The new study has been reported in The American Journal of Pathology.
‘CD109 is a biomarker that can recognize when blood vessels are normalized, a period were anticancer therapies work best.’
Tumor growth needs the formation of new blood vessels (angiogenesis). Angiogenesis
inhibitors alone have failed to invoke significant response rates or prolong survival in solid tumor patients. But combination therapy using angiogenesis inhibitors and anticancer drugs has been effective, with patient outcomes superior to chemotherapy alone; it can improve drug delivery into tumor tissues and prolong progression-free survival.
"Vascular normalization by angiogenesis inhibitors, such as vascular endothelial growth factor (VEGF) signaling inhibitors, is a promising method for improvement of chemotherapy
However, it is unclear how we can recognize the 'window of opportunity' for the tumor vascular normalizing period for effective timing of anticancer drug treatment. Therefore, biomarkers delineating this window are essential," explained Nobuyuki Takakura, MD, PhD, Professor, Department of Signal Transduction, and Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Researchers showed that proliferating vascular endothelial cells (ECs) are different from dormant ones. They measured PSF1 gene promoter activity, which is associated with DNA replication and rapid proliferation of somatic cells by using enhanced green fluorescent protein (EGFP) tat fluoresced to sow gene activation. Since normal skin ECs are dormant, no EGFP signals were observed in normal adult skin vasculature.
After subcutaneous injection of tumor cells,
- Some ECs in and near the tumor showed expression of EGFP
- ECs that were high in EGFP expression were larger and more complex than cells that did not express EGFP
Experimentation on non-proliferative ECs helped the researchers find out that the silenced cells strongly expressed VEGFR1 (vascular endothelial growth factor (VEGF) - a principle driver of tumor angiogenesis) and a cell surface protein called CD109.
Moreover, CD109 expression in ECs increased three to five days after injection of bevacizumab
into mice that bore a human colorectal adenocarcinoma, coinciding with normalization of tumor vessels. The researchers thus distinguished between proangiogenic ECs and quiescent ECs by their PSF1 gene promoter activity. Therefore, it can be concluded that CD109 expression in ECs marked normalized or silenced blood vessels in the tumor vasculature.
"Since CD109 is highly expressed in dormant ECs, we suggest it can be used to detect normalized blood vessels, thus allowing identification of the 'window of opportunity' for optimal delivery of chemotherapeutics," remarked Dr. Takakura.
- Goel S, Wong AH-K, Jain RK. "Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease." Cold Spring Harbor Perspectives in Medicine. (2012); 2(3):a006486. DOI:10.1101/cshperspect.a006486.