Involvement of endothelial progenitor cells in tumor vascularization.
ABSTRACT The generation of new microvasculature progresses by the process of angiogenesis, which involves the invasion and proliferation of endothelial cells from existing blood vessels into the local environment. In recent years, de novo generation of endothelial cells from circulating or local precursor endothelial cells is thought to also contribute to the neovasculature, a process that is referred to as vasculogenesis. In the adult, endothelial progenitor cells (EPC) are believed to be recruited from the bone marrow, migrate to sites requiring neovascularization and participate in the assembly of newly-forming blood vessels. A growing number of studies report that EPC participate in tumor progression and influence the efficacy of anticancer chemotherapeutics, and thus are attractive targets for cancer treatments. However, recent evidence calls into question the ability of marrow-derived EPC to act as a bona fide precursor for adult vasculogenesis. This review focuses on studies reporting or precluding the importance of EPC in tumor vasculogenesis. The putative sources of these cells and difficulties associated with their detection are discussed.
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ABSTRACT: Adults maintain a reservoir of hematopoietic stem cells that can enter the circulation to reach organs in need of regeneration. We developed a novel model of retinal neovascularization in adult mice to examine the role of hematopoietic stem cells in revascularizing ischemic retinas. Adult mice were durably engrafted with hematopoietic stem cells isolated from transgenic mice expressing green fluorescent protein. We performed serial long-term transplants, to ensure activity arose from self-renewing stem cells, and single hematopoietic stem-cell transplants to show clonality. After durable hematopoietic engraftment was established, retinal ischemia was induced to promote neovascularization. Our results indicate that self-renewing adult hematopoietic stem cells have functional hemangioblast activity, that is, they can clonally differentiate into all hematopoietic cell lineages as well as endothelial cells that revascularize adult retina. We also show that recruitment of endothelial precursors to sites of ischemic injury has a significant role in neovascularization.Nature Medicine 07/2002; 8(6):607-12. · 22.86 Impact Factor
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ABSTRACT: Tumor growth is dependent in part on "neoangiogenesis." Functional involvement of bone marrow (BM)-derived cells in this process has been demonstrated. However, it remains controversial as to whether tumor endothelium itself is BM derived. Here we sought to address this issue with an endothelial-specific, inducible transgenic model. We generated Cretransgenic mice (endothelial-SCL-Cre-ER(T)) using the tamoxifen-inducible Cre-ER(T) recombinase driven by the 5' endothelial enhancer of the stem cell leukemia (SCL) locus. These mice were intercrossed with Cre reporter strains in which beta-galactosidase (LacZ) or enhanced yellow fluorescent protein (EYFP) are expressed upon Cre-mediated recombination. After tamoxifen administration, endothelial LacZ staining was observed in embryonic and adult tissues. Cre-mediated recombination was also observed in newly generated tumor endothelium. In adult BM cells we could only detect trace amounts of recombination by flow cytometry. Subsequently, BM from endothelial-SCL-Cre-ER(T);R26R mice was transplanted into irradiated recipients. When tumors were grown in recipient mice, which received tamoxifen, no tumor LacZ staining was detected. However, when tumors were grown in endothelial-SCL-Cre-ER(T);R26R mice 3 weeks after the cessation of tamoxifen treatment, there was widespread endothelial LacZ staining present. Thus, this genetic model strongly suggests that BM cells do not contribute to tumor endothelium and demonstrates the lineage relation between pre-existing endothelium and newly generated tumor endothelial cells.Blood 10/2004; 104(6):1769-77. · 9.06 Impact Factor
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ABSTRACT: About 50% of cancer patients receive radiation therapy. Here we investigated the hypothesis that tumor response to radiation is determined not only by tumor cell phenotype but also by microvascular sensitivity. MCA/129 fibrosarcomas and B16F1 melanomas grown in apoptosis-resistant acid sphingomyelinase (asmase)-deficient or Bax-deficient mice displayed markedly reduced baseline microvascular endothelial apoptosis and grew 200 to 400% faster than tumors on wild-type microvasculature. Thus, endothelial apoptosis is a homeostatic factor regulating angiogenesis-dependent tumor growth. Moreover, these tumors exhibited reduced endothelial apoptosis upon irradiation and, unlike tumors in wild-type mice, they were resistant to single-dose radiation up to 20 grays (Gy). These studies indicate that microvascular damage regulates tumor cell response to radiation at the clinically relevant dose range.Science 06/2003; 300(5622):1155-9. · 31.20 Impact Factor