Abstract
Prostate cancer research is hampered by the lack of in vivo preclinical models that accurately reflect patient tumour biology and the clinical heterogeneity of human prostate cancer. To overcome these limitations we propagated and characterised a new collection of patient-derived prostate cancer xenografts. Tumour fragments from 147 unsupervised, surgical prostate samples were implanted subcutaneously into immunodeficient Rag2-/-γC-/- mice within 24 hours of surgery. Histologic and molecular characterisation of xenografts was compared with patient characteristics, including androgen-deprivation therapy, and exome sequencing. Xenografts were established from 47 of 147 (32%) implanted primary prostate cancers. Only 14% passaged successfully resulting in 20 stable lines; derived from 20 independent patient samples. Surprisingly, only three of the 20 lines (15%) were confirmed as prostate cancer; one line comprised of mouse stroma, and 16 were verified as human donor-derived lymphoid neoplasms. PCR for Epstein-Barr Virus (EBV) nuclear antigen, together with exome sequencing revealed that the lymphomas were exclusively EBV-associated. Genomic analysis determined that 14 of the 16 EBV+ lines had unique monoclonal or oligoclonal immunoglobulin heavy chain gene rearrangements, confirming their B-cell origin. We conclude that the generation of xenografts from tumour fragments can commonly result in B-cell lymphoma from patients carrying latent EBV. We recommend routine screening, of primary outgrowths, for latent EBV to avoid this phenomenon.
Highlights
The limitations of current preclinical models are increasingly cited as a key cause of the low success rate of oncology drug development [1]
To confirm that the source of latent Epstein-Barr Virus (EBV) was due to the proliferation of human B lymphocytes we looked for immunoglobulin heavy chain (IgH) rearrangements which occur in B lymphocytes during maturation (Fig 5A)
We were unable to prevent lymphoma development despite the use of androgen supplementation. These data highlight the importance of thorough characterisation of xenograft outgrowths
Summary
The limitations of current preclinical models are increasingly cited as a key cause of the low success rate of oncology drug development [1]. Supplementing mice with androgens and the use of mouse embryonic mesenchyme has improved engraftment efficiency [11], but the biggest improvement has been the development of mice lacking natural killer (NK) T cells, for tumours that are difficult to establish as a xenograft [10]. Despite these improvements, there are very few prostate cancer PDX lines available that are ‘near-patient’ and from the primary disease [12]
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