Massi Daniela, Marconi Chiara, Franchi Alessandro, Bianchini Francesca, Paglierani Milena, Ketabchi Sheyda, Miracco Clelia, Santucci Marco, Calorini Lido
Dipartimento di Patologia Umana ed Oncologia, Università di Firenze, Florence 50134, Italy.
Hum Pathol. 2007 Oct;38(10):1516-25. doi: 10.1016/j.humpath.2007.02.018. Epub 2007 Jul 19.
Tumor-associated macrophages (TAMs) may elicit contrasting effects on tumor growth, depending on their biological activities. Macrophages use arginine either to synthesize nitric oxide (NO) through the inducible NO synthase (iNOS) or to produce ornithine through arginase activity. Although the effects of NO are primarily cytotoxic, production of ornithine may promote tumor cell proliferation. Thus, iNOS/arginase balance in TAMs may be crucial in tumor progression. The aim of this study was (a) to explore iNOS and arginase expression in TAMs associated with human melanoma at different stages of tumor progression and (b) to explore whether melanoma cells influence iNOS and/or arginase expression in TAMs under basal condition and in the presence of interferon gamma and/or lipopolysaccharide. Immunohistochemical analyses performed on tissue sections from in situ melanoma, invasive melanoma of different pT categories, and metastatic melanoma revealed that (a) the percentage of iNOS-positive TAMs was significantly higher in in situ and thin melanomas in comparison with more advanced, thicker tumors; (b) the percentage of arginase-positive TAMs did not change among the pT categories analyzed; and (c) the percentage of iNOS-positive TAMs was greater than that of arginase-positive TAMs in peritumoral and intratumoral locations of thin melanomas (pT1). Moreover, by the use of an in vitro experimental protocol represented by B16 murine melanoma cells cocultivated with inflammatory macrophages, we found that melanoma cells stimulate iNOS expression and NO production in macrophages. In conclusion, our in vivo and in vitro results suggest that, mainly in early melanoma lesions, iNOS prevails over arginase in TAMs, a phenomenon possibly stimulated by contact with tumor cells. However, macrophages stimulated by murine melanoma cells secreted a level of NO compatible with an antitumor activity only in the presence of interferon gamma.
肿瘤相关巨噬细胞（TAM）对肿瘤生长可能产生相反的影响，这取决于它们的生物学活性。巨噬细胞利用精氨酸，要么通过诱导型一氧化氮合酶（iNOS）合成一氧化氮（NO），要么通过精氨酸酶活性产生鸟氨酸。虽然NO的作用主要是细胞毒性的，但鸟氨酸的产生可能促进肿瘤细胞增殖。因此，TAM中iNOS/精氨酸酶的平衡可能在肿瘤进展中起关键作用。本研究的目的是：（a）探讨与人类黑色素瘤不同进展阶段相关的TAM中iNOS和精氨酸酶的表达；（b）探讨黑色素瘤细胞在基础条件下以及在存在干扰素γ和/或脂多糖的情况下是否会影响TAM中iNOS和/或精氨酸酶的表达。对原位黑色素瘤、不同pT类别的浸润性黑色素瘤和转移性黑色素瘤的组织切片进行免疫组织化学分析，结果显示：（a）与更晚期、更厚的肿瘤相比，原位和薄黑色素瘤中iNOS阳性TAM的百分比显著更高；（b）在所分析的pT类别中，精氨酸酶阳性TAM的百分比没有变化；（c）在薄黑色素瘤（pT1）的瘤周和瘤内位置，iNOS阳性TAM的百分比大于精氨酸酶阳性TAM的百分比。此外，通过使用由B16小鼠黑色素瘤细胞与炎性巨噬细胞共培养所代表的体外实验方案，我们发现黑色素瘤细胞刺激巨噬细胞中iNOS的表达和NO的产生。总之，我们的体内和体外结果表明，主要在早期黑色素瘤病变中，TAM中iNOS的表达高于精氨酸酶，这种现象可能是由与肿瘤细胞接触所刺激的。然而，只有在存在干扰素γ的情况下，受小鼠黑色素瘤细胞刺激的巨噬细胞分泌的NO水平才与抗肿瘤活性相符。
