RESUMO
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.
Assuntos
Fibrossarcoma/patologia , Receptores de Hialuronatos/metabolismo , Interleucina-33/metabolismo , Neoplasias Pulmonares/patologia , Macrófagos/imunologia , Glicoproteínas de Membrana/metabolismo , Células-Tronco Neoplásicas/patologia , Animais , Apoptose , Proliferação de Células , Fibrossarcoma/etiologia , Fibrossarcoma/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Receptores de Hialuronatos/genética , Interleucina-33/genética , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos DBA , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/metabolismo , Sarcoma Experimental/etiologia , Sarcoma Experimental/metabolismo , Sarcoma Experimental/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Coagulação Sanguínea/genética , Deficiência do Fator XI/sangue , Deficiência do Fator XI/genética , Fator XI/genética , Alelos , Substituição de Aminoácidos , Análise Mutacional de DNA , Éxons , Fator XI/química , Fator XI/metabolismo , Deficiência do Fator XI/diagnóstico , Estudos de Associação Genética , Genótipo , Humanos , Íntrons , Mutação , FenótipoRESUMO
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.
