‘ New biomarker to help improve chemotherapy’

◗ Combination therapy using angiogenesis inhibitors and anticancer drugs can improve drug delivery into tumour tissues and prolong progression-free survival

◗ Researchers have found that active proliferating vascular endothelial cells ( ECs) in mice could be distinguished from dormant ones

Tokyo, April 9: Scientists have identified a biomarker that can visualise blood vessel activity, thus optimising the timing of anticancer therapies.

Angiogenesis, the formation of new blood vessels, is essential for tumour growth.

Combination therapy using angiogenesis inhibitors and anticancer drugs can improve drug delivery into tumour tissues and prolong progression- free survival.

“Vascular normalisation by angiogenesis inhibitors, such as vascular endothelial growth factor ( VEGF) signalling inhibitors, is a promising method for improvement of chemotherapy,” said Nobuyuki Takakura, a professor at Osaka University in Japan.

“However, it is unclear how we can recognise the ‘ window of opportunity’ for the tumour vascular normalising period for effective timing of anticancer drug treatment. Therefore, biomarkers delineating this window are essential,” said Takakura.

In a study published in the American Journal of Pathology, researchers showed that active proliferating vascular endothelial cells ( ECs) in mice could be distinguished from dormant ones.

They measured the promoter activity of DNA replication factor partner of Sld5- 1 ( PSF1) in ECs using enhanced green fluorescent protein ( EGFP) that allows visualisation of gene activity as fluorescence.

No EGFP signals were observed in normal adult skin vasculature, which was expected as normal skin ECs are dormant. However, after subcutaneous injection of tumour cells, some ECs in and near the tumour shifted to EGFP- positivity.

PSF1 promotor activity was also found to correlate well with tumour cell growth. ECs that were high in EGFP expression were larger

and had greater intracellular complexity than cells that were EGFP negative.

“Our data showed that PSF1- promotor- EGFP mice may be utilised to visualise proliferating ECs by their EGFP expression,” said Takakura.

“Experimentation on non- proliferative ECs revealed that these quiet cells strongly expressed VEGFR1 and a cell surface protein CD109.

“CD109 expression in ECs increased three to five days after injection of bevacizumab into human colorectal adenocarcinoma HT29- bearing mice, coinciding with normalisation of tumour vessels,” said Takakura.

“Though on day 5 after bevacizumab injection, functional vessels increased and hypoxic regions significantly decreased, by day 8, hypoxic regions increased again,” he said.

These results enabled researchers to successfully distinguish between proangiogenic ECs and quiescent ECs by their PSF1 gene promoter activity, which is associated with DNA replication and rapid proliferation of somatic cells. Therefore, CD109 expression in ECs marked normalised or silenced blood vessels in the tumour vasculature.