Abstract
BackgroundEndothelial progenitor cells (EPCs) have been demonstrated to have stem-cell like as well as mature endothelial functions. However, controversy remains as to their origins, immunophenotypic markings, and contribution to the tumor vascular network and tumor survival.MethodsFlow cytometric analysis and sorting was used to isolate Flk-1+/c-Kit+/CD45- cells. Matrigel and methycellulose assays, flow cytometry, and gene array analyses were performed to characterize several murine EPC cell populations. Human tumor xenografts were used to evaluate the impact of EPCs on tumor growth and vascular development.ResultsFlk-1+/c-Kit+/CD45- cells were present at low levels in most murine organs with the highest levels in adipose, aorta/vena cava, and lung tissues. Flk-1+/c-Kit+/CD45- cells demonstrated stem cell qualities through colony forming assays and mature endothelial function by expression of CD31, uptake of acLDL, and vascular structure formation in matrigel. High passage EPCs grown in vitro became more differentiated and lost stem-cell markers. EPCs were found to have hemangioblastic properties as demonstrated by the ability to rescue mice given whole body radiation. Systemic injection of EPCs increased the growth of human xenograft tumors and vessel density.ConclusionsFlk-1+/C-Kit+/CD45- cells function as endothelial progenitor cells. EPCs are resident in most murine tissue types and localize to human tumor xenografts. Furthermore, the EPC population demonstrates stem-cell and mature endothelial functions and promoted the growth of tumors through enhanced vascular network formation. Given the involvement of EPCs in tumor development, this unique host-derived population may be an additional target to consider for anti-neoplastic therapy.
Highlights
Endothelial progenitor cells (EPCs) have been demonstrated to have stem-cell like as well as mature endothelial functions
Samples were processed in a sequential manner to isolate cells that were positive for the endothelial marker Flk-1 (VEGFR2), for the stem cell marker c-Kit positive fraction
The dual population of Flk-1+/c-Kit+ cells was analyzed for CD45 expression and only those cells that were CD45 negative were selected for further assays
Summary
Endothelial progenitor cells (EPCs) have been demonstrated to have stem-cell like as well as mature endothelial functions. Gill et al demonstrated the rapid mobilization of Flk-1+/AC133+ cells into the peripheral blood after vascular trauma which coated artificial blood vessel grafts [2]. These results suggested the presence of a circulating endothelial progenitor cell (EPC) population with both stem-cell like. The potential for adult peripheral blood to contain a cellular subpopulation with the ability to repair damaged vasculature has generated intense interest in this field. Patients with pathological disorders such as stroke, heart disease, peripheral vascular disease, myocardial infarction, pulmonary diseases, and potentially the many complications of diabetes could benefit from a renewable cell population that repairs damaged vasculature [6,7,8,9,10,11,12]. The existence of a secondary network for tumor blood vessel generation and/or maintenance may be partially responsible for resistance mechanisms to anti-neoplastic therapies and the limited clinical benefit seen using anti-angiogenic inhibitors [18,19,20,21]
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