Abstract
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Objectives Subcutaneous xenograft mouse model of prostate cancer has been widely used for preclinical studies in cancer imaging and therapy. Despite its simplicity and convenience, subcutaneous xenograft model has some limitations due to difference of cellular matrix, blood flow, pH and microenvironment between subcutaneous and prostate tissues. The objective of this study is to develop an orthotopic mouse model of prostate cancer for preclinical studies in cancer imaging and therapy.
Methods The PC-3 cells in logarithmic growth phase were digested by 0.25% trypsin and resuspended as 5 × 107/ml in saline. The seminal vesicle gland and prostate tissue of athymic nu/nu mice were exposed by abdominal surgery while the mice were anaesthetized by inhalation of 1.5% isoflurane. The PC-3 cancer cells (1 × 105 cells) in 20 μl normal saline were injected into left prostate capsule to establish orthotopic xenograft tumor, and the equal volume of saline was injected at the same position in control mice. Establishment and growth of orthotopic PC-3 tumors were evaluated by longitudinal 11C-choline PET/CT at 2, 4, 6, and 8 weeks post implantation of PC-3 cells, respectively. Upon completion of last PET/CT at 8 weeks post implantation of tumor cells, orthotopic xenograft prostate tumor tissues were collected for post mortem histological analysis.
Results Increased 11C-choline uptake by the orthotopic xenograft PC-3 tumors was detected by 11C-choline PET/CT at 4 weeks post tumor cell implantation, along with change of tissue density at tumor cell injection site by CT scan (Fig. 1). PET quantitative analysis demonstrated SUVmax 4.91±0.89 within region of interest (ROI) drawn from tumor cell implantation site, compared to SUVmax 2.55±0.34 measured from contralateral side of capsule. Furthermore, SUVmax were 2.24±0.47 from the normal saline injected site and 2.01±0.41 from contralateral side in control mice. Xenograft prostate tumors in the mice could be detected by palpation starting 5 weeks after implantation of tumor cell and the tumor-bearing mice developed dyscrasia 6 weeks after tumor cell implantation. Establishment and growth of orthotopic xenograft tumor were further confirmed by histological analysis of postmortem prostate tissues, showing tumor growth in mouse prostate and invasion into seminal vesicles.
Conclusions An orthotopic xenograft mouse model of prostate cancer was established by implantation of PC-3 human prostate cancer cells in the prostate tissue, validate by 11C-choline PET/CT and postmortem tissue analysis. This orthotopic xenograft mouse model of prostate cancer is expected to be useful for preclinical studies in development of theranostic radiopharmaceuticals or probes for prostate cancer imaging and therapy. Research Support: This project was supported by National Science Fund of China (81301250 to Cai H). Fig. 1 Increased 11C-choline uptake by orthotopic xenograft tumors was detected by 11C-choline PET/CT. A. Focally increased 11C-choline activity was visualized in left aspect of the mouse prostate intra-capsularlly injected with PC-3 tumor cells, corresponding to tumor mass localized by tissue analysis. B. Physiological low uptake of 11C-choline in both sides of prostate in control mouse on 11C-choline PET/CT, in correlation with normal mouse prostate and semial vesicle.