Investigating associations of cyclooxygenase-2 expression with angiogenesis, proliferation, macrophage and T-lymphocyte infiltration in canine melanocytic tumours

Abstract

Cyclooxygenase-2 (COX-2) is known to be involved in tumour progression and has been suggested as a therapeutic target in many human and animal malignancies. A number of different pathways subjacent to cancer hallmarks are considered to be involved in COX-2-mediated tumour progression, although these are still largely undefined. Our aim is to investigate associations between COX-2 expression and angiogenesis, proliferation and the inflammatory microenvironment in canine melanocytic tumours. Understanding the involvement of COX-2 with cancer hallmarks might enable us to adapt therapeutic strategies for canine melanomas, an aggressive and often lethal malignancy with value in comparative oncology. Immunohistochemical staining of COX-2, Ki-67 (proliferation index), vascular endothelial growth factor (VEGF), factor VIII (microvessel density), CD3 (lymphocytes) and MAC387 (macrophages) was performed in 51 melanocytic tumours (31 malignant melanomas, 20 melanocytomas). Statistical associations between COX-2 and the other parameters detected were analysed. In melanocytic tumours (n=51), both COX-2 labelling extension and intensity showed a statistically significant association with angiogenesis by factor VIII, VEGF, Ki-67, CD3+ T lymphocytes and MAC387. Within malignant melanomas, COX-2 expression has shown significant associations with microvessel density (factor VIII), lymphocyte and macrophage infiltration and, considering all melanocytic tumours, COX-2 was also associated with VEGF intensity and Ki-67 cell proliferation. Our results point to a role for COX-2 in angiogenesis and in the establishment of an inflammatory microenvironment, favourable to melanoma tumour progression. Further mechanistic studies are warranted to dissect molecular pathways in which COX-2 is involved. Present evidence suggests that COX-2 inhibitors might be useful as an adjuvant treatment to hinder canine melanoma progression.

Cyclooxygenase‐2 expression is associated with infiltration of inflammatory cells in oral and skin canine melanomas

“…The positivity for S-100, Melan-A, PNL-2 26 and COX-2 27 was indicated by the presence of distinct brown cytoplasmic labelling and it was used a semiquantitative method previously described. 13,23 The number of COX-2 positive cells was evaluated semi-quantitatively, with the distribution score defined by the estimated percentage of positive cells in five fields at ×400 magnification: 0 = absence, 1 = fewer than 10% stained cells, 2 = between 10% and 30%, 3 = between 31% and 60%, 4 = more than 61% stained cells. For staining intensity, values from 0 to 3 were attributed: 0 = absence (−), 1 = weak staining (+), 2 = moderate staining (++), and 3 = strong staining (+++).…”

“…22 A study that evaluated the COX-2 expression with angiogenesis, tumour proliferation, presence of macrophages and T-lymphocyte infiltrate in canine melanomas found associations with microvessel density (MVD) (FACTOR VIII), lymphocyte infiltration and macrophages. 23 However, the association between COX-2 expression and molecular markers of inflammatory infiltrate, angiogenesis and proliferation are not well described in either human or canine. Building on previous reports of canine melanomas and COX-2 expression.…”

“…Building on previous reports of canine melanomas and COX-2 expression. 13,23 The aim of this study was to define the COX-2 expression profile in the skin and oral canine melanomas, and to characterize mononuclear cell infiltrate and the relationship with angiogenesis. We hypothesized that overexpression of COX-2 in malignant melanocytic neoplasms in dogs may lead to a worse prognosis because it is related to lymphocyte modulation and increases the angiogenic and proliferative capacity of the tumour.…”

Role of monocyte recruitment in hemangiosarcoma metastasis in dogs

“…Previous studies have evaluated macrophage infiltrates in canine melanoma, mammary carcinoma, seminoma, glioma and nasal carcinoma . In canine mammary tumours, an association between a high density of tumour‐associated macrophages (TAMs) and significantly decreased overall survival times was reported .…”

Macrophages in skin melanoma-the key element in melanomagenesis (Review)

“…Osteopontin combined with PGE2 substantially increases the influence on angiogenesis by enhancing the expression of MMP-9 (36). Another study revealed that the increased expression of COX-2 in melanoma tumor types is associated with increased VEGF expression, density of micro vessels and inflammatory infiltration formed of macrophages (37,38).…”