Abstract
Lymph node colonization by tumor cells is one of the key determinants of melanoma staging and prognosis, and tumor-associated macrophages (TAMs) are the predominant type of inflammatory cell in the tumor environment which secretes vascular endothelial growth factor (VEGF)-C, the most potent lymphangiogenic growth factor. In the present study, to elucidate the mechanism involved in VEGF-C expression in TAMs, murine peritoneal macrophages were co-cultivated with syngeneic B16 melanoma cells to mimic the reciprocal interactions between tumor cells and macrophages found in spontaneous tumors. In the present study, upon contact with tumor cells, macrophages were found to express a higher level of VEGF-C which was associated with an increase in the expression of IL-1β and TNF-α and their receptors. Antibodies against the IL-1β and TNF-α receptors were added to media that had been conditioned by the macrophage-tumor cell co-cultures and inhibition of VEGF-C was observed in macrophages co-cultivated with the tumor cells. Furthermore, when IL-1β and TNF-α were used at a non-toxic level, they enhanced peritoneal lymph node colonization by melanoma cells. Thus, in the present study, macrophagic IL-1β and TNF-α were observed to promote VEGF-C expression in TAMs, as well as melanoma lymph node metastasis, suggesting that inhibiting the signaling between tumor cells and TAMs may be required to inhibit lymphangiogenesis and lymph node metastasis.
Highlights
The extent of lymph node involvement is one of the major determinants for the staging and prognosis of melanoma [1]
These findings suggest that macrophage IL‐1β and TNF‐α are responsible for vascular endothelial growth factor (VEGF)‐C expression in tumor‐associated macrophages (TAMs), which may lead to lymphangiogenesis and melanoma lymph node metastasis
The present study shows that, inflammatory macrophages co‐cultivated with B16 murine melanoma cells express enhanced VEGF‐C mRNA which was found to be associated with an autocrine loop of activity between macrophage IL‐1β and TNF‐α and their receptors
Summary
The extent of lymph node involvement is one of the major determinants for the staging and prognosis of melanoma [1]. Lymph node colonization by tumor cells was proposed to be a passive process involving tumor cell spread through pre‐existing afferent lymphatic vessels. Among the inflammatory host cells, tumor‐associated macrophages (TAMs) have been found to release high levels of VEGF‐C [9] and VEGF‐C has been reported to promote macrophage recruitment, in addition to lymphangiogenesis, in VEGF‐C‐overexpressing human melanoma cells transplanted into nude mice [10]. The present study aimed to elucidate the mechanisms involved in VEGF‐C expression in TAMs, in order to identify novel approaches to inhibit lymph node dissemination. In vivo tumor cell‐macrophage interactions were mimicked through co‐culturing B16 murine melanoma cells with syngeneic peritoneal macrophages
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