RESUMO
Impaired tumor necrosis factor receptor-1 (TNFR-1) signaling has been found in some malignant tumors with poor prognosis. However, the exact role of TNFR-1 signaling in fibrosarcoma remains unclear. Here, we explored the question by comparing the growth of TNFR-1 deficient (Tnfr1 (-)) and TNFR-1 competent (Tnfr1 (+)) fibrosarcoma FB61 cells (FB61-m and FB61-R1) in mice. TNFR-1 expression on fibrosarcoma cells delayed their growth in vivo but not in vitro. Moreover, reduced FB61-R1 tumor growth was also obtained in TNFR-1 knockout mice. The mechanism relies mainly on the TNFR-1-mediated downregulation of vascular endothelial growth factor (VEGF) production by tumor cells. Importantly, treatment of FB61-m tumors with melphalan resulted in a short delay of tumor growth, followed by a quick remission. However, when FB61-R1 tumors were treated with melphalan, tumor growth was similarly delayed at first and then completely rejected. Our results reveal evidence for TNFR-1 on tumor cells as a prerequisite in chemotherapy for fibrosarcoma, and provide novel insight into the therapeutic approach against some types of tumors using TNFR-1 angonist.
Assuntos
Fibrossarcoma/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Melfalan/administração & dosagem , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Animais , Regulação para Baixo/efeitos dos fármacos , Fibrossarcoma/genética , Fibrossarcoma/patologia , Humanos , Camundongos , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/biossínteseRESUMO
TNF, an inflammatory cytokine that is enriched in the tumor microenvironment, promotes tumor growth and subverts innate immune responses to cancer cells. We previously reported that tumors implanted in TNF receptor-deficient (Tnfr-/-) mice are spontaneously rejected; however, the molecular mechanisms underlying this rejection are unclear. Here we report that TNF signaling drives the peripheral accumulation of myeloid-derived suppressor cells (MDSCs). MDSCs expand extensively during inflammation and tumor progression in mice and humans and can enhance tumor growth by repressing T cell-mediated antitumor responses. Peripheral accumulation of MDSCs was drastically impaired in Tnfr-/- mice. Signaling of TNFR-2, but not TNFR-1, promoted MDSC survival through upregulation of cellular FLICE-inhibitory protein (c-FLIP) and inhibition of caspase-8 activity. Loss of TNFRs impaired the induction of MDSCs from bone marrow cells, but this could be reversed by treatment with caspase inhibitors. These results demonstrate that TNFR-2 signaling promotes MDSC survival and accumulation and helps tumor cells evade the immune system.
Assuntos
Células Mieloides/imunologia , Neoplasias/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Evasão Tumoral , Fator de Necrose Tumoral alfa/imunologia , Animais , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/biossíntese , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/imunologia , Caspase 8/genética , Caspase 8/imunologia , Caspase 8/metabolismo , Linhagem Celular Tumoral , Rejeição de Enxerto/genética , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Rejeição de Enxerto/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células Mieloides/metabolismo , Células Mieloides/patologia , Transplante de Neoplasias , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/genética , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Persistently high serum levels of soluble tumor-necrosis factor (TNF) receptor 2 (sTNFR2) have been observed in septic shock and many inflammatory diseases. However, its origin and regulation during these pathological processes are still largely unknown. In this study, murine bone marrow (BM) chimeras selectively expressing TNFR2 on either BM-derived or non-BM-derived cells were generated and challenged with lipopolysaccharide (LPS). The results show that TNFR2 expression on non-BM-derived cells is crucial for both the sensitivity of mice to LPS and the downregulation of sTNFR2 in serum. Most importantly, sTNFR2 was released from both BM- and non-BM-derived cells. Non-BM TNFR1 expression influenced the sensitivity of mice to LPS challenge but not the level of serum sTNFR2. These results provide the first in vivo evidence for the origin and regulation of sTNFR2 in serum and could aid in the development of novel anti-TNF strategies against septic shock.
