Exosomal Sonic Hedgehog derived from cancer‐associated fibroblasts promotes proliferation and migration of esophageal squamous cell carcinoma

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most common and aggressive malignancies in China. Cancer‐associated fibroblasts (CAFs) can actively communicate with and stimulate tumor cells, thereby contributing to the development and progression of tumors. Yet, whether CAFs‐derived exosomes have a role in the progression of ESCC is largely unknown. Here, we find that Sonic Hedgehog (SHH) is highly expressed in CAFs lysis solution, conditioned medium of cultured CAFs (CAF‐CM) and CAFs‐derived exosomes, and esophageal cancer cell lines educated by CAF‐CM and CAFs‐derived exosomes can improve their growth and migration abilities in vitro and in vivo. Besides, those effects can be partly neutralized by cyclopamine, inhibitor of the Hedgehog signaling pathway. Thus, our research elucidates the crucial role of CAFs‐derived exosomes in the growth and progression of ESCC, and may open up new avenues in the treatment of ESCC.

The Role of Cancer-Associated Fibroblasts in Tumor Progression

“…Additional CAF effects in colorectal cancers include maintenance of cancer cell stemness, as described by Liu et al when CAF-conditioned media was observed to promote clonogenicity of colorectal cancer cells, which in turn conferred radioresistance through CAF-derived exosomes [ 91 , 92 ]. When exploring esophageal cancers, Zhao et al demonstrated that CAFs expressing α-SMA enhanced progression of esophageal squamous cell carcinomas by promoting Shh expression, and notably this effect was partially reversible in vitro and in vivo by using cyclopamine to inhibit the Hedgehog signaling pathway [ 50 ].…”

The Significance of Exosomal RNAs in the Development, Diagnosis, and Treatment of Gastric Cancer

“…As referred to above, exosomes contain an array of proteins, lipids, DNAs, mRNAs, and ncRNAs, and the exchange of exosomes among cells plays important roles in many aspects of human health and disease. The study of exosomes’ roles in cancer has progressed at a rapid pace, and exosomes have been implicated in several hallmark features of cancers, such as tumorigenesis, tumor growth, epithelial mesenchymal transition (EMT), metastasis, angiogenesis, immune escape, and drug resistance [ 36 , 37 , 38 , 39 , 40 , 41 ]. In GC, accumulated studies have assessed the efficacy of exosomal contents in the initiation and development of GC.…”

The Role of Cancer-Associated Fibroblasts and Extracellular Vesicles in Tumorigenesis

“…Numerous studies have investigated the role of CAF-derived EVs and the influence of their contents on recipient cancer cells. The influence of specific CAF-derived EV cargo on cancer cells has been described in a wide range of cancers (Table 2) [12,13,[78][79][80][81][82][83][84][85][86][87][88][89][90][140][141][142][143][144][145][146][147][148][149][150][151][152][153][154][155][156]. The ability of CAF-derived EVs to promote tumorigenic effects in recipient cancer cells has been linked to proteins and non-coding RNAs, including miRNAs and lncRNAs.…”

“…Several studies have observed that the protein contents of CAF-derived EVs are able to induce changes in recipient cancer cells, including increased migration, invasion, EMT, and metastasis [13,80,84,87,90,140,141,145,146,149,151,153]. Specific protein cargo has been shown to stimulate pro-tumor activity but can also regulate the uptake of CAF-derived EVs by recipient cancer cells.…”