Tumor-secreted exosomal Wnt2B activates fibroblasts to promote cervical cancer progression

Luo-Jiao Liang,Rui-Ming Yan,Sha Wu,Wei Wang,Yang Yang,Wen-Fei Wei,Liang-Sheng Fan,Xiang-Guang Wu,Chen-Fei Zhou,Xiao-Jing Chen

doi:10.1038/s41389-021-00319-w

Abstract

The activation of stromal fibroblasts into cancer-associated fibroblasts (CAFs) has been suggested to promote primary tumor growth and progression; however, the mechanisms underlying the crosstalk between tumors and fibroblasts that drives stromal heterogeneity remain unknown. Here, we show that high Wnt2B levels were positively correlated with the number of CAFs in cervical cancer (CC). More importantly, Wnt2B was characteristically enriched in CC cell-secreted exosomes and transferred into fibroblasts to promote fibroblast activation via Wnt/β-catenin signaling, and inhibiting exosomal release or the Wnt/β-catenin signaling pathway diminished the activation induced by exosomal Wnt2B. Moreover, circulating exosomal Wnt2B also promoted CAF conversion in vitro and its expression was significantly higher in CC patients. In conclusion, our findings indicate that CC cell-derived Wnt2B can induce the activation of fibroblasts into CAFs, mainly via exosome-dependent secretion, thus providing directions for the development of diagnostic and therapeutic targets for CC progression.

Highlights

It has recently been suggested that cancer progression is the result of evolving crosstalk between different cell types within the tumor microenvironment (TME)[1]
Since Wnt2B expression gradually increased during cervical carcinogenesis and was positively correlated with highrisk HPV infection, but not significantly associated with age (Fig. 1B–D and Table S1), we further investigated the relationship between Wnt2B expression and cancer-associated fibroblasts (CAFs) density
TME is a dynamic system orchestrated by intercellular crosstalk that is responsible for tumor progression[3]

Summary

Introduction

It has recently been suggested that cancer progression is the result of evolving crosstalk between different cell types within the tumor microenvironment (TME)[1]. Activated fibroblasts, which are characterized by α-smooth muscle actin (α-SMA) expression[4,5], are transiently present during normal wound healing[6,7] but persistently present in tumor tissues, where they are known as cancer-associated fibroblasts (CAFs)[8,9]. In addition to their lack of physiological role in homeostasis, extensive evidence suggests that CAFs are involved in stimulating cancer cell proliferation and progression[8,10], confirming the biological and clinical significance of CAFs in the TME. The mechanisms via which normal fibroblasts (NFs) are transformed into CAFs by cancer cells remain largely unclear in CC

Methods

Results

Conclusion