title: iPSC-derived cancer stem cells provide a model of tumor vasculature.
abstract: To grow beyond a size of approximately 1-2 mm3, tumor cells activate many processes to develop blood vasculature. Growing evidences indicate that the formation of the tumor vascular network is very complex, and is not restricted to angiogenesis. Cancer cell-derived tumor vasculatures have been recently described. Among them, endothelial differentiation of tumor cells have been directly related to cancer stem cells, which are cells within a tumor that possess the capacity to self-renew, and to exhibit multipotential heterogeneous lineages of cancer cells. Vasculogenic mimicry has been described to be formed by cancer cells expressing stemness markers. Thus, cancer stem cells have been proposed to contribute to vasculogenic mimicry, though its relation is yet to be clarified. Here, we analyzed the tumor vasculature by using a model of mouse cancer stem cells, miPS-LLCcm cells, which we have previously established from mouse induced pluripotent stem cells and we introduced the DsRed gene in miPS-LLCcm to trace themin vivo. Various features of vasculature were evaluatedin ovo,in vitro, andin vivo. The tumors formed in allograft nude mice exhibited angiogenesis in chick chorioallantoic membrane assay. In those tumors, along with penetrated host endothelial vessels, we detected endothelial differentiation from cancer stem cells and formation of vasculogenic mimicry. The angiogenic factors such as VEGF-A and FGF2 were expressed predominantly in the cancer stem cells subpopulation of miPS-LLCcm cells. Our results suggested that cancer stem cells play key roles in not only the recruitment of host endothelial vessels into tumor, but also in maturation of endothelial linage of cancer stem cell's progenies. Furthermore, the undifferentiated subpopulation of the miPS-LLCcm participates directly in the vasculogenic mimicry formation. Collectively, we show that miPS-LLCcm cells have advantages to further study tumor vasculature and to develop novel targeting strategies in the future.
authors.affiliation: Department of Biotechnology, Graduate School of Natural Science and Technology, Okayama University 3.1.1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Marta
authors.initials: M
authors.lastname: Prieto-Vila
authors.affiliation: Translational Medicine Research Center, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University 56# Xinjian South Road, Taiyuan 030001, Shanxi, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Yan
authors.affiliation: Department of Biotechnology, Graduate School of Natural Science and Technology, Okayama University 3.1.1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Anna Sanchez
authors.initials: AS
authors.lastname: Calle
authors.affiliation: Department of Biotechnology, Graduate School of Natural Science and Technology, Okayama University 3.1.1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Neha
authors.initials: N
authors.lastname: Nair
authors.affiliation: Cancer Biology Graduate Program, School of medicine, Wayne State University 10 E Warren Avenue, Suite 2215, Detroit, Michigan 48201, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Hurley
authors.affiliation: Department of Biotechnology, Graduate School of Natural Science and Technology, Okayama University 3.1.1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Tomonari
authors.initials: T
authors.lastname: Kasai
authors.affiliation: Laboratory of Bioorganic and Medicinal Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical sciences, Okayama University 1-1-1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kakuta
authors.affiliation: Department of Biotechnology, Graduate School of Natural Science and Technology, Okayama University 3.1.1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Masuda
authors.affiliation: Department of Biotechnology, Graduate School of Natural Science and Technology, Okayama University 3.1.1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Murakami
authors.affiliation: Department of Biotechnology, Graduate School of Natural Science and Technology, Okayama University 3.1.1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Mizutani
authors.affiliation: Department of Biotechnology, Graduate School of Natural Science and Technology, Okayama University 3.1.1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Seno
keywords: CAM assay; Cancer stem cells; angiogenesis; differentiation; endothelial cell; tube formation; tumor vasculature; vasculogenic mimicry