INTRODUCTION
Prostate cancer ranks as the second most prevalent form of cancer among men globally, with its incidence rate escalating as they age[1]. The majority of prostate cancer cases are adenocarcinomas, classified using the Gleason grading system[2]. However, as a rare subtype, prostatic urothelial carcinoma typically originates from the prostatic urethra urothelium[3]. It may be associated with the proximal prostatic duct. Hsu et al's article details the case of an 82-year-old man diagnosed with both prostate adenocarcinoma and urothelial carcinoma[4]. It provides a comprehensive account of his diagnostic journey, treatment regimen, surgical intervention, and postoperative monitoring, while also delving into the mechanisms underlying the coexistence of these two malignancies. In clinical practice, the coexistence of prostate adenocarcinoma and urothelial carcinoma is exceedingly rare. This not only complicates the diagnostic and treatment processes but also presents new challenges to current strategies for managing prostate cancer. Drawing upon current literature and the most recent research findings, this article delves into the mechanisms underlying the coexistence of prostate adenocarcinoma and urothelial carcinoma.
COEXISTENCE MECHANISM
The study of prostate adenocarcinoma in conjunction with urothelial carcinoma remains in its nascent stages. The majority of reports consist of individual cases or studies with small sample sizes, lacking the support of large-scale, multicenter data. Understanding the mechanisms behind their coexistence is crucial for clinical diagnosis, treatment, and prognosis evaluation.
The case detailed in Hsu et al's article involved an elderly male patient[4]. Perhaps we can propose a hypothesis: Androgen receptor (AR) is the key to the co-occurrence of the two tumors. Androgens can bind to the AR and transport extracellular androgens into the nucleus via this receptor. The resulting androgen-AR complexes then attach to DNA, modulating gene expression. This process influences their function in the regulation of the reproductive, immune, and endocrine systems[5]. Activation of the AR and AR-driven transcriptional programs are central to prostate cancer pathophysiology. AR plays a key role in prostate cancer, especially castration-resistant prostate cancer, through mechanisms such as point mutation, overexpression, and altered androgen biosynthesis[6]. Likewise, AR activation promotes urothelial carcinogenesis and tumor growth[7]. A systematic review and meta-analysis have uncovered a high incidence of prostate cancer within cystoprostatectomy specimens from patients diagnosed with urothelial bladder cancer. This discovery could further support the notion that AR signaling serves as a common pathway in the development of these two types of cancer[8]. This phenomenon can be elucidated at the cellular pathway level. For instance, the AR synergizes with MMP-9 and COX-2 to facilitate the migration and invasion of urothelial carcinoma and prostate cancer, thereby contributing to the development of these two types of cancer[9,10]. MMP-9, a matrix metalloproteinase, is responsible for degrading collagen and extracellular matrix components, thereby facilitating the spread of cancer cells. COX-2, an enzyme that produces prostaglandins such as PGE2, plays a pivotal role in inflammation and is frequently overexpressed in prostate and urothelial cancers, correlating with cancer progression and resistance to apoptosis. The prostaglandins produced by COX-2 can stimulate MMP-9 through heightened inflammation, leading to elevated levels of MMP-9 within the tumor microenvironment. The expression of growth factors within the tumor microenvironment could play a significant role in the concurrent development of prostate adenocarcinoma and urothelial carcinoma. The functional interplay between AR and a cascade of growth factor signaling events, such as those involving epidermal growth factor (EGF), fibroblast growth factor, insulin-like growth factor 1, vascular endothelial growth factor, and transforming growth factor-beta, orchestrates the cell cycle, apoptosis, and differentiation processes in prostate cancer cells[11]. The downregulation of AR can suppress the growth of urothelial carcinoma by inducing cellular apoptosis, decreasing cellular proliferation, and curtailing cellular migration[12]. For example, EGF can promote bladder cancer progression and invasion by enhancing AR transactivation[13]. Testosterone propels the growth of prostate cancer by activating AR through ligand binding. Initial serum testosterone levels are correlated with the risk of developing prostate cancer and the outcomes of the disease[14,15]. Testosterone has the potential to optimize its levels by modulating the expression of enzymes responsible for steroid metabolism, which convert androgen precursors into active androgens within prostate tumor cells. Research has indicated that testosterone exhibits an anti-inflammatory effect in LPS-induced prostate epithelial cells by suppressing the JAK/STAT1 signaling pathway. This suppression could explain why prostate urothelial carcinoma tends to remain confined to the prostate, rather than spreading to the bladder[16,17].
Prostate cancer combined with urothelial carcinoma may also involve tumor collision phenomenon. In tumor biology, collision tumors are a rare and complex phenomenon involving two different tumor cell populations that invade each other or grow adjacent to each other in the same tissue or organ, but without mixing of cellular components[18]. This phenomenon not only prompts an in-depth investigation into tumor biology but also offers a novel perspective on our comprehension of cellular lineage determination. The emergence of collision tumors induces substantial alterations in the microenvironment. Cells from distinct lineages, when interacting within the same microenvironment, may provoke changes in cellular signaling, thereby influencing cell fate selection[19]. For instance, a particular type of tumor cell might release specific factors that either suppress or stimulate the growth or differentiation of another type of tumor cell. Direct interaction between tumor cells and the cytokines they secrete can result in reciprocal signaling. These signals have the potential to modify gene expression within cells, thereby impacting their capacity to proliferate, migrate, and differentiate[20,21]. For instance, via contact-dependent signaling among cells, they can modify their differentiation state to accommodate alterations in their surrounding environment (Figure 1).
Figure 1 Coexistence and transformation mechanisms of adenocarcinoma and urothelial carcinoma of the prostate.
EMT: Epithelial-mesenchymal transition; MET: Mesenchymal-epithelial transition.
TRANSFORMATION MECHANISM
The transformation of prostate cancer into urothelial carcinoma is an exceedingly rare yet clinically significant phenomenon, attributed to multiple intricate mechanisms. Trans differentiation, which involves the direct conversion of one mature cell type into another, could also serve as a mechanism for this transformation in prostate cancer. This process may entail the reprogramming of particular genes and signaling pathways, rendering cancer cells highly plastic and adaptable. The theory of pluripotent cancer stem cells posits that prostate cancer cells can be effectively reprogrammed into induced pluripotent stem cells. These cells have the potential to differentiate into urothelial-like cells under a range of conditions. This process may entail the activation of particular microenvironmental signals and gene regulatory pathways[22]. Furthermore, this transition may encompass both the epithelial-mesenchymal transition (EMT) and the mesenchymal-epithelial transition (MET). The EMT is a cellular process wherein epithelial cells undergo molecular alterations to adopt characteristics akin to mesenchymal cells. MET represents the reversal of EMT, characterized by the reversion of cellular state from a mesenchymal phenotype back to an epithelial one. In the course of EMT, cancer cells boost their ability to invade and migrate by shedding epithelial traits and adopting those of mesenchymal cells. Subsequently, during MET, these cells have the potential to reacquire epithelial characteristics. Under certain conditions, a subset of stem cells can differentiate into urothelial-like cells, endowing them with features akin to urothelial carcinoma[23,24]. Gene mutations and epigenetic changes are also critical to this process. These changes may lead to abnormal cell cycle regulation and genomic instability, further promoting cancer cells' phenotypic transformation and malignant behavior. The tumor protein P63 (P63) serves as a marker for basal epithelial cells and is essential for the proper development of various epithelial tissues, such as the bladder and prostate. P63 exhibits both tumor suppressive and oncogenic characteristics and plays a pivotal role in the differentiation of prostate and urothelial cells. Dysregulation of P63 could result in aberrant differentiation, potentially elevating the risk of cancer coexistence. Prostate progenitor cells are believed to be the origin of prostate cancer tumors. PTEN and TP53 are pivotal in governing the self-renewal and differentiation processes of prostate progenitor cells. The absence of PTEN/TP53 in the prostate epithelium triggers the transformation of multipotent progenitor cells and induces an epithelial-to-mesenchymal transition, which in turn fosters tumor heterogeneity and enhances metastatic potential[25] (Figure 1).
