Therapy-Induced Acute Recruitment of Circulating Endothelial Progenitor Cells to Tumors

Abstract

The contribution of bone marrow-derived circulating endothelial progenitor cells (CEPs) to tumor angiogenesis has been controversial, primarily because of their low numbers in blood vessels of untreated tumors. We show that treatment of tumor-bearing mice with vascular disrupting agents (VDAs) leads to an acute mobilization of CEPs, which home to the viable tumor rim that characteristically remains after such therapy. Disruption of this CEP spike by antiangiogenic drugs or by genetic manipulation resulted in marked reductions in tumor rim size and blood flow as well as enhanced VDA antitumor activity. These findings also provide a mechanistic rationale for the enhanced efficacy of VDAs when combined with antiangiogenic drugs.

Endothelial progenitor cells for cancer gene therapy

“…19,20 Treatment of tumor-bearing mice with vascular disrupting agents recruited EPCs to the tumors. 21 In patients with hepatocellular carcinoma, CD 133 + EPCs incorporated into tumor vessels. 22 In contrast to these studies, no contribution of bone marrow-derived cells to tumorigenesis was found by others.…”

Role of endothelial progenitor cells in breast cancer angiogenesis: from fundamental research to clinical ramifications

“…Although the molecular pathways involved in EPC mobilization remain to be determined, several stimuli including VEGF, stroma cell derived factor-1a (SDF-1a), placental growth factor (PlGF), granulocyte colony stimulating factor (G-CSF) and estrogens were described to be involved in the mobilization of EPC from the bone marrow to tumor sites [31,[34][35][36][37][38][39]. VEGF can activate matrix metalloproteinase-9 which that cleaves the membrane-bound stem cell cytokine mKit Ligand in bone marrow stromal cells, to liberate soluble sKit Ligand, which then stimulates cKitpositive EPC to migrate from a quiescent bone marrow niche to a permissive microenvironment, activating EPC from a quiescent to a proliferative state [40].…”

“…Thus, the significantly higher levels of EPC paralleling clinical severity suggest the possible relevance of these cells in metastatic progression of tumors, and point out their potential use as biomarker and/or target in cancer therapy. Surprisingly, Shaked et al [38] found that treatment of tumor-bearing mice with vascular disrupting agents, which target the established but abnormal tumor vasculature, leads to an acute mobilization of EPC. These cells subsequently colonize the viable tumor rim that usually remains after such therapy, and drives ''rebound revascularization'' and tumor regrowth/recovery.…”

Circulating Endothelial Progenitors and Tumor Resistance to Vascular-Targeting Therapies

“…Subsequent studies in which authors scrutinized the contribution of CEPs to tumor blood vessels have had conflicting results, and a consensus on the extent and functional significance of this phenomenon is still lacking (6)(7)(8). In more recent studies, investigators also have suggested that certain cytotoxic drugs, such as vascular-disrupting agents (VDA) and taxanes, increase the number of CEPs in the peripheral blood of mice and enhance their incorporation in the tumor vasculature (9,10). VDAs are microtubule-destabilizing drugs that cause the rapid collapse of intratumoral blood vessels, leading to tumor necrosis and shrinkage.…”

“…Shaked and colleagues (9) have previously shown that a single VDA dose induces a transient CEP spike in the mouse circulation as soon as 4 hours after drug administration. Neutralization of this CEP spike with the use of a blocking antibody against vascular endothelial growth factor receptor-2 (VEGFR-2) inhibited the incorporation of CEPs in the tumor blood vessels and delayed tumor revascularization and regrowth (9).…”