FAP positive cancer‐associated fibroblasts promote tumor progression and radioresistance in esophageal squamous cell carcinoma by transferring exosomal lncRNA AFAP1‐AS1

Jun 27, 2024Molecular carcinogenesis

Fibroblasts with FAP help esophageal cancer grow and resist radiation by sending lncRNA AFAP1-AS1 in tiny packages

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Abstract

FAP expression in stromal cancer-associated fibroblasts was positively correlated with poor survival among 174 esophageal squamous cell carcinoma patients.

High FAP expression in cancer-associated fibroblasts is associated with nerve invasion, vascular invasion, depth of invasion, lymph node metastasis, and lack of clinical complete response.
Culturing esophageal squamous cell carcinoma cells with conditioned medium from FAP-positive cancer-associated fibroblasts significantly increased cancer cell proliferation, migration, invasion, and radioresistance compared to FAP-negative fibroblasts.
FAP-positive cancer-associated fibroblasts transfer the lncRNA AFAP1-AS1 to esophageal squamous cell carcinoma cells via exosomes.
AFAP1-AS1 has been shown to promote radioresistance by enhancing DNA damage repair in esophageal squamous cell carcinoma cells.
Clinically, elevated plasma levels of AFAP1-AS1 correlate with poor responses to definitive chemoradiotherapy in esophageal squamous cell carcinoma patients.

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Cancer-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in the tumor microenvironment, which play important roles in regulating tumor progression and therapy resistance by transferring exosomes to cancer cells. However, how CAFs modulate esophageal squamous cell carcinoma (ESCC) progression and radioresistance remains incompletely understood. The expression of fibroblast activation protein (FAP) in CAFs was evaluated by immunohistochemistry in 174 ESCC patients who underwent surgery and 78 pretreatment biopsy specimens of ESCC patients who underwent definitive chemoradiotherapy. We sorted CAFs according to FAP expression, and the conditioned medium (CM) was collected to culture ESCC cells. The expression levels of several lncRNAs that were considered to regulate ESCC progression and/or radioresistance were measured in exosomes derived from FAPCAFs and FAPCAFs. Subsequently, cell counting kit-8, 5-ethynyl-2'-deoxyuridine, transwell, colony formation, and xenograft assays were performed to investigate the functional differences between FAPCAFs and FAPCAFs. Finally, a series of in vitro and in vivo assays were used to evaluate the effect of AFAP1-AS1 on radiosensitivity of ESCC cells. FAP expression in stromal CAFs was positively correlated with nerve invasion, vascular invasion, depth of invasion, lymph node metastasis, lack of clinical complete response and poor survival. Culture of ESCC cells with CM/FAPCAFs significantly increased cancer proliferation, migration, invasion and radioresistance, compared with culture with CM/FAPCAFs. Importantly, FAPCAFs exert their roles by directly transferring the functional lncRNA AFAP1-AS1 to ESCC cells via exosomes. Functional studies showed that AFAP1-AS1 promoted radioresistance by enhancing DNA damage repair in ESCC cells. Clinically, high levels of plasma AFAP1-AS1 correlated with poor responses to dCRT in ESCC patients. Our findings demonstrated that FAPCAFs promoted radioresistance in ESCC cells through transferring exosomal lncRNA AFAP1-AS1; and may be a potential therapeutic target for ESCC treatment. + -+ -+ -+ +

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FAP positive cancer‐associated fibroblasts promote tumor progression and radioresistance in esophageal squamous cell carcinoma by transferring exosomal lncRNA AFAP1‐AS1

Abstract

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