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Microbes & Immunity The feature of bladder cancer stem cells

of cells within the basal layer of bladder tissue expressing Therefore, the identification and isolation of BCSCs offer
cytokeratin (CK) 14. These CK14 cells demonstrated new targets for targeted therapy.
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the ability to give rise to all bladder cell types. Notably,
the sphere-forming efficiency of CK14 cells was 9.21%, 3.1. The origin of BCSCs
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significantly higher than CK14 cells, which exhibited a Controversy surrounds the origin of BCSCs, with one
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sphere-forming efficiency of only 0.56%. These findings hypothesis positing that BCSCs originate from BESCs or
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suggest the presence of a subset of BESCs marked by CK14 differentiated somatic cells. Under specific conditions,
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within bladder basal cells. Similarly, research by Chan differentiated cells and immature precursor cells may
et al. at Baylor College of Medicine in the United States reprogram into TSCs. Through whole-exome sequencing
suggested that CD44 is specifically expressed in bladder and analysis of 59 single cells derived from four subsets
basal cells. Considering CD44’s status as a biomarker of – BCSCs, BC non-stem cells (BCNSCs), BESCs, and
BCSCs, this finding suggests a relationship between bladder epithelium non-stem cells (BENSCs) – obtained
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basal cells of the urothelium and the origin of BCSCs. from three pairs of primary BC and normal bladder
tissues, our group identified 21 mutation genes specific
2.2. Intermediate cells to BCSCs. Mechanically, the combined mutations of the
Basal cells give rise to adjacent intermediate cells with ARID1A, GPRC5A, and MLL2 facilitate the conversion
diameters ranging from 10 to 40 μm, characterized by a of BCNSCs into BCSCs, significantly enhancing the self-
surface covered with microvilli and exhibiting a pear-like renewal and tumorigenicity of BCNSCs. Results from the
shape. 36,37 A common molecular feature shared by basal evolutionary tree constructed according to the order of
and intermediate cells is P63, which is absent in urothelial gene mutations indicate that the origin of BCSCs could
cells. Compared to basal cells, intermediate cells exhibit be attributed to the accumulation of mutations in BESCs
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decreased expression of CK5 and CK17, along with or the dedifferentiation of BCNSCs. This study provides
elevated expression of carcinoembryonic antigen-related insight into the genetic basis and origin of human BCSCs,
cell adhesion molecule 6 (CEACAM6) and CK18. 40-42 with significant implications for the precise prevention and
treatment of BC. The observed heterogeneity in BCSCs
2.3. Urothelial cells may stem from their diverse origins, thereby complicating
Intermediate cells ultimately differentiate into urothelial target therapeutic approaches.
cells with diameters ranging from 70 to 100 μm, 3.1.1. Accumulation of mutations in normal adult
distinguished by distinct asymmetric unit membranes and stem cells and tissue progenitor cells
well-defined, polygonal, and dome-shaped morphological
features. 34,36 While urothelial cells are not completely sealed The understanding of normal bladder cells has been
structures, they possess the ability to absorb certain low- relatively comprehensive compared to that of BC.
molecular-weight and high-molecular-weight substances Researchers led by Jason Van Batavia from Columbia
from urine, which are subsequently further metabolized University conducted lineage tracing experiments to
and transported to the subepithelial connective tissue. investigate the fate of bladder cells during BC formation.
The expression of CD44 is decreased in urothelial cells, Their study revealed that basal cells served as progenitors
along with downregulated levels of CK5, CK10, and for carcinoma in situ (CIS), NMIBC, and squamous cell
CK14. 40,43,44 Conversely, CK18 and CK8 are upregulated carcinoma, while intermediate cells acted as progenitors
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in urothelial cells compared to intermediate cells. 40,44 for papillary tumors. The study provides evidence for
The co-expression of uroplakins and CK20 signifies the the relationship between BC and normal bladder cells.
complete differentiation of urothelial cells. 45,46 Furthermore, researchers led by Huanjun Wang from Sun
Yat-sen University have suggested that both CD44 and
3. BCSCs ALDH1A1 of BCSCs are enriched in basal cells, implying
Recent evidence supports the existence of BCSCs. Wang that BCSCs may originate from the basal cells. 47
et al. from Sun Yat-sen University, utilizing single-cell To explore the relationship between BC and BESCs,
transcriptome sequencing of BC cells from 13 patients, Shin et al. from Stanford University in the United States
identified eight subpopulations within CD44 BCSCs constructed a BC mouse model exhibiting both CIS and
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based on distinct molecular features. The distribution of MIBC. They labeled mouse basal cells and their progeny
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these subpopulations varied among BC patients with low cells through Sonic Hedgehog (SHH) (a BESCs marker).
recurrence risk, high recurrence risk, and those who had Although numerous unlabeled bladder intermediate
already experienced recurrence, suggesting a potential role and urothelial cells were initially present, all MIBC cells
of BCSC heterogeneity in drug resistance and BC relapse. were eventually labeled. These findings indicate that both

Volume 1 Issue 1 (2024) 28 doi: 10.36922/mi.2377