CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer

Hu, Jiaping; Wang, W.; Lan, Xiao-Liang; Zeng, Zhao Chong; Liang, Yingke; Yan, Yi; Song, Fuyao; Wang, F. F.; Zhu, Xiaoxia; Liao, Wenting; Ding, Yan‐Qing; Li, Liang

doi:10.1186/s12943-019-1019-x

Cited by 556 publications

(512 citation statements)

References 40 publications

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“…To talk about a mature construct, we need to consider other important players, such as stromal or immune cells, that are known to play a key role in cancer growth and progression [50]. Future analyses will be focused to test the efficacy of multi-drug treatments and how the analyzed parameters may be modified by enriched recellularization with essential CRC microenvironment components, such as tumor-infiltrating lymphocyte and cancer-associated fibroblast, that are shown to promote chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition mechanisms [51]. To address these topics and to improve the 3D patient-derived culture model, experiments inflow and dynamic systems need to be added to a present culture setting.…”

Section: Discussionmentioning

confidence: 99%

Recellularized Colorectal Cancer Patient-Derived Scaffolds as In Vitro Pre-Clinical 3D Model for Drug Screening

Sensi

D’Angelo

Piccoli

et al. 2020

Cancers

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Colorectal cancer (CRC) shows highly ineffective therapeutic management. An urgent unmet need is the random assignment to adjuvant chemotherapy of high-risk stage II and stage III CRC patients without any predictive factor of efficacy. In the field of drug discovery, a critical step is the preclinical evaluation of drug cytotoxicity, efficacy, and efficiency. We proposed a patient-derived 3D preclinical model for drug evaluation that could mimic in vitro the patient’s disease. Surgically resected CRC tissue and adjacent healthy colon mucosa were decellularized by a detergent-enzymatic treatment. Scaffolds were recellularized with HT29 and HCT116 cells. Qualitative and quantitative characterization of matched recellularized samples were evaluated through histology, immunofluorescences, scanning electron microscopy, and DNA amount quantification. A chemosensitivity test was performed using an increasing concentration of 5-fluorouracil (5FU). In vivo studies were carried out using zebrafish (Danio rerio) animal model. Permeability test and drug absorption were also determined. The decellularization protocol allowed the preservation of the original structure and ultrastructure. Five days after recellularization with HT29 and HCT116 cell lines, the 3D CRC model exhibited reduced sensitivity to 5FU treatments compared with conventional 2D cultures. Calculated the half maximal inhibitory concentration (IC50) for HT29 treated with 5FU resulted in 11.5 µM in 3D and 1.3 µM in 2D, and for HCT116, 9.87 µM in 3D and 1.7 µM in 2D. In xenograft experiments, HT29 extravasation was detected after 4 days post-injection, and we obtained a 5FU IC50 fully comparable to that observed in the 3D CRC model. Using confocal microscopy, we demonstrated that the drug diffused through the repopulated 3D CRC scaffolds and co-localized with the cell nuclei. The bioengineered CRC 3D model could be a reliable preclinical patient-specific platform to bridge the gap between in vitro and in vivo drug testing assays and provide effective cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Recellularized Colorectal Cancer Patient-Derived Scaffolds as In Vitro Pre-Clinical 3D Model for Drug Screening

Sensi

D’Angelo

Piccoli

et al. 2020

Cancers

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“…Blockade of MYL9 function is a critical factor for reducing the matrix-remodelling and invasion-promoting abilities of cancer-associated broblasts [34]. Tumorassociated broblasts promote the resistance of tumor cells to chemotherapy [35]. In addition, the high expression level of MYLK promotes the migration and invasion of gastric cancer cells [36].…”

Section: Discussionmentioning

confidence: 99%

Identification of Hub Genes to Control Cancer Stem cell Characteristics in Colon Adenocarcinoma Through Bioinformatics Analysis and Validation by Western Blotting

Liu

Zhang

Teng

et al. 2020

Preprint

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Background: Cancer stem cells (CSCs) are involved in the development of cancer. This study aimed to identify hallmark genes associated with the adjustment of CSC properties.Methods: The COAD data from The Cancer Genome Atlas(TCGA) database were assessed based on the mRNA stemness index (mRNAsi) and corrected mRNAsi. Then, both of them were analyzed with differentially expressed genes (DEGs). The gene modules were pinpointed through weighted gene co-expression network analysis (WGCNA). The genes of the most interest module were functionally annotated through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The Search Tool for the Retrieval of Interacting Genes (STRING) was adopted to obtain protein-protein interaction (PPI) networks, and the hub genes were identified in the light of the Molecular Complex Detection (MCODE) and Cytoscape plugin cytoHubba. Upstream genes were analyzed via the DisNor. In addition, the associations between clinical variables and hub genes were estimated. The bioinformatic results were verified based on Gene Expression Profling Integrative Analysis (GEPIA), Oncomine and Gene Expression Omnibus (GEO). Finally, the protein expression of the hub genes was verified by western blotting.Results: Both the corrected mRNAsi and mRNAsi increased within COAD tissues relative to those within normal colon tissues, which showed a significantly decreasing trend in COAD as the clinical stage. GO indicated the biological processes, including muscle cell differentiation, multicellular organismal signaling, muscle system process and muscle contraction. KEGG revealed Tight junction, Dilated cardiomyopathy (DCM), Vascular smooth muscle contraction, and the cGMP PKG signal transduction pathway. The seven hub genes (ACTA2, CALD1, LMOD1, MYL9, MYLK, TAGLN and TPM2) were identified in the brown module. Most of them were associated with clinical stage; MYL9, TAGLN and TPM2 were associated with overall survival. TGFB1, SRF, ROCK1 and PRKCA were the upstream genes through the DisNor. In the Oncomine, GEO and GEPIA databases, the expression of seven hub genes were down-regulated. In TCGA and GEPIA databases, the tendency of the seven hub genes was decreased with the advance in stage. Conclusions: The hub genes identified in the present study meight play a vital role in the preservation of COAD stem cells.

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“…a ) and decreased mitochondria apoptosis by inhibiting FBXW7 and MOAP1 through Wnt/beta‐catenin pathway (Table and Fig. b ) . Inhibiting CAF‐derived exosomal RNAs provides an alternative modality for the prediction and treatment of therapy resistance in cancer.…”

Section: Exosome and Tumor Developmentmentioning

confidence: 99%

“…1b). 15 Inhibiting CAF-derived exosomal RNAs provides an alternative modality for the prediction and treatment of therapy resistance in cancer.…”

Section: Therapy Resistancementioning

confidence: 99%

The cancer exosomes: Clinical implications, applications and challenges

Tang

Hou

et al. 2019

Intl Journal of Cancer

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The exosome is a small functional vesicle enriched in selected proteins, lipids and nucleic acids, displaying distinct molecular heterogeneity. Exosomes released can transform the extracellular matrix microenvironments, transmit signals and molecules to recipient cells and trigger changes in their pathophysiological functions. Tumor‐derived exosomes mediate the interactions of tumor cells and microenvironment significantly, and they stimulate tumor growth and development through specific signaling pathways related to metastasis, therapeutic resistance and immunosuppression. Exosome biogenesis from tumors often represents abundant biological information, and novel and efficient isolation and detection methods of exosomes provide a promising approach for tumor diagnosis and prognosis estimation. Moreover, exosome can even be developed as therapeutic agents for multiple disease models based on effective material transport characteristics and biofilm specificity. This review reports the clinical implications and challenges of exosomes in cancer progression, therapy resistance, metastasis and immune escape, and underlying cancerogenic pathological phenotypes including fibrosis and viral infection.

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CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer

Cited by 556 publications

References 40 publications

Recellularized Colorectal Cancer Patient-Derived Scaffolds as In Vitro Pre-Clinical 3D Model for Drug Screening

Recellularized Colorectal Cancer Patient-Derived Scaffolds as In Vitro Pre-Clinical 3D Model for Drug Screening

Identification of Hub Genes to Control Cancer Stem cell Characteristics in Colon Adenocarcinoma Through Bioinformatics Analysis and Validation by Western Blotting

The cancer exosomes: Clinical implications, applications and challenges

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