In cancer, myeloid cells have tumor-supporting roles. We reported that the protein GPNMB (glycoprotein nonmetastatic B) was profoundly upregulated in macrophages interacting with tumor cells. Here, using mouse tumor models, we show that macrophage-derived soluble GPNMB increases tumor growth and metastasis in Gpnmb-mutant mice (DBA/2J). GPNMB triggers in the cancer cells the formation of self-renewing spheroids, which are characterized by the expression of cancer stem cell markers, prolonged cell survival and increased tumor-forming ability. Through the CD44 receptor, GPNMB mechanistically activates tumor cells to express the cytokine IL-33 and its receptor IL-1R1L. We also determined that recombinant IL-33 binding to IL-1R1L is sufficient to induce tumor spheroid formation with features of cancer stem cells. Overall, our results reveal a new paracrine axis, GPNMB and IL-33, which is activated during the cross talk of macrophages with tumor cells and eventually promotes cancer cell survival, the expansion of cancer stem cells and the acquisition of a metastatic phenotype.

在癌症中，骨髓细胞具有支持肿瘤的作用。我们报道了蛋白 GPNMB（糖蛋白非转移性 B）在与肿瘤细胞相互作用的巨噬细胞中显着上调。在这里，我们使用小鼠肿瘤模型显示巨噬细胞衍生的可溶性 GPNMB 增加了 Gpnmb 突变小鼠 (DBA/2J) 的肿瘤生长和转移。GPNMB 在癌细胞中触发自我更新球状体的形成，其特点是表达癌症干细胞标志物、延长细胞存活率和增加肿瘤形成能力。通过 CD44 受体，GPNMB 机械地激活肿瘤细胞以表达细胞因子 IL-33 及其受体 IL-1R1L。我们还确定重组 IL-33 与 IL-1R1L 结合足以诱导具有癌症干细胞特征的肿瘤球体形成。总体，