Vascular endothelial growth factor plays a critical role in the formation of the pre-metastatic niche via prostaglandin E2

Liu,Shili; Jiang,Man; Zhao,Qiang; Li,Shancheng; Peng,Yanping; Zhang,Pengfei; Han,Mingyong

doi:10.3892/or.2014.3516

Vascular endothelial growth factor plays a critical role in the formation of the pre-metastatic niche via prostaglandin E2

Authors:
- Shili Liu
- Man Jiang
- Qiang Zhao
- Shancheng Li
- Yanping Peng
- Pengfei Zhang
- Mingyong Han
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Affiliations: Department of Medical Microbiology, School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China, Cancer Therapy and Research Center, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, P.R. China
Published online on: September 24, 2014 https://doi.org/10.3892/or.2014.3516
Pages: 2477-2484

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Abstract

Factors secreted by primary tumors can alter the microenvironment at distant organ sites, generating pre-metastatic niches for subsequent metastatic cancer cell colonization. Breast cancer cells have a propensity to home preferentially to the lung, but the underlying molecular mechanisms whereby primary breast carcinoma-derived factors affect the pre-metastatic lung environment before the arrival of the tumor cells are poorly understood. In this study, 4T1 mammary carcinoma cells were subcutaneously injected into the mammary glands of mice, resulting in the induction of inflammation, increased total vessel density and recruitment of bone marrow-derived cells (BMDCs) in pre-metastatic lungs. Subsequent examination revealed that the sites of inflammatory cell clusters in the lungs were tumor metastasis sites. Moreover, vascular endothelial growth factor (VEGF) induced prostaglandin E2 (PGE2) production in mouse pulmonary microvascular endothelial cells (MPVECs) and enhanced the adhesion of 4T1 cells. Treatment with the cyclooxygenase-2 inhibitor celecoxib significantly reduced 4T1 cell adhesion to MPVECs, and also reduced cancer metastasis and the inflammatory response. These results suggest that VEGF may be an underlying carcinoma-derived factor responsible for formation of the pre-metastatic niche in the lung of 4T1 cell-bearing mice. This study, therefore, demonstrated that primary tumors can alter the lung microenvironment during the pre-metastatic phase by triggering an inﬂammatory response and PGE2 production. Primary tumor-derived VEGF might thus be a crucial factor responsible for the formation of the pre-metastatic niche by inducing PGE2 production.

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1	Nguyen DX, Bos PD and Massagué J: Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer. 9:274–284. 2009. View Article : Google Scholar : PubMed/NCBI
2	Fidler IJ: The organ microenvironment and cancer metastasis. Differentiation. 70:498–505. 2002. View Article : Google Scholar : PubMed/NCBI
3	Das Roy L, Pathangey LB, Tinder TL, Schettini JL, Gruber HE and Mukherjee P: Breast-cancer-associated metastasis is significantly increased in a model of autoimmune arthritis. Breast Cancer Res. 11:Jul 30–2009.(Epub ahead of print). View Article : Google Scholar
4	Hiratsuka S, Watanabe A, Aburatani H and Maru Y: Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol. 8:1369–1375. 2006. View Article : Google Scholar : PubMed/NCBI
5	Kaplan RN, Riba RD, Zacharoulis S, et al: VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 438:820–827. 2005. View Article : Google Scholar
6	Hanahan D and Weinberg RA: The hallmarks of cancer. Cell. 100:57–70. 2000. View Article : Google Scholar
7	Chen SF, Fei X and Li SH: A new simple method for isolation of microvascular endothelial cells avoiding both chemical and mechanical injuries. Microvasc Res. 50:119–128. 1995. View Article : Google Scholar : PubMed/NCBI
8	Lu H, Ouyang W and Huang C: Inflammation, a key event in cancer development. Mol Cancer Res. 4:221–233. 2006. View Article : Google Scholar : PubMed/NCBI
9	Fidler IJ: The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 3:453–458. 2003.
10	Murdoch C, Muthana M, Coffelt SB and Lewis CE: The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer. 8:618–631. 2008. View Article : Google Scholar : PubMed/NCBI
11	Kim S, Takahashi H, Lin WW, et al: Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature. 457:102–106. 2009. View Article : Google Scholar : PubMed/NCBI
12	Carmeliet P: VEGF as a key mediator of angiogenesis in cancer. Oncology. 69:4–10. 2005. View Article : Google Scholar : PubMed/NCBI
13	Mantovani A, Allavena P, Sica A and Balkwill F: Cancer-related inflammation. Nature. 454:436–444. 2008. View Article : Google Scholar
14	Padua D, Zhang XH and Wang Q: TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell. 133:66–77. 2008. View Article : Google Scholar : PubMed/NCBI
15	Serafini P, Borrello I and Bronte V: Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol. 16:53–65. 2006. View Article : Google Scholar : PubMed/NCBI
16	Yang L, Huang J, Ren X, et al: Abrogation of TGFbeta signaling in mammary carcinomas recruits Gr-1⁺CD11b⁺ myeloid cells that promote metastasis. Cancer Cell. 13:23–35. 2008. View Article : Google Scholar : PubMed/NCBI
17	Olkhanud PB, Baatar D, Bodogai M, et al: Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells. Cancer Res. 69:5996–6004. 2009. View Article : Google Scholar : PubMed/NCBI
18	Huang Y, Song N, Ding Y, et al: Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis. Cancer Res. 69:7529–7537. 2009. View Article : Google Scholar : PubMed/NCBI
19	Kitamura T, Kometani K, Hashida H, et al: SMAD4-deficient intestinal tumors recruit CCR1⁺ myeloid cells that promote invasion. Nat Genet. 39:467–475. 2007. View Article : Google Scholar : PubMed/NCBI
20	Dawson MR, Duda DG, Fukumura D and Jain RK: VEGFR1-activity independent metastasis formation. Nature. 461:E4–E5. 2009. View Article : Google Scholar : PubMed/NCBI
21	Erler JT, Bennewith KL, Cox TR, et al: Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell. 15:35–44. 2009. View Article : Google Scholar : PubMed/NCBI
22	Duda DG, Cohen KS, Kozin SV, et al: Evidence for incorporation of bone marrow-derived endothelial cells into perfused blood vessels in tumors. Blood. 107:2774–2776. 2006. View Article : Google Scholar : PubMed/NCBI
23	Dawson MR, Duda DG, Chae SS, Fukumura D and Jain RK: VEGFR1 activity modulates myeloid cell infiltration in growing lung metastases but is not required for spontaneous metastasis formation. PLoS One. 4:e65252009. View Article : Google Scholar : PubMed/NCBI
24	Bos CL, Richel DJ, Ritsema T, et al: Prostanoids and prostanoid receptors in signal transduction. Int J Biochem Cell Biol. 36:1187–1205. 2004. View Article : Google Scholar : PubMed/NCBI
25	Ma X, Kundu N, Ioffe OB, et al: Prostaglandin E receptor EP1 suppresses breast cancer metastasis and is linked to survival differences and cancer disparities. Mol Cancer Res. 8:1310–1318. 2010. View Article : Google Scholar : PubMed/NCBI
26	Narumiya S, Sugimoto Y and Ushikubi F: Prostanoid receptors: structures, properties, and functions. Physiol Rev. 79:1193–1226. 1999.PubMed/NCBI
27	Yang T and Du Y: Distinct roles of central and peripheral prostaglandin E2 and EP subtypes in blood pressure regulation. Am J Hypertens. 25:1042–1049. 2012. View Article : Google Scholar : PubMed/NCBI
28	Gupta GP, Nguyen DX, Chiang AC, et al: Mediators of vascular remodeling co-opted for sequential steps in lung metastasis. Nature. 446:765–770. 2007. View Article : Google Scholar : PubMed/NCBI
29	Nozawa H, Chiu C and Hanahan D: Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci USA. 103:12493–12498. 2006. View Article : Google Scholar : PubMed/NCBI
30	Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al: Polarization of tumor-associated neutrophil (TAN) phenotype by TGF-beta: ‘N1’ versus ‘N2’ TAN. Cancer Cell. 16:183–194. 2009.PubMed/NCBI
31	Chang SH, Liu CH, Conway R, et al: Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression. Proc Natl Acad Sci USA. 101:591–596. 2004. View Article : Google Scholar : PubMed/NCBI