Proinflammatory CXCL12-CXCR4/CXCR7 Signaling Axis Drives Myc-Induced Prostate Cancer in Obese Mice

Overview

Journal Cancer Res

Specialty Oncology

Date 2017 Jul 9

PMID 28687617

Citations 57

Authors

Achinto Saha

Songyeon Ahn

Jorge Blando

Fei Su

Mikhail G Kolonin

John DiGiovanni

Affiliations

Soon will be listed here.

Abstract

Obesity is a prognostic risk factor in the progression of prostate cancer; however, the molecular mechanisms involved are unclear. In this study, we provide preclinical proof of concept for the role of a proinflammatory CXCL12-CXCR4/CXCR7 signaling axis in an obesity-driven mouse model of myc-induced prostate cancer. Analysis of the stromal vascular fraction from periprostatic white adipose tissue from obese HiMyc mice at 6 months of age revealed a dramatic increase in mRNAs encoding various chemokines, cytokines, growth factors, and angiogenesis mediators, with CXCL12 among the most significantly upregulated genes. Immunofluorescence staining of ventral prostate tissue from obese HiMyc mice revealed high levels of CXCL12 in the stromal compartment as well as high staining for CXCR4 and CXCR7 in the epithelial compartment of tumors. Prostate cancer cell lines derived from HiMyc tumors (HMVP2 and derivative cell lines) displayed increased protein expression of both CXCR4 and CXCR7 compared with protein lysates from a nontumorigenic prostate epithelial cell line (NMVP cells). CXCL12 treatment stimulated migration and invasion of HMVP2 cells but not NMVP cells. These effects of CXCL12 on HMVP2 cells were inhibited by the CXCR4 antagonist AMD3100 as well as knockdown of either CXCR4 or CXCR7. CXCL12 treatment also produced rapid activation of STAT3, NFκB, and MAPK signaling in HMVP2 cells, which was again attenuated by either AMD3100 or knockdown of CXCR4 or CXCR7. Collectively, these data suggest that CXCL12 secreted by stromal cells activates invasiveness of prostate cancer cells and may play a role in driving tumor progression in obesity. Targeting the CXCL12-CXCR4/CXCR7 axis could lead to novel approaches for offsetting the effects of obesity on prostate cancer progression. .

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References

Leri A, Liu Y, Claudio P, Kajstura J, Wang X, Wang S . Insulin-like growth factor-1 induces Mdm2 and down-regulates p53, attenuating the myocyte renin-angiotensin system and stretch-mediated apoptosis. Am J Pathol. 1999; 154(2):567-80. PMC: 1850006. DOI: 10.1016/S0002-9440(10)65302-3. View

Ribeiro R, Monteiro C, Cunha V, Azevedo A, Oliveira M, Monteiro R . Tumor cell-educated periprostatic adipose tissue acquires an aggressive cancer-promoting secretory profile. Cell Physiol Biochem. 2012; 29(1-2):233-40. DOI: 10.1159/000337604. View

Trayhurn P, Wood I . Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr. 2004; 92(3):347-55. DOI: 10.1079/bjn20041213. View

Ouchi N, Parker J, Lugus J, Walsh K . Adipokines in inflammation and metabolic disease. Nat Rev Immunol. 2011; 11(2):85-97. PMC: 3518031. DOI: 10.1038/nri2921. View

Dirat B, Ader I, Golzio M, Massa F, Mettouchi A, Laurent K . Inhibition of the GTPase Rac1 mediates the antimigratory effects of metformin in prostate cancer cells. Mol Cancer Ther. 2014; 14(2):586-96. DOI: 10.1158/1535-7163.MCT-14-0102. View

Klopp A, Zhang Y, Solley T, Amaya-Manzanares F, Marini F, Andreeff M . Omental adipose tissue-derived stromal cells promote vascularization and growth of endometrial tumors. Clin Cancer Res. 2011; 18(3):771-82. PMC: 3481843. DOI: 10.1158/1078-0432.CCR-11-1916. View

Wu Y, Tang S, Sun G, Sun K . CXCR7 mediates TGFβ1-promoted EMT and tumor-initiating features in lung cancer. Oncogene. 2015; 35(16):2123-32. DOI: 10.1038/onc.2015.274. View

Jung Y, Kim J, Shiozawa Y, Wang J, Mishra A, Joseph J . Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis. Nat Commun. 2013; 4:1795. PMC: 3649763. DOI: 10.1038/ncomms2766. View

Strom S, Yamamura Y, Forman M, Pettaway C, Barrera S, DiGiovanni J . Saturated fat intake predicts biochemical failure after prostatectomy. Int J Cancer. 2008; 122(11):2581-5. DOI: 10.1002/ijc.23414. View

10.

Sakao K, Vyas A, Chinni S, Amjad A, Parikh R, Singh S . CXCR4 is a novel target of cancer chemopreventative isothiocyanates in prostate cancer cells. Cancer Prev Res (Phila). 2015; 8(5):365-74. PMC: 4417382. DOI: 10.1158/1940-6207.CAPR-14-0386. View

11.

Conley-LaComb M, Saliganan A, Kandagatla P, Chen Y, Cher M, Chinni S . PTEN loss mediated Akt activation promotes prostate tumor growth and metastasis via CXCL12/CXCR4 signaling. Mol Cancer. 2013; 12(1):85. PMC: 3751767. DOI: 10.1186/1476-4598-12-85. View

12.

Singh S, Singh U, Grizzle W, Lillard Jr J . CXCL12-CXCR4 interactions modulate prostate cancer cell migration, metalloproteinase expression and invasion. Lab Invest. 2004; 84(12):1666-76. DOI: 10.1038/labinvest.3700181. View

13.

Hattermann K, Mentlein R . An infernal trio: the chemokine CXCL12 and its receptors CXCR4 and CXCR7 in tumor biology. Ann Anat. 2013; 195(2):103-10. DOI: 10.1016/j.aanat.2012.10.013. View

14.

English K . Mechanisms of mesenchymal stromal cell immunomodulation. Immunol Cell Biol. 2012; 91(1):19-26. DOI: 10.1038/icb.2012.56. View

15.

Nesbit C, Tersak J, Prochownik E . MYC oncogenes and human neoplastic disease. Oncogene. 1999; 18(19):3004-16. DOI: 10.1038/sj.onc.1202746. View

16.

Akashi T, Koizumi K, Tsuneyama K, Saiki I, Takano Y, Fuse H . Chemokine receptor CXCR4 expression and prognosis in patients with metastatic prostate cancer. Cancer Sci. 2008; 99(3):539-42. PMC: 11158982. DOI: 10.1111/j.1349-7006.2007.00712.x. View

17.

Saha A, Blando J, Tremmel L, DiGiovanni J . Effect of Metformin, Rapamycin, and Their Combination on Growth and Progression of Prostate Tumors in HiMyc Mice. Cancer Prev Res (Phila). 2015; 8(7):597-606. PMC: 4491032. DOI: 10.1158/1940-6207.CAPR-15-0014. View

18.

Kondo Y, Homma Y, Aso Y, Kakizoe T . Promotional effect of two-generation exposure to a high-fat diet on prostate carcinogenesis in ACI/Seg rats. Cancer Res. 1994; 54(23):6129-32. View

19.

Nakao N, Nakayama T, Yahata T, Muguruma Y, Saito S, Miyata Y . Adipose tissue-derived mesenchymal stem cells facilitate hematopoiesis in vitro and in vivo: advantages over bone marrow-derived mesenchymal stem cells. Am J Pathol. 2010; 177(2):547-54. PMC: 2913350. DOI: 10.2353/ajpath.2010.091042. View

20.

Walters M, Ebsworth K, Berahovich R, Penfold M, Liu S, Al Omran R . Inhibition of CXCR7 extends survival following irradiation of brain tumours in mice and rats. Br J Cancer. 2014; 110(5):1179-88. PMC: 3950859. DOI: 10.1038/bjc.2013.830. View