gw-4869 and Neoplasm-Metastasis

Immunosuppressive chemoresistance is a major challenge in lung cancer treatment. Exosomes present in the tumor microenviroment are implicated in chemoresistant-related immune suppression, and metastasis but the exact pathogenic role of lung-derived exosomes is still uncertain. Recent reports reveal that lung cancer pathogenesis is strictly associated with a exosomal tumor supportive status and a dysfunctional immune system. In this study, we investigate the role of Kras-derived exosomes in chemoresistant immunosuppression in which neoplastic cells create a metabolic-sustained microenvironment. Findings reveal that Kras-derived exosomes induce regulation of SMARCE1/NCOR1 chromatin remodeling genes promoting pre-metastatic niche formation in naive mice and consequently increase lung metastatic burden. Furthermore, exosomal Kras inhibition downregulated transcription factor BACH2/GATA-3 expression in lung tumor tissues by shifting pyruvate/PKM2 dependent metabolism, contributing to a tumor-restraining status. Further co-treatment with carboplatin triggered RIP3/TNFa dependent necroptosis in ex vivo cells accompanied by differential expression of immunosuppressive miR-146/miR-210 regulators in metastatic lung cancer patients. Overall, these findings demonstrate the multifaceted roles of Kras-derived exosomes in sustaining lung immunosuppressive metastasis and provide new opportunities for effective metastasis inhibition, especially in chemoresistant tumors.

Topics: Aniline Compounds; Animals; Basic-Leucine Zipper Transcription Factors; Benzylidene Compounds; Carboplatin; Carrier Proteins; Chromatin Assembly and Disassembly; Chromosomal Proteins, Non-Histone; DNA-Binding Proteins; Exosomes; GATA3 Transcription Factor; Humans; Immunosuppression Therapy; Lung Neoplasms; Membrane Proteins; Mice; Mice, Nude; MicroRNAs; Models, Animal; Necroptosis; Neoplasm Metastasis; Nuclear Receptor Co-Repressor 1; Proto-Oncogene Proteins p21(ras); Receptor-Interacting Protein Serine-Threonine Kinases; Thyroid Hormone-Binding Proteins; Thyroid Hormones; Tumor Microenvironment

Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer and frequently diagnosed at an advanced stage. It is prone to develop unpredictable metastases even with proper treatment. Antiangiogenic therapy is the most effective medical treatment for metastatic ccRCC. Thus, exploration of novel approaches to inhibit angiogenesis and metastasis may potentially lead to a better therapeutic option for ccRCC. Among all the types of cancer, renal cancer samples exhibited the maximum upregulation of ApoC1 as referred to in the Oncomine database. The expression of ApoC1 was increased accompanied by ccRCC progression. A high level of ApoC1 was closely related to poor survival time in ccRCC patients. Furthermore, ApoC1 was over-expressed in the highly invasive ccRCC cells as compared to that in the low-invasive ccRCC cells. Besides, ApoC1 promoted metastasis of ccRCC cells via EMT pathway, whereas depletion of ApoC1 alleviated these effects. ApoC1 as a novel pro-metastatic factor facilitates the activation of STAT3 and enhances the metastasis of ccRCC cells. Meanwhile, ApoC1 in the exosomes were transferred from the ccRCC cells to the vascular endothelial cells and promoted metastasis of the ccRCC cells via activating STAT3. Finally, the metastatic potential of the ccRCC cells driven by ApoC1 was suppressed by DPP-4 inhibition. Our study not only identifies a novel ApoC1-STAT3 pathway in ccRCC metastasis but also provides direction for the exploration of novel strategies to predict and treat metastatic ccRCC in the future.

Topics: Aniline Compounds; Apolipoprotein C-I; Benzylidene Compounds; Carcinoma, Renal Cell; Dipeptidyl Peptidase 4; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Kidney Neoplasms; Neoplasm Metastasis; RNA, Small Interfering; STAT3 Transcription Factor; Survival Analysis; Transcription, Genetic; Tumor Cells, Cultured