Expression of Cyclooxygenase-2 and Ki-67 in Actinic Keratosis and Cutaneous Squamous Cell Carcinoma in Dogs

Sabrina Dos Santos Costa Poggiani, Mário Roberto Hatayde, Renée Laufer-Amorim, Juliana Werner

Department of Veterinary Clinic, School of Veterinary Medicine and Animal Science, Sao Paulo State University, Botucatu, Brazil.
Department of Veterinary Medicine and Surgery, School of Veterinary Medicine and Animal Science, Sao Paulo State University, Jaboticabal, Brazil.
Department of Veterinary Medicine, Pioneer Union of Social Integration, Brasilia, Brazil.
Werner & Werner Laboratory, Curitiba, Brazil.

DOI: 10.4236/ojvm.2012.22007                

Abstract

Actinic keratosis is a common disease in humans, which also affects dogs. Lesions occur in chronically sun exposed areas, such as flank, ventral and lateral abdomen. It has been reported that actinic keratosis is a pre-neoplastic disease which may evolve into squamous cell carcinoma (SCC), which is one of the most frequent malignant neoplasm in dogs. The aim of this research was to investigate the relationship between COX-2 and cell proliferation on the outcome of dogs with actinic keratosis and cutaneous squamous cell carcinoma. This study included 10 skin sections of actinic keratosis (G1) and 10 cutaneous SCC (G2). Data including age, breed, gender and histopathological findings were documented. Paraffin-embedded tissues were retrieved for COX-2 and Ki-67 staining. American Pit Bull Terrier dogs were the most affected ones in both G1 and G2, the mean age was 4.3 (±0.8) years and 5.6 (±1.7) years, respectively. Mean score of COX-2 immunostaining in G1 and G2 was 8.16 (±3.51) and 8.56 (±1.03), respectively. Mean percentage of immunopositive cells for Ki-67 in G1 and G2 was 15.77 (±8.81) and 17.71 (±12.21), respectively. There was no association between COX-2 expression and Ki-67, recurrence, survival and metastasis rate (p > 0.05). These findings highlight the role of COX-2 and Ki-67 in carcinogenesis, but do not confirm the relationship between COX-2 expression and increased cell proliferation in dogs. COX-2 may play a role in carcinogenesis, but this pathway is not responsible for cellular proliferation in actinic keratosis and cutaneous SCC in dogs. Both markers were not useful tools to differentiate the outcome of affected dogs.

Keywords

Skin; Cancer; Dog

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	M. Lebwohl, “Actinic Keratosis: Epidemiology a Progression to Squamous Cell Carcinoma,” British Journal of Dermatology, Vol. 149, No. 66, 2003, pp. 31-33. doi:10.1046/j.0366-077X.2003.05621.x
[2]	E. Papadogiannakis, V. Kontos and K. Frangia, “A Case of Canine Squamous Cell Carcinoma Secondary to Solar Keratosis (Actinic Carcinoma in Situ),” Journal of the Hellenic Veterinary Medical Society, Vol. 59, No. 1, 2008, pp. 64-70.
[3]	C. Favrot, M. Welle, M. Heimann, D. L. Godson and F. Guscetti, “Clinical, Histologic, and Immunohistochemical Analyses of Feline Squamous Cell Carcinoma in Situ,” Veterinary Pathology, Vol. 46, No. 1, 2009, pp. 25-33. doi:10.1354/vp.46-1-25
[4]	T. L. Gross, P. J. Ihrke, E. J. Walder and V. K. Affolter, “Skin Diseases of the Dog and Cat: Clinical and Histopathologic Diagnosis,” Blackwell, Oxford, 2005, p. 932. doi:10.1002/9780470752487
[5]	J.-P. Ortonne, “From Actinic Keratosis to Squamous Cell Carcinoma,” British Journal of Dermatology, Vol. 146, No. 61, 2002, pp. 20-23. doi:10.1046/j.1365-2133.146.s61.6.x
[6]	C. J. Cockerell, “Pathology and Pathobiology of the Actinic (Solar) Keratosis,” British Journal of Dermatology, Vol. 149, No. 66, 2003, pp. 34-36. doi:10.1046/j.0366-077X.2003.05625.x
[7]	J.-P. Ortonne, “Anti-Inflammatory vs. Inflammatory Treatments for Actinic Keratosis,” Journal of Cosmetic Dermatology, Vol. 2, No.3-4, 2003, pp. 135-140. doi:10.1111/j.1473-2130.2004.00093.x
[8]	J. Rowert-huber, M. J. Patel, T. Forschner, C. Ulrich, J. eberle, H. Kerl, W. Sterry and E. Stockfleth, “Actinic Keratosis Is an Early in Situ Squamous Cell Carcinoma: A Proposal for Reclassification,” British Journal of Dermatology, Vol. 156, No. 3, 2007, pp. 8-12. doi:10.1111/j.1365-2133.2007.07860.x
[9]	E. Stockfleth and H. Kerl, “Guidelines for the Management of Actinic Keratosis,” European Journal of Dermatology, Vol. 16, No. 6, 2006, pp.599-606.
[10]	E. M. P. Almeida, C. Piché, J. Sirois and M. Doré, “Expression of Cyclo-oxygenase-2 in Naturally Occuring Squamous Cell Carcinomas in Dogs,” The Journal of Histochemistry & Cytochemistry, Vol. 49, No. 7, 2001, pp. 867-875. doi:10.1177/002215540104900707
[11]	D. Scott, W. H. Miller and C. E. Griffin, “Small Animal Dermatology,” 6th Edition, Saunders, Philadelphia, 2001, p. 1528.
[12]	R. L. Howe, “Inflammation and Breast Cancer. Cyclooxygenase/Prostaglandin Signaling and Breast Cancer,” Breast Cancer Research, Vol. 9, No. 4, 2007, pp. 210-219. doi:10.1186/bcr1678
[13]	S. Y. Buckman, A. Gresham, P. Hale, G. Hruza, J. Anast, J. Masferrer and A. P. Pentland, “COX-2 Expression Is Induced by UVB Exposure in Human Skin: Implications for the Development of Skin Cancer,” Carcinogenesis, Vol. 19, No. 5, 1998, pp. 723-729. doi:10.1093/carcin/19.5.723
[14]	A. B. de Nardi, C. R. Daleck, C. H. M. Souza, R. L. Amorim, S. Rodaski, C. Calderon and R. Torres, “Cyclo-oxygenase-2 Expression in Mammary Tumors in Dogs and Its Correlation to Histologic and Biologic Behavior,” Veterinary and Comparative Oncology, Vol. 3, No. 1, 2005, pp. 56-57. doi:10.1111/j.1476-5810.2005.064ak.x
[15]	D. A. P. C. Zuccari, M. V. Pavam, A. C. B. Terzian, R. S. Pereira, C. M. Ruiz and J. A. Andrade, “Immunohistochemical Evaluation of E-cadherin, Ki-67 and PCNA in Canine Mammary Neoplasias: Correlation of Prognostic Factores and Clinical Outcome,” Pesquisa Veterinária Brasileira, Vol. 28, No. 4,2008, pp. 207-215. doi:10.1590/S0100-736X2008000400003
[16]	S. Roels, K. Tilmant and R. Ducatelle, “PCNA and Ki67 Prolieration Markers as Criteria for Prediction of Clinical Behaviour of Melanocytic Tumours in Cats and Dogs,” Journal of Comparative Pathology, Vol. 121, No. 1, 1999, pp. 13-24. doi:10.1053/jcpa.1998.0291
[17]	C. Laprie, J. Abadie, M.-F. Amardeilh, J.-L. L. E. Net, M. Lagadic and M. Delverdier, “MIB-1 Immunoreactivity Correlates with Biologic Behaviour in Canine Cutaneous Melanoma,” Veterinary Dermatology, Vol. 12, No. 3, 2001, pp. 139-147. doi:10.1046/j.1365-3164.2001.00236.x
[18]	J. D. Webster, “Evaluation of Prognostic Markers for Canine Mast Cell Tumors Treated with Vinblastine and Prednisone,” BMC Veterinary Research, Vol. 4, 2008, pp. 32. doi:10.1186/1746-6148-4-32
[19]	O. Kiyokazu, Y. Tetsushi, N. Koji and N. Isao, “Prognostic Significance of Surgical Margin, Ki-67 and Cyclin D1 Protein Expression in Grade II Canine Cutaneous Mast Cell Tumor,” Journal of Veterinary Medical Science, Vol. 69, No. 11, 2007, pp. 1117-1121. doi:10.1292/jvms.69.1117
[20]	C. W. Oh and N. Penneys, “P27 e MIB-1 Expression in Actinic Keratosis, Bowen Disease, and Squamous Cell Carcinoma,” The American Journal of Dermatopathology, Vol. 26, No. 1, , 2004, pp. 22-26. doi:10.1097/00000372-200402000-00004
[21]	G. Neufang, G. Fürstenberger, M. Heidt, F. Marks and K. Müller-Decker, “Abnormal Differentiation of Epidermis in Transgenic Mice Constitutively Expressing Cyclo-oxygenase-2 in Skin,” Proceedings National Academy of Sciences of the United States of America, Heidelberg, 2001, pp. 7629-7634.
[22]	F. Naghshvar, Z. Torabizadeh, O. Emadian, A. Khalilian, I. Maleki and K. Enami, “Correlation of Cyclooxygenase 2 (Cox-2) Presentation and Inflammatory Cells Infiltration in Colorectal Cancer: A Histopathological and Immunohistochemical Study,” Research Journal of Biological Sciences, Vol. 3, No. 8, 2008, pp. 916-918.
[23]	A. Grützkau, S. Krüger-Krasagakes, H. Baumeister, C. Schwarz, H. Kogel, P. Welker, U. Lippert, B. M. Henz and A. Moller, “Synthesis, Storage, and Release of Vascular Endothelial Growth Factor/Vascular Permeability Factor (VEGF/VPF) by Human Mast Cells: Implications for the Biological Significance of VEGF206,” Molecular Biology of the Cell, Vol. 9, No. 4, 1998, pp. 875-884.
[24]	K. Subbaramaiah, N. Altorki, W. J. Chung, J. R. Mestre, A. Sampat and A. J. Dannenberg, “Inhibition of Cyclo-oxygenase-2 Gene Expression by p53,” Journal of Biological Chemistry, Vol. 274, No. 16, 1999, pp. 10911-10915. doi:10.1074/jbc.274.16.10911
[25]	B. Tammenhain, M. R. Farias, A. Obladen and J. Werner, “Estudo Retrospectivo da Dermatite Actínica em Caes da Raca pit Bull Terrier,” Proceedings Congresso Brasileiro da Associacao Nacional de Clínicos Veterinários de Pequenos Animais, Maceió, 2008, pp. 1-3.
[26]	N. Zaugg, G. Nespeca, B. Hauser, M. Ackermann and C. Favrot, “Detection of Novel Papillomaviruses in Canine Mucosal, Cutaneous and in Situ Squamous Cell Carcinoma,” Veterinary Dermatology, Vol. 16, No. 5, 2005, pp. 290-298. doi:10.1111/j.1365-3164.2005.00467.x
[27]	E. F. Velazquez, G. Avala, H. Liu, A. Chaux, M. Zanotti, J. Torres, S. I. Cho, J. E. Barreto, F. Soares and A. L. Cubilla, “Histologic Grade and Perineural Invasion Are More Important than Tumor Thickness as Predictor of Nodal Metastasis in Penile Squamous Cell Carcinoma Invading 5 to 10 mm,” American Journal of Surgical Pathology, Vol. 32, No. 7, 2008, pp. 974-979. doi:10.1097/PAS.0b013e3181641365
[28]	V. F. Z. Marinho, K. Metze, F. S. F. Sanches, G. F. S. Rocha and H. Gobbi, “Marcadores Moleculares em cancer de Mama Preditivos de Metástases Axilares,” Revista da Associacao Médica Brasileira, Vol. 54, No. 3, 2008, pp. 203-207.
[29]	P. M. Carpenter, K. G. Linden, C. E. McLaren, K.-T. Li, S. Arain, R. J. Barr, P. Hite, J. D. Sun and F. L. Meyskens, “Nuclear Morphometry and Molecular Biomarkers of Actinic Keratosis, Sun-Damaged, and Nonexposed Skin,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 13, No. 12, 2004, pp. 1996-2002.
[30]	M. Ulrich, A. Maltusch, J. R?wert-huber, S. González, W. Sterry, E. Stockfleth and S. Astner, “Actinic Keratoses: Non-Invasive Diagnosis for Field Cancerisation,” British Journal of Dermatology, Vol. 156, No. 3, 2007, pp. 13-17. doi:10.1111/j.1365-2133.2007.07865.x
[31]	B. Berman, L. Bienstock, L. Kuritzky, E. J. Mayeaux, S. K. Tyring, “Actinic Keratoses: Sequelae and Treatments,” The Journal of Family Practice, Vol. 55, 2006, pp. 1-8.
[32]	T. A. Silva, G. Coelho, A. L. Bocca and F. F. Cavalcante Neto, “Expression of Apoptotic, Cell Proliferation Regulatory, and Structural Proteins in Actinic Keratosis and Their Association with Dermal Elastosis,” Journal of Cutaneous Pathology, Vol. 34, No. 4, 2006, pp. 315-323. doi:10.1111/j.1600-0560.2006.00621.x
[33]	N. Pronovost, M. M. Suter, E. Mueller, J. Sirois and M. Doré, “Expression and Regulation of Cyclooxygenase-2 in Normal and Neoplastic Canine Keratinocytes,” Veterinary and Comparative Oncology, Vol. 2, No. 4, 2004, pp. 222-233. doi:10.1111/j.1476-5810.2004.00055.x