Establishing an appropriate preclinical model is crucial for translational cancer research. The most common way that has been adopted by far is grafting cancer cell lines, derived from patients. Although this xenograft model is easy to generate, but has several limitations because this cancer model could not represent the unique features of each cancer patient sufficiently. Moreover, accumulating evidences demonstrate cancer is a highly heterogeneous disease so that a tumor is comprised of cancer cells with diverse characteristics. In attempt to avoid these discrepancies between xenograft model and patients’ tumor, a patient-derived xenograft (PDX) model has been actively generated and applied. The PDX model can be developed by the implantation of cancerous tissue from a patient’s tumor into an immune-deficient mouse directly, thereby it preserves both cell-cell interactions and tumor microenvironment. In addition, the PDX model has shown advantages as a preclinical model in drug screening, biomarker development and co-clinical trial. In this review, we will summarize the methodology and applications of PDX in detail, and cover critical issues for the development of this model for preclinical research.

The interferon-inducible Sp100 proteins are thought to play roles in the chromatin pathway and in transcriptional regulation. Sp100A, the smallest isoform, is one of the major components of PML nuclear bodies (NBs) that exhibit intrinsic antiviral activity against several viruses. Since PML NBs are disrupted by the immediate-early 1 (IE1) protein during human cytomegalovirus (HCMV) infection, the modulation of Sp100 protein expression or activity during infection has been suggested. Here, we show that Sp100 proteins are lost largely in the late stages of HCMV infection. This event required viral gene expression and involved posttranscriptional control. The mutant virus with deletion of the sequence for IE1 (CR208) did not have Sp100 loss. In CR208 infection, PML depletion by RNA interference abrogated the accumulation of SUMO-modified Sp100A and of certain high-molecular-weight Sp100 isoforms but did not significantly affect unmodified Sp100A, suggesting that the IE1-induced disruption of PML NBs is not sufficient for the complete loss of Sp100 proteins. Sp100A loss was found to require proteasome activity. Depletion of all Sp100 proteins by RNA silencing enhanced HCMV replication and major IE (MIE) gene expression. Sp100 knockdown enhanced the acetylation level of histones associated with the MIE promoter, demonstrating that the repressive effect of Sp100 proteins may involve, at least in part, the epigenetic control of the MIE promoter. Sp100A was found to interact directly with IE1 through the N-terminal dimerization domain. These findings indicate that the IE1-dependent loss of Sp100 proteins during HCMV infection may represent an important requirement for efficient viral growth.During the early stages of human cytomegalovirus (HCMV) infection, the 72-kDa immediate-early 1 (IE1 or IE72) protein targets the subnuclear structures referred to as PML nuclear bodies (NBs) (also known as nuclear domain 10 [ND10] or PML oncogenic domains [PODs]), in which input viral genomes are deposited and IE transcription occurs (22). However, the targeting of IE1 to PML NBs is transient, and subsequently, PML NBs are disrupted in an IE1-dependent manner and both IE1 and the components of PML NBs, including PML and Sp100 proteins, are relocalized into the nucleoplasm (4, 25, 27, 53). Several lines of evidence suggest that this early event promotes viral replication. The overexpression of PML conferred resistance to HCMV infection (3), and the analysis of IE1 mutants demonstrated that the ability of IE1 to disrupt PML NBs was correlated with its transactivation activity and efficient viral growth in cells transfected with HCMVbacterial artificial chromosome (BAC) DNA (30). In addition, the depletion of PML by RNA interference has been reported to promote viral replication efficiency (47). These results support the notion that PML NBs are intrinsic defense sites at which the epigenetic silencing of input viral DNA genome may take place and that the components of PML NBs perform antiviral roles against a variety of DNA and RNA vir...