A Preclinical Xenograft Model Identifies Castration-Tolerant Cancer-Repopulating Cells in Localized Prostate Tumors

This study uses a preclinical xenograft model to reveal prostate cancer cells that exist in untreated localized disease, survive androgen withdrawal, and are potential therapeutic targets. The Enemy Within Prostate cancer is one of the most common types of cancer in men. In advanced stages, it is typically treated with medications that mimic castration, depriving the tumor of androgen stimulation. Unfortunately, these cancers eventually become castration-resistant and begin to grow even in the absence of hormonal input. What isn’t known is how these cancer cells develop the ability to survive androgen deprivation, and whether some types of stem-like castration-resistant cells are already present in prostate cancer from early stages or evolve later during the course of treatment. Now, Toivanen and colleagues shed some light on this mystery, with a report of castration-tolerant cells derived from early localized tumors that had not yet been exposed to anti-androgen therapy. The authors used primary prostate tumors from 12 men with localized cancer, implanting them in a mouse xenograft model to study the effects of androgen deprivation on the tumors’ survival. Castration of the host mice led to rapid regression, but not disappearance of the tumors. Even after a prolonged period of castration (4 weeks), some residual tumor foci persisted. When testosterone stimulation was restored in the host animals, these residual cells rebounded, regenerating masses that were histologically similar to the original tumors. This work by Toivanen et al. indicates that some prostate cancer cells can survive castration and later repopulate the tumor when androgen stimulation is available. Thus far, there is no indication that these castration-tolerant cells can proliferate in the absence of androgens, unlike the cells found in more advanced “castration-resistant” prostate cancer. Additional work will be needed to clarify whether these might be a type of prostate cancer stem cells, and what makes them different from the population of “androgen-sensitive” cancer cells that do not survive androgen depletion. Although there are many questions that must still be answered about the biology of these castration-tolerant cells, this work raises the intriguing possibility that we may eventually be able to specifically target and eradicate them, thus preventing prostate cancer recurrence in patients. A lack of clinically relevant experimental models of human prostate cancer hampers evaluation of potential therapeutic agents. Currently, androgen deprivation therapy is the gold standard treatment for advanced prostate cancer, but inevitably, a subpopulation of cancer cells survives and repopulates the tumor. Tumor cells that survive androgen withdrawal are critical therapeutic targets for more effective treatments, but current model systems cannot determine when they arise in disease progression and are unable to recapitulate variable patient response to treatment. A model system was developed in which stromal-supported xenografts from multiple patients with early-stage localized disease can be tested for response to castration. The histopathology of these xenografts mimicked the original tumors, and short-term host castration resulted in reduced proliferation and increased apoptosis in tumor cells. After 4 weeks of castration, residual populations of quiescent, stem-like tumor cells remained. Without subsequent treatment, these residual cells displayed regenerative potential, because testosterone readministration resulted in emergence of rapidly proliferating tumors. Therefore, this model may be useful for revealing potential cellular targets in prostate cancer, which exist before the onset of aggressive incurable disease. Specific eradication of these regenerative tumor cells that survive castration could then confer survival benefits for patients.