RESUMO
The microbiome assisted tumor microenvironment (TME) supports the tumors by modulating multiple mechanisms. Recent studies reported that microbiome dysbiosis is the main culprit of immune suppressive phenotypes of TME. Further, it has been documented that immune suppressive stimulate metastatic phenotype in TME via modulating signaling pathways, cell differentiation, and innate immune response. This review aims at providing comprehensive developments in microbiome and breast TME interface. The combination of microbiome and breast cancer, breast TME and microbiome or microbial dysbiosis, microbiome and risk of breast cancer, microbiome and phytochemicals or anticancer drugs were as used keywords to retrieve literature from PubMed, Google scholar, Scopus, Web of Science from 2015 onwards. Based on the literature, we presented the impact of TME assisted microbiome dysbiosis and estrobolome in breast cancer risk, drug resistance, and antitumor immunity. We have discussed the influence of antibiotics on the breast microbiome. we also presented the possible dietary phytochemicals that target microbiome dysbiosis to restore the tumor suppression immune environment in breast TME. We presented the microbiome as a possible marker for breast cancer diagnosis. This study will help in the identification of microbiome as a novel target and diagnostic markers and phytochemicals and microbiome metabolites for breast cancer treatment.
Assuntos
Neoplasias da Mama , Microbiota , Mama , Neoplasias da Mama/tratamento farmacológico , Disbiose , Feminino , Humanos , Microambiente TumoralRESUMO
Glioma is a highly complex brain tumor characterized by the dysregulation of proteins and genes that leads to tumor metastasis. Cathepsin B and uPAR are overexpressed in gliomas and they are postulated to play central roles in glioma metastasis. In this study, efficient downregulation of cathepsin B and uPAR by siRNA treatments significantly reduced glioma cell adhesion to laminin as compared to vitronectin, fibronectin, or collagen I in U251 and 4910 glioma cell lines. Brain glioma tissue array analysis showed high expression of CD151 in clinical samples when compared with normal brain tissue. Cathepsin B and uPAR siRNA treatment led to the downregulation of CD151 and laminin-binding integrins α3 and ß1. Co-immunoprecipitation experiments revealed that downregulation of cathepsin B and uPAR decreased the interaction of CD151 with uPAR cathepsin B, and α3ß1 integrin. Studies on the downstream signaling cascade of uPAR/CD151/α3ß1 integrin have shown that phosphorylation of FAK, SRC, paxillin, and expression of adaptor cytoskeletal proteins talin and vinculin were reduced with knockdown of cathepsin B, uPAR, and CD151. Treatment with the bicistronic construct reduced interactions between uPAR and CD151 as well as lowering α3ß1 integrin, talin, and vinculin expression levels in pre-established glioma tumors of nude mice. In conclusion, our results show that downregulation of cathepsin B and uPAR alone and in combination inhibit glioma cell adhesion by downregulating CD151 and its associated signaling molecules in vitro and in vivo. Taken together, the results of the present study show that targeting the uPAR-cathepsin B system has possible therapeutic potential.
Assuntos
Catepsina B/metabolismo , Adesão Celular , Movimento Celular , Glioma/patologia , Integrina alfa3beta1/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Tetraspanina 24/metabolismo , Animais , Apoptose , Western Blotting , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Catepsina B/antagonistas & inibidores , Catepsina B/genética , Moléculas de Adesão Celular/metabolismo , Proliferação de Células , Regulação para Baixo , Citometria de Fluxo , Imunofluorescência , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Glioma/genética , Glioma/metabolismo , Humanos , Técnicas Imunoenzimáticas , Imunoprecipitação , Integrina alfa3beta1/antagonistas & inibidores , Integrina alfa3beta1/genética , Camundongos , Camundongos Nus , Fosforilação , RNA Interferente Pequeno/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Tetraspanina 24/antagonistas & inibidores , Tetraspanina 24/genética , Células Tumorais Cultivadas , CalininaRESUMO
Oxidative stress has emerged as an important pathogenic factor in the development of breast cancer. Cholesterol-rich membrane rafts or lipid rafts (LRs) are reported to play an important role in oxidative stress-induced signal transduction. NADPH oxidase-dependent reactive oxygen species (ROS) production is implicated in oxidative stress in human mammary epithelial cells. In the present study, we determined the expression and regulation of membrane-bound subunits by LRs in human breast cancer cells. We report that basal levels of gp91phox and p22phox are expressed in breast cancer cells. We demonstrate for the first time that disruption of LRs resulted in the downregulation of NADPH oxidase subunits in breast cancer cells. Cholesterol depletion by 10 mM methyl-ß-cyclodextrin (MßCD) translocated both gp91phox and p22phox out of LRs. Moreover, lipid raft disruption decreased NADPH oxidase activity (21.1 ± 0.5% in MCF-7 and 28.9 ± 1.0 in BT-549 cells), which was reversed by cholesterol repletion (95%). Therefore, the results suggest that the integrity of LRs plays an important role in the regulation of NADPH oxidase activity in breast cancer cells.