Spontaneous murine tumors in the development of patient-derived xenografts: a potential pitfall

Ann M. Moyer,Richard M. Weinshilboum,Jason P. Sinnwell,Travis J. Dockter,Liewei Wang,Vera J. Suman,Daniel W. Visscher,Matthew P. Goetz,Judy C. Boughey,Jia Yu

doi:10.18632/oncotarget.27001

Abstract

Patient-derived xenografts (PDX) are generated in immune deficient mice and demonstrate histologic and molecular features similar to their corresponding human tumors. However, murine tumors (non-human) spontaneously occur in these models. 120 consecutive patients with high-risk primary breast cancer enrolled in the prospective neoadjuvant BEAUTY study had tumor tissue obtained at the time of diagnosis. These tumor cells, including initial tissue and subsequent generations, were injected into either NSG (n = 365) or NOD-SCID (n = 396) female mice. Mice with initial tumor growth sufficient for transfer to the 2nd generation underwent histologic review by pathologists, including Ki67 staining. After passaging the tumors for up to 4 generations, at least one primary mouse tumor was detected from 24 of the 54 PDX-lines, for a frequency of 3.2% (24 mice out of 761 mice), including murine lymphomas (n = 13), mammary tumors (n = 7), osteosarcomas (n = 2), and hemangiosarcomas (n = 2). While true PDX showed scattered strong staining with Ki67, murine tumors were Ki67 negative. No significant differences (p = 0.062) were observed comparing development of murine tumors in NOD-SCID (n = 8) vs NSG mice (n = 16). While PDX are a useful tool in cancer research, there is a potential for spontaneous murine tumors to arise, which could alter results of studies utilizing PDX. Morphologic review by a pathologist, potentially along with Ki67 staining, is necessary to ensure that tumor growth represents the desired PDX prior to use in downstream studies. This study is the first prospective study evaluating the frequency, type, and time frame for development of non-human tumors.

Highlights

Significant resources are expended to study tumor biology and develop new therapeutic modalities, it has been estimated that as few as 5–10% of compounds with antineoplastic properties during pre-clinical testing succeed in gaining FDA approval [1, 2]
While Patient-derived xenografts (PDX) are a useful tool in cancer research, there is a potential for spontaneous murine tumors to arise, which could alter results of studies utilizing PDX
Patient-derived xenografts (PDX), which are generated by implanting tumor tissue from individual patients into immunocompromised or humanized mice, are a feasible alternative that overcome some of the limitations of traditional model systems in cancer research [3, 4]

Summary

Introduction

Significant resources are expended to study tumor biology and develop new therapeutic modalities, it has been estimated that as few as 5–10% of compounds with antineoplastic properties during pre-clinical testing succeed in gaining FDA approval [1, 2]. This is likely in part due to the limitations of model systems that have traditionally been employed in cancer research, including cell lines and animal models. These tumors may show different growth characteristics and are typically histologically distinguishable from human tumors, they represent a potential pitfall that if not identified and excluded, could lead to propagation and use of models that do not represent the patient’s tumor, resulting in erroneous conclusions

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Results

Conclusion