Tumor‑derived exosomes educate fibroblasts to promote salivary adenoid cystic carcinoma metastasis via NGF‑NTRK1 pathway

Abstract

Salivary adenoid cystic carcinoma (SACC) is a rare head and neck malignancy characterized by unpredictable expansion, considerable perineural invasion and high risk of metastasis; however, the underlying mechanism of SACC progression remains unclear. Cancer-associated fibroblasts localized within the tumor microenvironment may promote cancer malignant transformation by enhancing tumor growth, blood vessel formation, inflammation development and metastasis occurrence. Small extracellular vesicles, including exosomes, are mediators of intercellular communication and can influence major tumor-associated pathways. The present study aimed to explore the exosome-mediated communication between SACC cells and fibroblasts. The results from confocal microscopy demonstrated that exosomes derived from the human cell line SACC-83 were internalized by the human periodontal ligament fibroblast (HPLF) cells. Following exosome internalization, HPLF cells appeared to enhance SACC-83 cell metastasis and were educated toward a protumorigenesis phenotype according to transcriptome RNA sequencing and reverse transcription-quantitative polymerase chain reaction analysis. This phenomenon included exosome-mediated stimulation of proinflammatory cytokines and nerve growth factor (NGF) secretion. Furthermore, NGF blockage reduced the enhanced SACC-83 cell invasion stimulated by the supernatant isolated from exosome-educated HPLF cells. In addition, the results reported that neurotrophic receptor tyrosine kinase 1 (NTRK1), which is the high-affinity NGF receptor, was significantly upregulated in human SACC-83 cells. These results demonstrated that SACC-83 cell-derived exosomes educated HPLF cells toward the protumorigenic phenotype via the NGF-NTRK1 pathway, which suggested that this type of exosomes may be used as a potential therapeutic target for SACC.

Genome-wide analysis identifies critical DNA methylations within NTRKs genes in colorectal cancer

“…Similar to gene fusion, the aberrant expression of NTRKs gene is a critical event in cancers. NTRK1 promoted proliferation and metastasis of cancer cells and lead to poor prognosis in multiple cancers [14][15][16][17][18], while it suppressed cell proliferation in neuroblastoma [19]. NTRK2 was shown to serve as an oncogene in multiple cancers [20][21][22][23], and its increased expression was associated with poor outcome [24,25].…”

Extracellular vesicle-orchestrated crosstalk between cancer-associated fibroblasts and tumors

“…performed transcriptome RNA sequencing and reverse transcriptome quantitative polymerase chain reaction analysis on human periodontal ligament fibroblasts (HPLFs) that had ingested salivary adenoid cystic carcinoma cell-derived EVs, and the results confirmed that HPLFs were cultured as a pre-tumorigenetic phenotype [33] . This phenomenon is associated with EV-mediated stimulation of proinflammatory cytokines and secretion of nerve growth factor (NGF) [33] . In addition, secretion analysis of EVs collected from Hodgkin's lymphoma (HL) cells revealed enhanced release of pro-inflammatory cytokines (such as IL-1α, IL-6, and TNF-α), growth factors (G-CSF and GM-CSF), and pro-angiogenic factors (such as VEGF) [34] .…”

“…Xu et al. performed transcriptome RNA sequencing and reverse transcriptome quantitative polymerase chain reaction analysis on human periodontal ligament fibroblasts (HPLFs) that had ingested salivary adenoid cystic carcinoma cell-derived EVs, and the results confirmed that HPLFs were cultured as a pre-tumorigenetic phenotype [33] . This phenomenon is associated with EV-mediated stimulation of proinflammatory cytokines and secretion of nerve growth factor (NGF) [33] .…”

Tumor-Derived Extracellular Vesicles: Modulation of Cellular Functional Dynamics in Tumor Microenvironment and Its Clinical Implications

“…Moreover, exosomes carrying miR-122 released by breast cancer cells reduced glucose uptake by normal recipient cells in pre-metastatic niche, increasing nutrient supply for metastatic cells Fong et al, 2015 ). Then, the metastatic effect by TEVs can also be mediated by their effect in stromal cells like fibroblasts ( Fang et al, 2018 ; Xu et al, 2019 ); macrophages ( Liang et al, 2019 ; Zhao et al, 2020 ) and in bone stroma ( Dai et al, 2019 ) at long distances ( Figure 1B ).…”