Tumour endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan.
Tumour blood vessels are gateways for distant metastasis. Recent studies have revealed that tumour endothelial cells (TECs) demonstrate distinct phenotypes from their normal counterparts. We have demonstrated that features of TECs are different depending on tumour malignancy, suggesting that TECs communicate with surrounding tumour cells. However, the contribution of TECs to metastasis has not been elucidated. Here, we show that TECs actively promote tumour metastasis through a bidirectional interaction between tumour cells and TECs. Co-implantation of TECs isolated from highly metastatic tumours accelerated lung metastases of low metastatic tumours. Biglycan, a small leucine-rich repeat proteoglycan secreted from TECs, activated tumour cell migration via nuclear factor-κB and extracellular signal-regulated kinase 1/2. Biglycan expression was upregulated by DNA demethylation in TECs. Collectively, our results demonstrate that TECs are altered in their microenvironment and, in turn, instigate tumour cells to metastasize, which is a novel mechanism for tumour metastasis.
Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.|Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan.
Nako
N
Maishi
Department of Cell Physiology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
Yusuke
Y
Ohba
Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.|Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan.
Kosuke
K
Akiyama
Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan.
Noritaka
N
Ohga
Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
Jun-Ichi
J
Hamada
Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan.
Hiroko
H
Nagao-Kitamoto
Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.|Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan.
Mohammad Towfik
MT
Alam
Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan.
Kazuyuki
K
Yamamoto
Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan.
Taisuke
T
Kawamoto
Department of Gerodontology, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan.
Nobuo
N
Inoue
Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
Akinobu
A
Taketomi
Department of Oral Pathology and Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan.
Masanobu
M
Shindoh
Department of Cardiovascular and Thoracic Surgery, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
Yasuhiro
Y
Hida
Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.|Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan.
Kyoko
K
Hida
D000818:Animals; D058578:Biglycan / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation*; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D000067996:RAW 264.7 Cells; D015854:Up-Regulation
C546884:BGN protein, human; D058578:Biglycan; D016328:NF-kappa B