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Open Access 01-12-2019 | Metastasis | Research

Extracellular vesicles of carcinoma-associated fibroblasts creates a pre-metastatic niche in the lung through activating fibroblasts

Authors: Jing Kong, Hongzhu Tian, Fuyin Zhang, Zebing Zhang, Jiao Li, Xue Liu, Xiancheng Li, Jing Liu, Xiaojie Li, Dong Jin, Xuesong Yang, Bo Sun, Tao Guo, Yong Luo, Yao Lu, Bingcheng Lin, Tingjiao Liu

Published in: Molecular Cancer | Issue 1/2019

Abstract

Objectives

Carcinoma-associated fibroblasts (CAFs) have been known to promote cancer progression by modifying the primary tumor microenvironment. We aimed to elucidate the intercellular communication between CAFs and secondary organs in salivary adenoid cystic carcinoma (SACC) metastasis.

Methods

Pre-metastatic and metastatic animal models of SACC were established using extracellular vesicles (EVs) from CAFs and SACC cells. Lung fibroblasts (LFs) were treated with EVs and their transcriptomic alterations were identified by RNA sequencing. ITRAQ were performed to analyze EV cargos. TC I-15 was used to inhibit EV uptake by LFs and SACC lung metastasis in vivo.

Results

Here, we show that CAF EVs induced lung pre-metastatic niche formation in mice and consequently increased SACC lung metastasis. The pre-metastatic niche induced by CAF EVs was different from that induced by SACC EVs. CAF EVs presented a great ability for matrix remodeling and periostin is a potential biomarker characterizing the CAF EV-induced pre-metastatic niche. We found that lung fibroblast activation promoted by CAF EVs was a critical event at the pre-metastatic niche. Integrin α2β1 mediated CAF EV uptake by lung fibroblasts, and its blockage by TC I-15 prevented lung pre-metastatic niche formation and subsequent metastasis. Plasma EV integrin β1 was considerably upregulated in the mice bearing xenografts with high risk of lung metastasis.

Conclusions

We demonstrated that CAF EVs participated in the pre-metastatic niche formation in the lung. Plasma EV integrin β1 might be a promising biomarker to predict SACC metastasis at an early stage. An integrated strategy targeting both tumor and stromal cells is necessary to prevent SACC metastasis.

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Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6:392–401.PubMedCrossRef

De Wever O, Van Bockstal M, Mareel M, Hendrix A, Bracke M. Carcinoma-associated fibroblasts provide operational flexibility in metastasis. Semin Cancer Biol. 2014;25:33–46.PubMedCrossRef

Denys H, Derycke L, Hendrix A, Westbroek W, Gheldof A, Narine K, et al. Differential impact of TGF-beta and EGF on fibroblast differentiation and invasion reciprocally promotes colon cancer cell invasion. Cancer Lett. 2008;266:263–74.PubMedCrossRef

Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121:335–48.PubMedCrossRef

Fullar A, Kovalszky I, Bitsche M, Romani A, Schartinger VH, Sprinzl GM, et al. Tumor cell and carcinoma-associated fibroblast interaction regulates matrix metalloproteinases and their inhibitors in oral squamous cell carcinoma. Exp Cell Res. 2012;318:1517–27.PubMedPubMedCentralCrossRef

Deng Y, Cheng J, Fu B, Liu W, Chen G, Zhang Q, et al. Hepatic carcinoma-associated fibroblasts enhance immune suppression by facilitating the generation of myeloid-derived suppressor cells. Oncogene. 2017;36:1090–101.PubMedCrossRef

Nakagawa H, Liyanarachchi S, Davuluri RV, Auer H, Martin EW Jr, de la Chapelle A, et al. Role of cancer-associated stromal fibroblasts in metastatic colon cancer to the liver and their expression profiles. Oncogene. 2004;23:7366–77.PubMedCrossRef

Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005;438:820–7.PubMedPubMedCentralCrossRef

Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A, et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell. 2009;15:35–44.PubMedPubMedCentralCrossRef

10.

Kowanetz M, Wu X, Lee J, Tan M, Hagenbeek T, Qu X, et al. Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes. Proc Natl Acad Sci U S A. 2010;107:21248–55.PubMedPubMedCentralCrossRef

11.

Hiratsuka S, Ishibashi S, Tomita T, Watanabe A, Akashi-Takamura S, Murakami M, et al. Primary tumours modulate innate immune signalling to create pre-metastatic vascular hyperpermeability foci. Nat Commun. 2013;4:1853.PubMedCrossRef

12.

Liu Y, Cao X. Characteristics and significance of the pre-metastatic niche. Cancer Cell. 2016;30:668–81.PubMedCrossRef

13.

Chen XW, Yu TJ, Zhang J, Li Y, Chen HL, Yang GF, et al. CYP4A in tumor-associated macrophages promotes pre-metastatic niche formation and metastasis. Oncogene. 2017;36:5045–57.PubMedPubMedCentralCrossRef

14.

Plebanek MP, Angeloni NL, Vinokour E, Li J, Henkin A, Martinez-Marin D, et al. Pre-metastatic cancer exosomes induce immune surveillance by patrolling monocytes at the metastatic niche. Nat Commun. 2017;8:1319.PubMedPubMedCentralCrossRef

15.

Rachman-Tzemah C, Zaffryar-Eilot S, Grossman M, Ribero D, Timaner M, Maki JM, et al. Blocking surgically induced Lysyl oxidase activity reduces the risk of lung metastases. Cell Rep. 2017;19:774–84.PubMedPubMedCentralCrossRef

16.

Rucci N, Sanita P, Angelucci A. Roles of metalloproteases in metastatic niche. Curr Mol Med. 2011;11:609–22.PubMedCrossRef

17.

Sceneay J, Smyth MJ, Moller A. The pre-metastatic niche: finding common ground. Cancer Metastasis Rev. 2013;32:449–64.PubMedCrossRef

18.

Peinado H, Zhang H, Matei IR, Costa-Silva B, Hoshino A, Rodrigues G, et al. Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer. 2017;17:302–17.PubMedCrossRef

19.

Minciacchi VR, Freeman MR, Di Vizio D. Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes. Semin Cell Dev Biol. 2015;40:41–51.PubMedPubMedCentralCrossRef

20.

Chin AR, Wang SE. Cancer tills the Premetastatic field: mechanistic basis and clinical implications. Clin Cancer Res. 2016;22:3725–33.PubMedPubMedCentralCrossRef

21.

van Niel G, D'Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19:213–28.PubMedCrossRef

22.

Schey KL, Luther JM, Rose KL. Proteomics characterization of exosome cargo. Methods. 2015;87:75–82.PubMedPubMedCentralCrossRef

23.

Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.PubMedCrossRef

24.

Jin X, Chen Y, Chen H, Fei S, Chen D, Cai X, et al. Evaluation of tumor-derived Exosomal miRNA as potential diagnostic biomarkers for early-stage non-small cell lung Cancer using next-generation sequencing. Clin Cancer Res. 2017;23:5311–9.PubMedCrossRef

25.

Fong MY, Zhou W, Liu L, Alontaga AY, Chandra M, Ashby J, et al. Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol. 2015;17:183–94.PubMedPubMedCentralCrossRef

26.

Hewson C, Morris KV. Form and function of exosome-associated long non-coding RNAs in Cancer. Curr Top Microbiol Immunol. 2016;394:41–56.PubMed

27.

Thakur BK, Zhang H, Becker A, Matei I, Huang Y, Costa-Silva B, et al. Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res. 2014;24:766–9.PubMedPubMedCentralCrossRef

28.

Clayton A, Turkes A, Dewitt S, Steadman R, Mason MD, Hallett MB. Adhesion and signaling by B cell-derived exosomes: the role of integrins. FASEB J. 2004;18:977–9.PubMedCrossRef

29.

Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527:329–35.PubMedPubMedCentralCrossRef

30.

Liu Y, Gu Y, Han Y, Zhang Q, Jiang Z, Zhang X, et al. Tumor Exosomal RNAs promote lung pre-metastatic niche formation by activating alveolar epithelial TLR3 to recruit neutrophils. Cancer Cell. 2016;30:243–56.PubMedCrossRef

31.

Yang WW, Yang LQ, Zhao F, Chen CW, Xu LH, Fu J, et al. Epiregulin promotes lung metastasis of salivary adenoid cystic carcinoma. Theranostics. 2017;7:3700–14.PubMedPubMedCentralCrossRef

32.

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

33.

Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. 2015;17:816–26.PubMedPubMedCentralCrossRef

34.

Gartland A, Erler JT, Cox TR. The role of lysyl oxidase, the extracellular matrix and the pre-metastatic niche in bone metastasis. J Bone Oncol. 2016;5:100–3.PubMedPubMedCentralCrossRef

35.

Gao M, Hao Y, Huang MX, Ma DQ, Luo HY, Gao Y, et al. Clinicopathological study of distant metastases of salivary adenoid cystic carcinoma. Int J Oral Maxillofac Surg. 2013;42:923–8.PubMedCrossRef

36.

Li J, Jia Z, Kong J, Zhang F, Fang S, Li X, et al. Carcinoma-associated fibroblasts Lead the invasion of salivary gland adenoid cystic carcinoma cells by creating an invasive track. PLoS One. 2016;11:e0150247.PubMedPubMedCentralCrossRef

37.

Miller MW, Basra S, Kulp DW, Billings PC, Choi S, Beavers MP, et al. Small-molecule inhibitors of integrin alpha2beta1 that prevent pathological thrombus formation via an allosteric mechanism. Proc Natl Acad Sci U S A. 2009;106:719–24.PubMedPubMedCentralCrossRef

38.

Glentis A, Oertle P, Mariani P, Chikina A, El Marjou F, Attieh Y, et al. Cancer-associated fibroblasts induce metalloprotease-independent cancer cell invasion of the basement membrane. Nat Commun. 2017;8:924.PubMedPubMedCentralCrossRef

39.

Yu T, Yang G, Hou Y, Tang X, Wu C, Wu XA, et al. Cytoplasmic GPER translocation in cancer-associated fibroblasts mediates cAMP/PKA/CREB/glycolytic axis to confer tumor cells with multidrug resistance. Oncogene. 2017;36:2131–45.PubMedCrossRef

40.

Leca J, Martinez S, Lac S, Nigri J, Secq V, Rubis M, et al. Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness. J Clin Invest. 2016;126:4140–56.PubMedPubMedCentralCrossRef

41.

Richards KE, Zeleniak AE, Fishel ML, Wu J, Littlepage LE, Hill R. Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene. 2017;36:1770–8.PubMedCrossRef

42.

Chen Y, Zeng C, Zhan Y, Wang H, Jiang X, Li W. Aberrant low expression of p85alpha in stromal fibroblasts promotes breast cancer cell metastasis through exosome-mediated paracrine Wnt10b. Oncogene. 2017;36:4692–705.PubMedPubMedCentralCrossRef

43.

Zhang X, Sai B, Wang F, Wang L, Wang Y, Zheng L, et al. Hypoxic BMSC-derived exosomal miRNAs promote metastasis of lung cancer cells via STAT3-induced EMT. Mol Cancer. 2019;18:40.PubMedPubMedCentralCrossRef

44.

Norris RA, Damon B, Mironov V, Kasyanov V, Ramamurthi A, Moreno-Rodriguez R, et al. Periostin regulates collagen fibrillogenesis and the biomechanical properties of connective tissues. J Cell Biochem. 2007;101:695–711.PubMedPubMedCentralCrossRef

45.

Kudo A. Periostin in fibrillogenesis for tissue regeneration: periostin actions inside and outside the cell. Cell Mol Life Sci. 2011;68:3201–7.PubMedPubMedCentralCrossRef

46.

Zhou W, Ke SQ, Huang Z, Flavahan W, Fang X, Paul J, et al. Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth. Nat Cell Biol. 2015;17:170–82.PubMedPubMedCentralCrossRef

Title: Extracellular vesicles of carcinoma-associated fibroblasts creates a pre-metastatic niche in the lung through activating fibroblasts
Authors: Jing Kong
Hongzhu Tian
Fuyin Zhang
Zebing Zhang
Jiao Li
Xue Liu
Xiancheng Li
Jing Liu
Xiaojie Li
Dong Jin
Xuesong Yang
Bo Sun
Tao Guo
Yong Luo
Yao Lu
Bingcheng Lin
Tingjiao Liu
Publication date: 01-12-2019
Publisher: BioMed Central
Keyword: Metastasis
Published in: Molecular Cancer / Issue 1/2019
Electronic ISSN: 1476-4598
DOI: https://doi.org/10.1186/s12943-019-1101-4

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Abstract

Objectives

Methods

Results

Conclusions

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