Antitumor effect of FP3 in a patient-derived tumor tissue xenograft model of gastric carcinoma through an antiangiogenic mechanism

Jin,Ketao; Lan,Huanrong; Cao,Feilin; Xu,Zhenzhen; Han,Na; Li,Guangliang; He,Kuifeng; Teng,Lisong

doi:10.3892/ol.2012.603

Antitumor effect of FP3 in a patient-derived tumor tissue xenograft model of gastric carcinoma through an antiangiogenic mechanism

Authors:
- Ketao Jin
- Huanrong Lan
- Feilin Cao
- Zhenzhen Xu
- Na Han
- Guangliang Li
- Kuifeng He
- Lisong Teng
View Affiliations

Affiliations: Department of Surgical Oncology, Taizhou Hospital, Wenzhou Medical College, Linhai, Zhejiang 317000, P.R. China, Department of Gynecology and Obstetrics, Taizhou Hospital, Wenzhou Medical College, Linhai, Zhejiang, P.R. China, Department of Surgical Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zheijiang, P.R. China, Cancer Chemotherapy Center, Zhejiang Cancer Hospital, Zhejiang University of Chinese Medicine, Hangzhou, Zhejiang 310003, P.R. China
Published online on: February 10, 2012 https://doi.org/10.3892/ol.2012.603
Pages: 1052-1058

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

FP3 (KH902/KH903) is a novel vascular endothelial growth factor (VEGF) blocker with antiangiogenic properties. Previous studies revealed that FP3, a humanized fusion protein that combines ligand binding elements from the extracellular domains of VEGF receptors 1 and 2 and the Fc portion of IgG1, has an inhibitory effect on the VEGF-mediated proliferation and migration of human umbilical vein endothelial cells, and VEGF-mediated vessel sprouting of rat aortic rings in vitro. Thus, FP3 was considered as a new promising agent in treating human choroidal neovascularization (CNV) caused by age-related macular degeneration (AMD). FP3 also has an antitumor effect in a non-small cell lung cancer cell line (A549) xenograft model in nude mice. However, little is known of the direct effects of FP3 on tumor vessels. In this study, we investigated the effects of FP3 on blood vessels in a patient-derived tumor tissue (PDTT) xenograft model of gastric carcinoma, using large tumors with established vasculature. Treatment with FP3 caused robust and early changes in endothelial cells and pericytes of vessels in the PDTT xenograft model. Vascular density decreased and vascular sprouting was suppressed by treatment with FP3. Pericytes did not degenerate to the same extent as endothelial cells, and those on surviving tumor vessels achieved a more normal phenotype. Our results revealed that FP3 has a direct and rapid antiangiogenic effect on tumor vessels, which was achieved mainly via regression of tumor vasculature, inhibition of new and recurrent vessel growth, and normalization of existing tumor vasculature.

View Figures

View References

1	Hanahan D and Weinberg RA: Hallmarks of cancer: the next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
2	Paku S and Paweletz N: First steps of tumor-related angiogenesis. Lab Invest. 65:334–346. 1991.PubMed/NCBI
3	Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD and Wiegand SJ: Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science. 284:1994–1998. 1999. View Article : Google Scholar : PubMed/NCBI
4	Döme B, Paku S, Somlai B and Tímár J: Vascularization of cutaneous melanoma involves vessel co-option and has clinical significance. J Pathol. 197:355–362. 2002.PubMed/NCBI
5	Vermeulen PB, Colpaert C, Salgado R, Royers R, Hellemans H, Van Den Heuvel E, Goovaerts G, Dirix LY and Van Marck E: Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia. J Pathol. 195:336–342. 2001. View Article : Google Scholar : PubMed/NCBI
6	Paku S, Kopper L and Nagy P: Development of the vasculature in ‘pushing-type’ liver metastases of an experimental colorectal cancer. Int J Cancer. 115:893–902. 2005.
7	Kurz H, Burri PH and Djonov VG: Angiogenesis and vascular remodeling by intussusception: from form to function. News Physiol Sci. 18:65–70. 2003.PubMed/NCBI
8	Osawa M, Masuda M, Kusano K and Fujiwara K: Evidence for a role of platelet endothelial cell adhesion molecule-1 in endothelial cell mechanosignal transduction: is it a mechanoresponsive molecule? J Cell Biol. 158:773–785. 2002. View Article : Google Scholar : PubMed/NCBI
9	Sundberg C, Nagy JA, Brown LF, Feng D, Eckelhoefer IA, Manseau EJ, Dvorak AM and Dvorak HF: Glomeruloid microvascular proliferation follows adenoviral vascular permeability factor/vascular endothelial growth factor-164 gene delivery. Am J Pathol. 158:1145–1160. 2001. View Article : Google Scholar
10	Asahara T and Kawamoto A: Endothelial progenitor cells for postnatal vasculogenesis. Am J Physiol Cell Physiol. 287:572–579. 2004. View Article : Google Scholar
11	Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe'er J, Trent JM, Meltzer PS and Hendrix MJ: Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol. 155:739–752. 1999. View Article : Google Scholar : PubMed/NCBI
12	Hendrix MJ, Seftor EA, Hess AR and Seftor RE: Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer. 3:411–421. 2003. View Article : Google Scholar : PubMed/NCBI
13	Ferrara N: Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 25:581–611. 2004. View Article : Google Scholar : PubMed/NCBI
14	Hicklin DJ and Ellis LM: Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 23:1011–1027. 2005. View Article : Google Scholar : PubMed/NCBI
15	Ferrara N, Gerber HP and LeCouter J: The biology of VEGF and its receptors. Nat Med. 9:669–676. 2003. View Article : Google Scholar : PubMed/NCBI
16	Teng LS, Jin KT, He KF, Wang HH, Cao J and Yu DC: Advances in combination of antiangiogenic agents targeting VEGF-binding and conventional chemotherapy and radiation for cancer treatment. J Chin Med Assoc. 73:281–288. 2010. View Article : Google Scholar : PubMed/NCBI
17	Teng LS, Jin KT, He KF, Zhang J, Wang HH and Cao J: Clinical applications of VEGF-trap (aflibercept) in cancer treatment. J Chin Med Assoc. 73:449–456. 2010. View Article : Google Scholar : PubMed/NCBI
18	Jin K, He K, Teng F, Li G, Wang H, Han N, Xu Z, Cao J, Wu J, Yu D and Teng L: FP3: a novel VEGF blocker with antiangiogenic effects in vitro and antitumour effects in vivo. Clin Transl Oncol. 13:878–884. 2011. View Article : Google Scholar : PubMed/NCBI
19	Zhang M, Zhang J, Yan M, Li H, Yang C and Yu D: Recombinant anti-vascular endothelial growth factor fusion protein efficiently suppresses choridal neovasularization in monkeys. Mol Vis. 14:37–49. 2008.
20	Zhang M, Yu D, Yang C, Xia Q, Li W, Liu B and Li H: The pharmacology study of a new recombinant human VEGF receptor-fc fusion protein on experimental choroidal neovascularization. Pharm Res. 26:204–210. 2009. View Article : Google Scholar : PubMed/NCBI
21	Zhang M, Zhang J, Yan M, Luo D, Zhu W, Kaiser PK and Yu DC; KH902 Phase 1 Study Group. A phase 1 study of KH902, a vascular endothelial growth factor receptor decoy, for exudative age-related macular degeneration. Ophthalmology. 118:672–678. 2011. View Article : Google Scholar : PubMed/NCBI
22	Inai T, Mancuso M, Hashizume H, Baffert F, Haskell A, Baluk P, Hu-Lowe DD, Shalinsky DR, Thurston G, Yancopoulos GD and McDonald DM: Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol. 165:35–52. 2004. View Article : Google Scholar
23	Jin K, Teng L, Shen Y, He K, Xu Z and Li G: Patient-derived human tumour tissue xenografts in immunodeficient mice: a systematic review. Clin Transl Oncol. 12:473–480. 2010. View Article : Google Scholar : PubMed/NCBI
24	Jin K, He K, Li G and Teng L: Personalized cancer therapy using a patient-derived tumor tissue xenograft model: a translational field worthy of exploring further? Pers Med. 7:597–606. 2010. View Article : Google Scholar
25	Jin K, He K, Teng F, Han N, Li G, Xu Z and Teng L: Heterogeneity in primary tumors and corresponding metastases: could it provide us with any hints to personalize cancer therapy? Pers Med. 8:175–182. 2011. View Article : Google Scholar
26	Jin K, He K, Han N, Li G, Wang H, Xu Z, Jiang H, Zhang J and Teng L: Establishment of a PDTT xenograft model of gastric carcinoma and its application in personalized therapeutic regimen selection. Hepatogastroenterology. 58:1814–1822. 2011.PubMed/NCBI
27	Mancuso MR, Davis R, Norberg SM, O'Brien S, Sennino B, Nakahara T, Yao VJ, Inai T, Brooks P, Freimark B, Shalinsky DR, Hu-Lowe DD and McDonald DM: Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest. 116:2610–2621. 2006. View Article : Google Scholar : PubMed/NCBI
28	Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK and McDonald DM: Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol. 160:985–1000. 2002. View Article : Google Scholar : PubMed/NCBI
29	Baluk P, Morikawa S, Haskell A, Mancuso M and McDonald DM: Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol. 163:1801–1815. 2003. View Article : Google Scholar : PubMed/NCBI
30	Willett CG, Boucher Y, Di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV, et al: Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 10:145–147. 2004. View Article : Google Scholar
31	Baffert F, Le T, Sennino B, Thurston G, Kuo CJ, Hu-Lowe D and McDonald DM: Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling. Am J Physiol Heart Circ Physiol. 290:H547–559. 2006. View Article : Google Scholar : PubMed/NCBI
32	Byrne AT, Ross L, Holash J, Nakanishi M, Hu L, Hofmann JI, Yancopoulos GD and Jaffe RB: Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res. 9:5721–5728. 2003.
33	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
34	Jain RK: Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 307:58–62. 2005. View Article : Google Scholar : PubMed/NCBI