Tumor Cells and Microenvironmental Interaction in Natural Course of Canine Transmissible Venereal Tumor

Yıl 2024, , 51 - 57, 04.07.2024

Tuğçe Anteplioğlu , Tilbe Su Yapıcı , Mehmet Eray Alçığır

https://doi.org/10.35864/evmd.1474684

Öz

Canine transmissible venereal tumors (CTVT) is a naturally occurring tumor that is mostly transmitted between dogs through coitus. This study aims to investigate the effect of CTVT on molecular expression and disease progression by studying the tumor microenvironment (TME). For this purpose, biopsy samples taken from ten female dogs were evaluated histopathologically and CTVT was diagnosed. The expression of markers such as CD163, CD68, CD44, TGF-beta and bFGF was evaluated by immunoperoxidase tests. Histopathologically, CTVT cells exhibited pleomorphism, ranging from round to polygonal. Some cells exhibited prominent vacuoles and hypochromatic nuclei, while others exhibited hyperchromatic nuclei containing mitotic figures within the thin fibrovascular wall. Immunohistochemically, TGF-beta and CD44 expression was higher in CTVT cells compared to CD68 and bFGF, while bFGF expression was higher in fibrocytes and spindle cells compared to other markers. The results indicate that CD44 and TGF-beta may play a pivotal role in fibrovascular processes, CD163 and CD68 may facilitate interactions between stromal components and mesenchymal cells, and bFGF, TGF-beta and CD68 may contribute to the arrest of tumoral progression and the initiation of the regression phase. These findings underscore the necessity for further studies to elucidate the role of markers at different stages of CTVT progression.

Anahtar Kelimeler

CTVT, dog, histopathology, immunoexpression, microenvironment

Köpek Aktarılabilir Venereal Tümörlerinin Doğal Seyri Sırasında Tümör ile Mikroçevre Etkileşimi

Öz

Köpeklerde Aktarılabilen Venereal Tümörler (CTVT), doğal olarak oluşan ve çoğunlukla cinsel temas yoluyla köpekler arasında aktarılan bir tümördür. Bu çalışma, CTVT'nin tümör mikroçevresini (TME) inceleyerek moleküler ekspresyon ve hastalık ilerlemesi üzerindeki etkisini araştırmayı amaçlamaktadır. Bunun için; on dişi köpekten alınan biyopsi örnekleri histopatolojik olarak değerlendirildi ve CTVT tanısı konuldu. CD163, CD68, CD44, TGF-beta ve bFGF gibi belirteçlerin immünoperoksidaz testlerle ekspresyonları değerlendirildi. Histopatolojik olarak; CTVT hücrelerinin yuvarlaktan poligonal şekle kadar değişen pleomorfizm gösterdiği, bazı hücrelerin belirgin vakuoller ve hipokromatik çekirdeklere sahip olduğu bazılarınınsa ince fibrovasküler duvar içinde mitotik figürler içeren hiperkromatik çekirdeklerinin olduğu görüldü. İmmünohistokimyasal olarak, CTVT hücrelerinde TGF-beta ve CD44 ekspresyonu CD68 ve bFGF'ye kıyasla daha yüksek olduğu; bFGF ekspresyonunun ise fibrositlerde ve iğsi hücrelerde diğer belirteçlere göre daha yüksek olduğu gözlendi. Sonuçlar, CD44 ve TGF-beta'nın fibrovasküler süreçlerde önemli roller oynayabileceğini, CD163 ve CD68'in ise stromal bileşenler ve mezenkimal hücreler arasındaki etkileşimleri kolaylaştırabileceğini ve bFGF, TGF-beta ve CD68'in tümöral ilerlemenin durdurulmasına ve gerileme evresinin başlatılmasına katkı sağlayabileceğini göstermektedir. Bu bulgular, CTVT ilerlemesinin farklı aşamalarında belirteçlerin rolünü anlamak için daha fazla çalışma gerektiğini vurgulamaktadır.

Anahtar Kelimeler

CTVT, histopatoloji, immünoekspresyon, köpek, mikroçevre

Kaynakça

• Alkan, H., Satilmis, F., Alcigir, M. E., Kivrak, M. B., & Aydin, I. (2017). Clinicopathological Evaluation of Disseminated Metastases of Transmissible Venereal Tumor in a Spayed Bitch. Acta Scientiae Veterinariae, 45, 6.
• Ardizzone A, Bova V, Casili G, Repici A, Lanza M, Giuffrida R, Colarossi C, Mare M, Cuzzocrea S, Esposito E. (2023). Role of Basic Fibroblast Growth Factor in Cancer: Biological Activity, Targeted Therapies, and Prognostic Value. Cells; 12(7):1002.
• Birhan, G., & Chanie, M. (2015). A review on canine transmissible venereal tumor: from morphologic to biochemical and molecular diagnosis. Academic Journal of Animal Diseases, 4(3), 185-195. Cangul T. (2001). Improved classification, diagnosis and prognosis of canine round cell tumours. http:// www.vetscite.org/publish/articles/000038/article.html
• Chan, M. K., Chan, E. L., Ji, Z. Z., Chan, A. S., Li, C., Leung, K. T., To, K. F., & Tang, P. M. (2023). Transforming growth factor-β signaling: from tumor microenvironment to anticancer therapy. Exploration of targeted anti-tumor therapy, 4(2), 316–343.
• Cingi, C. C., Yeni, D., Yazici, E., Cine, T. A., & Mehmet, U. (2020). Investigation of transmissible venereal tumor in male dogs by cytological examination. Indian Journal of Animal Research, 54(12), 1544-1548.
• Cohen, D. (1973): The biological behaviour of TVT in immunosuppressed dogs. Eur. J. Cancer 3, 163-164. do Prado Duzanski, A., Flórez, L. M. M., Fêo, H. B., Romagnoli, G. G., Kaneno, R., & Rocha, N. S. (2022). Cell-mediated immunity and expression of MHC class I and class II molecules in dogs naturally infected by canine transmissible venereal tumor: Is there complete spontaneous regression outside the experimental CTVT?. Research in veterinary science, 145, 193–204.
• Duzanski, A. P., Fêo, H. B., Montoya, L. M., Seullner, C. V., & Rocha, N. S. (2017). Canine Transmissible Venereal Tumor: Is Its Biological Behavior Changing?. Anatomical record (Hoboken, N.J. : 2007), 300(6), 1009–1010. Flórez, L. M., Ballestero, H. F., Duzanski, A. P., Bersano, P. R., Lima, J. F., Cruz, F. L., ... & Rocha, N. S. (2016). Immunocytochemical characterization of primary cell culture in canine transmissible venereal tumor. Pesquisa Veterinária Brasileira, 36, 844-850.
• Flórez, M. M., Fêo, H. B., Da Silva, G. N., Yamatogi, R. S., Aguiar, A. J., Araújo Jr, J. P., & Rocha, N. S. (2017). Cell cycle kinetics, apoptosis rates and gene expressions of MDR‐1, TP53, BCL‐2 and BAX in transmissible venereal tumour cells and their association with therapy response. Veterinary and Comparative Oncology, 15(3), 793-807.
• Frampton, D., Schwenzer, H., Marino, G., Butcher, L. M., Pollara, G., Kriston-Vizi, J., ... & Fassati, A. (2018). Molecular signatures of regression of the canine transmissible venereal tumor. Cancer cell, 33(4), 620-633. Ganguly, B., Das, U., & Das, A. K. (2016). Canine transmissible venereal tumour: a review. Veterinary and comparative oncology, 14(1), 1-12.
• Hao, Y., Baker, D., & Ten Dijke, P. (2019). TGF-β-mediated epithelial-mesenchymal transition and cancer metastasis. International journal of molecular sciences, 20(11), 2767.
• Hiblu, M. A., Khabuli, N. M., & Gaja, A. O. (2019). Canine transmissible venereal tumor: First report of three clinical cases from Tripoli, Libya. Open veterinary journal, 9(2), 103–105.
• Hsiao, Y. W., Liao, K. W., Hung, S. W., & Chu, R. M. (2004). Tumor-infiltrating lymphocyte secretion of IL-6 antagonizes tumor-derived TGF-β1 and restores the lymphokine-activated killing activity. The Journal of Immunology, 172(3), 1508-1514.
• Kanca, H., Tez, G., Bal, K., Ozen, D., Alcigir, E., & Atalay Vural, S. (2018). Intratumoral recombinant human interferon alpha‐2a and vincristine combination therapy in canine transmissible venereal tumour. Veterinary Medicine and Science, 4(4), 364-372.
• Ke, C. H., Tomiyasu, H., Lin, Y. L., Huang, W. H., Huang, H. H., Chiang, H. C., & Lin, C. S. (2022). Canine transmissible venereal tumour established in immunodeficient mice reprograms the gene expression profiles associated with a favourable tumour microenvironment to enable cancer malignancy. BMC Veterinary Research, 18, 1-14.
• Luna, GL. (1968) Manual of histologic- Staining methods of the armed forces institute of pathology. 3ªed. London: McGraw-Hill Book Company. Mukaratirwa, S., & Gruys, E. (2003). Canine transmissible venereal tumour: cytogenetic origin, immunophenotype, and immunobiology. A review. Veterinary Quarterly, 25(3), 101-111.
• Pai, C. C., Kuo, T. F., Mao, S. J., Chuang, T. F., Lin, C. S., & Chu, R. M. (2011). Immunopathogenic behaviors of canine transmissible venereal tumor in dogs following an immunotherapy using dendritic/tumor cell hybrid. Veterinary immunology and immunopathology, 139(2-4), 187-199.
• Ponta, H., Sherman, L., & Herrlich, P. A. (2003). CD44: from adhesion molecules to signalling regulators. Nature reviews Molecular cell biology, 4(1), 33-45. Primeaux, M., Gowrikumar, S., & Dhawan, P. (2022). Role of CD44 isoforms in epithelial-mesenchymal plasticity and metastasis. Clinical & experimental metastasis, 39(3), 391-406.
• Setthawongsin, C., Teewasutrakul, P., Tangkawattana, S., Techangamsuwan, S., & Rungsipipat, A. (2019). Conventional-vincristine sulfate vs. modified protocol of vincristine sulfate and L-asparaginase in canine transmissible venereal tumor. Frontiers in veterinary science, 6, 300.
• Shankaran, V., Ikeda, H., Bruce, A. T., White, J. M., Swanson, P. E., Old, L. J., & Schreiber, R. D. (2001). IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature, 410(6832), 1107-1111.
• Siddle, H. V., & Kaufman, J. (2015). Immunology of naturally transmissible tumours. Immunology, 144(1), 11-20. Silveira, A. C. T., Gerardi, D., Mouro, J. V., Costa, M. T., & Alessi, A. C. (2009). Immunohistochemical expression of B and T-lymphocytes and TGF-β in experimentally transplanted canine venereal tumor. Ciência Rural, 39, 1148-1154.
• Skytthe, M. K., Graversen, J. H., & Moestrup, S. K. (2020). Targeting of CD163+ Macrophages in Inflammatory and Malignant Diseases. International journal of molecular sciences, 21(15), 5497.
• Thangathurai, R.K., Balasubramaniam, G.A., Dharmaceelan, S., Balachandran, P.V., Srinivasan, P., Sivaseelan, S., & Manohar, B.M. (2008). Cytological diagnosis and its histological correlation in canine transmissible venereal tumour. Veterinarski Arhiv, 78, 369-376.
• Turner, N., & Grose, R. (2010). Fibroblast growth factor signalling: from development to cancer. Nature Reviews Cancer, 10(2), 116-129.
• Ujvari, B., Papenfuss, A. T., & Belov, K. (2016). Transmissible cancers in an evolutionary context. Inside the cell, 1(1), 17-26.
• Xu, H., Tian, Y., Yuan, X., Wu, H., Liu, Q., Pestell, R. G., & Wu, K. (2015). The role of CD44 in epithelial–mesenchymal transition and cancer development. OncoTargets and therapy, 3783-3792.
• Zayas, Y. R., Molina, M. A. F., Guerra, R. T., & Padilla, C. R. (2019). Evaluation of a Canine Transmissible Venereal Tumour Cell Line with Tumour Immunity Capacity but Without Tumorigenic Property. Journal of veterinary research, 63(2), 225–233.
• Zhang, J., Li, S., Liu, F., & Yang, K. (2022). Role of CD68 in tumor immunity and prognosis prediction in pan-cancer. Scientific reports, 12(1), 7844.