Pien Tze Huang suppresses VEGF-C-mediated lymphangiogenesis in colorectal cancer

Lin,Jiumao; Feng,Jianyu; Jin,Yiyi; Yan,Zhaokun; Lai,Zijun; Peng,Jun

doi:10.3892/or.2016.5186

Pien Tze Huang suppresses VEGF-C-mediated lymphangiogenesis in colorectal cancer

Authors:
- Jiumao Lin
- Jianyu Feng
- Yiyi Jin
- Zhaokun Yan
- Zijun Lai
- Jun Peng
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Affiliations: Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
Published online on: October 20, 2016 https://doi.org/10.3892/or.2016.5186
Pages: 3568-3576

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Abstract

Colorectal cancer (CRC) is one of the most common malignancies worldwide. The majority of patients are not suitable for surgery due to the presence of metastatic disease at the time of diagnosis, which has led to a high mortality rate for patients with CRC. Lymphangiogenesis, formation of new lymphatic vessels, plays an critical role in cancer progression particularly in cancer metastasis. Vascular endothelial growth factor-C (VEGF-C) has been previously demonstrated to play a pivotal role in cancer metastasis and therefore has become an attractive target for anticancer treatments. Pien Tze Huang (PZH) is a well-known traditional Chinese formula, which has exhibited significant therapeutic effects against CRC. However, the molecular mechanisms underlying its anticancer effects, particularly in regards to antimetastasis activity, still require further elucidation. In the present study, we evaluated the effects of PZH on cell migration and VEGF-C expression using various human CRC cell lines. Moreover, using a VEGF‑C-stimulated human lymphatic endothelial cell (HLEC) model, we demonstrated that PZH suppresses lymphangiogenesis by attenuating cell migration and tube formation. This indicates that PZH possesses significant antimetastatic activity. Moreover, suppression of lymphangiogenesis by PZH via the downregulation of VEGF-C may be a potential molecular mechanism by which PZH inhibits metastasis in CRC.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI
2	Becouarn Y and Rougier P: Clinical efficacy of oxaliplatin monotherapy: Phase II trials in advanced colorectal cancer. Semin Oncol. 25:(Suppl 5). S23–S31. 1998.
3	Ng M, Roy-Chowdhury S, Lum SS, Morgan JW and Wong JH: The impact of the ratio of positive to total lymph nodes examined and outcome in colorectal cancer. Am Surg. 75:873–876. 2009.PubMed/NCBI
4	Jemal A, Clegg LX, Ward E, Ries LA, Wu X, Jamison PM, Wingo PA, Howe HL, Anderson RN and Edwards BK: Annual report to the nation on the status of cancer, 1975–2001, with a special feature regarding survival. Cancer. 101:3–27. 2004. View Article : Google Scholar : PubMed/NCBI
5	Sundlisaeter E, Dicko A, Sakariassen PØ, Sondenaa K, Enger PØ and Bjerkvig R: Lymphangiogenesis in colorectal cancer - prognostic and therapeutic aspects. Int J Cancer. 121:1401–1409. 2007. View Article : Google Scholar : PubMed/NCBI
6	Onogawa S, Kitadai Y, Tanaka S, Kuwai T, Kimura S and Chayama K: Expression of VEGF-C and VEGF-D at the invasive edge correlates with lymph node metastasis and prognosis of patients with colorectal carcinoma. Cancer Sci. 95:32–39. 2004. View Article : Google Scholar : PubMed/NCBI
7	Kim JG, Chae YS, Sohn SK, Cho YY, Moon JH, Park JY, Jeon SW, Lee IT, Choi GS and Jun SH: Vascular endothelial growth factor gene polymorphisms associated with prognosis for patients with colorectal cancer. Clin Cancer Res. 14:62–66. 2008. View Article : Google Scholar : PubMed/NCBI
8	Parr C and Jiang WG: Quantitative analysis of lymphangiogenic markers in human colorectal cancer. Int J Oncol. 23:533–539. 2003.PubMed/NCBI
9	Royston D and Jackson DG: Mechanisms of lymphatic metastasis in human colorectal adenocarcinoma. J Pathol. 217:608–619. 2009. View Article : Google Scholar : PubMed/NCBI
10	Folkman J: Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 29:(Suppl 16). S15–S18. 2002. View Article : Google Scholar
11	Hsu JY and Wakelee HA: Monoclonal antibodies targeting vascular endothelial growth factor: Current status and future challenges in cancer therapy. BioDrugs. 23:289–304. 2009. View Article : Google Scholar : PubMed/NCBI
12	Chinese Pharmacopoeia Commission, . Pharmacopoeia of the People's Republic of China. 1. Chinese Medical Science and Technology Press; Beijing: pp. 573–575. 2010
13	Shen A, Hong F, Liu L, Lin J, Wei L, Cai Q, Hong Z and Peng J: Pien Tze Huang inhibits the proliferation of human colon carcinoma cells by arresting G1/S cell cycle progression. Oncol Lett. 4:767–770. 2012.PubMed/NCBI
14	Lin JM, Wei LH, Chen YQ, Liu XX, Hong ZF, Sferra TJ and Peng J: Pien Tze Huang induced apoptosis in human colon cancer HT-29 cells is associated with regulation of the Bcl-2 family and activation of caspase 3. Chin J Integr Med. 17:685–690. 2011. View Article : Google Scholar : PubMed/NCBI
15	Shen AL, Hong F, Liu LY, Lin JM, Zhuang QC, Hong ZF and Peng J: Effects of Pien Tze Huang on angiogenesis in vivo and in vitro. Chin J Integr Med. 18:431–436. 2012. View Article : Google Scholar : PubMed/NCBI
16	Wei L, Chen P, Chen Y, Shen A, Chen H, Lin W, Hong Z, Sferra TJ and Peng J: Pien Tze Huang suppresses the stem-like side population in colorectal cancer cells. Mol Med Rep. 9:261–266. 2014.PubMed/NCBI
17	Shen A, Lin J, Chen Y, Lin W, Liu L, Hong Z, Sferra TJ and Peng J: Pien Tze Huang inhibits tumor angiogenesis in a mouse model of colorectal cancer via suppression of multiple cellular pathways. Oncol Rep. 30:1701–1706. 2013.PubMed/NCBI
18	Shen A, Chen H, Chen Y, Lin J, Lin W, Liu L, Sferra TJ and Peng J: Pien Tze Huang overcomes multidrug resistance and epithelial-mesenchymal transition in human colorectal carcinoma cells via suppression of TGF-β pathway. Evid Based Complement Alternat Med. 2014:6794362014. View Article : Google Scholar : PubMed/NCBI
19	Lin W, Zhuang Q, Zheng L, Cao Z, Shen A, Li Q, Fu C, Feng J and Peng J: Pien Tze Huang inhibits liver metastasis by targeting TGF-β signaling in an orthotopic model of colorectal cancer. Oncol Rep. 33:1922–1928. 2015.PubMed/NCBI
20	Grau S: Expression of lymphangiogenesis-related factors in malignant gliomas. Neurosci Res. 60:40–49. 2008.PubMed/NCBI
21	Saad RS, Lindner JL, Liu Y and Silverman JF: Lymphatic vessel density as prognostic marker in esophageal adenocarcinoma. Am J Clin Pathol. 131:92–98. 2009. View Article : Google Scholar : PubMed/NCBI
22	Liu HT, Ma R, Yang QF, Du G and Zhang CJ: Lymphangiogenic characteristics of triple negativity in node-negative breast cancer. Int J Surg Pathol. 17:426–431. 2009. View Article : Google Scholar : PubMed/NCBI
23	Oliver G and Detmar M: The rediscovery of the lymphatic system: Old and new insights into the development and biological function of the lymphatic vasculature. Genes Dev. 16:773–783. 2002. View Article : Google Scholar : PubMed/NCBI
24	Caunt M, Mak J, Liang WC, Stawicki S, Pan Q, Tong RK, Kowalski J, Ho C, Reslan HB, Ross J, et al: Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell. 13:331–342. 2008. View Article : Google Scholar : PubMed/NCBI
25	Bahram F and Claesson-Welsh L: VEGF-mediated signal transduction in lymphatic endothelial cells. Pathophysiology. 17:253–261. 2010. View Article : Google Scholar : PubMed/NCBI
26	Girling JE and Rogers PA: Regulation of endometrial vascular remodelling: Role of the vascular endothelial growth factor family and the angiopoietin-TIE signalling system. Reproduction. 138:883–893. 2009. View Article : Google Scholar : PubMed/NCBI
27	Saintigny P, Kambouchner M, Ly M, Gomes N, Sainte-Catherine O, Vassy R, Czernichow S, Letoumelin P, Breau JL, Bernaudin JF, et al: Vascular endothelial growth factor-C and its receptor VEGFR-3 in non-small-cell lung cancer: Concurrent expression in cancer cells from primary tumour and metastatic lymph node. Lung Cancer. 58:205–213. 2007. View Article : Google Scholar : PubMed/NCBI
28	Chang L, Kaipainen A and Folkman J: Lymphangiogenesis new mechanisms. Ann NY Acad Sci. 979:111–119. 2002. View Article : Google Scholar : PubMed/NCBI
29	Su JL, Chen PS, Chien MH, Chen PB, Chen YH, Lai CC, Hung MC and Kuo ML: Further evidence for expression and function of the VEGF-C/VEGFR-3 axis in cancer cells. Cancer Cell. 13:557–560. 2008. View Article : Google Scholar : PubMed/NCBI
30	Tammela T and Alitalo K: Lymphangiogenesis: Molecular mechanisms and future promise. Cell. 140:460–476. 2010. View Article : Google Scholar : PubMed/NCBI
31	Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, et al: Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol. 2:737–744. 2000. View Article : Google Scholar : PubMed/NCBI
32	Rojiani MV, Alidina J, Esposito N and Rojiani AM: Expression of MMP-2 correlates with increased angiogenesis in CNS metastasis of lung carcinoma. Int J Clin Exp Pathol. 3:775–781. 2010.PubMed/NCBI