, X. Wang, W. Xiong, T. Zhang, P. Jiang, W. Qi, T. Zhou, Z. Yang, W. Wang, J. Ma, G. Gao, X. Yang, OxLDL promotes lymphangiogenesis and lymphatic metastasis in gastric cancer by upregulating VEGFC expression and secretion, Int J Oncol, 54 (2019) 572-584.

[10] Y. Yang, Y. Cao, The impact of VEGF on cancer metastasis and systemic disease, Semin Cancer Biol, (2022).

[11] P. Zhang, L. Chen, Y. Song, X. Li, Y. Sun, Y. Xiao, Y. Xing, Tetraiodothyroacetic acid and transthyretin silencing inhibit pro-metastatic effect of L-thyroxin in anoikis-resistant prostate cancer cells through regulation of MAPK/ERK pathway, Exp Cell Res, 347 (2016) 350-359.

[12] P. Zhang, Z. Xing, X. Li, Y. Song, J. Zhao, Y. Xiao, Y. Xing, Tyrosine receptor kinase B silencing inhibits anoikisresistance and improves anticancer efficiency of sorafenib in human renal cancer cells, Int J Oncol, 48 (2016) 1417-1425.

[13] Z.H. Liu, F.F. Zheng, Y.L. Mao, L.F. Ye, J. Bian, D.H. Lai, Y.L. Ye, Y.P. Dai, Effects of programmed death-ligand 1 expression on OK-432 immunotherapy following transurethral resection in non-muscle invasive bladder cancer, Oncol Lett, 13 (2017) 4818-4824.

[14] Y. Kageyama, Y. Sakai, G. Arai, N. Hyochi, M. Suzuki, H. Masuda, S. Kawakami, T. Hayashi, T. Okuno, T. Kobayashi, K. Kihara, Intracavitary administration of OK-432 with subcutaneous priming for malignant ascites in a case of advanced renal cell carcinoma, Int J Urol, 9 (2002) 57-59.

[15] M. Tang, Y. Zhao, N. Liu, E. Chen, Z. Quan, X. Wu, C. Luo, Overexpression of HepaCAM inhibits bladder cancer cell proliferation and viability through the AKT/FoxO pathway, J Cancer Res Clin Oncol, 143 (2017) 793-805.

[16] M. Okamoto, T. Oshikawa, T. Tano, G. Ohe, S. Furuichi, H. Nishikawa, S.U. Ahmed, S. Akashi, K. Miyake, O. Takeuchi, S. Akira, Y. Moriya, S. Matsubara, Y. Ryoma, M. Saito, M. Sato, Involvement of Toll-like receptor 4 signaling in interferon-gamma production and antitumor effect by streptococcal agent OK-432, J Natl Cancer Inst, 95 (2003) 316-326.

[17] A. Fujino, Y. Moriya, Y. Morikawa, K. Hoshino, T. Watanabe, N. Shimojima, M. Kitajima, A role of cytokines in OK-432 injection therapy for cystic lymphangioma: an approach to the mechanism, J Pediatr Surg, 38 (2003) 1806-1809.

[18] D. Kong, D. Zhang, Q. Cui, K. Wang, J. Tang, Z. Liu, G. Wu, Sapylin (OK-432) alters inflammation and angiogenesis in vivo and vitro, Biomed Pharmacother, 113 (2019) 108706.

[19] X. Cai, W. Zhang, G. Chen, R.F. Li, Y.F. Sun, Y.F. Zhao, Mesenchymal status of lymphatic endothelial cell: enlightening treatment of lymphatic malformation, Int J Clin Exp Med, 8 (2015) 12239-12251.

[20] C.H. Yeang, G.C. Ma, J.C. Shih, Y.S. Yang, C.P. Chen, S.P. Chang, S.H. Wu, C.S. Liu, S.J. Kuo, H.C. Chou, W.L. Hwu, A.D. Cameron, N.A. Ginsberg, Y.S. Lin, M. Chen, Genome-wide gene expression analysis implicates the immune response and lymphangiogenesis in the pathogenesis of fetal chylothorax, PLoS One, 7 (2012) e34901.

[21] M. Jung, B. Oren, J. Mora, C. Mertens, S. Dziumbla, R. Popp, A. Weigert, N. Grossmann, I. Fleming, B. Brune, Lipocalin 2 from macrophages stimulated by tumor cell-derived sphingosine 1-phosphate promotes lymphangiogenesis and tumor metastasis, Sci Signal, 9 (2016) ra64.

[22] X.G. Wu, C.F. Zhou, Y.M. Zhang, R.M. Yan, W.F. Wei, X.J. Chen, H.Y. Yi, L.J. Liang, L.S. Fan, L. Liang, S. Wu, W. Wang, Cancer-derived exosomal miR-221-3p promotes angiogenesis by targeting THBS2 in cervical squamous cell carcinoma, Angiogenesis, 22 (2019) 397-410.

[23] K. Pan, L. Lv, H.X. Zheng, J.J. Zhao, Q.Z. Pan, J.J. Li, D.S. Weng, D.D. Wang, S.S. Jiang, A.E. Chang, Q. Li, J.C. Xia, OK-432 synergizes with IFN-gamma to confer dendritic cells with enhanced antitumor immunity, Immunol Cell Biol, 92 (2014) 263-274.

[24] T. Koya, R. Yanagisawa, Y. Higuchi, K. Sano, S. Shimodaira, Interferon-alpha-inducible Dendritic Cells Matured with OK-432 Exhibit TRAIL and Fas Ligand Pathway-mediated Killer Activity, Sci Rep, 7 (2017) 42145.

[25] Y.F. Tian, K. Tang, W. Guan, T. Yang, H. Xu, Q.Y. Zhuang, Z.Q. Ye, OK-432 Suppresses Proliferation and Metastasis by Tumor Associated Macrophages in Bladder Cancer, Asian Pac J Cancer Prev, 16 (2015) 4537-4542.

[26] G. Zhu, Q. Huang, W. Zheng, Y. Huang, J. Hua, S. Yang, J. Zhuang, J. Wang, J. Chang, J. Xu, J. Ye, LPS Upregulated VEGFR-3 Expression Promote Migration and Invasion in Colorectal Cancer via a Mechanism of Increased NF-kappaB Binding to the Promoter of VEGFR-3, Cell Physiol Biochem, 39 (2016) 1665-1678.

[27] Q. Du, L. Jiang, X. Wang, M. Wang, F. She, Y. Chen, Tumor necrosis factor-alpha promotes the lymphangiogenesis of gallbladder carcinoma through nuclear factor-kappaB-mediated upregulation of vascular endothelial growth factor-C, Cancer Sci, 105 (2014) 1261-1271.