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

Cancer Med. 2020 Apr;9(7):2500-2513. doi: 10.1002/cam4.2873. Epub 2020 Feb 7.

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.

Keywords: Sonic Hedgehog; cancer-associated fibroblasts; esophageal squamous cell carcinoma; exosomes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Cancer-Associated Fibroblasts / metabolism
  • Cancer-Associated Fibroblasts / pathology*
  • Cell Movement*
  • Cell Proliferation*
  • Esophageal Neoplasms / genetics
  • Esophageal Neoplasms / metabolism
  • Esophageal Neoplasms / pathology
  • Esophageal Squamous Cell Carcinoma / genetics
  • Esophageal Squamous Cell Carcinoma / metabolism
  • Esophageal Squamous Cell Carcinoma / pathology*
  • Exosomes / genetics
  • Exosomes / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Signal Transduction
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • Hedgehog Proteins
  • SHH protein, human