Expression of cyclo-oxygenase-2 in macrophages associated with cutaneous melanoma at different stages of progression

Abstract

The biological significance of the almost constant presence of macrophages in the tumoral microenvironment is an issue debated by several authors. The major difficulty in understanding the role played by tumor-associated macrophages (TAMs) in tumor progression is due to the contrasting effects of TAMs found in different studies. In addition, there is a limited information on which of the many biological activities expressed by TAMs are critical in inducing stimulatory or inhibitory effect on tumor growth. The aim of our study was: (a) to explore to what extent cyclo-oxygenase-2 (COX-2) in TAMs associated with human melanoma is expressed at different stages of tumor progression; and (b) to explore whether COX-2 expression in TAMs is stimulated by melanoma cells. In order to answer this question, we determined COX-2 positive TAMs associated with cutaneous melanocytic nevi, in situ, invasive and metastatic melanoma. In addition, we investigated whether COX-2 is expressed in peritoneal thioglycollate-elicited macrophages after co-cultivation with murine B16 melanoma cells. We found that COX-2-positive TAMs, as revealed by immunohistochemical analysis, were rare in common nevi and "dysplastic nevi", but present in a high percentage in in situ and thin melanoma. COX-2-positive TAMs were also found in more advanced tumors and metastatic melanoma, although at a significantly lower percentage in these latter. The in vitro protocol revealed that COX-2 was expressed in peritoneal macrophages upon contact with B16 murine melanoma cells, but not with normal murine fibroblasts. On the whole, the results of in vivo and in vitro studies suggest that COX-2 expressed in TAMs appears to act as an effective biomarker of melanoma progression, and melanoma cells themselves might stimulate COX-2 in macrophages.

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

“…By osteopontin signalling, COX-2 expression is upregulated in macrophages, inducing increased MMP-9 secretion to promote angiogenesis and invasiveness of melanocytic tumours [52]. An in-vitro study has reported that only upon contact with melanoma cells could macrophages express COX-2 [53]. Furthermore, macrophages seem to be capable of inducing COX-2 expression in breast carcinomas, amplifying IL-1β signalling through the MAPK pathway, which is involved in tumour progression [54].…”

Melatonin Enhances the Anti-Tumor Effect of Fisetin by Inhibiting COX-2/iNOS and NF-κB/p300 Signaling Pathways

“…Many reports have demonstrated the wide range of effects for COX-2 product PGE2 in carcinogenesis and tumor development, including inducing angiogenesis, promoting cellular proliferation, inhibiting cell apoptosis, stimulating tumor invasion, and so on [28]. In melanoma, COX-2 is associated with tumor progression [29]–[31].Similarly, inducible NO synthases (iNOS) and its product NO have also shown overexpression in different types of cancer, including melanoma. iNOS is overexpressed in most cultured melanoma cells and in human melanoma samples [32], [33].…”

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

“…The presence of macrophages in primary lesions was revealed in cutaneous melanomas (19), uveal melanomas (20,21) and sinonasal melanomas (22). In the case of cutaneous lesions, they are predominantly located in the primary foci, and to a lesser extent in metastatic foci (19).…”

“…In the case of cutaneous lesions, they are predominantly located in the primary foci, and to a lesser extent in metastatic foci (19). Elevated numbers of macrophages within a melanoma is markedly associated with poor prognosis (23).…”

“…The percentage of COXs-positive TAMs is highest in in situ and in thin melanomas, and lower in highly advanced and metastatic melanomas. It has been demonstrated that the expression of this thoroughly studied mediator of inflammation is a marker of melanoma progression (19). Macrophages stimulated by osteopontin from the melanoma microenvironment start to synthesize the COX-2 protein (37).…”