Tumour endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan

Abstract

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.

Tumor endothelial cells express high pentraxin 3 levels

“…Total RNA was extracted with an RNeasy Micro kit (Qiagen, Valencia, CA, USA). cDNA was synthesized using ReverTra‐Plus (Toyobo, Osaka, Japan), as previously described . Quantitative ‐PCR was performed with SsoFast™ EvaGreen® Supermix (Bio‐Rad, Hercules, CA, USA).…”

Complex interplay between tumor microenvironment and cancer therapy

“…First, TECs usually have irregular shape and size [51]; second, TECs have distinct responsiveness to EGF, adrenomedullin and VEGF compared with normal endothelial cells [52][53][54]. Through a bidirectional interaction between tumor cells, TECs actively promote cancer metastasis [55]. Previous study also suggested that TECs isolated from highly metastatic tumors significantly enhanced the metastatic ability of weakly metastatic cancer cells in co-transplantation experiments [55].…”

“…Through a bidirectional interaction between tumor cells, TECs actively promote cancer metastasis [55]. Previous study also suggested that TECs isolated from highly metastatic tumors significantly enhanced the metastatic ability of weakly metastatic cancer cells in co-transplantation experiments [55]. Mechanistically, DNA demethylation in TECs causes upregulation and secretion of biglycan, which is a small leucine-rich repeat proteoglycan.…”

“…Mechanistically, DNA demethylation in TECs causes upregulation and secretion of biglycan, which is a small leucine-rich repeat proteoglycan. Tumor cell migration is then activated by biglycan via NF-kB and extracellular signal-regulated kinase 1/2 (ERK1/2) [55].…”

Bone marrow blood vessels: normal and neoplastic niche

“…Whether or not Biglycan produced by TEC can bind these factors is unknown and could provide grounds for further investigation to elucidate this matter. 91,92 …”