RESUMO
Metastasis is a crucial stage in tumour progression, and cancer-associated fibroblasts (CAFs) support metastasis through their participation in extracellular matrix (ECM) stiffness. CD248 is a possible biomarker for non-small cell lung cancer (NSCLC)-derived CAFs, but its role in mediating ECM stiffness to promote NSCLC metastasis is unknown. We investigated the significance of CD248+ CAFs in activating the Hippo axis and promoting connective tissue growth factor (CTGF) expression, which affects the stromal collagen I environment and improves ECM stiffness, thereby facilitating NSCLC metastasis. In this study, we found that higher levels of CD248 in CAFs induced the formation of collagen I, which in turn increased extracellular matrix stiffness, thereby enabling NSCLC cell infiltration and migration. Hippo axis activation by CD248+ CAFs induces CTGF expression, which facilitates the formation of the collagen I milieu in the stromal matrix. In a tumour lung metastasis model utilizing fibroblast-specific CD248 gene knockout mice, CD248 gene knockout mice showed a significantly reduced ability to develop tumour lung metastasis compared to that of WT mice. Our findings demonstrate that CD248+ CAFs activate the Hippo pathway, thereby inducing CTGF expression, which in turn facilitates the collagen I milieu of the stromal matrix, which promotes NSCLC metastasis.
Assuntos
Fibroblastos Associados a Câncer , Carcinoma Pulmonar de Células não Pequenas , Fator de Crescimento do Tecido Conjuntivo , Matriz Extracelular , Via de Sinalização Hippo , Neoplasias Pulmonares , Camundongos Knockout , Proteínas Serina-Treonina Quinases , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Animais , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Matriz Extracelular/metabolismo , Camundongos , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Fator de Crescimento do Tecido Conjuntivo/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Linhagem Celular Tumoral , Antígenos CD/metabolismo , Antígenos CD/genética , Metástase Neoplásica , Transdução de Sinais , Regulação Neoplásica da Expressão Gênica , Movimento Celular , Microambiente TumoralRESUMO
Chemotherapy-resistant non-small cell lung cancer (NSCLC) presents a substantial barrier to effective care. It is still unclear how cancer-associated fibroblasts (CAFs) contribute to NSCLC resistance to chemotherapy. Here, we found that CD248+ CAFs released IL-8 in NSCLC, which, in turn, enhanced the cisplatin (CDDP) IC50 in A549 and NCI-H460 while decreasing the apoptotic percentage of A549 and NCI-H460 in vitro. The CD248+ CAFs-based IL-8 secretion induced NSCLC chemoresistance by stimulating nuclear factor kappa B (NF-κB) and elevating ATP-binding cassette transporter B1 (ABCB1). We also revealed that the CD248+ CAFs-based IL-8 release enhanced cisplatin chemoresistance in NSCLC mouse models in vivo. Relative to wild-type control mice, the CD248 conditional knockout mice exhibited significant reduction of IL-8 secretion, which, in turn, enhanced the therapeutic efficacy of cisplatin in vivo. In summary, our study identified CD248 activates the NF-κB axis, which, consecutively induces the CAFs-based secretion of IL-8, which promotes NSCLC chemoresistance. This report highlights a potential new approach to enhancing the chemotherapeutic potential of NSCLC-treating cisplatin.
Assuntos
Antineoplásicos , Fibroblastos Associados a Câncer , Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Interleucina-8 , Neoplasias Pulmonares , Animais , Camundongos , Antígenos CD , Antígenos de Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Interleucina-8/genética , Interleucina-8/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , NF-kappa B , HumanosRESUMO
Nonsmall cell lung cancer (NSCLC) is among the most prevalent malignant tumours threatening human health. In the tumour microenvironment (TME), cancer-associated fibroblasts (CAFs) induce M2-polarized macrophages, which strongly regulate tumour progression. However, little is known about the association between CAFs and M2 macrophages. CD248 is a transmembrane glycoprotein found in several cancer cells, tumour stromal cells, and pericytes. Here, we isolated CAFs from tumour tissues of NSCLC patients to detect the relationship between CD248 expression and patient prognosis. We knocked down the expression of CD248 on CAFs to detect CXCL12 secretion and macrophage polarization. We then examined the effects of CD248-expressing CAF-induced M2 macrophage polarization to promote NSCLC progression in vitro and in vivo. We found that CD248 is expressed mainly in NSCLC-derived CAFs and that the expression of CD248 correlates with poor patient prognosis. Blocking CXCL12 receptor (CXCR4) drastically decreased M2 macrophage chemotaxis. CD248 promotes CAFs secreting CXCL12 to mediate M2-polarized macrophages to promote NSCLC progression both in vitro and in vivo. Collectively, our data suggest that CD248-positive CAFs induce NSCLC progression by mediating M2-polarized macrophages.