Metronomic gemcitabine targeted tumor vascular microenvironment decreases the population of CD133(+) cells in hepatocarcinoma xenografts.

Recently, compelling evidence shows that cancer stem-like cells (CSLC) are thought to be critical for initiation and propagation of many types of cancers. Most of CSLC are dependent upon the vascular microenvironments that promote their long-term growth and self-renewal. However, it is not known if when we disrupted their vascular microenvironments, CSLC would be eliminated. Considering these possibilities, we have investigated the influence of different chemotherapy regimens on the CSLC population of hepatocarcinoma xenografts model. The mouse models of hepatocarcinoma were treated with different therapeutic regimens: low-dose metronomic (LDM) regimens, combination therapies of Bolus dose and low-dose metronomic regimens, for the purpose of comparison, a conventional cytotoxic schedule of maximum tolerated dose (MTD) chemotherapy using gemcitabine (GEM). All therapies produced a significant tumor growth delay. LDM GEM and Bolus+LDM GEM significantly reduced the tumor spheres, whereas MTD GEM had no effect on the tumor spheres. Furthermore, Bolus+LDM GEM could more significantly decrease both the population of CSLC and the levels of viable endothelial progenitor cells (EPC). Overall, our data indicate that Bolus+LDM GEM is a potent treatment regimen for inhibiting angiogenesis, attacking the tumor vascular microenvironments, and decreasing the population of CSLC. Targeting the unique microenvironment of CSLC may be the key to effective cancer therapy, and shows great promise for the clinical practice.