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Open Access Research

Circulating mouse Flk1+/c-Kit+/CD45- cells function as endothelial progenitors cells (EPCs) and stimulate the growth of human tumor xenografts

Jeffery S Russell1* and J Martin Brown2

Author Affiliations

1 Head and Neck/Endocrine Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA

2 Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, 1050A Arastradero Rd., Rm A246, Palo Alto, CA 94304-1334, USA

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Molecular Cancer 2014, 13:177  doi:10.1186/1476-4598-13-177

Published: 22 July 2014

Abstract

Background

Endothelial 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.

Methods

Flow 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.

Results

Flk-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.

Conclusions

Flk-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.

Keywords:
Vasculogenesis; Endothelial progenitor cell; Angiogenesis; Tumor; Microenvironment; Therapy; Resistance