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The Influence of a Human Embryonic Stem Cell–Derived Microenvironment on Targeting of Human Solid Tumor Xenografts

¹ Rambam Medical Center, ² Rappaport Faculty of Medicine and Research Institute, ³ Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel

Requests for reprints: Maty Tzukerman, Rambam Medical Center, Rappaport Faculty of Medicine and Research Institute, 1 Efron Street, Haifa, 31096 Israel. Phone: 972-4-829-5277; Fax: 972-4-851-2380; E-mail: bimaty{at}techunix.technion.ac.il or Karl Skorecki, E-mail: skorecki{at}tx.technion.ac.il.

The awareness of the important role that the surrounding tissue microenvironment and stromal response play in the process of tumorigenesis has grown as a result of in vivo models of tumor xenograft growth in immunocompromised mice. In the current study, we used human embryonic stem cells in order to study the interactions of tumor cells with the surrounding microenvironment of differentiated human cell tissues and structures. Several cancer cell types stably expressing an H2A-green fluorescence protein fusion protein, which allowed tracking of tumor cells, were injected into mature teratomas and developed into tumors. The salient findings were: (a) the observation of growth of tumor cells with high proliferative capacity within the differentiated microenvironment of the teratoma, (b) the identification of invasion by tumor cells into surrounding differentiated teratoma structures, and (c) the identification of blood vessels of human teratoma origin, growing adjacent to and within the cancer cell–derived tumor. Mouse embryonic stem cell–derived teratomas also supported cancer cell growth, but provided a less suitable model for human tumorigenesis studies. Anticancer immunotherapy treatment directed against A431 epidermoid carcinoma cell–related epitopes induced the complete regression of A431-derived tumor xenografts following direct i.m. injection in immunocompromised mice, as opposed to corresponding tumors growing within a human embryonic stem cell–derived microenvironment, wherein remnant foci of viable tumor cells were detected and resulted in tumor recurrence. We propose using this novel experimental model as a preclinical platform for investigating and manipulating the stromal response in tumor cell growth as an additional tool in cancer research. (Cancer Res 2006; 66(7): 3792-801)

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