The expression of cancer stem cells and its effects on the propensity for recurrence and metastasis in bladder cancer: a systematic review

Bladder cancer is one of the most frequent cancers of the urinary tract, associated with high recurrence rates and metastasis. Cancer stem cells (CSCs) are a subpopulation of cancer cells characterized by high self-renewal and differentiation capacities, resulting in increased cancer recurrence, larger tumor size, higher rates of metastasis, higher resistance to treatment, and overall poorer prognosis. This study aimed to evaluate the role of CSCs as a prognostic tool to predict the risks of metastasis and recurrence in bladder cancer. A literature search was conducted across seven databases from January 2000 to February 2022 for clinical studies investigating the use of CSCs to determine the prognosis of bladder cancer. The following keywords were used: ("Bladder Cancer" OR "Transitional Cell Carcinoma" OR "Urothelial Carcinoma") AND ("Stem Cell" OR "Stem Gene") AND ("Metastasis" OR "Recurrence"). A total of 12 studies were deemed eligible for inclusion. SOX2, IGF1R, SOX4, ALDH1, CD44, Cripto-1, OCT4, ARRB1, ARRB2, p-TFCP2L1, CDK1, DCLK1, and NANOG, which were all identified as CSC markers, have been implicated in the recurrence and metastasis of tumor in bladder cancer, which played a role as prognostic factor of bladder cancer. Given the pluripotent and highly proliferative properties of CSCs. CSCs may play a role in the complex biological behavior of bladder cancer, including, but not limited to, its high rates of recurrence, metastasis, and resistance to treatment. The detection of cancer stem cell markers offers a promising approach in determining the prognosis of bladder cancer. Further studies in this area are thus warranted and may contribute significantly to the overall management of bladder cancer.Cancer stem cells; Bladder cancer; Recurrency of bladder cancer; Metastasis of bladder cancer; Prognosis factor of bladder cancer

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(which was not certified by peer review)
The copyright holder for this preprint this version posted May 19, 2022. ; https://doi.org/10.1101/2022.05.18.22275252 doi: medRxiv preprint . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.  is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2022. ; https://doi.org/10.1101/2022.05.18.22275252 doi: medRxiv preprint We identified several BCSCs in this review, which included SOX2, SOX4, 154 ALDH1, CD44, Nanog, Cripto-1, OCT4, CD133, β-arrestin-1 (ARRB1) and β-arrestin-2 155 (ARRB2), IGF1R, p-TFCP2L1, and CDK1. Eight out of 12 studies included performed 156 Kaplan-Meier survival analysis to compare the effect of respective BCSCs expression on 157 clinicopathological parameters. All of the gene were found to be significant prognostic 158 factors based on univariate analysis. Moreover, multivariate analysis using Cox regression 159 also showed that the majority of gene expression were independent prognostic factors; thus, 160 it may play a role as a potentially valuable marker in predicting the recurrence-free, 161 metastasis-free, or disease-free (recurrence/metastasis-free) with P<0.05 Table 3.

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. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 178 By identifying and understanding the molecular mechanism of In recurrent and metastatic 179 BCa, numerous stem cell phenotypes, such as beta arrestins, SOX2, SOX4, transcription 180 factor CP2 like 1 (TFCP2L1), and doublecortin-like kinase 1 (DCLK1), have all been 181 identified and described.

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Two studies reporting a significant relationship between high expression of SOX2 183 with poor recurrence-free survival also found that SOX2 was highly expressed in tumors 184 with poor pathological differentiation; thus, marking its role in BCa malignancy. SOX2 185 plays a role in promoting cell proliferation and enhancing cell survival during low-serum 186 stress. BCa cancer cells' survival and spheroid-forming capability enhancement were 187 induced by AKT phosphorylation due to IGF2/IGF1R induction, which was thought to be 188 involved in molecular mechanism of SOX2 expression leading to poor tumor prognosis.
189 Its mechanism made SOX2 a potential therapeutic target for BCa treatment. [6,17] 190 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 19, 2022. ; https://doi.org/10.1101/2022.05.18.22275252 doi: medRxiv preprint