It Takes A Village: Why It’s Been So Hard to Grow Prostate Cancer Patient-Derived Explants

There are many features that distinguish prostate cancer from other common solid tumors, but one of the more frustrating for researchers has been the difficulty transplanting human tumors into laboratory mice. For most solid tumors, transplantation across species varies in yield, despite the use of immune-incompetent mice and support of various growth factors; but prostate cancer stands out as being of particularly low yield. As a result, we are limited in our literature to a handful of commonly used xenografts, some of which have been studied for decades and bear little resemblance to human disease, specifically bone metastases. The lack of pre-clinical models of prostate cancer and other hard to grow tumors that spread and result in metastases is a major deficiency in the field and a source of major funding (see RFA-CA-17-003). 

In the September issue of European Urologic Oncology, Shafi et al. published their results of a novel model system to generate prostate cancer patient-derived explants (PDE), which highlight the importance of tumor microenvironment features1. In brief, they demonstrate that stromal factors in the transplanted tumor tissue are maintained in the foreign host and that these desmoplastic indices impact the subsequent responsiveness/dependency of the tumor on androgen receptor targeted therapies. These same stromal factors are not only critical to the survival and growth of tumor cells in a foreign tissue (think also metastasis), but they also drive disease resistance. While their models still come short of creating the kind of bone microenvironment that so commonly characterizes metastatic castration-resistant prostate cancer, they do highlight the importance of these stromal factors in the biology of disease progression. It is a fascinating concept that treatment resistance is not simply a selection process of resistant epithelial cell biology but instead is borne out of the microenvironment milieu. This makes sense when we commonly see incomplete, partial or mixed responses to therapy that many times result in a different metastatic pattern that was originally present when therapy started. 

Yes, establishing new prostate cancer tumors explants is hard; it undoubtedly will require a village of factors and conditions that we still may not fully understand. But within that village may lie therapeutic targets to change or halt the process most characteristic of lethal prostate cancer: metastasis.

Written by: Daniel J. George, MD, Medical Oncologist, Professor of Medicine, Professor of Surgery, Duke Cancer Institute, Durham, North Carolina

Reference:
1. Shafi AA et al. Patient-derived Models Reveal Impact of the Tumor Microenvironment on Therapeutic Response. Eur Urol Oncol. 2018 Sep;1(4):325-337.
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