CXC Chemokine Ligand 12 and G Protein-Coupled Receptor 30 Expressions in Canine Mammary Tumors of Mixed Origin

Abstract

Canine mammary tumors (CMT) included complex interactions in the etiopathogenesis. It is the most common problem of neoplasia in female dogs. The aim of this study was to reveal the roles of chemokine CXC Ligand 12 (CXCL12) and G protein coupled receptor 30 (GPCR30) expressions in the inflammatory process and neoplastic development in canine mammary glands. Therefore, after clinical and pathomorphological evaluation, 18 cases of mixed origin malignant forms (mixed-type carcinoma-n=6, complex-type carcinoma-n=3, carcinosarcoma-n=7, carcinoma and malignant myoepithelioma-n=2)] were examined in the study. Inflammatory cells accompanying neoplastic changes, were determined to consist of predominantly neutrophils and leukocytes, followed by lymphocytes, plasma cells and macrophages. The CXCL12 and GPCR30 expressions were scored. immunohistochemically. Most of the expressions for both markers were moderate in  the mammary gland and duct epithelial cells, myoepithelial cells and inflammatory cells. Fibrocytes and fibroblasts gave a mild reaction in general, and no reaction was found in the myxoid, chondroid and osteoid matrix. There was considered to be a close relationship between mixed composition  CMT and subacute inflammation, and thus  it was concluded that inflammtory cells may trigger or initiate neoplastic transformation in the cellular environment including differentiated cells of the mammary gland.  

Keywords

• Chemoattractive cytokine,G protein,clinicopathology,mammary tumor,dog

Mikst Orjinli Köpek Meme Tümörlerinde CXC Chemokine Ligand 12 ve G Protein Coupled Receptor 30 Ekspresyonları

Abstract

Köpek meme tümörleri etiyopatogenezinde karmaşık bir seri etkileşimleri içerir. Dişi köpeklerde en yaygın karşılaşılan problemdir. Bu çalışmada, köpek meme tümörlerinde yangısal süreç ve tümör gelişimde bir çeşit chemokin olan chemokine CXC Ligand 12 (CXCL12) ile G protein coupled receptor 30 (GPCR30) ekspresyonlarının rollerini ortaya koymak amaçlandı. Bu amaçla, klinik ve patomorfolojik değerlendirmeden sonra, malignant formda mikst orjinli 18 olgu (mixed-type carcinoma-n=6, complex-type carcinoma-n=3, carcinosarcoma-n=7, carcinoma and malignant myoepithelioma-n=2) çalışmaya dahil edildi. Neoplazik değişikliklere eşlik eden yangısal hücreler ağırlıklı olarak nötrofil lökosit ve sırasıyla lenfosit, plazma hücresi ile makrofajlardan oluşuyordu. İmmunohistokimyasal olarak CXCL12 ve GPCR30 ekpsresyonları skorlandı. Her iki belirteçte ekspresyonların çoğu meme bezleri, duktal epitel hücreler, miyoepitel hücreleri ile yangısal hücrelerde orta şiddetteydi. Ancak, fibrosit ve fibroblastlarda genelde hafif şiddetteydi. Mikst orjinli köpek meme tümörleri ile subakut yangı arasında yakın bir ilişki olduğu düşünüldü. Ayrıca, yangısal hücrelerin meme bezlerinin farklılaşmasını içeren hücresel çevrenin bu mikst neoplazik dönüşümünü tetikleyebileceği veya başlatabileceği sonucuna varıldı.   

Keywords

• Şemoatraktif sitokin,G protein,klinikopatoloji,meme tümörü,köpek

References

1. Anadol, E., Yar Saglam, A.S., Gultiken, N., Karakas, K., Alcigir, E., Alkan, H., Kanca H. Expression of iNOS, COX-2 and VEGF in canine mammary tumours and non-neoplastic mammary glands: Association with clinicopathological features and tumour grade. Acta Vet Hung. 2017; 65(3):382-393.
2. Boimel PJ, Smirnova T, Zhou ZN, Wyckoff J, Park H, Coniglio SJ, Qian BZ, Stanley ER, Cox D, Pollard JW, Muller WJ, Condeelis J, Segall JE. Contribution of CXCL12 secretion to invasion of breast cancer cells. Breast Cancer Res. 2012; 14:R23.
3. Boldizsar H, Szenci O, Muray T, Csenki J. Studies on canine mammary tumours. I. Age, seasonal and breed distribution. Acta Vet Hung. 1992; 40(1-2): 75-87.
4. Cassali GD, Lavalle GE, De Nardi AB. Consensus for the diagnosis, prognosis and treatment of canine mammary tumors. Brazil J Vet Pathol. 2011; 4(2): 153–180.
5. Crump M, Sawka CA, DeBoer G, Buchanan RB, Ingle JN, Forbes J, Meakin JW, Shelley W, Pritchard KI. An individual patient-based meta-analysis of tamoxifen versus ovarian ablation as first line endocrine therapy for premenopausal women with metastatic breast cancer. Breast Cancer Res Treat. 1997; 44(3):201-10.
6. Dewan MZ, Ahmed S, Iwasaki Y, Ohba K, Toi M, Yamamoto N. Stromal cell-derived factor-1 and CXCR4 receptor interaction in tumor growth and metastasis of breast cancer. Biomed Pharmacotherapy 2006; 60:273–276.
7. Dorsam RT, Gutkind JS. G-protein-coupled receptors and cancer. Nat. Rev Cancer. 2007; 7: 79–94.
8. Egenvall A, Bonnett BN, Ohagen P, Olson P, Hedhammar A, von Euler H. Incidence of and survival after mammary tumors in a population of over 80,000 insured female dogs in Sweden from 1995 to 2002. Prev Vet Med. 2005; 69(1-2): 109-127.

9. Feigin ME, Xue B, Hammell MC, Muthuswamy SK. G-protein–coupled receptor GPR161 is overexpressed in breast cancer and is a promoter of cell proliferation and invasion. PNAS. 2014; 111 (11): 4191–4196.
10. Filardo EJ, Quinn JA, Bland KI, Frackelton AR Jr. Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol. 2000; 14(10):1649-1660.
11. Girgert R, Emons G, Gründker C. Inactivation of GPR30 reduces growth of triple-negative breast cancer cells: possible application in targeted therapy. Breast Cancer Res Treat. 2012; 134(1):199-205.
12. Goldschmidt M, Peña L, Rasotto R, Zappulli V. Classification and grading of canine mammary tumors. Vet Pathol. 2011; 48(1):117-1131.
13. Hartmann T, Burger J, Glodek A, Fujii N, Burger M. CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells. Oncogene. 2005; 23;24(27):4462-71.
14. Hurley JV, Jabara AG. 1964. Properties of “cartilage” in canine mammary tumors. Arch Pathol. 77:343–347.
15. Kang H, Mansel R, Jiang W. Genetic manipulation of stromal cell-derived factor-1 attests the pivotal role of the autocrine SDF-1-CXCR4 pathway in the aggressiveness of breast cancer cells. Int J Oncol. 2005; 26: 1429–1434.
16. Li S, Huang S, Peng SB. Overexpression of G protein-coupled receptors in cancer cells: Involvement in tumor progression. Int J Oncol. 2005; 27, 1329–1339.
17. Luker KE, Luker GD. Functions of CXCL12 and CXCR4 in breast cancer. Cancer Lett. 2006; 238: 30–41.
18. Luttrell LM, Daaka Y, Lefkowitz RJ. Regulation of tyrosine kinase cascades by G-protein-coupled receptors. Curr Opin Cell Biol 1999; 11:177–183.
19. Maggiolini M, Vivacqua A, Fasanella G, Recchia AG, Sisci D, Pezzi V, Montanaro D, Musti AM, Picard D, Ando S. The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17beta-estradiol and phytoestrogens in breast cancer cells. J Biol Chem. 2004; 279:27008–27016.
20. Misdorp W. Veterinary cancer epidemiology. Vet Quart. 1996; 18: 32- 36.
21. Misdorp W, Else RW, Hellmen E. Histological Classification of Mammary Tumors of the Dog and the Cat, World Health Organization, Geneva, Switzerland. 1999.
22. Moe L. Population-based incidence of mammary tumours in some dog breeds. J Reprod Fertil Suppl. 2001; 57: 439-443.
23. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001; 410(6824):50–6.
24. Perez-Alenza MD, Pena L, Del Castillo N, Nieto A. Factors influencing the incidence and prognosis of canine mammary tumors. J Small Anim Pract 2000; 41: 287-291.
25. Priester WA. Occurrence of mammary neoplasms in bitches in relation to breed, age, tumour type, and geographical region from which reported. J Small Anim Pract. 1979; 20(1): 1-11.
26. Pulley, LT. Ultrastructural and histochemical demonstration of myoepithelium in mixed tumors of the canine mammary gland. Am J Vet Res. 1973; 34(12): 1513–1522.
27. Ramalho LNZ, Ribeiro-Silva A, Cassali GD, Zucoloto S. The expression of p63 and cytokeratin 5 in mixed tumors of the canine mammary gland provides new insights into the histogenesis of these neoplasms. Vet Pathol. 2006; 43(4):424–429.
28. Salvucci O, Yao L, Villalba S, Sajewicz A, Pittaluga S, Tosato G. Regulation of endothelial cell branching morphogenesis by endogenous chemokine stromal-derived factor-1. Blood. 2002; 99:2703–2711.
29. Simpson JF, Gray R, Dressler LG, Cobau CD, Falkson CI, Gilchrist KW, Pandya KJ, Page DL, Robert NJ. Prognostic value of histologic grade and proliferative activity in axillary node-positive breast cancer: results from the Eastern Cooperative Oncology Group Companion Study, EST 4189. J Clin Oncol. 2000; 18: 2059–2069.
30. Spiegelberg BD, Hamm HE. 2007. RolesofG-protein-coupledreceptorsignaling in cancerbiology and gene transcription.Curr Opin Genet Dev. 2007; 17: 40–44.
31. Tateyama S, Cotchin E. Alkaline phosphatase reaction of canine mammary mixed tumours: a light and electron microscopic study. Res Vet Sci. 1977; 23(3), 356–364.
32. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity. 2000; 12:121–127.