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Microbes & Immunity The feature of bladder cancer stem cells

types, cancer-associated fibroblasts (CAFs), endothelial currently identified BCSC markers are also expressed on
cells, pericytes, and various additional tissue-resident the surface of normal bladder basal cells, thereby limiting
cell types. These host cells play important roles in their widespread application. For instance, CD44 serves as
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the cancer pathogenesis. CAFs are the predominant a marker for BCSCs, yet it is predominantly expressed in
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components of the tumor microenvironments and bladder basal cells. Similarly, CK5 is expressed in bladder
influence the stemness of cancer cells. It has been reported basal cells, rendering these two markers unsuitable choices
that SCLC14A1 CAF confers stemness to BC cells by as therapeutic targets. Targeting these markers might
+
secreting WNT5A, maintaining the level of β catenin, and inadvertently harm bladder basal cells, potentially leading
activating the WNT pathway. Another study uncovered to tissue damage. Furthermore, the activation of related
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inflammatory ICAM1 CAF, which secretes FGF2, binds to stem cell pathways for tissue healing could potentially
CD44, and maintains the stemness of BCSCs. Recently, increase the risk of cancer transformation. Therefore, the
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Luo et al. have found the heterogeneity and plasticity primary goal for the future is to identify a combination
of CAFs in the tumor microenvironment through pan- of markers that are distinct from those found on normal
cancer single-cell analysis. These studies have proven tissue cells, thereby enhancing the specificity of targeted
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that CAFs exhibit high heterogeneity, contributing to the therapy.
overall heterogeneity of BCSCs. Ma et al. revealed that Some clinical trials of chimeric antigen receptor
inflamed CAFs possess a positive correlation with the (CAR)-T cell therapy for patients with BC have been
response rate of immunotherapy. Given these studies, registered, although experimental data have not
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the communication of various CAFs with BCSCs needs yet been disclosed. The targets of relative research
to be explored in the future. This exploration may offer focus on pan-cancer targets, such as MUC1, HER2
more reliable proof for choosing strategies to treat (NCT03740256), PD-1, and ROR2 (NCT03960060). 147,148
patients with BC. In the future, combining pan-cancer targets with

Apart from CAFs, mesenchymal stem cells and biomarkers of BCSCs might lead to the eradication of
BCNSCs also contribute to the niche of BCSCs. The BC cells while preventing damage to bladder tissue.
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specific mechanisms underlying this contribution require Moreover, BCSCs have low expression of HLA class 1
further clarification in future studies. Small molecular antigen, making it difficult for cytotoxic T lymphocytes
metabolites in the tumor microenvironment also play (CTL) to specifically eliminate BCSCs. In 2021,
important roles in supporting tumor cell survival. For Miyata et al. first identified a glutamate receptor,
example, lactic acid and fatty acid have been identified as ionotropic, kainite 2 (GRIK2)-derived antigenic peptide
significant contributors. Some metabolites even promote (LMYDAVHVV) specifically expressed by BCSCs.
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the stemness of TSCs. 143,144 However, direct evidence of the In an in vitro immune selection model, specific CTLs
interaction between metabolites and BCSCs is currently decreased the ratio of BCSCs from 6.11% to 1.16%.
lacking. With improvement in spatial metabolomic However, the ratio of BCSCs increased from 6.11% to
technology, more metabolism-related targets of BCSCs are 10.9% under the treatment without specific CTLs. 149
expected to be uncovered. 145,146 In addition to targeting surface markers, current
The methods used to isolate BCSCs exhibit high targeted therapies mainly focus on inhibitors of signaling
heterogeneity, relying on various combinations of stem pathways and the conjugation of therapeutic drugs with
markers and their source. While human BC cell lines exhibit antibodies against BCSCs markers to achieve specific
excellent homogeneity, their prolonged cultivation leads to eradication of BCSCs. However, most research is still at
significant differences in characteristics compared to primary the stage of animal and in vitro experiments, far from
BC samples, thus failing to fully represent the characteristics clinical studies. Large-scale screening can be conducted
of primary BC and BCSCs. Therefore, BCSCs obtained from for existing inhibitors to identify specific inhibitors
primary BC samples are considered more convincing. The targeting BCSCs without affecting normal cells. Once
majority of reported BCSCs are isolated from cell lines, and the specificity of the identified target molecules in BC
further validation of these research results in primary BC is proven and supported by experimental data, it can
samples is necessary. Research employing patient-derived expedite the entry of corresponding drugs into clinical
BCSCs will enhance the possibility of translating laboratory trials for BC.
findings into clinical settings. BC is a widespread and highly heterogeneous
To minimize adverse side effects, targeted therapy malignant tumor, and precision medicine is the trend in its
requires highly specific biomarkers. However, most of the treatment. With the development of omics technologies,

Volume 1 Issue 1 (2024) 42 doi: 10.36922/mi.2377