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

Xu,Zhengli; Zheng,Xing; Zheng,Jianming

doi:10.3892/ol.2019.10740

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

Authors:
- Zhengli Xu
- Xing Zheng
- Jianming Zheng
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Affiliations: Department of Stomatology, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China, Department of Stomatology, The Third Affiliated Hospital of Naval Medical University, Shanghai 200438, P.R. China, Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China
Published online on: August 14, 2019 https://doi.org/10.3892/ol.2019.10740
Pages: 4082-4091
Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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1	Venteicher AS, Walcott BP, Sheth SA, Snuderl M, Patel AP, Curry WT and Nahed BV: Clinical features of brain metastasis from salivary gland tumors. J Clin Neurosci. 20:1533–1537. 2013. View Article : Google Scholar : PubMed/NCBI
2	Ellington CL, Goodman M, Kono SA, Grist W, Wadsworth T, Chen AY, Owonikoko T, Ramalingam S, Shin DM, Khuri FR, et al: Adenoid cystic carcinoma of the head and neck: Incidence and survival trends based on 1973–2007 Surveillance, Epidemiology and End Results data. Cancer. 118:4444–4451. 2012. View Article : Google Scholar : PubMed/NCBI
3	Ho AS, Kannan K, Roy DM, Morris LG, Ganly I, Katabi N, Ramaswami D, Walsh LA, Eng S, Huse JT, et al: The mutational landscape of adenoid cystic carcinoma. Nat Genet. 45:791–798. 2013. View Article : Google Scholar : PubMed/NCBI
4	Shiga K, Hara M, Nagasaki T, Sato T, Takahashi H and Takeyama H: Cancer-associated fibroblasts: Their characteristics and their roles in tumor growth. Cancers. 7:2443–2458. 2015. View Article : Google Scholar : PubMed/NCBI
5	Madar S, Goldstein I and Rotter V: ‘Cancer associated fibroblasts’-more than meets the eye. Trends Mol Med. 19:447–453. 2013. View Article : Google Scholar : PubMed/NCBI
6	Liotta LA and Kohn EC: The microenvironment of the tumour-host interface. Nature. 411:375–379. 2001. View Article : Google Scholar : PubMed/NCBI
7	Xing F, Saidou J and Watabe K: Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front Biosci (Landmark Ed). 15:166–179. 2010. View Article : Google Scholar : PubMed/NCBI
8	Che Y, Geng B, Xu Y, Miao X, Chen L, Mu X, Pan J, Zhang C, Zhao T, Wang C, et al: Helicobacter pylori-induced exosomal MET educates tumour-associated macrophages to promote gastric cancer progression. J Cell Mol Med. 22:5708–5719. 2018. View Article : Google Scholar : PubMed/NCBI
9	Zhang H, Deng T, Liu R, Bai M, Zhou L, Wang X, Li S, Wang X, Yang H, Li J, et al: Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis. Nat Commu. 8:150162017. View Article : Google Scholar
10	Ringuette Goulet C, Bernard G, Tremblay S, Chabaud S, Bolduc S and Pouliot F: Exosomes induce fibroblast differentiation into cancer-associated fibroblasts through TGFβ signaling. Mol Cancer Res. 16:1196–1204. 2018. View Article : Google Scholar : PubMed/NCBI
11	Théry C, Amigorena S, Raposo G and Clayton A: Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol Chapter. 3:Unit 3.22. 2006.
12	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
13	Andreu Z and Yáñez-Mó M: Tetraspanins in extracellular vesicle formation and function. Front Immunol. 5:4422014. View Article : Google Scholar : PubMed/NCBI
14	Ruivo CF, Adem B, Silva M and Melo SA: The biology of cancer exosomes: Insights and new perspectives. Cancer Res. 77:6480–6488. 2017. View Article : Google Scholar : PubMed/NCBI
15	Deryugina EI and Quigley JP: Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 25:9–34. 2006. View Article : Google Scholar : PubMed/NCBI
16	Hao L, Xiao-Lin N, Qi C, Yi-Ping Y, Jia-Quan L and Yan-Ning L: Nerve growth factor and vascular endothelial growth factor: Retrospective analysis of 63 patients with salivary adenoid cystic carcinoma. Int J Oral Sci. 2:35–44. 2010. View Article : Google Scholar : PubMed/NCBI
17	Wang L, Sun M, Jiang Y, Yang L, Lei D, Lu C, Zhao Y, Zhang P, Yang Y and Li J: Nerve growth factor and tyrosine kinase A in human salivary adenoid cystic carcinoma: Expression patterns and effects on in vitro invasive behavior. J Oral Maxillofac Surg. 64:636–641. 2006. View Article : Google Scholar : PubMed/NCBI
18	Kobayashi K, Ando M, Saito Y, Kondo K, Omura G, Shinozaki-Ushiku A, Fukayama M, Asakage T and Yamasoba T: Nerve growth factor signals as possible pathogenic biomarkers for perineural invasion in adenoid cystic carcinoma. Otolaryngol Head Neck Surg. 153:218–224. 2015. View Article : Google Scholar : PubMed/NCBI
19	Frierson HF Jr, El-Naggar AK, Welsh JB, Sapinoso LM, Su AI, Cheng J, Saku T, Moskaluk CA and Hampton GM: Large scale molecular analysis identifies genes with altered expression in salivary adenoid cystic carcinoma. Am J Pathol. 161:1315–1323. 2002. View Article : Google Scholar : PubMed/NCBI
20	Bakst RL and Wong RJ: Mechanisms of perineural invasion. J Neurol Surg B Skull Base. 77:96–106. 2016. View Article : Google Scholar : PubMed/NCBI
21	Kalluri R and Zeisberg M: Fibroblasts in cancer. Nat Rev Cancer. 6:392–401. 2006. View Article : Google Scholar : PubMed/NCBI
22	Bhowmick NA, Neilson EG and Moses HL: Stromal fibroblasts in cancer initiation and progression. Nature. 432:332–337. 2004. View Article : Google Scholar : PubMed/NCBI
23	Richards KE, Zeleniak AE, Fishel ML, Wu J, Littlepage LE and Hill R: Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene. 36:1770–1778. 2017. View Article : Google Scholar : PubMed/NCBI
24	Li YY, Tao YW, Gao S, Li P, Zheng JM, Zhang SE, Liang J and Zhang Y: Cancer-associated fibroblasts contribute to oral cancer cells proliferation and metastasis via exosome-mediated paracrine miR-34a-5p. EBioMedicine. 36:209–220. 2018. View Article : Google Scholar : PubMed/NCBI
25	Colotta F, Allavena P, Sica A, Garlanda C and Mantovani A: Cancer-related inflammation, the seventh hallmark of cancer: Links to genetic instability. Carcinogenesis. 30:1073–1081. 2009. View Article : Google Scholar : PubMed/NCBI
26	Voronov E, Shouval DS, Krelin Y, Cagnano E, Benharroch D, Iwakura Y, Dinarello CA and Apte RN: IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci USA. 100:2645–2650. 2003. View Article : Google Scholar : PubMed/NCBI
27	Apte RN, Dotan S, Elkabets M, White MR, Reich E, Carmi Y, Song X, Dvozkin T, Krelin Y and Voronov E: The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions. Cancer Metastasis Rev. 25:387–408. 2006. View Article : Google Scholar : PubMed/NCBI
28	Chow MT and Luster AD: Chemokines in cancer. Cancer Immunol Res. 2:1125–1131. 2014. View Article : Google Scholar : PubMed/NCBI
29	He S, He S, Chen CH, Deborde S, Bakst RL, Chernichenko N, McNamara WF, Lee SY, Barajas F, Yu Z, et al: The chemokine (CCL2-CCR2) signaling axis mediates perineural invasion. Mol Cancer Res. 13:380–390. 2015. View Article : Google Scholar : PubMed/NCBI
30	Muller A, Sonkoly E, Eulert C, Gerber PA, Kubitza R, Schirlau K, Franken-Kunkel P, Poremba C, Snyderman C, Klotz LO, et al: Chemokine receptors in head and neck cancer: Association with metastatic spread and regulation during chemotherapy. Int J Cancer. 118:2147–2157. 2006. View Article : Google Scholar : PubMed/NCBI
31	Zhu Z, Friess H, diMola FF, Zimmermann A, Graber HU, Korc M and Buchler MW: Nerve growth factor expression correlates with perineural invasion and pain in human pancreatic cancer. J Clin Oncol. 17:2419–2428. 1999. View Article : Google Scholar : PubMed/NCBI
32	Kolokythas A, Cox DP, Dekker N and Schmidt BL: Nerve growth factor and tyrosine kinase A receptor in oral squamous cell carcinoma: Is there an association with perineural invasion? J Oral Maxillofac Surg. 68:1290–1295. 2010. View Article : Google Scholar : PubMed/NCBI
33	Zheng P, Chen L, Yuan X, Luo Q, Liu Y, Xie G, Ma Y and Shen L: Exosomal transfer of tumor-associated macrophage-derived miR-21 confers cisplatin resistance in gastric cancer cells. J Exp Clin Cancer Res. 36:532017. View Article : Google Scholar : PubMed/NCBI