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Exosomal Wnt-induced dedifferentiation of colorectal cancer cells contributes to chemotherapy resistance.

ABSTRACT: Cancer stem cells (CSCs) are inherently resistant to chemotherapy, and CSCs in chemotherapy-failed recurrent tumors are enriched; however, the cellular origin of chemotherapy-induced CSC enrichment remains unclear. Communication with stromal fibroblasts may induce cancer cell dedifferentiation into CSCs through secreted factors. We recently demonstrated that fibroblast-derived exosomes promote chemoresistance in colorectal cancer (CRC). Here, we report that fibroblasts confer CRC chemoresistance via exosome-induced reprogramming (dedifferentiation) of bulk CRC cells to phenotypic and functional CSCs. At the molecular level, we provided evidence that the major reprogramming regulators in fibroblast-exosomes are Wnts. Exosomal Wnts were found to increase Wnt activity and drug resistance in differentiated CRC cells, and inhibiting Wnt release diminished this effect in vitro and in vivo. Together, our results indicate that exosomal Wnts derived from fibroblasts could induce the dedifferentiation of cancer cells to promote chemoresistance in CRC, and suggest that interfering with exosomal Wnt signaling may help to improve chemosensitivity and the therapeutic window.

SUBMITTER: Hu YB

PROVIDER: S-EPMC6756234 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Exosomal Wnt-induced dedifferentiation of colorectal cancer cells contributes to chemotherapy resistance.

Hu Y-B YB Yan C C Mu L L Mi Y-L YL Zhao H H Hu H H Li X-L XL Tao D-D DD Wu Y-Q YQ Gong J-P JP Qin J-C JC

Oncogene 20181102 11

Cancer stem cells (CSCs) are inherently resistant to chemotherapy, and CSCs in chemotherapy-failed recurrent tumors are enriched; however, the cellular origin of chemotherapy-induced CSC enrichment remains unclear. Communication with stromal fibroblasts may induce cancer cell dedifferentiation into CSCs through secreted factors. We recently demonstrated that fibroblast-derived exosomes promote chemoresistance in colorectal cancer (CRC). Here, we report that fibroblasts confer CRC chemoresistance ...[more]

PMID: 30390075

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Project description:Liquid biomarkers for the early detection of resistance to chemotherapy are important for improving prognosis. This study investigated the usefulness of plasma exosomal microRNA-125b (ex-miRNA-125b) for the early detection of resistance to modified fluorouracil, leucovorin and oxaliplatin (mFOLFOX6)-based first-line chemotherapy in patients with advanced or recurrent (advanced/recurrent) colorectal cancer (CRC). First, ex-miRNAs associated with resistance to mFOLFOX6-based chemotherapy were profiled via miRNA microarray analysis. In this analysis, ex-miR-125b exhibited the greatest upregulation in patients with progressive disease (PD) compared with the findings for patients with stable disease (SD) and healthy controls. Next, another 55 patients with advanced/recurrent CRC who received mFOLFOX6-based first-line chemotherapy underwent a validation study of ex-miR-125b. Blood samples were collected before and during treatment until tumor progression. Ex-miRNA levels were measured via TaqMan microRNA assays. Patients with CRC had significantly higher ex-miR-125b levels than healthy controls. In patients with partial responses, ex-miR-125b levels at the Response Evaluation Criteria in Solid Tumors (RECIST) judgment point were significantly lower than those measured before treatment. In patients with SD, ex-miR-125b levels did not differ before and during treatment. In patients with PD, ex-miR-125b levels at the RECIST judgment point were significantly higher than those measured before treatment. These changes in ex-miR-125b levels were significantly different between groups even 1 month after the initiation of chemotherapy. Progression-free survival (PFS) was significantly worse in patients with high baseline ex-miR-125b levels than in those with low levels. In the Cox analysis, baseline ex-miR-125b levels and KRAS mutation were indicated to be independent prognostic factors for PFS. The present results suggest that plasma ex-miR-125b levels may be useful for the early detection of resistance to mFOLFOX6-based first-line chemotherapy. Furthermore, ex-miR-125b before chemotherapy is a predictive biomarker for PFS in patients with advanced/recurrent CRC.

Project description:BACKGROUND: We have determined that butyrate, which is derived from the fermentation of dietary fiber in the colonic lumen, hyperactivates Wnt activity in colorectal (CRC) cells, and that this upregulation of Wnt signaling is causatively related to the induction of apoptosis. To better understand the genetic program regulated by butyrate-mediated Wnt hyperactivation, we performed total human genome microarray analyses on HCT-116 CRC cells in the presence or absence of a physiologically relevant concentration of butyrate. To evaluate changes in Wnt-specific gene expression, Wnt activity was suppressed with inducible dominant negative Tcf4 (DN-Tcf4). Six biological replicates of a full human genome microarray were performed, and the data deposited into the Gene Expression Omnibus database, according to Minimum Information About A Microarray Experiment standards. RESULTS: Reporter assay and western blot data confirm that DN-Tcf4 is expressed at high levels in stably transfected HCT-116 cells upon cotreatment with doxycycline and butyrate, and that these cells exhibit a marked repression of butyrate-mediated Wnt hyperactivation. Analysis of six biological replicates of microarray analyses indicated that 1008 genes are modulated by butyrate (>two-fold, P?<?0.01) in a Wnt signaling-specific manner, while 1587 genes are similarly modulated at P?<?0.05. The modulated genes include members of a variety of gene families; including the Biological Process category, such as regulation of development, regulation of metabolism, cytokine and chemokine mediated signaling pathways, and DNA replication; the Cellular Component category such as cytoskeleton and organelle factors, and intermediate filaments; and the Molecular Function category, such as GTPase activator activity. CONCLUSIONS: We have identified, for the first time, in CRC cells, the total array of direct and indirect Wnt-target genes whose expression is modulated by butyrate. Knowledge of the molecular mechanisms determining the response of CRC cells to butyrate in vitro may assist in determining more effective preventive and therapeutic strategies against CRC.

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Exosomal Wnt-induced dedifferentiation of colorectal cancer cells contributes to chemotherapy resistance.

Publications

Exosomal Wnt-induced dedifferentiation of colorectal cancer cells contributes to chemotherapy resistance.

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