Renal Cancer Stem Cells: Characterization and Targeted Therapies

In a previous study, we found that DNAJB8, a heat shock protein (HSP) 40 family member is expressed in kidney cancer stem‐like cells (CSC)/cancer‐initiating cells (CIC) and that it has a role in the maintenance of kidney CSC/CIC. Heat shock factor (HSF) 1 is a key transcription factor for responses to stress including heat shock, and it induces HSP family expression through activation by phosphorylation. In the present study, we therefore examined whether heat shock (HS) induces CSC/CIC. We treated the human kidney cancer cell line ACHN with HS, and found that HS increased side population (SP) cells. Western blot analysis and qRT‐PCR showed that HS increased the expression of DNAJB8 and SOX2. Gene knockdown experiments using siRNAs showed that the increase in SOX2 expression and SP cell ratio depends on DNAJB8 and that the increase in DNAJB8 and SOX2 depend on HSF1. Furthermore, treatment with a mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, decreased the expression of DNAJB8 and SOX2 and the ratio of SP cells. Taken together, the results indicate that heat shock induces DNAJB8 by activation of HSF1 and induces cancer stem‐like cells.

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“…Several markers have been used for isolation of kidney cancer stem cells . In the present study, we showed that cell stress induces SP cells.…”

Section: Discussionsupporting

confidence: 60%

Cellular stress induces cancer stem‐like cells through expression of DNAJB8 by activation of heat shock factor 1

et al. 2018

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“…CD73 expression was also significantly correlated with invasive character observed in clinical tissue samples, and thus CD73 was proposed as a biomarker and potential therapeutic target for pNET CSCs. In our study, CD73 expression appears not to be associated with the expression of several common well-known CSC markers [ 37 ] ( Supplementary Figure 4 ) in RCC. CD105, CD133 and CD24 only marginally coexpressed either in CD73 high or CD73 low cell population, but CD44 represented a major subpopulation in both two population cells.…”

Section: Discussionmentioning

confidence: 68%

Ecto-5′-nucleotidase (CD73) is a biomarker for clear cell renal carcinoma stem-like cells

Song

Cui

et al. 2017

Oncotarget

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Identification of a specific biomarker for cancer stem cells (CSCs) is of potential applications in the development of effective therapeutic strategies for renal cell carcinoma (RCC). In this study, both the RCC cell line 786-O and surgically removed clear cell RCC (ccRCC) tissues were implemented to grew as spheroids in serum-free medium supplemented with mitogens. This subpopulation possessed key characteristics defining CSCs. We also identified that surgically removed ccRCC tissues were heterogenic and there was a subpopulation of cells that was highly stained with rhodamine-123. Based on membrane-proteomic analyses, CD73 was identified as a candidate biomarker. We further found that CD73high cells were highly tumorigenic. As few as 100 CD73high cells were capable of forming xenograft tumors in non obese diabetic/severe combined immunodeficiency disease mice, whereas 1 × 105 CD73low cells did not initiate tumor formation. During successive culture, the CD73high population regenerated both CD73high and CD73low cells, whereas the CD73low population remained low expression level of CD73. Furthermore, the CD73high cells were more resistant to radiation and DNA-damaging agents than the CD73low cells, and expressed a panel of ‘stemness’ genes at a higher level than the CD73low cells. These findings suggest that a high level of CD73 expression is a bona fide biomarker of ccRCC stem-like cells. Future research will aim at the elucidation of the underlying mechanisms of CD73 in RCC development and the distinct aspects of ccRCC stem-like cells from other tumor types.

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“…c-MYB regulates the processes of self-renewal and differentiation, preventing the differentiation of cells [5,37,72,[74][75][76]. On the other hand, surface markers specific to tumor stem cells have not been established in renal tumors; however, it has been proposed that CXCR4 is essential for the maintenance of renal tumor stem cells [77], and it could be a good candidate as a specific marker of tumor stem cells [78][79][80]. Taken together, the reduction in the expression of MYBBP1A induces the activation of c-MYB, which ultimately results in an increase in the tumor stem cell phenotype.…”

Section: Mybbp1a and Cancermentioning

confidence: 99%

The Tumor Suppressor Roles of MYBBP1A, a Major Contributor to Metabolism Plasticity and Stemness

Felipe‐Abrio

Carnero

2020

Cancers

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The MYB binding protein 1A (MYBBP1A, also known as p160) acts as a co-repressor of multiple transcription factors involved in many physiological processes. Therefore, MYBBP1A acts as a tumor suppressor in multiple aspects related to cell physiology, most of them very relevant for tumorigenesis. We explored the different roles of MYBBP1A in different aspects of cancer, such as mitosis, cellular senescence, epigenetic regulation, cell cycle, metabolism plasticity and stemness. We especially reviewed the relationships between MYBBP1A, the inhibitory role it plays by binding and inactivating c-MYB and its regulation of PGC-1α, leading to an increase in the stemness and the tumor stem cell population. In addition, MYBBP1A causes the activation of PGC-1α directly and indirectly through c-MYB, inducing the metabolic change from glycolysis to oxidative phosphorylation (OXPHOS). Therefore, the combination of these two effects caused by the decreased expression of MYBBP1A provides a selective advantage to tumor cells. Interestingly, this only occurs in cells lacking pVHL. Finally, the loss of MYBBP1A occurs in 8%–9% of renal tumors. tumors, and this subpopulation could be studied as a possible target of therapies using inhibitors of mitochondrial respiration.

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Renal Cancer Stem Cells: Characterization and Targeted Therapies

Cited by 34 publications

References 127 publications

Cellular stress induces cancer stem‐like cells through expression of DNAJB8 by activation of heat shock factor 1

Cellular stress induces cancer stem‐like cells through expression of DNAJB8 by activation of heat shock factor 1

Ecto-5′-nucleotidase (CD73) is a biomarker for clear cell renal carcinoma stem-like cells

The Tumor Suppressor Roles of MYBBP1A, a Major Contributor to Metabolism Plasticity and Stemness

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