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Full Length Article | Open Access

Peritoneal adipose stem cell-derived extracellular vesicles mediate the regulation of ovarian cancer cell proliferation and migration through EGFR-NF-κB signaling

Lian Wanga,b,c,1(), Ning Luoa,1, Jihui Zhua, Zubaidan Sulaimana, Wenhan Yangb,c,d, Ke Hub,c,d, Guihai Aia, Weihong Yanga, Xiaowen Shaoa, Shengkai Jinb,c,d, Xue Zhange,f, Yantao Fanb, Dan Denge,f(), Zhongping Chenga(), Zhengliang Gaob,c,d,g()
Department of Gynecology and Obstetrics, Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
Department of Anesthesiology, Shanghai Gongli Hospital, Naval Military Medical University, Shanghai 200135, China
Shanghai Engineering Research Center of Organ Repair, Shanghai University School of Medicine, Shanghai 200444, China
Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), Shanghai University School of Medicine, Nantong, Jiangsu 216002, China
Department of Dermatology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
China-Japan Friendship Medical Research Institute, School of Medicine, Shanghai University, Shanghai 200444, China

Peer review under responsibility of Chongqing Medical University.

1 These authors contributed equally to this work.

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Abstract

Peritoneal dissemination frequently develops in patients with ovarian cancer (OC) and is associated with recurrence and metastasis. However, the cellular components and mechanisms supporting OC peritoneal metastasis are poorly understood. To elucidate these, we utilized RNA sequencing to investigate the cellular composition and function. Insights from transcriptome analyses suggested that OC cells from malignant ascites persisted in a quiescent state of low metabolic activity and after metastases to the peritoneum, arrested OC cells were reactivated and induced back to the cell cycle, suggesting that the peritoneum served as a favor tumor microenvironment. To elucidate the mechanisms, we then developed long-range migration and competitive inhibition assays and showed that peritoneal adipose-derived stem cells-derived extracellular vesicles (ADSCs-EVs) mediated preferential migration of OC cells toward peritoneal ADSCs but not other representative cells from the peritoneal cavity. In line with phenotypic changes, transcriptomic analysis revealed that patient peritoneal ADSCs-EVs stimulated the expression of numerous genes associated with OC cell proliferation and migration; among them, the epidermal growth factor receptor (EGFR) and nuclear factor kappa B (NF-κB) signaling pathways were highly enriched. We also found that peritoneal ADSCs produced and secreted key EGFR signaling molecules, including EGF and EGFR, into ADSCs-EVs. Upon fusion with OC cells, ADSCs-EVs up-regulated the EGFR-NF-κB axis and promoted OC cell proliferation and migration. Interference with either ADSCs-EVs production or EGFR signaling abolished the proliferation and migration effect. The results show that ADSCs modulate OC cell proliferation and migration at multiple layers, constituting a key mechanism in OC progression.

Keywords

Adipose-derived stem cellsEGFR/NK-κB axisExtracellular vesiclesMetastasisOvarian cancer

References

1

Yousefi M, Dehghani S, Nosrati R, et al. Current insights into the metastasis of epithelial ovarian cancer - Hopes and hurdles. Cell Oncol. 2020;43(4):515-538.

Crossref Google Scholar
2

Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1(6):417-425.

Crossref Google Scholar
3

Terraneo N, Jacob F, Dubrovska A, Grünberg J. Novel therapeutic strategies for ovarian cancer stem cells. Front Oncol. 2020;10:319.

Crossref Google Scholar
4

Chekerov R, Hilpert F, Mahner S, et al. Sorafenib plus topotecan versus placebo plus topotecan for platinum-resistant ovarian cancer (TRIAS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2018;19(9):1247-1258.

Crossref Google Scholar
5

Wang SE. Extracellular vesicles and metastasis. Cold Spring Harb Perspect Med. 2020;10(7):a037275.

Crossref Google Scholar
6

Yoshihara M, Iyoshi S, Mogi K, et al. Ovarian cancer: novel mechanisms and therapeutic targets regarding the microenvironment in the abdominal cavity. J Obstet Gynaecol Res. 2023;49(11):2620-2628.

Crossref Google Scholar
7

Chu Y, You M, Zhang J, et al. Adipose-derived mesenchymal stem cells enhance ovarian cancer growth and metastasis by increasing thymosin beta 4X-linked expression. Stem Cell Int. 2019;2019:9037197.

Google Scholar
8

Tang H, Chu Y, Huang Z, Cai J, Wang Z. The metastatic phenotype shift toward myofibroblast of adipose-derived mesenchymal stem cells promotes ovarian cancer progression. Carcinogenesis. 2020;41(2):182-193.

Crossref Google Scholar
9

Landen CN Jr, Birrer MJ, Sood AK. Early events in the pathogenesis of epithelial ovarian cancer. J Clin Oncol. 2008;26(6):995-1005.

Crossref Google Scholar
10

Rosen ED, Spiegelman BM. What we talk about when we talk about fat. Cell. 2014;156(1–2):20-44.

Google Scholar
11

Motohara T, Masuda K, Morotti M, et al. An evolving story of the metastatic voyage of ovarian cancer cells: cellular and molecular orchestration of the adipose-rich metastatic microenvironment. Oncogene. 2019;38(16):2885-2898.

Crossref Google Scholar
12

Nieman KM, Kenny HA, Penicka CV, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. 2011;17(11):1498-1503.

Crossref Google Scholar
13

Ladanyi A, Mukherjee A, Kenny HA, et al. Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. Oncogene. 2018;37(17):2285-2301.

Crossref Google Scholar
14

Sabol RA, Giacomelli P, Beighley A, Bunnell BA. Adipose stem cells and cancer: concise review. Stem Cell. 2019;37(10):1261-1266.

Crossref Google Scholar
15

Strong AL, Ohlstein JF, Biagas BA, et al. Leptin produced by obese adipose stromal/stem cells enhances proliferation and metastasis of estrogen receptor positive breast cancers. Breast Cancer Res. 2015;17(1):112.

Crossref Google Scholar
16

Sabol RA, Bowles AC, Côté A, et al. Leptin produced by obesity-altered adipose stem cells promotes metastasis but not tumorigenesis of triple-negative breast cancer in orthotopic xenograft and patient-derived xenograft models. Breast Cancer Res. 2019;21(1):67.

Crossref Google Scholar
17

Strong AL, Semon JA, Strong TA, et al. Obesity-associated dysregulation of calpastatin and MMP-15 in adipose-derived stromal cells results in their enhanced invasion. Stem Cell. 2012;30(12):2774-2783.

Crossref Google Scholar
18

Reggiani F, Labanca V, Mancuso P, et al. Adipose progenitor cell secretion of GM-CSF and MMP9 promotes a stromal and immunological microenvironment that supports breast cancer progression. Cancer Res. 2017;77(18):5169-5182.

Crossref Google Scholar
19

Kilroy GE, Foster SJ, Wu X, et al. Cytokine profile of human adipose-derived stem cells: expression of angiogenic, hematopoietic, and pro-inflammatory factors. J Cell Physiol. 2007;212(3):702-709.

Crossref Google Scholar
20

Lyes MA, Payne S, Ferrell P, Pizzo SV, Hollenbeck ST, Bachelder RE. Adipose stem cell crosstalk with chemo-residual breast cancer cells: implications for tumor recurrence. Breast Cancer Res Treat. 2019;174(2):413-422.

Crossref Google Scholar
21

Wang Y, Liu J, Jiang Q, et al. Human adipose-derived mesenchymal stem cell-secreted CXCL1 and CXCL8 facilitate breast tumor growth by promoting angiogenesis. Stem Cell. 2017;35(9):2060-2070.

Crossref Google Scholar
22

Robado de Lope L, Alcíbar OL, Amor López A, Hergueta-Redondo M, Peinado H. Tumour-adipose tissue crosstalk: fuelling tumour metastasis by extracellular vesicles. Philos Trans R Soc Lond B Biol Sci. 2018;373(1737):20160485.

Crossref Google Scholar
23

Wang L, Jin S, Dai P, et al. p57Kip2 is a master regulator of human adipose derived stem cell quiescence and senescence. Stem Cell Res. 2020;44:101759.

Crossref Google Scholar
24

Bunnell BA, Flaat M, Gagliardi C, Patel B, Ripoll C. Adipose-derived stem cells: isolation, expansion and differentiation. Methods. 2008;45(2):115-120.

Crossref Google Scholar
25

Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-317.

Crossref Google Scholar
26

Cvjetkovic A, Lötvall J, Lässer C. The influence of rotor type and centrifugation time on the yield and purity of extracellular vesicles. J Extracell Vesicles. 2014;3:3.

Google Scholar
27

Lobb RJ, Becker M, Wen SW, et al. Optimized exosome isolation protocol for cell culture supernatant and human plasma. J Extracell Vesicles. 2015;4:27031.

Crossref Google Scholar
28

Qin Y, Wang L, Gao Z, Chen G, Zhang C. Bone marrow stromal/stem cell-derived extracellular vesicles regulate osteoblast activity and differentiation in vitro and promote bone regeneration in vivo. Sci Rep. 2016;6:21961.

Crossref Google Scholar
29

Pertea M, Kim D, Pertea GM, Leek JT, Salzberg SL. Transcript-level expression analysis of RNA-seq experiments with HISAT, StringTie and Ballgown. Nat Protoc. 2016;11(9):1650-1667.

Crossref Google Scholar
30

Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30(7):923-930.

Crossref Google Scholar
31

Raudvere U, Kolberg L, Kuzmin I, et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 2019;47(W1):W191-W198.

Crossref Google Scholar
32

Snel B, Lehmann G, Bork P, Huynen MA. STRING: a web-server to retrieve and display the repeatedly occurring neighbourhood of a gene. Nucleic Acids Res. 2000;28(18):3442-3444.

Crossref Google Scholar
33

von Mering C, Huynen M, Jaeggi D, Schmidt S, Bork P, Snel B. STRING: a database of predicted functional associations between proteins. Nucleic Acids Res. 2003;31(1):258-261.

Crossref Google Scholar
34

Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021:customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021;49(D1):D605-D612.

Crossref Google Scholar
35

Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545-15550.

Crossref Google Scholar
36

Holbro T, Hynes NE. ErbB receptors: directing key signaling networks throughout life. Annu Rev Pharmacol Toxicol. 2004;44:195-217.

Crossref Google Scholar
37

Zhang H, Deng T, Liu R, et al. Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis. Nat Commun. 2017;8:15016.

Crossref Google Scholar
38

Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883-899.

Crossref Google Scholar
39

Park J, Morley TS, Kim M, Clegg DJ, Scherer PE. Obesity and cancer: mechanisms underlying tumour progression and recurrence. Nat Rev Endocrinol. 2014;10(8):455-465.

Crossref Google Scholar
40

Anderson KG, Stromnes IM, Greenberg PD. Obstacles posed by the tumor microenvironment to T cell activity: a case for synergistic therapies. Cancer Cell. 2017;31(3):311-325.

Crossref Google Scholar
41

De Sanctis F, Ugel S, Facciponte J, Facciabene A. The dark side of tumor-associated endothelial cells. Semin Immunol. 2018;35:35-47.

Crossref Google Scholar
42

Au Yeung CL, Co NN, Tsuruga T, et al. Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nat Commun. 2016;7:11150.

Crossref Google Scholar
43

Chu Y, Zhu C, Wang Q, et al. Adipose-derived mesenchymal stem cells induced PAX8 promotes ovarian cancer cell growth by stabilizing TAZ protein. J Cell Mol Med. 2021;25(9):4434-4443.

Crossref Google Scholar
44

Chu Y, Tang H, Guo Y, et al. Adipose-derived mesenchymal stem cells promote cell proliferation and invasion of epithelial ovarian cancer. Exp Cell Res. 2015;337(1):16-27.

Crossref Google Scholar
45

Kamat P, Schweizer R, Kaenel P, et al. Human adipose-derived mesenchymal stromal cells may promote breast cancer progression and metastatic spread. Plast Reconstr Surg. 2015;136(1):76-84.

Crossref Google Scholar
46

Scioli MG, Storti G, D’Amico F, et al. Adipose-derived stem cells in cancer progression: new perspectives and opportunities. Int J Mol Sci. 2019;20(13):3296.

Crossref Google Scholar
47

van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19(4):213-228.

Crossref Google Scholar
48

Huang SH, Li Y, Zhang J, Rong J, Ye S. Epidermal growth factor receptor-containing exosomes induce tumor-specific regulatory T cells. Cancer Invest. 2013;31(5):330-335.

Crossref Google Scholar
49

Shostak K, Chariot A. EGFR and NF-κB: partners in cancer. Trends Mol Med. 2015;21(6):385-393.

Crossref Google Scholar
50

Psyrri A, Kassar M, Yu Z, et al. Effect of epidermal growth factor receptor expression level on survival in patients with epithelial ovarian cancer. Clin Cancer Res. 2005;11(24):8637-8643.

Crossref Google Scholar
51

Matsuda N, Wang X, Lim B, et al. Safety and efficacy of panitumumab plus neoadjuvant chemotherapy in patients with primary HER2-negative inflammatory breast cancer. JAMA Oncol. 2018;4(9):1207-1213.

Crossref Google Scholar
52

Cremolini C, Antoniotti C, Lonardi S, et al. Activity and safety of cetuximab plus modified FOLFOXIRI followed by maintenance with cetuximab or bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a randomized phase 2 clinical trial. JAMA Oncol. 2018;4(4):529-536.

Crossref Google Scholar
53

Herbst RS, Redman MW, Kim ES, et al. Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study. Lancet Oncol. 2018;19(1):101-114.

Crossref Google Scholar
Genes & Diseases
Volume 12 Issue 2,
March 2025
Article number: 101283
DOI: 10.1016/j.gendis.2024.101283
Cite this article:
Wang L, Luo N, Zhu J, et al. Peritoneal adipose stem cell-derived extracellular vesicles mediate the regulation of ovarian cancer cell proliferation and migration through EGFR-NF-κB signaling. Genes & Diseases, 2025, 12(2): 101283. https://doi.org/10.1016/j.gendis.2024.101283
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