Targeting Inflammatory Signaling in Prostate Cancer Castration Resistance

Abstract

Although castration-resistant prostate cancer (CRPC) as a whole, by its name, refers to the tumors that relapse and/or regrow independently of androgen after androgen deprivation therapy (ADT), untreated tumor, even in early-stage primary prostate cancer (PCa), contains androgen-independent (AI) PCa cells. The transformation of androgen-dependent (AD) PCa to AI PCa under ADT is a forced evolutionary process, in which the small group of AI PCa cells that exist in primary tumors has the unique opportunity to proliferate and expand selectively and dominantly, while some AD PCa cells that have escaped from ADT-induced death acquire the capability to survive in an androgen-depleted environment. The adaptation and reprogramming of both PCa cells and the tumor microenvironment (TME) under ADT make PCa much stronger than primary tumors so that, currently, there are no effective therapeutic methods available for the treatment of CRPC. Many mechanisms have been found to be related to the emergence and maintenance of PCa castration resistance; in this review, we focus on the role of inflammatory signaling in both PCa cells and the TME for the emergence and maintenance of CRPC and summarize the recent advances of therapeutic strategies that target inflammatory signaling for the treatment of CRPC.

Focus on the tumor microenvironment: A seedbed for neuroendocrine prostate cancer

“…The addition of IL-6 receptor inhibitors during co-culture prevented NE marker upregulation in progeny cells. Thus, tumor-infiltrating M2-TAMs promote the NED process by activating downstream IL-6 signaling (Wang et al, 2018;Zhong et al, 2021).…”

“…Inflammatory factors transmit signals promoting androgen-independent (AI) cells self-renewal and proliferation. AI cells are important bridges in NEPC Frontiers in Cell and Developmental Biology frontiersin.org formation, autonomously secrete the proinflammatory factors IL-8, IL-6, and TGF-β, protect themselves against apoptosis, and induce NED (Archer et al, 2020;Kiely and Ambs, 2021;Zhong et al, 2021). The summary of the roles of non-cellular components can be seen in Figure 1.…”

“…NF-κB induces stemness and lineage transformation in pancreatic and skin cancers (Liu Z. et al, 2021). In PCa, NF-κB upregulates the stem cell TFs TWIST2, SOX2, Oct4, and Nanog, which control the numbers of cancer stem cells (CSCs) (Thomas-Jardin et al, 2020;Zhong et al, 2021). SOX2 causes prostate cancer cells to dedifferentiate into CSCs and activate the proto-oncogene SPINK1, which induces CSC differentiation into neuroendocrine tumor cells (Bhatia and Ateeq, 2019;Tiwari et al, 2020;Yamada and Beltran, 2021).…”

“…It activates the PCa immune response and recruits various inflammatory cells for their infiltration (Long et al, 2020). In the early stages of tumor formation, tumor-killing NK and CD8 + T cells as well as M1-TAMs are the primary infiltrating inflammatory cells and inhibit tumor cell proliferation (Zhong et al, 2021). In the later stages of tumor formation, however, the infiltrating inflammatory cells are transformed into various inhibitory inflammatory cells that secrete IL-8, IL-6, and TGFβ, which promote NEPC formation (Jia et al, 2014;Long et al, 2020).…”

Choosing Kinase Inhibitors for Androgen Deprivation Therapy-Resistant Prostate Cancer

“…Androgen deprivation therapy (ADT) is a systemic therapy for advanced PCa. Although a majority of patients initially respond to ADT, the responses are transient and almost all cancers eventually develop castration resistance [ 4 , 5 , 6 , 7 , 8 , 9 ]. Castration-resistant PCa (CRPC) is associated with a very poor prognosis, and the treatment of which is a serious clinical challenge [ 4 , 5 , 6 , 7 ].…”