Low-level monocyte chemoattractant protein-1 stimulation of monocytes leads to tumor formation in nontumorigenic melanoma cells
Low-level monocyte chemoattractant protein-1 stimulation of monocytes leads to tumor formation in nontumorigenic melanoma cells
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DOI：
10.4049/jimmunol.166.11.6483
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发表时间：
2001-06-01
影响因子：
4.4
通讯作者：
Herlyn, M
中科院分区：
文献类型：
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作者：
Nesbit, M;Schaider, H;Herlyn, M
肿瘤通常产生用于募集宿主细胞的趋化因子，但肿瘤浸润性炎性细胞（如单核细胞/巨噬细胞）对于疾病结果的生物学意义尚不清楚。在这里，我们发现，所有30个黑色素瘤细胞系分泌单核细胞趋化蛋白-1（MCP-1），而正常黑色素细胞没有。当来自生物学早期非致瘤阶段的低MCP-1产生的黑素瘤细胞被转导以过表达MCP-1基因时，肿瘤形成依赖于趋化因子分泌和单核细胞浸润的水平;低水平的MCP-1分泌和适度的单核细胞浸润导致肿瘤形成，而高分泌与大量单核细胞/巨噬细胞浸润到肿瘤块中有关，导致其在注射到小鼠体内后几天内被破坏。单核细胞/巨噬细胞刺激的肿瘤生长是由于血管生成增加。用抗TNF-α的mAb抑制体外血管形成，当由黑素瘤细胞与人单核细胞的共培养物分泌时，TNF-α诱导胶原凝胶下的内皮细胞形成分支管状结构。这些研究表明，肿瘤来源的MCP-1的生物学效应是双相的，这取决于分泌水平。这与单核细胞浸润的程度相关，单核细胞浸润导致肿瘤血管化和TNF-α产生增加。
Tumors commonly produce chemokines for recruitment of host cells, but the biological significance of tumor-infiltrating inflammatory cells, such as monocytes/macrophages, for disease outcome is not clear. Here, we show that all of 30 melanoma cell lines secreted monocyte chemoattractant protein-1 (MCP-1), whereas normal melanocytes did not. When low MCP-1-producing melanoma cells from a biologically early, nontumorigenic stage were transduced to overexpress the MCP-1 gene, tumor formation depended on the level of chemokine secretion and monocyte infiltration; low-level MCP-1 secretion with modest monocyte infiltration resulted in tumor formation, whereas high secretion was associated with massive monocyte/macrophage infiltration into the tumor mass, leading to its destruction within a few days after injection into mice. Tumor growth stimulated by monocytes/macrophages was due to increased angiogenesis. Vessel formation in vitro was inhibited with mAbs against TNF-alpha, which, when secreted by cocultures of melanoma cells with human monocytes, induced endothelial cells under collagen gels to form branching, tubular structures. These studies demonstrate that the biological effects of tumor-derived MCP-1 are biphasic, depending on the level of secretion. This correlates with the degree of monocytic cell infiltration, which results in increased tumor vascularization and TNF-alpha production.