Regulatory signaling network in the tumor microenvironment of prostate cancer bone and visceral organ metastases and the development of novel therapeutics

Abstract

This article describes cell signaling network of metastatic prostate cancer (PCa) to bone and visceral organs in the context of tumor microenvironment and for the development of novel therapeutics. The article focuses on our recent progress in the understanding of: 1) The plasticity and dynamics of tumor–stroma interaction; 2) The significance of epigenetic reprogramming in conferring cancer growth, invasion and metastasis; 3) New insights on altered junctional communication affecting PCa bone and brain metastases; 4) Novel strategies to overcome therapeutic resistance to hormonal antagonists and chemotherapy; 5) Genetic-based therapy to co-target tumor and bone stroma; 6) PCa-bone-immune cell interaction and TBX2-WNTprotein signaling in bone metastasis; 7) The roles of monoamine oxidase and reactive oxygen species in PCa growth and bone metastasis; and 8) Characterization of imprinting cluster of microRNA, in tumor–stroma interaction. This article provides new approaches and insights of PCa metastases with emphasis on basic science and potential for clinical translation. This article referenced the details of the various approaches and discoveries described herein in peer-reviewed publications. We dedicate this article in our fond memory of Dr. Donald S. Coffey who taught us the spirit of sharing and the importance of focusing basic science discoveries toward translational medicine.

Impact of Extraskeletal Metastases on Skeletal-Related Events in Metastatic Castration-Resistant Prostate Cancer with Bone Metastases

“…As anticipated, patients with BESM displayed worse survival outcomes. This is consistent with previous studies [21,27,28] and raises awareness of a patient population for whom novel approaches are urgently required.…”

“…Therefore, patients with BESM are at higher SRE risk and should receive a more conservative treatment schedule (i.e., every 4 weeks), at least during the first year of treatment. It remains unknown whether humoral factors affecting bone resorption are produced by extraskeletal metastases and/or whether cancer cells can circulate from different metastatic sites (outside of bone to bone and vice versa) to restimulate microenvironment [10,20,21]. Despite similar metastatic bone disease burden and disease biology, this cohort shows an impact of BESM on SREsthat is not captured by corrected uNTX and bALP levels.…”

“…Visceral metastases have long been considered a negative prognostic factor for survival in mCRPC [7,12,21]. In this large and high-quality cohort of patients with mCRPC and bone metastases receiving BTAs, patients with bone plus extraskeletal metastases had a similar baseline and 3-month normalization patterns of bone remodeling markers as patients with bone-only metastases, but a higher risk of SREs, SSEs, and death irrespective of bone disease volume and disease aggressiveness features.…”

Neuroendocrine Differentiation of Prostate Cancer—An Intriguing Example of Tumor Evolution at Play

“…In addition, recent progress has led to a widespread appreciation of the reciprocal communications between PCa cells and the cells of the tumor microenvironment (TME), e.g., mast cells, macrophages, bone marrow stromal cells (BMSCs), and cancer associated fibroblasts (CAFs), and how these interactions are critical in shaping PCa progression including NED [24,25,26,27,28,29,30]. The primary factors that make NEPC the most lethal form of PCa is due to the lack of response of the AR to ADT, in part due to weak or absent AR and prostate-specific antigen (PSA); thereby, presenting a therapeutic challenge in the clinic.…”

In honor of Dr. Donald S. Coffey – Prostate cancer biology and therapy

“…Senescent tumor cells generate a catabolic state with increased glycolysis, protein turnover and other metabolic changes that represent targets for drugs, like metformin, to be applied in a synthetic lethal approach. Dr. Leland W. K. Chung and colleagues [8] described the cell signaling network of metastatic PCa to bone and visceral organs in the context of tumor microenvironment. These works provide new targets for treatment and new insights into the basic science of PCa metastasis.…”