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,...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 UR1L. 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.展开更多
基金supported by IG grants from the Italian Association for Cancer Research(AIRC)to P.A.grants from the Italian Ministry of Health(GR-2013-02356521)to E.M.B.
文摘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 UR1L. 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.
