Regulation of COX‐2 Expression in Canine Prostate Carcinoma: Increased COX‐2 Expression is Not Related to Inflammation

Abstract

Background: Cyclooxygenase‐2 (COX‐2) expression has been documented in human and canine prostate carcinoma (PCA). Canine PCA is a histologically heterogeneous tumor, sometimes including inflammatory infiltrates. However, it is unknown whether COX‐2 expression in canine PCA is related to the histologic type of tumor, to the presence of inflammation, or to both. Moreover, little is known about the mechanisms regulating COX‐2 expression in neoplastic tissue. Hypothesis: COX‐2 expression is related to the presence of inflammation in canine PCA and correlates with the degree of tumor differentiation. Methods: The expression of COX‐2 was examined in 28 cases of canine PCA by immunohistochemistry. In addition, a neoplastic and a nonneoplastic canine prostatic cell line were used to investigate the effects of interleukin‐6 (IL‐6), tumor necrosis factor‐ç (TNF‐ç), phorbol 12‐myristate 13‐acetate (PMA), epithelial growth factor (EGF), and specific signal transduction pathway inhibitors on COX‐2 expression. Results: Twenty‐four of the 28 prostate tumors showed COX‐2 expression. The presence of inflammatory infiltrates in tumor tissue was associated with lower COX‐2 expression scores. In vitro, TNF‐ç, IL‐6, and EGF increased COX‐2 expression in nonneoplastic cells but not in PCA cells, where baseline expression was high. COX‐2 expression in PCA cells could be suppressed by means of specific phosphatidyl inositol‐3 kinase (PI3K), protein kinase C (PKC), or inhibitor of extracellular signal‐related kinase (ERK/MAPK) inhibitors. Conclusions and Clinical Importance: COX‐2 is expressed in canine PCA; however, expression is not related to the presence of inflammatory infiltrates. This conclusion is further supported by the finding that the cytokines TNF‐ç and IL‐6 and their involved signaling pathways do not stimulate COX‐2 expression in malignant canine prostate cells.

Cyclooxygenase-2 Expression Is Related With Localization, Proliferation, and Overall Survival in Canine Melanocytic Neoplasms

“…Similarly, L'Eplattenier et al 26 observed that COX-2 expression in canine prostatic carcinoma cells is independent of the presence of an inflammatory infiltrate. Thus, these results and our observations suggest that COX-2 could develop alternative functions in melanoma progression to its naturally proinflammatory activity.…”

Cyclooxygenase-2 Expression in Animal Cancers

“…Constitutive expression of COX-2 was demonstrated in the canine mammary cell line CMT12 and in a canine neoplastic prostatic cell line. 11,65 The endogenous COX-2 expression in the neoplastic prostatic cell line was shown to be dependent on different signaling pathways (PI3K, PKC, and ERK/MAPK). 65 Our laboratory has also shown that NS398, a specific inhibitor of COX-2, significantly blocked PGE 2 synthesis (Fig.…”

“…33 Several later reports confirmed the overexpression of COX-2 in prostatic cancer and its absence in normal prostate in the canine species. 65,78,111 Experimentally, treatment of dogs with estrogen has been shown to induce squamous metaplasia and COX-2 expression in the prostate. 21 So far, only one clinical study has investigated the effect of COX inhibitors on canine prostatic carcinoma.…”

“…124 This does not appear to be the case in dogs as the presence of inflammatory infiltrates was associated with lower COX-2 expression, and the COX-2 expression did not vary with the degree of differentiation of the tumors. 65 Canine Transitional Cell Carcinoma. Urinary bladder cancer affects each year more than 67,000 people in the United States, with the most common form being invasive transitional cell carcinoma (TCC).…”

Growth Factors and COX2 Expression in Canine Perivascular Wall Tumors

“…35,45 COX2 expression has been demonstrated in several canine and feline tumors, and its inhibition is considered a promising adjuvant therapy. 6,8,29,30,38,[39][40][41] The aims of this study are as follows:…”