Epithelial and Stromal Characteristics of Primary Tumors Predict the Bone Metastatic Subtype of Prostate Cancer and Patient Survival after Androgen-Deprivation Therapy

Abstract

Prostate cancer (PC) bone metastases can be divided into transcriptomic subtypes, by us termed MetA-C. The MetB subtype, constituting about 20% of the cases, is characterized by high cell cycle activity, low androgen receptor (AR) activity, and a limited response to standard androgen deprivation therapy (ADT). Complementary treatments should preferably be introduced early on if the risk of developing metastases of the MetB subtype is predicted to behigh. In this study, we therefore examined if the bone metastatic subtype and patient outcome after ADT could be predicted by immunohistochemical analysis of epithelial and stromal cell markers in primary tumor biopsies obtained at diagnosis (n = 98). In this advanced patient group, primary tumor International Society of Urological Pathology (ISUP) grade was not associated with outcome or metastasis subtype. In contrast, high tumor cell Ki67 labeling (proliferation) in combination with low tumor cell immunoreactivity for PSA, and a low fraction of AR positive stroma cells in the primary tumors were prognostic for poor survival after ADT. Accordingly, the same tissue markers were associated with developing metastases enriched for the aggressive MetB subtype. The development of the contrasting MetA subtype, showing the best response to ADT, could be predicted by the opposite staining pattern. We conclude that outcome after ADT and metastasis subtype can, at least to some extent, be predicted by analysis of primary tumor characteristics, such as tumor cell proliferation and PSA expression, and AR expression in stromal cells.

Metabolomic profiles of intact tissues reflect clinically relevant prostate cancer subtypes

“…Our approach provided an unambiguous differentiation of tumor samples based on metabolite levels related to different processes of clinical and prognostic significance. Our findings could be well correlated to the tumor cell differentiation based on the ISUP grading system and to the combined evaluation of tumor cell proliferation and androgen dependency based on the Ki67/PSA immunoreactive score [ 14 , 15 , 27 , 34 ].…”

“…With respect to PC heterogeneity, we characterized the metabolic differences between molecular PC subtypes based on the combined Ki67/PSA immunoreactivity score; a useful marker for tumor aggressiveness and providing prognostic information independent to the Gleason and ISUP grading. By using this score, subtype A defines a set of patients where active monitoring could be the preferred treatment [ 7 , 14 , 15 ]. The clear changes seen between the subtype A (Ki67 low/PSA high) tumors and the subtype B (Ki67 high/PSA low) cases are most prominently reflected in tissue levels of seven metabolites.…”

“…To differentiate the non-AB subtype was difficult, since its metabolic pattern lay between the patterns found for the A and B subtypes. Not surprisingly, patients with a non-AB subtype are known to have an intermediate prognosis compared to A and B patients [ 14 , 15 ].…”

“…There, Ki67 was used as a surrogate marker for tumor cell proliferation and prostate specific antigen (PSA) as marker for tumor cell differentiation and androgen dependency. Importantly, the Ki67/PSA immunoreactivity score of diagnostic tumor biopsies seems to allow prediction of patient prognosis and bone metastatic subtype [ 14 , 15 ]. Together, those various subtypes provide valuable insights into prostate tumor heterogeneity and mechanisms involved in tumor progression [ 16 , 17 ], but validated classifiers are still absent in the clinical environment to enable tailored subtype-specific therapies.…”

An In Vitro Evaluation and Network Pharmacology Analysis of Prospective Anti-Prostate Cancer Activity from Perilla frutescens

“…In fact, ligand and dimerization-free PDGFRα are about as bone-metastatic compared to the complete form of the receptor for PCa, indicative of PDGF-independent mechanism on its metastatic ability [ 89 , 90 ]. In comparison, the high expression of PDGFRβ in prostate tumor stroma was associated with PCa aggressiveness and low patient survivability [ 92 , 93 ]. PDGF-induced proliferation of mesangial cells was inhibited upon exposure to RA [ 94 ].…”