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

  • Mol Cancer. 2019 Dec 3;18(1):175. doi: 10.1186/s12943-019-1101-4.
Jing Kong  1 ,  Hongzhu Tian  1 ,  Fuyin Zhang  2 ,  Zebing Zhang  3 ,  Jiao Li  1 ,  Xue Liu  1 ,  Xiancheng Li  4 ,  Jing Liu  5 ,  Xiaojie Li  1 ,  Dong Jin  1 ,  Xuesong Yang  6 ,  Bo Sun  2 ,  Tao Guo  7 ,  Yong Luo  8 ,  Yao Lu  9 ,  Bingcheng Lin  8  9 ,  Tingjiao Liu  10
Affiliations
  • 1. Department of Oral Pathology, College of Stomatology, Dalian Medical University, West Section No. 9, South Road of Lvshun, Dalian, 116044, China.
  • 2. Department of Oral Surgery, the Second Affiliated Hospital, Dalian Medical University, Dalian, China.
  • 3. Department of Oral Pathology, College of Stomatology, Jilin University, Changchun, China.
  • 4. Department of Urology, the Second Affiliated Hospital, Dalian Medical University, Dalian, China.
  • 5. Sino-UK Regenerative Medicine Center, the First Affiliated Hospital, Dalian Medical University, Dalian, China.
  • 6. Department of Biochemistry and Molecular Biology, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian Medical University, Dalian, China.
  • 7. Department of Thoracic Surgery, The First Affiliated Hospital, Dalian Medical University, Dalian, China.
  • 8. Faculty of Chemical, Environmental and Biological Science and Technology, Dalian Technology University, Dalian, China.
  • 9. Department of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
  • 10. Department of Oral Pathology, College of Stomatology, Dalian Medical University, West Section No. 9, South Road of Lvshun, Dalian, 116044, China. [email protected].
PMID: 31796058 DOI: 10.1186/s12943-019-1101-4
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.

Keywords
Carcinoma-associated fibroblast; Extracellular vesicles; Lung metastasis; Pre-metastatic niche.
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