Challenges and Prospects of Patient-Derived Xenografts for Cancer Research

SIMPLE SUMMARY: The patient-derived xenograft (PDX) model is the in vivo standard for cancer research as a preclinical platform. Besides its merits, we describe the general rationale of various PDX models and the standard procedures of orthotopic models of gastric adenocarcinoma. We also present challenges with these models, such as loss of heterogeneity, selection bias, clonal evolution, unsuitability for immune-oncology studies, viral infections, host stroma contaminations, and oncogenic transformation of host cells, among others. Additionally, we present the emerging research prospects, such as using 3D organoid culture, humanized mouse models, syngeneic mouse models to improve interrogations, and an intronic qPCR method of biosample authentication and quantification. ABSTRACT: We discuss the importance of the in vivo models in elucidating cancer biology, focusing on the patient-derived xenograft (PDX) models, which are classic and standard functional in vivo platforms for preclinical evaluation. We provide an overview of the most representative models, including cell-derived xenografts (CDX), tumor and metastatic cell-derived xenografts, and PDX models utilizing humanized mice (HM). The orthotopic models, which could reproduce the cancer environment and its progression, similar to human tumors, are particularly common. The standard procedures and rationales of gastric adenocarcinoma (GAC) orthotopic models are addressed. Despite the significant advantages of the PDX models, such as recapitulating key features of human tumors and enabling drug testing in the in vivo context, some challenges must be acknowledged, including loss of heterogeneity, selection bias, clonal evolution, stroma replacement, tumor micro-environment (TME) changes, host cell carryover and contaminations, human-to-host cell oncogenic transformation, human and host viral infections, as well as limitations for immunologic research. To compensate for these limitations, other mouse models, such as syngeneic and humanized mouse models, are currently utilized. Overall, the PDX models represent a powerful tool in cancer research, providing critical insights into tumor biology and potential therapeutic targets, but their limitations and challenges must be carefully considered for their effective use. Lastly, we present an intronic quantitative PCR (qPCR) method to authenticate, detect, and quantify human/murine cells in cell lines and PDX samples.