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Microbes & Immunity The feature of bladder cancer stem cells

following subsections elucidate different drug resistance underscore the significant drug resistance exhibited by
mechanisms in BCSCs. OV6 BCSCs.
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3.4.1. ALDH To investigate the specific mechanism underlying this
drug resistance, they used verteporfin (an inhibitor blocking
The ALDH superfamily belongs to the group of NAD(P)- the interaction between YAP and TEAD), CP-673451 (a
dependent enzymes. The ALDH superfamily includes PDGFR inhibitor), and cisplatin to treat xenograft tumors
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11 families: ALDH1s (1A1, 1A2,1A3,1B1, 1L1, and 1L2), derived from OV6 BCSCs. Encouragingly, xenograft
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ALDH2, ALDH3s (3A1, 3A2, 3B1, and 3B2), ALDH4A1, tumors treated solely with cisplatin did not display a
ALDH5A1, ALDH6A1, ALDH7A1, ALDH8A1, significant difference in growth compared to the untreated
ALDH9A1, ALDH16A1, and ALDH18A1. ALDH group, indicating a resistance of OV6 BCSCs to cisplatin.
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superfamily is involved in detoxification reactions involving However, the combination treatment of verteporfin or
various aldehydes, and ALDH1A1 is considered a marker CP-673451 with cisplatin significantly inhibited tumor
of TSCs. 84,85 Activation of ALDH has been associated with growth. This finding suggests that the YAP/TEAD1/
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drug resistance, as evidenced by ALDH high breast cancer PDGF-BB/PDGFR pathway underpins the drug resistance
cells exhibiting significant resistance to drugs such as observed in tumors originating from OV6 BCSCs.
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doxorubicin, paclitaxel, and radiation therapy. Specifically, Consequently, the integration of inhibitors targeting this
the knockdown of ALDH1A1 significantly decreased pathway alongside conventional treatments holds promise
the drug resistance of breast cancer cells, resulting in a in enhancing the effectiveness of therapy and overcoming
more than one-fold decline in survival rate. A similar drug resistance.
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phenomenon has been observed in colorectal cancer and
ovarian cancer. 87,88 3.5. Metastatic mechanism
Researchers from Lawrence Livermore National Fifty percent of patients with MIBC experience recurrence
Laboratory, led by Miranda J. Sarachine Falso, have after surgery, with a majority of cases involving distant
revealed that the 5637 cell line exhibited 9.64% ALDH high tumor metastasis. The primary biological process
cells, the T24 cell line showed 8.84% ALDH high cells, and the underlying this recurrence is EMT, which not only
TCCSUP cell line manifested only 3.27% ALDH high cells, orchestrates organ formation and embryonic development
as identified through flow cytometry. The corresponding but also drives tumor metastasis and invasion. 90,91
IC values for cisplatin were determined to be 1.7 μM, 1.5 Conversely, mesenchymal-epithelial transition (MET)
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μM, and 0.2 μM for the 5637, T24, and TCCSUP cell lines, represents the reverse process of EMT. Through EMT,
respectively. A discernible trend was observed wherein tumor cells can detach from the primary tumor tissue
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the sensitivity to cisplatin increased correspondingly with and migrate to distant sites, particularly those with
the decreasing percentage of ALDH high cells across these tissues rich in blood vessels. Upon reaching these new
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cell lines. ALDH, serving as a marker for BCSCs, plays tissues, stromal cells adapt to their new environment and
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a pivotal role in the metabolism of chemotherapy drugs form secondary tumors through MET. Unlike ordinary
and provides a shield of protection to BCSCs. This insight tumor cells, which possess limited ability to establish
underscores the potential significance of targeting ALDH carcinoma in situ upon metastasis, TSCs exhibit robust
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as a prospective strategy for overcoming drug resistance tumorigenic capabilities and serve as the tumor initiators
in BC. of tumorigenesis after metastasis. Subsequently, this review
delineates experimental evidence and proposes potential
3.4.2. YAP/TEAD1/PDGF-BB/PDGFR mechanisms elucidating the migratory abilities of BCSCs
Wang et al. have revealed a remarkable increase in the in the subsequent subsections, with the aim of identifying
proportion of OV6 BCSCs within J82 and UMUC3 cells, therapeutic targets for the comprehensive treatment of
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escalating from below 3% to over 35% following cisplatin MIBC.
treatment. Subsequent analysis revealed that post-
treatment with 25 μM cisplatin, the relative survival rate 3.5.1. p27/STAT3/EMT
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of OV6 BCSCs surpassed 0.6%, while OV6 BCNSCs In our previous investigation, our group observed a
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exhibited a survival rate below 0.2%. Apoptotic assays pronounced elevation (220%) in the expression of signal
unveiled that post-cisplatin treatment, OV6 BCSCs transducer and activator of transcription 3 (STAT3) within
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maintained an average apoptosis rate below 11.995 ± BCSCs compared to BCNSCs. Notably, this heightened
1.6%, whereas OV6 BCNSCs in J82 exhibited the highest STAT3 expression exhibited a positive correlation with
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apoptosis rate at 85.4 ± 9.45%, with UMUC3 registering the metastatic ability of BC. Specifically, Zhao et al.
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an apoptotic rate of 47.5 ± 5.1%. These findings observed that cytoplasmic overexpressed p27 bound to
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Volume 1 Issue 1 (2024) 37 doi: 10.36922/mi.2377