ABSTRACT
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.
Subject(s)
Fibrosarcoma/pathology , Hyaluronan Receptors/metabolism , Interleukin-33/metabolism , Lung Neoplasms/pathology , Macrophages/immunology , Membrane Glycoproteins/metabolism , Neoplastic Stem Cells/pathology , Animals , Apoptosis , Cell Proliferation , Fibrosarcoma/etiology , Fibrosarcoma/metabolism , Gene Expression Regulation, Neoplastic , Humans , Hyaluronan Receptors/genetics , Interleukin-33/genetics , Lung Neoplasms/etiology , Lung Neoplasms/metabolism , Male , Membrane Glycoproteins/genetics , Mice , Mice, Inbred DBA , Neoplastic Stem Cells/immunology , Neoplastic Stem Cells/metabolism , Sarcoma, Experimental/etiology , Sarcoma, Experimental/metabolism , Sarcoma, Experimental/pathology , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysSubject(s)
Blood Coagulation/genetics , Factor XI Deficiency/blood , Factor XI Deficiency/genetics , Factor XI/genetics , Alleles , Amino Acid Substitution , DNA Mutational Analysis , Exons , Factor XI/chemistry , Factor XI/metabolism , Factor XI Deficiency/diagnosis , Genetic Association Studies , Genotype , Humans , Introns , Mutation , PhenotypeABSTRACT
The antiproliferative effect of Tempol, a stable nitroxide free radical, was investigated on the p53-negative human leukemia cell line HL60. A concentration- and time-dependent inhibition of cell growth was observed that appears to be due to induction of apoptosis. Involvement of oxidative stress is indicated by a concentration-dependent increase in intracellular peroxides and a parallel decrease in total cellular glutathione; in addition, increased survival rates were observed in cells simultaneously treated with Tempol and the antioxidant N-acetylcysteine. Tempol did not affect the relative levels of Bax and Bcl2, whereas p21(WAF1/CIP1) was enhanced in a concentration- and time-dependent fashion; this effect was partially inhibited by N-acetylcysteine, was maintained for up to 8 h after Tempol removal, and seemed to depend on continuing protein synthesis. The increase in p21(WAF1/CIP1) was accompanied by a parallel accumulation of cells in the G(1) phase of the cycle and by a decrease in the 110 kDa form of pRb. Our results suggest that p53-independent induction of p21(WAF1/CIP1) mediates the antiproliferative effect of Tempol; on the basis of this observation, the nitroxide could be proposed as an useful adjunct to the treatment of p53-deficient tumors, which are often refractory to standard chemotherapy.
