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stem- like cell features following the activation of the polycomb repressor complex
and over-expression of pluripotency genes like Nanog, Oct4, Sox2, Lin28, and others. This is linked to an increase in the cells’ ability to form clones and prostaspheres invitro and tumorigenicity invivo. Importantly, miR-200b and miR-200c
connect EMT phenotypes to CSCs markers throughout the process. Reversed EMT
and decreased self-renewal ability are caused by over-expression of miR-200 family, which regulates the expression of Notch1 and/or Lin28B [150]. The link between
EMT induction and the development of a prostate CSC-like phenotype after androgen deprivation has also been demonstrated by Sun and colleagues [119]. After
castration, the gene expression proles of the prostate tissues in normal and castrated mice show a reversal of E-cadherin expression and an upregulation of mesenchymal markers such N-cadherin, Zeb1, Twist, and slug. Several mesenchymal
markers, such as Vimentin, Zeb1, Zeb2, Twist1, Snail1, and Slug, are shown to be
greatly elevated in the Lin−CD44+CD133+Sca-1+CD117+ cells, according to
microarray gene analysis. Mouse prostate non-stem cells, as contrasted with those
Lin−CD44−CD133−Sca-1−CD117 [119].
In another investigation, Fang and colleagues illustrated that the Wnt/β-Catenin
pathway is negatively regulated by β-ionone, which in turn inhibits the EpithelialMesenchymal Transition (EMT) in prostate cancer cells [151]. Human PC-3 prostate cancer cells (PC3) and Human 22RV1 prostate adenocarcinoma cells (22RV1)
showed considerable inhibition of migration, invasion, and EMT after being treated
with β-ionone. Also, naked mice that were given xenografts to grow under the skin
showed no signs of tumor growth or EMT when given β-ionone. After being treated
with β-ionone, the study also discovered that the EMT-promoting protein β-catenin
was downregulated. Upstream migration, invasion, and EMT processes were
impeded by β-ionone because it sped up the ubiquitination and degradation of
β-catenin in PCa, according to additional mechanistic investigations.
A member of the immunoglobulin superfamily, Contactin1 (Cntn-1) is a glycoprotein found on neuronal membranes that aids in cell attachment. Several different
forms of carcinoma have demonstrated that the protein uses EMT-dependent promotion to increase cell invasion, migration, and metastasis [152]. In prostate cancer
cell lines and xenografts, downregulation of Cntn-1 led to reduced PI3K/Akt signaling activity and docetaxel resistance [153]. Given the substantial correlation between
Pten loss and PI3K/AKT dysregulation with advanced prostate cancer and CRPC,
our preclinical study highlights the possibility of a joint function between EMT and
common driver mutations for prostate cancer.
Recent research reveals that restoring Pten in breast cancer models suppresses
EMT and stemness CSCs activity via Abi1 (Abelson interactor 1) downregulation
[154]. Previous studies have also demonstrated that Pten depletion promotes
EMT.Actin cytoskeletal reorganization and intercellular adhesion have both been
linked to the adaptor protein Abi1. Through its regulation of the EMT-WNT pathway, Abi1 recently regulated prostate cancer development and epithelial plasticity
[154]. Activation of the FYN-STAT3 axis and the non-canonical WNT receptor
Fzd2 were both identied as pathways by which Abi1 regulates EMT [154]. Another
recognized EMT driver, TGF-β1, was found to increase progression through
5 Prostate Cancer andMetastasis: AnEmphasis onEMT Mechanism
127
migration, invasion, and tumor initiation by means of an isoform that is produced
through alternative splicing of CD44 [155]. Furthermore, NOTCH signaling activates the estrogen receptor, which makes it a key role in stem-like basal cells, and
this pathway is involved in EMT and metastasis [156].
Moreover, Zhang and co-workers indicated that the NF-κB pathway is used by
prostate cancer cells to halt EMT and proliferation when Notch-4 is silenced [157].
Notch-4 expression was shown to be signicantly higher in the prostate cancer cell
lines DU145, PC3, and LnCAP as compared to the non-malignant prostate epithelial cell line RWPE1, according to the current study. Reducing Notch-4 expression
in DU145 and PC3 prostate cancer cell lines reduced their vitality and proliferation.
A decrease in Notch-4 considerably enhanced apoptosis in PC3 cells, according to
another research. Reductions in cell motility and invasion as well as changes to
EMT marker expression were seen with Notch-4 silencing. Researchers tested the
hypothesis that Notch-4 ablation reduces NF-κB activity by activating NF-κB p50
and p65in PC3 cells with PMA.The ndings show that PMA administration hindered the effects of Notch-4 ablation on PC3 cell biology, such as cell proliferation,
cell death, migration, invasion, and EMT.The current study’s ndings demonstrate
that prostate cancer progression can be inhibited by RNAi targeting Notch-4
expression.
When describing the tumor microenvironment (TME) and immune landscape,
the genetic background plays a signicant role. The immunological makeup of the
tumor microenvironment (TME) in generated tumors varied signicantly between
genetically engineered mice models (GEMMs) bearing homozygous Pten deletion,
according to research by Bezzi and co-workers. Correlating to the attraction of
myeloid cells through distinct pathways, loss of the Zbtb7a gene in conjunction
with Pten loss increased Cxcl5 expression, while loss of Tp53in conjunction with
Pten loss increased Clcl17 expression [158]. In addition, basal cells, secretory luminal cells, and uncommon neuroendocrine cells are encased in the gland by stroma
and vasculature, according to classical investigations of the normal prostatic epithelium in mice [159]. Evidence of stem/progenitor cells in basal and luminal prostate
epithelial lineages has been provided by a number of in vitro organoid-forming
experiments [160] and stem cell enrichment tests [161–164].
5.5 Conclusion andPerspectives
Recent research on EMT has shown how crucial it is to decipher the relationships
between stemness, cell plasticity, and therapeutic efcacy. Moreover, interactions
with the tumor microenvironment (TME), migration, metastasis, and tumor invasiveness are all intricately tied to these processes. Several potential drivers and
effectors of EMT have the potential to serve as biomarkers for prognosis in cases of
metastatic illness. Much research into EMT’s function in cancer development and
treatment resistance has taken place within the previous decade. Additional research
is required to determine the best targets for improving the therapy of CRPC in
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prostate cancer. Although Notch and Wnt signaling have a more signicant role in
cancer stemness phenotypes and EMT in prostate cancer, SNAIL appears to be an
important driver of EMT in prostate cancer. For certain cancers, blocking both of
these mechanisms might work. At the same time, it may be possible to anticipate
EMT progression and treatment response by developing transcriptional markers of
the disease in humans. Additionally, epigenetic modications show potential; nonetheless, there is a risk that worldwide changes in methylation and histone modication can cause unanticipated changes in gene expression, which could result in
undesirable side effects. Previous research on other malignancies has shown that
targeting particular epigenetic effectors, including LSD1, that are known to be
involved in EMT, may also have signicant benets for prostate cancer. Additionally,
fresh perspectives for innovative treatment methods may emerge from a deeper
comprehension of how EMT and stemness inuence the immunological tumor
microenvironment of prostate cancer.
Conict of Interest The authors declare no conict of interest.
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Part III
Molecular Events