The effect of Kisspeptin-10 on mesenchymal stem cells migration in vitro and in vivo

Golzar, Fatemeh; Javanmard, Shaghayegh Haghjooy; Bahrambeigi, Vahid; Rafiee, Laleh

The effect of Kisspeptin-10 on mesenchymal stem cells migration in vitro and in vivo

Authors

Student's Research Centre; Physiology Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Background: Kisspeptins (kp) activate a receptor coupled to a Gαq subunit (GPR54 or KiSS-1R) receptor to perform a variety of functions, including inhibition of cell motility, chemotaxis, and metastasis. In this study we have investigated whether kp-10, the most potent member of the kisspeptin family, can modulate CXCR4 (C-X-C chemokine receptor type 4) expression and mesenchymal stem cells (MSCs) migration that may influence the development of tumors.
Materials and Methods: We compared the directional migration of MSCs treated with 10-100 or 500 nM kp-10 for 24 hours and no treated cells using an in vitro transmembrane migration assay. In addition, Chloromethylbenzamido Dialkylacarbocyanine (CM-Dil) labeled adipose-derived mesenchymal stem cells treated with 10-100 or 500 nM kp-10 and no treated cells were transfused via the tail vein to the melanoma tumor bearing C57BL/6 mice. After 24 hours, the mice were scarified, the tumors were dissected, and the tumor cell suspensions were analyzed by flow cytometry for detection of CM-Dil ⁺ MSCs.
Results: We have found that kp-10 increased the MSCs migration at 100 nM, while it decreased the MSCs migration at 500 nM, both in vitro and in vivo, with a significant increase of CXCR4 expression at 100 nM kp-10 compared to the no treated cells, but it had no significant difference between the various concentrations of kp-10.
Conclusion: Thus, our data showed that kp-10 can differently affect MSCs migration in various concentrations, probably through different effects on CXCR4 expression in various concentrations.

Keywords

References

1.	Houthuijzen JM, Daenen LG, Roodhart JM, Voest EE. The role of mesenchymal stem cells in anti-cancer drug resistance and tumour progression. Br J Cancer 2012;106:1901-6.
2.	Hung SC, Pochampally RR, Chen SC, Hsu SC, Prockop DJ. Angiogenic effects of human multipotent stromal cell conditioned medium activate the PI3K-Akt pathway in hypoxic endothelial cells to inhibit apoptosis, increase survival, and stimulate angiogenesis. Stem Cells 2007;25:2363-70.
3.	Mishra PJ, Mishra PJ, Humeniuk R, Medina DJ, Alexe G, Mesirov JP, et al. Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Res 2008;68:4331-9.
4.	Dawson MR, Chae SS, Jain RK, Duda DG. Direct evidence for lineage-dependent effects of bone marrow stromal cells on tumor progression. Am J Cancer Res 2011;1:144-54.
5.	Deak E, Seifried E, Henschler R. Homing pathways of mesenchymal stromal cells (MSCs) and their role in clinical applications. Int Rev Immunol 2010;29:514-29.
6.	Liu ZJ, Zhuge Y, Velazquez OC. Trafficking and differentiation of mesenchymal stem cells. J Cell Biochem 2009;106:984-91.
7.	Burger JA, Kipps TJ. CXCR4: A key receptor in the crosstalk between tumor cells and their microenvironment. Blood 2006;107:1761-7.
8.	Kucia M, Jankowski K, Reca R, Wysoczynski M, Bandura L, Allendorf DJ, et al. CXCR4-SDF-1 signalling, locomotion, chemotaxis and adhesion. J Mol Histol 2004;35:233-45.
9.	Zajac M, Law J, Cvetkovic DD, Pampillo M, McColl L, Pape C, et al. GPR54 (KISS1R) transactivates EGFR to promote breast cancer cell invasiveness. PLoS One 2011;6:e21599.
10.	Gottsch ML, Clifton DK, Steiner RA. From KISS1 to kisspeptins: An historical perspective and suggested nomenclature. Peptides 2009;30:4-9.
11.	Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem 2001;276: 34631-6.
12.	Castaño JP, Martínez-Fuentes AJ, Gutiérrez-Pascual E, Vaudry H, Tena-Sempere M, Malagón MM. Intracellular signaling pathways activated by kisspeptins through GPR54: Do multiple signals underlie function diversity? Peptides 2009;30:10-5.
13.	Ikeguchi M, Yamaguchi K, Kaibara N. Clinical significance of the loss of KiSS-1 and orphan G-protein-coupled receptor (hOT7T175) gene expression in esophageal squamous cell carcinoma. Clin Cancer Res 2004;10:1379-83.
14.	Sanchez-Carbayo M, Capodieci P, Cordon-Cardo C. Tumor suppressor role of KiSS-1 in bladder cancer: Loss of KiSS-1 expression is associated with bladder cancer progression and clinical outcome. Am J Pathol 2003;162:609-17.
15.	Dhar DK, Naora H, Kubota H, Maruyama R, Yoshimura H, Tonomoto Y, et al. Downregulation of KiSS-1 expression is responsible for tumor invasion and worse prognosis in gastric carcinoma. Int J Cancer 2004;111:868-72.
16.	Ringel MD, Hardy E, Bernet VJ, Burch HB, Schuppert F, Burman KD, et al. Metastin receptor is overexpressed in papillary thyroid cancer and activates MAP kinase in thyroid cancer cells. J Clin Endocrinol Metab 2002;87:2399.
17.	Jiang Y, Berk M, Singh LS, Tan H, Yin L, Powell CT, et al. KiSS1 suppresses metastasis in human ovarian cancer via inhibition of protein kinase C alpha. Clin Exp Metastasis 2005;22:369-76.
18.	Jiang T, Zhang SL, Lin B, Meng LR, Gao H. Expression and clinical significance of KISS-1 and GPR54 mRNA in endometrial carcinoma. Zhonghua Zhong Liu Za Zhi 2005;27:229-31.
19.	Masui T, Doi R, Mori T, Toyoda E, Koizumi M, Kami K, et al. Metastin and its variant forms suppress migration of pancreatic cancer cells. Biochem Biophys Res Commun 2004;315:85-92.
20.	Shirasaki F, Takata M, Hatta N, Takehara K. Loss of expression of the metastasis suppressor gene KiSS1 during melanoma progression and its association with LOH of chromosome 6q16.3-q23. Cancer Res 2001;61:7422-5.
21.	Skurk T, Ecklebe S, Hauner H. A novel technique to propagate primary human preadipocytes without loss of differentiation capacity. Obesity (Silver Spring) 2007;15:2925-31.
22.	Ren C, Kumar S, Chanda D, Chen J, Mountz JD, Ponnazhagan S. Therapeutic potential of mesenchymal stem cells producing interferon-alpha in a mouse melanoma lung metastasis model. Stem Cells 2008;26:2332-8.
23.	Chen Y, Yusenko MV, Kovacs G. Lack of KISS1R expression is associated with rapid progression of conventional renal cell carcinomas. J Pathol 2011;223:46-53.
24.	Huang YL, Qiu RF, Mai WY, Kuang J, Cai XY, Dong YG, et al. Effects of insulin-like growth factor-1 on the properties of mesenchymal stem cells in vitro. J Zhejiang Univ Sci B 2012;13:20-8.
25.	Hu KX, Wang MH, Fan C, Wang L, Guo M, Ai HS. CM-DiI labeled mesenchymal stem cells homed to thymus inducing immune recovery of mice after haploidentical bone marrow transplantation. Int Immunopharmacol 2011;11:1265-70.
26.	Eggenhofer E, Benseler V, Kroemer A, Popp FC, Geissler EK, Schlitt HJ, et al. Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol 2012;3:297.
27.	Navenot JM, Wang Z, Chopin M, Fujii N, Peiper SC. Kisspeptin-10-induced signaling of GPR54 negatively regulates chemotactic responses mediated by CXCR4: A potential mechanism for the metastasis suppressor activity of kisspeptins. Cancer Res 2005;65:10450-6.
28.	Navenot JM, Fujii N, Peiper SC. Activation of Rho and Rho-associated kinase by GPR54 and KiSS1 metastasis suppressor gene product induces changes of cell morphology and contributes to apoptosis. Mol Pharmacol 2009;75:1300-6.
29.	Dai LJ, Moniri MR, Zeng ZR, Zhou JX, Rayat J, Warnock GL. Potential implications of mesenchymal stem cells in cancer therapy. Cancer Lett 2011;305:8-20.
30.	Cho SG, Wang Y, Rodriguez M, Tan K, Zhang W, Luo J, et al. Haploinsufficiency in the prometastasis Kiss1 receptor Gpr54 delays breast tumor initiation, progression, and lung metastasis. Cancer Res 2011;71:6535-46.
31.	Cho SG, Li D, Stafford LJ, Luo J, Rodriguez-Villanueva M, Wang Y, et al. KiSS1 suppresses TNFalpha-induced breast cancer cell invasion via an inhibition of RhoA-mediated NF-kappaB activation. J Cell Biochem 2009;107:1139-49.
32.	Olbrich T, Ziegler E, Türk G, Schubert A, Emons G, Gründker C. Kisspeptin-10 inhibits bone-directed migration of GPR54-positive breast cancer cells: Evidence for a dose-window effect. Gynecol Oncol 2010;119:571-8.

Advanced Biomedical Research