Expression of cyclooxygenase-1 and 2 in naturally-occurring canine cancer☆
Introduction
Cyclooxygenase (cox) is a rate-limiting enzyme that catalyzes the formation of prostaglandins from arachidonic acid. Two isoforms of cox have been identified. Cox-1 is constitutively expressed in most tissues and appears to play a role in normal physiology (examples include cytoprotection of the stomach, platelet aggregation, and renal blood flow) [1], [2], [3], [4]. Cox-2 is an induced enzyme and is expressed by cells that are involved in inflammation and other pathological conditions such as arthritis, Alzheimer's disease, ischemia, and cancer [5], [6], [7]. Cox-2 protein and RNA expression have been described in several forms of human and canine carcinomas including carcinoma of the colon, breast, lung, prostate and urinary bladder [8], [9], [10], [11], [12], [13], [14]. Overexpression of cox-2 leads to production of high concentrations of prostaglandins, especially prostaglandin E2 (PGE2). High concentrations of PGE2 are produced by tumor cells, tumor-associated macrophages, and peripheral blood monocytes in people with urinary bladder, breast, lung, and colon cancer [15], [16], [17], [18], [19], and in dogs with naturally-occurring tumors such as urinary bladder transitional cell carcinoma (TCC), oral squamous cell carcinoma, and prostatic carcinoma [20]. PGE2 is believed to increase tumor cell resistance to apoptosis, enhance angiogenesis, increase tumor cell proliferation, induce immunosuppression, as well as having other direct effects on tumor cells [21], [22]. Epidemiological studies in people [23], [24] and studies in dogs with spontaneous tumors [25], [26], [27] have shown that non-selective cox inhibitors (which block cox-1 and cox-2) have antitumor and chemopreventive effects in several different forms of cancer. Cox, especially cox-2, is being further evaluated as a target for cancer prevention and treatment. Cox-2 inhibitors have been developed that selectively block cox-2. Since cox-1 inhibition is thought to be responsible for many of the side effects of non-selective cox inhibitors, cox-2 inhibitors are expected to be safer. In addition, dietary intervention to change the substrate for cox activity is showing promise in altering eicosanoid concentrations. Animal models are needed to study the effects of selective and non-selective cox inhibitors on cancer progression. Spontaneous cancer in pet dogs offers the unique opportunity to study cancers that develop in an environment shared with humans and that, in some cases, closely mimic the human condition [27]. The purpose of this study was to determine the expression of cox-1 and cox-2 in cancer in pet dogs in order to identify types of canine cancer that could serve as preclinical models to evaluate anticancer strategies targeting the cox-2 enzyme. This study has examined a variety of cancers including epithelial, mesenchymal, and lymphoid cancers. Eight forms of naturally-occurring canine cancer including prostatic carcinoma, mammary adenocarcinoma, oral cancers (squamous cell carcinoma, melanoma, and fibrosacrcoma, the three most common forms of oral cancer in the dog), lymphoma, osteosarcoma, and lung metastasis associated with osteosarcoma were studied.
Section snippets
Tissue samples
Tumor tissue samples were obtained by tru-cut needle biopsy or excisional biopsy from pet dogs with naturally-occurring cancer that presented to the Purdue Comparative Oncology Program in the Purdue University Veterinary Teaching Hospital for evaluation and treatment. Tumors included lymphoma (LSA), prostatic carcinoma (PCA), osteosarcoma (OSA), oral melanoma (MEL), oral squamous cell carcinoma (SCC), oral fibrosarcoma (FSA), and mammary carcinoma (MCA). Normal lymph node, prostate gland, bone,
Results
Samples from 101 canine tumor tissues were examined. In a small number of sections, small tissue sample size precluded performing immunohistochemistry for both cox-1 and cox-2.
Table 1 summarizes cox-1 and cox-2 expression in oral cancers. Seventeen of 26 (65%) SCC had cox-2 expression with moderate to high intensity staining, while 13 of 20 (65%) SCC had cox-1 protein detected. Cox-2 expression was also detected in 9 of 15 (60%) MEL cases with moderate to high intensity staining noted. Cox-1
Discussion
Studies to date with cox inhibitors show true promise for these agents having an important role in cancer prevention and treatment. Much information, however, is still lacking. Relevant animal models are needed to study the effects of cox inhibitors against cancer. Spontaneous cancers in pet dogs offer an intriguing opportunity to study cancer therapy strategies aimed at benefiting humans, as well as animals. Canine cox-1 and cox-2 have been cloned, and there is 96% and 93% sequence homology to
Acknowledgements
We thank The Pfizer Inc. of New York for their technical help.
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This work was supported by the Iams Company of Dayton, OH.