Immunohistochemical Characterisation of BMP-2,- 4, -7, TGF- β1 and Gremlin1 in Canine Osteosarcoma

Year 2024, Volume: 13 Issue: 1, 75 - 82, 20.03.2024

Yonca Betil Kabak , Sinem İnal , Mahmut Sözmen , Mustafa Yavuz Gülbahar

https://doi.org/10.53424/balikesirsbd.1382254

Abstract

Objective: This study aims to evaluate the expression of Bone morphogenic proteins (BMP) -2, -4, -7, Transforming growth factor (TGF) -β1, and Gremlin1 in different subtypes of naturally occurring canine osteosarcoma (OS) by immunohistochemical method and contribute to a better understanding of the tumor microenvironment. Materials and Methods: Formalin-fixed, paraffin-embedded blocks of 16 naturally occurring canine OS were used. The tumors were classified according to the modified WHO's international histological classification of pet tumors. Compact bone tissues from five normal dogs were used as controls. Results: Immunohistochemically, BMP-2,-4, -7, TGF-β1, and Gremlin1 were not expressed in control tissues. BMP-2, -4, -7, TGF-β1, and Gremlin1 were expressed by undifferentiated mesenchymal cells and extracellular matrix in all OS subtypes. However, it was seen that there were differences in the expressions of these factors in different components of the tumor tissue. Although BMP-2, -4, -7, TGF-β1, and Gremlin1 have antagonistic effects in some pathways, they were co-expressed simultaneously in some regions in different OS subtypes. Conclusion: It was concluded that BMP-2, -4, -7, TGF-β1, and Gremlin1 could be expressed together in the same or different components of tumor tissues, and each can affect the behavior of tumor cells with their together or independent roles.
Keywords: BMP-2, BMP-4, BMP-7, Osteosarcoma, TGF-β1.

Keywords

BMP-2, BMP-4, BMP-7, Osteosarcoma, TGF-β1

References

• Alfranca, A., Martinez-Cruzado, L., Tornin, J., Abarrategi, A., Amaral, T., de Alava, E., Menendez, P., Garcia-Castro, J., & Rodriguez, R. (2015). Bone microenvironment signals in osteosarcoma development. Cellular and Molecular Life Sciences, 72, 3097-3113. https://doi.org/10.1007/s00018-015-1918-y.
• Carreira, A. C., Alves, G. G., Zambuzzi, W. F., Sogayar, M. C., & Granjeiro, J. M. (2014). Bone morphogenetic proteins: structure, biological function and therapeutic applications. Archives of Biochemistry and Biophysics, 561, 64-73. https://doi.org/10.1016/j.abb .2014.07.011.
• Chen, D., Zhao, M., & Mundy, G. R. (2004). Bone morphogenetic proteins. Growth Factors, 22(4), 233-241. https://doi.org/10.1080/089771904123312798 90.
• Corre, I., Verrecchia, F., Crenn, V., Redini, F., & Trichet, V. (2020). The osteosarcoma microenvironment: a complex but targetable ecosystem. Cells, 9(4), 1-25. https://doi.org/10.3390/cells9040976.
• Craig, L., Dittmer, K., & Thompson, K. (2016). Bones and joints. In M. G. Maxie (Ed.), Jubb, Kennedy & Palmer’s pathology of domestic animals (6th ed., Vol. 1, pp. 17-163). Elsevier.
• Franchi, A., Arganini, L., Baroni, G., Calzolari, A., Capanna, R., Campanacci, D., Caldora, P., Masi, L., Brandi, M. L., & Zampi, G. (1998). Expression of transforming growth factor β isoforms in osteosarcoma variants: association of tgfβ1 with high‐grade osteosarcomas. Journal of Pathology, 185(3), 284-289. https://doi.org/10.1002/(SICI)1096-9896 (199807)185:3<284::AID-PATH94>3.0.CO;2-Z.
• Gazzerro, E., Pereira, R. C., Jorgetti, V., Olson, S., Economides, A. N., & Canalis, E. (2005). Skeletal overexpression of gremlin impairs bone formation and causes osteopenia. Endocrinology, 146(2), 655-665. https://doi.org/10.1210/en.2004-0766.
• Gu, Q., Luo, Y., Chen, C., Jiang, D., Huang, Q., & Wang, X. (2019). GREM1 overexpression inhibits proliferation, migration and angiogenesis of osteosarcoma. Experimental Cell Research, 384(1), 111619. https://doi.org/10.1016/j.yexcr.2019.111619.
• Haque, S., & Morris, J. C. (2017). Transforming growth factor-β: A therapeutic target for cancer. Human Vaccines & Immunotherapeutics, 13(8), 1741-1750. https://doi.org/10.1080/21645515.2017.1327107.
• Karagiannis, G. S., Musrap, N., Saraon, P., Treacy, A., Schaeffer, D. F., Kirsch, R., Riddell, R. H., & Diamandis, E. P. (2015). Bone morphogenetic protein antagonist gremlin-1 regulates colon cancer progression. Biological Chemistry, 396(2), 163-183. https://doi.org/10.1515/hsz-2014-0221.
• Kessler, E., Takahara, K., Biniaminov, L., Brusel, M., & Greenspan, D. S. (1996). Bone Morphogenetic Protein-1: The Type I Procollagen C-Proteinase. Science, 271(5247), 360-362. https://doi.org/10.1126 /science.271.5247.360.
• Kim, M., Yoon, S., Lee, S., Ha, S. A., Kim, H. K., Kim, J. W., & Chung, J. (2012). Gremlin-1 induces BMP-independent tumor cell proliferation, migration, and invasion. PLoS One, 7(4), 1-8. https://doi.org/10.137 1/journal.pone.0035100.
• Kloen, P., Gebhardt, M. C., Perez‐Atayde, A., Rosenberg, A. E., Springfield, D. S., Gold, L. I., & Mankin, H. J. (1997). Expression of transforming growth factor‐β (TGF‐β) isoforms in osteosarcomas: TGF‐β3 is related to disease progression. Cancer, 80(12), 2230-2239. https://doi.org/10.1002/(SICI)1097-0142 (19971215)80:12<2230::AID-CNCR3>3.0.CO;2-Y.
• Kubista, B., Klinglmueller, F., Bilban, M., Pfeiffer, M., Lass, R., Giurea, A., Funovics, P. T., Toma, C., Dominkus, M., & Kotz, R. (2011). Microarray analysis identifies distinct gene expression profiles associated with histological subtype in human osteosarcoma. International Orthopaedics, 35(3), 401-411. https://doi.org/10.1007/s00264-010-0996-6.
• Lamora, A., Talbot, J., Mullard, M., Brounais-Le Royer, B., Redini, F., & Verrecchia, F. (2016). TGF-β signaling in bone remodeling and osteosarcoma progression. Journal of Clinical Medicine, 5(11), 1-11. https://doi.org/10.3390/jcm5110096.
• Loukopoulos, P., & Robinson, W. F. (2007). Clinicopathological relevance of tumour grading in canine osteosarcoma. Journal of Comparative Pathology, 136(1), 65-73. https://doi.org/10.1016/j.j cpa.2006.11.005.
• Meuten, D. J. (2017). Tumors in domestic animals. In (5 ed., pp. 356-423). Wiley Blackwell.
• Mitola, S., Ravelli, C., Moroni, E., Salvi, V., Leali, D., Ballmer-Hofer, K., Zammataro, L., & Presta, M. (2010). Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2. Blood, 116(18), 3677-3680. https://doi.org/10.1182/blood-2010-06-291930.
• Namkoong, H., Shin, S. M., Kim, H. K., Ha, S.-A., Cho, G. W., Hur, S. Y., Kim, T. E., & Kim, J. W. (2006). The bone morphogenetic protein antagonist gremlin 1 is overexpressed in human cancers and interacts with YWHAH protein. BMC Cancer, 6(1), 1-13. https://doi.org/10.1186/1471-2407-6-74.
• Nguyen, A., Scott, M. A., Dry, S. M., & James, A. W. (2014). Roles of bone morphogenetic protein signaling in osteosarcoma. International Orthopaedics, 38(11), 2313-2322. https://doi.org/ 10.1007/s00264-014-2512-x .
• Park, K.-H., Kim, H., Moon, S., & Na, K. (2009). Bone morphogenic protein-2 (BMP-2) loaded nanoparticles mixed with human mesenchymal stem cell in fibrin hydrogel for bone tissue engineering. Journal of Bioscience and Bioengineering, 108(6), 530-537. https://doi.org/10.1016/j.jbiosc.2009.05.021.
• Sato, M., Kawana, K., Fujimoto, A., Yoshida, M., Nakamura, H., Nishida, H., Inoue, T., Taguchi, A., Takahashi, J., & Adachi, K. (2016). Clinical significance of Gremlin 1 in cervical cancer and its effects on cancer stem cell maintenance. Oncology Reports, 35(1), 391-397. https://doi.org/10.3892/or 2015.4367.
• Schott, C. R., Tatiersky, L. J., Foster, R. A., & Wood, G. A. (2018). Histologic grade does not predict outcome in dogs with appendicular osteosarcoma receiving the standard of care. Veterinary Pathology, 55(2), 202-211. https://doi.org/10.1177/0300985817747329.
• Sneddon, J. B., Zhen, H. H., Montgomery, K., van de Rijn, M., Tward, A. D., West, R., Gladstone, H., Chang, H. Y., Morganroth, G. S., & Oro, A. E. (2006). Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation. Proceedings of the National Academy of Sciences, 103(40), 14842-14847. https://doi.org/10.1073/pnas.0606857103.
• Sulzbacher, I., Birner, P., Trieb, K., Pichlbauer, E., & Lang, S. (2002). The expression of bone morphogenetic proteins in osteosarcoma and its relevance as a prognostic parameter. Journal of Clinical Pathology, 55(5), 381-385. https://doi.org/ 10.1136/jcp.55.5.381.
• Verrecchia, F., & Rédini, F. (2018). Transforming growth factor-β signaling plays a pivotal role in the interplay between osteosarcoma cells and their microenvironment. Frontiers in Oncology, 8, 1-11. https://doi.org/10.3389/fonc.2018.00133.
• Wu, M., Chen, G., & Li, Y.-P. (2016). TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Research, 4(1), 1-21. https://doi.org/10.1038/bonere s.2016.9.
• Yoshikawa, H., Rettig, W. J., Lane, J. M., Takaoka, K., Alderman, E., Rup, B., Rosen, V., Healey, J. H., Huvos, A. G., & Garin‐Chesa, P. (1994). Immunohistochemical detection of bone morphogenetic proteins in bone and soft‐tissue sarcomas. Cancer, 74(3), 842-847. https://doi.org/10.1002/1097-0142(19940801)74:3 <842::aid-cncr2820740309>3.0.co;2-b.