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Targeting HNRNPC as a means to activate the immune microenvironment could
potentially serve as a viable treatment approach for advanced prostate cancer [20].
10.5 Stromal Compartment inProstate Cancer
The prostatic stromal milieu encompasses several anatomical and physiological elements that are relevant to the proper functioning of the gland. The genesis and progression of PCa are inuenced by changes in several stromal elements. The
phenomenon of epithelial neoplastic change in the prostate gland is intricately
linked to its surrounding environment. In addition to the inuence of microenvironmental variables, molecular changes occurring inside the cells themselves are
known to exert a substantial impact on this process. The progression and spread of
prostate tumors are dependent on the complex interaction between malignant cells
and the components of the surrounding stroma [21]. Fibroblasts have a crucial role
in the composition of the prostatic stroma. Epithelial cells are preserved in their
structural integrity through continuous remodeling and dynamic interactions with
various components inside the organ [22]. Fibroblasts have a role in the production
of ECM by secreting collagen type I and type III.They also facilitate tissue regeneration by orchestrating the controlled creation of granulation tissue and subsequent
transformation into myobroblasts (MFB). During the process of prostatic neoplastic transformation, the stromal smooth muscle cells undergo replacement by a distinct type of broblasts known as CAF.The presence of cancer stroma has been
found to stimulate the upregulation of broblast-specic markers, including vimentin, broblast-specic protein (FSP), and alpha-smooth muscle actin (α-SMA),
while concurrently downregulating the expression of desmin [8]. CAFs are signicant contributors to the process of angiogenesis and the modication of ECM components. These effects are mediated by various factors, including interleukin-6
(IL-6), broblast growth factor (FGF), transforming growth factor beta (TGF-β),
hypoxia inducible factor 1 alpha (HIF-1α), growth differentiation factor 15 (GDF15),
vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF)
[23, 24]. According to Sahai etal. (2020), the interaction between tumor cells and
Cancer-associated broblasts results in the development of an unregulated “reactive
stroma,” which promotes the proliferation and aggressiveness of cancer cells and
inuences their response to treatment [25].
The development of prostate tumors is undeniably reliant, to some degree, on the
stimulation of angiogenesis. The development of blood vessels has a vital role in
promoting the survival and proliferation of cancer cells [26, 27]. Within the context
of normal prostatic tissue, a state of equilibrium is observed in the interplay among
smooth muscle cells, pericytes, and endothelial cells. Nevertheless, the vasculature
of tumors is distinguished by the abnormal development of juvenile blood vessels
that are permeable and do not possess pericyte coverage [28]. The process of angiogenesis, which involves the formation of new blood vessels, is facilitated by the
interaction among tumor cells and stromal endothelial cells. This interaction leads
10 Prostate Cancer andTumor Microenvironment
211
to the activation of an “angiogenic switch” by upregulating the expression of proangiogenic proteins, including vascular endothelial growth factor [28]. The study
conducted by Zhao etal. (2018) provided evidence supporting the notion that endothelial cells play a signicant role in the tumor microenvironment by promoting
metastatic activity through the suppression of androgen receptor (AR) expression
and transcriptional activity [29]. Consequently, the researchers suggested that inhibiting endothelial cells could potentially impede the progression of PCa.
Immune cells are often present within a state of normalcy in the prostatic tissue
of individuals who are in good health, and they serve a defensive function by guarding against the invasion of infections [30]. Histological investigations have revealed
a correlation between high-grade PCa and heightened inltration of stromal immune
cells, with variations in cellular composition based on the stage of the tumor [31].
The progress of a chronic inammatory state within the prostate can be inuenced
by ongoing stresses, including a high-fat diet, direct infection, estrogens, and urinary reux [32]. In the context of ongoing inammation, the stromal compartment
experiences an inow of various immune cells, including macrophages, natural
killer (NK) cells, CD3+ T cells, macrophages, CD20+ B cells, and mast cells [6].
Inammatory cells are known to generate substantial quantities of cytokines and
chemokines, including but not limited to tumor necrosis factor (TNF), interleukin-6
(IL-6), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), and nuclear
factor kappa B (NF-κB). These proteins, along with others, are involved in the
adjustment of angiogenesis, cellular proliferation, and inammation. Worthington
etal. (2012) assert that they facilitate the progression toward a malignant phenotype
in PCa [33]. The involvement of inammation in prostate cancer has facilitated the
exploration of new anti-inammatory medications for the prevention and potential
treatment of PCa [34].
The concept of “tight interlocking” refers to a close and interconnected relationship between different elements or components. The extracellular matrix (ECM)
that envelops prostate epithelial cells consists of many non-collagenous proteins
and collagenous bers, including osteocalcin, bronectin, osteonectin, cadherin,
vitronectin, and bone sialoprotein [35]. ECM serves as a structural support system
that facilitates the maintenance of cellular homeostasis within various organ systems. As the neoplastic process occurs and metastatic progression takes place, there
is an alteration in the expression of several extracellular constituents, resulting in
upregulation, downregulation, or loss. The expression of collagen type VII is
observed to decrease, while the manufacturing of bone sialoproteins is observed to
increase in association with advanced prostate cancer [36, 37]. The dependency of
metastatic development on the disruption of the ECM barrier is apparent. In order
for invasion and metastasis to take place, malignant cells are required to generate a
variety of proteases and protein-degrading enzymes [38]. Matrix metalloproteinases
(MMPs) are a class of peptidases that require zinc for their enzymatic activity.
These enzymes have a broad range of binding afnities toward ECM proteins,
including collagens, bronectins, and laminin [39]. The expression of MMPs,
including MMP-1, MMP-2, MMP-7, MMP-9, and MT1-MMP, becomes more evident in the stroma and bloodstream as PCa progresses. This suggests that these
212
molecules may have predictive value, as shown by Gong etal. (2014) [40]. However,
despite their theoretical potential in targeting PCa, MMP-inhibiting medicines such
as batimastat and marimastat could not demonstrate efcacy in phase III clinical
studies [41].
A. Nazari et al.
10.6 The Microenvironment ofPCA andtheMarkers
Associated withCancer Stem/Progenitor Cells
The initial discovery of prostate stem cells was documented in the 1980s by English
and coworkers (1987) [42]. Subsequently, there has been a growing acceptance
among the scientic community about the possibility that prostate cancer (PCa)
may originate from cancer stem cells (CSCs). There has been an increasing surge of
scientic inquiry focused on the characterization of these stem cells [43, 44]. The
distinctive capacity for plasticity, self-renewal, pluripotency, and the ability to
restore complete tumor heterogeneity have ushered in a new era of therapeutics and
diagnostics. Consequently, there is now a critical need to comprehensively comprehend the methods for detecting prostate cancer stem cells and identifying their
potential markers [45–47]. The resistance of prostate CSCs to therapeutic interventions, including radiotherapy, can be attributed to various intricate mechanisms.
These mechanisms contain the presence of a hypoxic microenvironment, enhanced
DNA repair capabilities, epithelial-to-mesenchymal transition processes [48],
increased intracellular scavenging of activation of anti-apoptotic signaling pathways, autophagy, and reactive oxygen species [49]. It is crucial to acknowledge that
prostate cancer stem cells represent a small proportion of the overall tumor mass,
primarily localized in the proximal areas of the prostatic ducts. The stem cells are
situated within specialized habitats that possess intricate microenvironments that
are strongly intertwined with the surrounding host cells. The prevailing consensus
in the scientic community is that prostate cancer stem cells are primarily found in
the basal cell compartment. However, there is continuous debate and extensive
research about the presence of these cells in the luminal compartment [50]. The
signicant decline in the survival rates of individuals with recurring or metastatic
tumors served as a primary catalyst for the exploration of CSCs in the context of
prostate cancer.
Harris and colleagues (2017) have shown that the formation and progression of
PCa are inuenced by a wide range of CSC indicators [51]. These markers not only
contribute to therapy resistance and the ability of cancer cells to colonize and proliferate in distant sites but also play a signicant role in the overall pathogenesis of
PCa. The extracellular markers associated with CSCs in PCa, although not particularly exclusive to this particular cancer type, include CD166/ALCAM, CD117/ckit, CXCR4, α6 integrin, CD133, Trop2, CD44, α2β1 integrin, E-cadherin,
cytokeratin 5, EpCAM, ABCG2, PSA, and AR variant 7 [52]. The intracellular indicators that have been identied include ALDH1, TG2, and EZH2. It is vital to
10 Prostate Cancer andTumor Microenvironment
213
acknowledge the conventional stemness markers, including Nanog, OCT3/4,
c-MYC, SOX2, and KLF4, as stated by Harris and Kerr (2017) [51]. After discussing the aforementioned indicators, it is necessary to emphasize the latest developments in the identication of prostate CSCs. In a recent study, Hu and coworkers
discovered a strong correlation between the expression of basic transcription factor
3 (BTF3) and the presence of stemness characteristics. The reduction in metastatic
potential and self-renewal capacities was observed in cases of basic transcription
factor 3 deletion, whereas an increase in these characteristics was observed in cases
of BTF3 overexpression. The proposed method is centered on the hypothesis that
BTF3 has the ability to enhance the stability of BMI1, a critical regulator of selfrenewal in prostate CSCs. The researchers additionally provided evidence to support the notion that BTF3 has the potential to serve as a strong predictor of an
unfavorable prognosis. Consequently, it can be utilized as a means to categorize
patients based on their risk levels [53]. Mawaribuchi and colleagues showed that the
recombinant lectin rBC2LCN exhibits potential as a cancer stem cell marker in
prostate cancer. The fraction of PC-3 rBC2LCN-positive cells displayed characteristics commonly associated with CSCs, including reduced proliferation, increased
cell motility, the ability to develop independently of anchorage, and resistance to
therapy [54].
Simeckova and colleagues conducted an evaluation of the expression of Skp2, a
crucial element of the SCF E3 ubiquitin ligase, which is commonly observed to be
upregulated in PCa and other neoplastic conditions. The ndings of the study indicated that Skp2 exhibited a signicant upregulation in PCa cells that possessed
characteristics like stem cells and mesenchymal cells, as opposed to epithelial cells.
It is important to mention that a shift from an epithelial to a non-epithelial/mesenchymal phenotype has been earlier demonstrated to be associated with the observed
invasiveness in cancer stemness [55].
The expression of the stemness trait was diminished in cells exhibiting a suppressed Skp2 gene. Furthermore, the downregulation of Skp2 resulted in a decrease
in the subpopulation of CD44+/CD24− prostate cancer stem cell (PCSC), providing
additional evidence for the signicant role of Skp2in maintaining the stem-like
properties of PCa [55]. Through the utilization of lineage retracing, Yoo and coworkers successfully recognized a specic subpopulation of Bmi1+ Sox2+ CRPC cells
that may serve as a plausible origin for the recurrence of disease in an invivo setting
[56]. The results of this study may provide support for the strategic focus on particular subgroups responsible for the observed effects, with the aim of developing targeted treatment interventions [56]. Federer-Gsponer etal. (2020) demonstrated the
presence of a stemness-associated marker pattern in both hormone naïve and
castration- resistant samples, suggesting a potential association with castration resistance [57]. An intriguing discovery was made regarding a distinct pattern of mutual
exclusivity observed in the expression of ALDH1A1 and ALDH1A3. It is important
to highlight that this particular trend was identied within publicly available datasets at the transcriptome level. Hence, it is imperative to do additional research in
order to unravel this pattern and gain a more comprehensive comprehension of the
distinct impact of these markers.
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Another type of marker that is important pertains to stromal markers. For example, Mahal and coworkers demonstrated the signicance of these markers by a comprehensive examination of radical prostatectomy samples at the genomic level [58].
After conducting an analysis that involved examining the correlation between
expression scores and classical stromal genes, as well as other important stromal
markers such as Transgelin (TAGLN), Caveolin-1 (CAV1), and Vimentin (VIM),
along with CD3 and CD4 markers and basal activity, the investigator reached the
conclusion that the highest 10% of stromal expression was linked to elevated
genomic risk scores (Decipher ≥0.6), Gleason 9 to 10 disease, an increased likelihood of metastasis (hazard ratio, 2.35; 95% CI, 1.37–4.02; p= 0.001), and high
Cancer of the Prostate Risk Assessment-Postsurgical (CAPRA-S) scores.
Furthermore, it was observed that an elevated stromal inltration score was linked
to a decrease in the expression of DNA repair genes and an increase in radiation
sensitivity genomic scores, as reported by Mahal etal. (2020) [56]. Yasumizu etal.
directed their attention toward the mucin 1 C-terminal subunit (MUC1-C) protein,
which exhibits signicant expression levels in castration-resistant neoplasms and
neuroendocrine prostate cancer. The overexpression of MUC1-C in androgendependent prostate cancer cells inhibits the functionality of both p53 signaling pathways and the androgen receptor [59]. Conversely, it also results in the upregulation
of OCT4, KLF4, MYC, and SOX2 (together referred to as the Yamanaka factors),
promoting an augmented state of pluripotency. Hence, from a therapeutic perspective, it is plausible to consider MUC1-C as a potential target for combating the
stemness of prostate cancer [59].
The present advancements primarily center around liquid biopsies as a minimally invasive approach for characterizing CSCs. However, a potential breakthrough in marker identication could involve transitioning from utilizing prostate
cancer cell lines to patient-derived tumors. This shift would offer a more comprehensive comprehension of metastatic mechanisms and treatment resistance processes. The utilization of patient-derived organoids, which possess the ability to
accurately mimic the molecular, biochemical, and structural characteristics of the
original tumor, has the potential to enhance ongoing research endeavors and address
the challenges associated with sustaining an invitro luminal phenotype [60].
Bone metastasis is a frequently observed occurrence in PCa and necessitates
signicant therapeutic intervention. When PCa spreads to the bone, the resulting
milieu can trigger changes in the epigenome and remodeling of cancer cells with
stem cell-like properties. This process enhances the ability of cancer cells to adapt
to the bone microenvironment, ultimately leading to the development of secondary
tumor metastasis [61]. The research team has earlier discovered that the RNA binding motif 3 (RBM3) has an impact on the stem cell-like characteristics of prostate
cancer by disrupting the process of alternative splicing of CD44. The current understanding of the ability of RBM3, a stress-response protein, to counteract the microenvironmental changes associated with PCa bone metastases is still lacking.
Through the process of co-culturing PCa cells with osteoblasts, researchers were
able to create a model that mimics the bone metastasis of PCa. This model allowed
them to observe that RBM3, a specic protein, increases the level of
10 Prostate Cancer andTumor Microenvironment
215
N6-methyladenosine (m6A) methylation on the messenger RNA (mRNA) of catenin
beta 1 (CTNNB1). This increase in methylation was found to be dependent on the
presence of methyltransferase 3 (METTL3), which is a catalytic subunit of the
N6-adenosine-methyltransferase complex. As a result, this alteration leads to a
reduction in the stability of CTNNB1 mRNA, subsequently causing the inactivation
of wingless homolog (Wnt) signaling. Consequently, this inhibits the remodeling of
prostate cancer cells by osteoblasts, so affecting their stemness. Therefore, the current investigation has the potential to enhance knowledge regarding the inhibitory
function of RBM3, specically in relation to bone metastases of prostate cancer [61].
10.7 Conclusion
The involvement of a reactive tumor stroma has been demonstrated to have a pivotal
impact on both the start and progression of tumors. Indeed, it is widely recognized
that prostate cancer stem cells (CSCs) have the potential to undergo a process of
recruitment, leading to their differentiation into myobroblasts or carcinomaassociated broblasts. Several crucial regulators of this recruiting and conversion
procedure have been found. The intricate and multifaceted interplay between the
carcinoma and the stroma is precisely regulated by the aforementioned parameters.
It is important to consider that the reactive stroma can develop early, potentially
even during preneoplastic stages. Additionally, the lack of success in clinical trials
involving inhibitors of angiogenesis and other processes related to the prostate
microenvironment in cancer underscores the need for further investigation.
Researchers should actively search for clinically signicant targets before the stromal components exert their complete cancer-promoting inuence [62]. Circulating
plasma and urine biomarkers hold signicant value and have the potential to contribute to the diagnosis, selection of treatment, and evaluation of response in the
context of PCa in the foreseeable future. Furthermore, it is imperative to recognize
that there are valuable insights to be gained from the limitations encountered in past
trials of anti-angiogenic drugs. Consequently, it is crucial that scientic endeavors
are focused on avenues that circumvent errors that have been previously made.
Furthermore, it is imperative to address the unfullled requirement of completely
harnessing the capabilities of biomarkers beyond prostate-specic antigen (PSA),
as the issues of excessive diagnosis and treatment of patients are of paramount concern. Two other biomarkers that have received approval from the US Food and Drug
Administration (FDA) are the prostate health index (PHI) and the prostate cancer
antigen 3 (PCA3). While the PHI is known for its affordability, the non-invasive
4Kscore blood test has also demonstrated the ability to predict clinically signicant
prostate cancer. Consequently, this has the potential to reduce the number of unnecessary biopsies. Additional urine liquid biopsy tests, such as Select MdX and
Exosome Dx, have demonstrated signicant potential. However, it is imperative to
conduct further investigations in order to create comprehensive clinical integration.
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A. Nazari et al.
Further investigation is necessary to achieve a comprehensive consensus on a specic marker, as suggested by Becerra etal. (2020) [63]. The process of changing the
neoplastic environment is a critical factor in driving tumor invasiveness. The efcacy of this process relies signicantly on the extent of extracellular matrix penetration, the reorganization of brillar components, and the interaction between cancer
and stroma.
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