Fluorescence Imaging of Tumors in Human Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models

Abstract

Patient-derived orthotopic xenografts (PDOX) mouse models can replicate the patient behavior of the tumor including metastasis. In order to develop imageable PDOX mouse models, we initially passaged patient tumors through transgenic nude mice expressing green fluorescent protein (GFP) and red fluorescent protein (RFP). The tumors acquired brightly fluorescent stroma from the transgenic host mice, which was stably associated with the tumors through growth and multiple passages. The fluorescent protein-expressing stroma included cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) in both the primary and metastatic tumors. It was possible to image the brightly fluorescent tumors noninvasively longitudinally as they progressed in non-transgenic nude mice, since the tumors stably acquired the fluorescent stroma. We subsequently showed that a single passage through an RFP mouse was sufficient to stably label a sarcoma PDOX. The telomerase-dependent GFP-containing adenovirus OBP-401 was used to label the cancer cells of a pancreatic cancer PDOX. The PDOX was previously grown in a RFP transgenic nude mouse that stably labeled the PDOX stroma cells bright red, thus providing a dual-color PDOX model with RFP stromal cells and GFP cancer cells.