CXCR4/CXCL12 Axis Promotes VEGF-mediated Tumor Angiogenesis Through Akt Signaling Pathway

Overview

Journal Biochem Biophys Res Commun

Publisher Elsevier

Specialty Biochemistry

Date 2007 Jun 15

PMID 17559806

Citations 143

Authors

Zhongxing Liang

JoAnn Brooks

Margaret Willard

Ke Liang

Younghyoun Yoon

Seunghee Kang

Hyunsuk Shim

Affiliations

Soon will be listed here.

Abstract

CXC chemokine receptor 4 (CXCR4) has been shown to play a critical role in chemotaxis and homing, which are key steps in cancer metastasis. There is also increasing evidence that links this receptor to angiogenesis; however, its molecular basis remains elusive. Vascular endothelial growth factor (VEGF), one of the major angiogenic factors, promotes the formation of leaky tumor vasculatures that are the hallmarks of tumor progression. Here, we investigated whether CXCR4 induces the expression of VEGF through the PI3K/Akt pathway. Our results showed that CXCR4/CXCL12 induced Akt phosphorylation, which resulted in upregulation of VEGF at both the mRNA and protein levels. Conversely, blocking the activation of Akt signaling led to a decrease in VEGF protein levels; blocking CXCR4/CXCL12 interaction with a CXCR4 antagonist suppressed tumor angiogenesis and growth in vivo. Furthermore, VEGF mRNA levels correlated well with CXCR4 mRNA levels in patient tumor samples. In summary, our study demonstrates that the CXCR4/CXCL12 signaling axis can induce angiogenesis and progression of tumors by increasing expression of VEGF through the activation of PI3K/Akt pathway. Our findings suggest that targeting CXCR4 could provide a potential new anti-angiogenic therapy to suppress the formation of both primary and metastatic tumors.

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References

Latil A, Bieche I, Pesche S, Valeri A, Fournier G, Cussenot O . VEGF overexpression in clinically localized prostate tumors and neuropilin-1 overexpression in metastatic forms. Int J Cancer. 2001; 89(2):167-71. DOI: 10.1002/(sici)1097-0215(20000320)89:2<167::aid-ijc11>3.0.co;2-9. View

Shim H, Lau S, Devi S, Yoon Y, Cho H, Liang Z . Lower expression of CXCR4 in lymph node metastases than in primary breast cancers: potential regulation by ligand-dependent degradation and HIF-1alpha. Biochem Biophys Res Commun. 2006; 346(1):252-8. DOI: 10.1016/j.bbrc.2006.05.110. View

Kijowski J, Baj-Krzyworzeka M, Majka M, Reca R, Marquez L, Christofidou-Solomidou M . The SDF-1-CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells. Stem Cells. 2001; 19(5):453-66. DOI: 10.1634/stemcells.19-5-453. View

Bruick R, McKnight S . Building better vasculature. Genes Dev. 2001; 15(19):2497-502. DOI: 10.1101/gad.931601. View

Spinella F, Rosano L, Di Castro V, Natali P, Bagnato A . Endothelin-1 induces vascular endothelial growth factor by increasing hypoxia-inducible factor-1alpha in ovarian carcinoma cells. J Biol Chem. 2002; 277(31):27850-5. DOI: 10.1074/jbc.M202421200. View

Kirkpatrick K, Ogunkolade W, Elkak A, Bustin S, Jenkins P, Ghilchik M . The mRNA expression of cyclo-oxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in human breast cancer. Curr Med Res Opin. 2002; 18(4):237-41. DOI: 10.1185/030079902125000633. View

Ferrara N . VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2002; 2(10):795-803. DOI: 10.1038/nrc909. View

Duyndam M, Hulscher S, van der Wall E, Pinedo H, Boven E . Evidence for a role of p38 kinase in hypoxia-inducible factor 1-independent induction of vascular endothelial growth factor expression by sodium arsenite. J Biol Chem. 2002; 278(9):6885-95. DOI: 10.1074/jbc.M206320200. View

Lamszus K, Ulbricht U, Matschke J, Brockmann M, Fillbrandt R, Westphal M . Levels of soluble vascular endothelial growth factor (VEGF) receptor 1 in astrocytic tumors and its relation to malignancy, vascularity, and VEGF-A. Clin Cancer Res. 2003; 9(4):1399-405. View

10.

Bergers G, Benjamin L . Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003; 3(6):401-10. DOI: 10.1038/nrc1093. View

11.

Yamakawa M, Liu L, Date T, Belanger A, Vincent K, Akita G . Hypoxia-inducible factor-1 mediates activation of cultured vascular endothelial cells by inducing multiple angiogenic factors. Circ Res. 2003; 93(7):664-73. DOI: 10.1161/01.RES.0000093984.48643.D7. View

12.

Mizukami Y, Li J, Zhang X, Zimmer M, Iliopoulos O, Chung D . Hypoxia-inducible factor-1-independent regulation of vascular endothelial growth factor by hypoxia in colon cancer. Cancer Res. 2004; 64(5):1765-72. DOI: 10.1158/0008-5472.can-03-3017. View

13.

Ferrara N, Hillan K, Gerber H, Novotny W . Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004; 3(5):391-400. DOI: 10.1038/nrd1381. View

14.

Arsham A, Plas D, Thompson C, Simon M . Akt and hypoxia-inducible factor-1 independently enhance tumor growth and angiogenesis. Cancer Res. 2004; 64(10):3500-7. DOI: 10.1158/0008-5472.CAN-03-2239. View

15.

Liang Z, Wu T, Lou H, Yu X, Taichman R, Lau S . Inhibition of breast cancer metastasis by selective synthetic polypeptide against CXCR4. Cancer Res. 2004; 64(12):4302-8. DOI: 10.1158/0008-5472.CAN-03-3958. View

16.

Darash-Yahana M, Pikarsky E, Abramovitch R, Zeira E, Pal B, Karplus R . Role of high expression levels of CXCR4 in tumor growth, vascularization, and metastasis. FASEB J. 2004; 18(11):1240-2. DOI: 10.1096/fj.03-0935fje. View

17.

Finkenzeller G, Weindel K, Zimmermann W, Westin G, Marme D . Activated Neu/ErbB-2 induces expression of the vascular endothelial growth factor gene by functional activation of the transcription factor Sp 1. Angiogenesis. 2004; 7(1):59-68. DOI: 10.1023/B:AGEN.0000037332.66411.f0. View

18.

Chen Z, Zhang X, Li M, Wang Z, Wieand H, Grandis J . Simultaneously targeting epidermal growth factor receptor tyrosine kinase and cyclooxygenase-2, an efficient approach to inhibition of squamous cell carcinoma of the head and neck. Clin Cancer Res. 2004; 10(17):5930-9. DOI: 10.1158/1078-0432.CCR-03-0677. View

19.

Pore N, Liu S, Shu H, Li B, Haas-Kogan D, Stokoe D . Sp1 is involved in Akt-mediated induction of VEGF expression through an HIF-1-independent mechanism. Mol Biol Cell. 2004; 15(11):4841-53. PMC: 524732. DOI: 10.1091/mbc.e04-05-0374. View

20.

Davidson N, Gelmann E, Lippman M, Dickson R . Epidermal growth factor receptor gene expression in estrogen receptor-positive and negative human breast cancer cell lines. Mol Endocrinol. 1987; 1(3):216-23. DOI: 10.1210/mend-1-3-216. View