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Extracellular Vesicles Promote the Formation of Pre-Metastasis Niche in Gastric Cancer.

ABSTRACT: Globally, gastric cancer (GC) ranks fourth in the incidence of malignant tumors. The early clinical manifestations of GC lack specificity. Most patients are already at an advanced stage when they are first diagnosed, and their late progression is mainly due to peritoneal metastasis. A pre-metastatic microenvironment is formed, before the macroscopic tumor metastasis. Extracellular vesicles (EVs) are nanovesicles released by cells into body fluids. Recent studies have shown that EVs can affect the tumor microenvironment by carrying cargos to participate in cell-to-cell communication. EVs derived from GC cells mediate the regulation of the pre-metastasis niche and act as a coordinator between tumor cells and normal stroma, immune cells, inflammatory cells, and tumor fibroblasts to promote tumor growth and metastasis. This review highlights the regulatory role of EVs in the pre-metastatic niche of GC and mulls EVs as a potential biomarker for liquid biopsy.

SUBMITTER: Tang D

PROVIDER: S-EPMC8841609 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Extracellular Vesicles Promote the Formation of Pre-Metastasis Niche in Gastric Cancer.

Tang Diya D Liu Shanshan S Shen Hong H Deng Gongping G Zeng Shan S

Frontiers in immunology 20220131

Globally, gastric cancer (GC) ranks fourth in the incidence of malignant tumors. The early clinical manifestations of GC lack specificity. Most patients are already at an advanced stage when they are first diagnosed, and their late progression is mainly due to peritoneal metastasis. A pre-metastatic microenvironment is formed, before the macroscopic tumor metastasis. Extracellular vesicles (EVs) are nanovesicles released by cells into body fluids. Recent studies have shown that EVs can affect th ...[more]

PMID: 35173726

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Project description:Gastric cancer is anatomically proximal to peritoneum. Gastric cancer peritoneal metastasis is a complex biological process which is corresponded with disharmony within dysfunctional adipose tissue and metabolism reprogramming. Laminin gamma 1 (LAMC1) is highly expressed in cancer cells of peritoneal metastatic sites, however, the mechanism of LAMC1-metiated gastric cancer metastases to adipose tissue-rich peritoneum remains unclear. In our study, immunohistochemical staining, single cell sequencing, a co-culture model, luciferase reporter, RNA immunoprecipitation (RIP), Chromatin immunoprecipitation (CHIP) and single-molecular magnetic tweezers assays were conducted, and our results showed that LAMC1 related to Perilipin-1 content was highly expressed in peritoneal metastatic sites and mainly secreted by tumor cells. Gastric cancer cells secreted LAMC1 in an autocrine manner to detached from the primary site and promoted preadipocytes mature, rupture and release of free fatty acids (FFAs) in the peritoneal microenvironment to form pre-metastatic niche by the paracrine pathway. Reversely, differentiated preadipocyte-derived conditioned medium inhibited glycolysis and enhanced fatty acid oxidation (FAO) rate to promote cell proliferation, mesenchymal-epithelial transformation which led to tumor peritoneal colonization. In terms of biological mechanisms, one of differentiated preadipocyte-derived FFAs, palmitic acid-activated STAT3 inhibited miR-193a-3p by binding to its promoter directly; Using single-molecular magnetic tweezers, this binding manner was proved to be stable, reversable and ATP-dependent. Moreover, miR-193a-3p regulated LAMC1 in a post-translational manner. Furthermore, high LAMC1 expression in serum predicted a higher risk of peritoneal metastasis. In conclusion, our results illustrated that palmitic acid/p-STAT3/miR-193a-3p/LAMC1 pathway promotes preadipocyte differentiation, pre-metastatic niche formation and gastric cancer cell colonization to peritoneum.

Project description:BackgroundLiver metastasis (LM) is one of the most common distant metastases of gastric cancer (GC). However, the mechanisms underlying the LM of GC (GC-LM) remain poorly understood. This study aimed to identify the tumour-secreted protein associated with GC-LM and to investigate the mechanisms by which this secreted protein remodels the liver microenvironment to promote GC-LM.MethodsData-independent acquisition mass spectrometry (DIA-MS), mRNA expression microarray, quantitative real-time PCR, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) were performed to identify and validate the GC-secreted proteins associated with GC-LM. A modified intrasplenic injection mouse model of LM was used to evaluate the progression and tumour burden of LM in vivo. Flow cytometry, immunofluorescence (IF), western blots (WB) and IHC were performed to validate the pre-metastatic niche (PMN) formation in the pre-modelling mouse models. mRNA sequencing of PMA-treated THP-1 cells with or without lipopolysaccharide binding protein (LBP) treatment was used to identify the functional target genes of LBP in macrophages. Co-immunoprecipitation (Co-IP), WB, ELISA, IF and Transwell assays were performed to explore the underlying mechanism of LBP in inducing intrahepatic PMN formation.ResultsLBP was identified as a critical secreted protein associated with GC-LM and correlated with a worse prognosis in patients with GC. LBP activated the TLR4/NF-κB pathway to promote TGF-β1 secretion in intrahepatic macrophages, which, in turn, activated hepatic satellite cells (HSCs) to direct intrahepatic fibrotic PMN formation. Additionally, TGF-β1 enhanced the migration and invasion of incoming metastatic GC cells in the liver. Consequently, selective targeting of the TGF-β/Smad signaling pathway with galunisertib demonstrated its efficacy in effectively preventing GC-LM in vivo.ConclusionsThe results of this study provide compelling evidence that serological LBP can serve as a valuable diagnostic biomarker for the early detection of GC-LM. Mechanistically, GC-derived LBP mediates the crosstalk between primary GC cells and the intrahepatic microenvironment by promoting TGF-β1 secretion in intrahepatic macrophages, which induces intrahepatic fibrotic PMN formation to promote GC-LM. Importantly, selectively targeting the TGF-β/Smad signaling pathway with galunisertib represents a promising preventive and therapeutic strategy for GC-LM.

Project description:Rationale: Breast cancer preferentially develops osteolytic bone metastasis, which makes patients suffer from pain, fractures and spinal cord compression. Accumulating evidences have shown that exosomes play an irreplaceable role in pre-metastatic niche formation as a communication messenger. However, the function of exosomes secreted by breast cancer cells remains incompletely understood in bone metastasis of breast cancer. Methods: Mouse xenograft models and intravenous injection of exosomes were applied for analyzing the role of breast cancer cell-derived exosomes in vivo. Effects of exosomes secreted by the mildly metastatic MDA231 and its subline SCP28 with highly metastatic ability on osteoclasts formation were confirmed by TRAP staining, ELISA, microcomputed tomography, histomorphometric analyses, and pit formation assay. The candidate exosomal miRNAs for promoting osteoclastogenesis were globally screened by RNA-seq. qRT-PCR, western blot, confocal microscopy, and RNA interfering were performed to validate the function of exosomal miRNA. Results: Implantation of SCP28 tumor cells in situ leads to increased osteoclast activity and reduced bone density, which contributes to the formation of pre-metastatic niche for tumor cells. We found SCP28 cells-secreted exosomes are critical factors in promoting osteoclast differentiation and activation, which consequently accelerates bone lesion to reconstruct microenvironment for bone metastasis. Mechanistically, exosomal miR-21 derived from SCP28 cells facilitates osteoclastogenesis through regulating PDCD4 protein levels. Moreover, miR-21 level in serum exosomes of breast cancer patients with bone metastasis is significantly higher than that in other subpopulations. Conclusion: Our results indicate that breast cancer cell-derived exosomes play an important role in promoting breast cancer bone metastasis, which is associated with the formation of pre-metastatic niche via transferring miR-21 to osteoclasts. The data from patient samples further reflect the significance of miR-21 as a potential target for clinical diagnosis and treatment of breast cancer bone metastasis.

Dataset Information

Extracellular Vesicles Promote the Formation of Pre-Metastasis Niche in Gastric Cancer.

Publications

Extracellular Vesicles Promote the Formation of Pre-Metastasis Niche in Gastric Cancer.

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