Antiangiogenic effects of recombinant human endostatin in lung cancers

He,Lang; Zhao,Chaofen; Li,Yunxiang; Du,Guocheng; Liu,Kang; Cui,Dandan; Tang,Lina; Wu,Xun; Wen,Shimin; Chen,Hong

doi:10.3892/mmr.2017.7859

Antiangiogenic effects of recombinant human endostatin in lung cancers

Authors:
- Lang He
- Chaofen Zhao
- Yunxiang Li
- Guocheng Du
- Kang Liu
- Dandan Cui
- Lina Tang
- Xun Wu
- Shimin Wen
- Hong Chen
View Affiliations

Affiliations: Department of Oncology, The Fifth People's Hospital of Chengdu, North Sichuan Medical College, Chengdu, Sichuan 611130, P.R. China, Department of Medical Oncology, Affiliated Hospital of Guizhou Medical University, Guizhou Cancer Hospital, Guiyang, Guizhou 550004, P.R. China, Department of Urology, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China, Department of Galactophore, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China, Institute of Tissue Engineering and Stem Cells, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China, Department of Clinical Medicine, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China, Cancer Center, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China, Tumor Department of TCM, Sichuan Cancer Hospital and Institute, Chengdu, Sichuan 610000, P.R. China
Published online on: October 24, 2017 https://doi.org/10.3892/mmr.2017.7859
Pages: 79-86
Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Antiangiogenic therapy, as a new anticancer method, can improve the anticancer effect of traditional therapies. Different antiangiogenic drugs may have different vascular normalization time windows. Whether the antiangiogenic treatment is within the vascular normalization time window is very important in the treatment of cancers. Previous studies have indicated that recombinant human endostatin (rh‑ES) can transiently normalize tumor microvessels. Yet the molecular mechanism and the time window of rh‑ES remains unclear. The aim of the present study was to explore the optimal time window and molecular mechanism of rh‑ES in inhibiting Lewis lung cancer (LLC). By comparatively accessing the changes in microvascular and hypoxic conditions of tumors in host mice treated with rh‑ES or saline for different days, the authors aimed to investigate the best administration time of rh‑ES treatment on human lung cancers and obtain a better understanding concerning the involved molecular mechanism. A total of 40 C57/BL6 mice with LLC xenografts were randomly divided into normal saline (NS) and rh‑ES groups (20 mice/group). 0.2 ml NS or 5 mg/kg rh‑ES were administrated via intraperitoneal injection (i.p.) into each mouse each day during the 9‑day experiment. A total of 5 mice from each group were sacrificed at day 2, 4, 6 or 9. CA9 and RGS5 expression levels of both groups were compared using immunohistochemistry, reverse transcription‑quantitative polymerase chain reaction and ELISA. Rh‑ES caused vascular normalization and improved hypoxia at days 4 and 6. Compared with the control (NS) group, both CA9 and RGS5 expression in rh‑ES group were significantly decreased at days 4 and 6 (P<0.05), while no significant change between two groups was observed at days 2 and 9. Rh‑ES can induce transient tumor vascular normalization and improves tissue hypoxia in LLC tumors. The vascular normalization window is accompanied by the reduction in RGS5 and CA expression.

View Figures

View References

1	Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, di Tomaso E, et al: Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell. 6:553–563. 2004. View Article : Google Scholar : PubMed/NCBI
2	Lin MI and Sessa WC: Antiangiogenic therapy: Creating a unique ‘window’ of opportunity. Cancer Cell. 6:529–531. 2004. View Article : Google Scholar : PubMed/NCBI
3	Jain RK: Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nat Med. 7:987–989. 2001. View Article : Google Scholar : PubMed/NCBI
4	Welén K, Jennbacken K, Tesan T and Damber JE: Pericyte coverage decreases invasion of tumour cells into blood vessels in prostate cancer xenografts. Prostate Cancer Prostatic Dis. 12:41–46. 2009. View Article : Google Scholar : PubMed/NCBI
5	Faraone D, Aguzzi MS, Toietta G, Facchiano AM, Facchiano F, Magenta A, Martelli F, Truffa S, Cesareo E, Ribatti D, et al: Platelet-derived growth factor-receptor alpha strongly inhibits melanoma growth in vitro and in vivo. Neoplasia. 11:732–742. 2009. View Article : Google Scholar : PubMed/NCBI
6	Manzur M and Ganss R: Regulator of G protein signaling 5: A new player in vascular remodeling. Trends Cardiovasc Med. 19:26–30. 2009. View Article : Google Scholar : PubMed/NCBI
7	Park SY, Kim YJ, Gao AC, Mohler JL, Onate SA, Hidalgo AA, Ip C, Park EM, Yoon SY and Park YM: Hypoxia increases androgen receptor activity in prostate cancer cells. Cancer Res. 66:5121–5129. 2006. View Article : Google Scholar : PubMed/NCBI
8	Yasuda H: Solid tumor physiology and hypoxia-induced chemo/radio-resistance: Novel strategy for cancer therapy: Nitric oxide donor as a therapeutic enhancer. Nitric Oxide. 19:205–216. 2008. View Article : Google Scholar : PubMed/NCBI
9	Bussink J, Kaanders JH and van der Kogel AJ: Tumor hypoxia at the micro-regional level: Clinical relevance and predictive value of exogenous and endogenous hypoxic cell markers. Radiother Oncol. 67:3–15. 2003. View Article : Google Scholar : PubMed/NCBI
10	O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR and Folkman J: Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell. 88:277–285. 1997. View Article : Google Scholar : PubMed/NCBI
11	Rahman MA, Dhar DK, Yamaguchi E, Maruyama S, Sato T, Hayashi H, Ono T, Yamanoi A, Kohno H and Nagasue N: Coexpression of inducible nitric oxide synthase and COX-2 in hepatocellular carcinoma and surrounding liver: Possible involvement of COX-2 in the angiogenesis of hepatitis C virus-positive cases. Clin Cancer Res. 7:1325–1332. 2001.PubMed/NCBI
12	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
13	Shi Y, Sun Y, Yu J, Ding C, Wang Z, Wang C, Wang D, Wang C, Wang Z, Wang M, et al: China experts consensus on the diagnosis and treatment of advanced stage primary lung cancer (2016 version). Asia Pac J Clin Oncol. 13:87–103. 2017. View Article : Google Scholar : PubMed/NCBI
14	Li N, Zheng D, Wei X, Jin Z, Zhang C and Li K: Effects of recombinant human endostatin and its synergy with cisplatin on circulating endothelial cells and tumor vascular normalization in A549 xenograft murine model. J Cancer Res Clin Oncol. 138:1131–1144. 2012. View Article : Google Scholar : PubMed/NCBI
15	Cui C, Mao L, Chi Z, Si L, Sheng X, Kong Y, Li S, Lian B, Gu K, Tao M, et al: A phase II, randomized, double-blind, placebo-controlled multicenter trial of Endostar in patients with metastatic melanoma. Mol Ther. 21:1456–1463. 2013. View Article : Google Scholar : PubMed/NCBI
16	Zhu H, Yang X, Ding Y, Liu J, Lu J, Zhan L, Qin Q, Zhang H, Chen X, Yang Y, et al: Recombinant human endostatin enhances the radioresponse in esophageal squamous cell carcinoma by normalizing tumor vasculature and reducing hypoxia. Sci Rep. 5:145032015. View Article : Google Scholar : PubMed/NCBI
17	Peng F, Xu Z, Wang J, Chen Y, Li Q, Zuo Y, Chen J, Hu X, Zhou Q, Wang Y, et al: Recombinant human endostatin normalizes tumor vasculature and enhances radiation response in xenografted human nasopharyngeal carcinoma models. PLoS One. 7:e346462012. View Article : Google Scholar : PubMed/NCBI
18	Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti HH, Rabie T, Kaden S, Gröne HJ, Hämmerling GJ, et al: Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature. 453:410–414. 2008. View Article : Google Scholar : PubMed/NCBI
19	Silini A, Ghilardi C, Figini S, Sangalli F, Fruscio R, Dahse R, Pedley RB, Giavazzi R and Bani M: Regulator of G-protein signaling 5 (RGS5) protein: A novel marker of cancer vasculature elicited and sustained by the tumor's proangiogenic microenvironment. Cell Mol Life Sci. 69:1167–1178. 2012. View Article : Google Scholar : PubMed/NCBI
20	Jin Y, An X, Ye Z, Cully B, Wu J and Li J: RGS5, a hypoxia-inducible apoptotic stimulator in endothelial cells. J Biol Chem. 284:23436–23443. 2009. View Article : Google Scholar : PubMed/NCBI
21	Turner KJ, Crew JP, Wykoff CC, Watson PH, Poulsom R, Pastorek J, Ratcliffe PJ, Cranston D and Harris AL: The hypoxia-inducible genes VEGF and CA9 are differentially regulated in superficial vs invasive bladder cancer. Br J Cancer. 86:1276–1282. 2002. View Article : Google Scholar : PubMed/NCBI