The Potential Role of CD44 and CD133 in Colorectal Stem Cell Cancer

Hassan, Wael Abdo; Muqresh, Mohamad Ayham; Omar, Mohamed

doi:10.7759/cureus.30509

Cited by 10 publications

(8 citation statements)

References 43 publications

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“…We opted to focus on studying the metabolic pathways in A2780 and IGROV1, which are representative models for poorly differentiated OV with a high likelihood of relapse and consistently exhibit high genomic instability [20,21]. To con rm that the spheroids have the characteristics of CSCs functionally and morphologically, we assessed the expression of CD44 and CD133 proteins, which are stem cell markers that contribute to sphere formation and tumor cell biogenesis [22,23], using western blotting. CD44 was signi cantly more abundant in 3D-spheroids relative than in conventional 2D-cultured cells in IGROV1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Targeting Metabolic Vulnerability by Combining NAMPT Inhibitors and Disulfiram for Treatment of Recurrent Ovarian Cancer

Lipkowitz,

Kudo,

Crooks

et al. 2024

Preprint

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Ovarian cancer (OV) has the highest mortality rate among gynecological cancers. As the OV progresses, tumor cells spread outside the ovaries to the peritoneal and abdominal cavities, forming cell clusters that float in the ascitic fluid caused by peritonitis carcinomatosa, leading to further dissemination and metastasis. These cell clusters are enriched with cancer stem cells (CSCs) which are responsible for treatment resistance, recurrence, and metastasis. Therefore, targeting CSCs is a potentially effective approach for treating OV. However, understanding how CSCs acquire treatment resistance and identifying targets against CSCs remains challenging. In this study, we demonstrate that 3D-spheroids of OV cell lines exhibit higher stemness than conventional adherent cells. Metabolomics profiling studies have revealed that 3D-spheroids maintain a high-energy state through increased glucose utilization in the citric acid cycle (TCA), efficient nucleotide phosphorylation, and elevated phosphocreatine as an energy buffer. We also found that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ production, is highly expressed and is a potential therapeutic target against CSCs, while also serving as a prognostic indicator in OV. Moreover, we identified a previously unrecognized anti-tumor mechanism whereby disulfiram, an aldehyde dehydrogenase (ALDH) inhibitor, synergistically inhibited mitochondrial function when combined with NAMPT inhibitors. Finally, the combination of a NAMPT inhibitor and disulfiram showed significant anti-tumor effects and extended survival in an animal model. Our findings demonstrate the potential of spheroids as a preclinical model for targeting OV CSCs and also indicate that the combination of NAMPT inhibitors and disulfiram is a promising therapeutic strategy to overcome recurrent OV.

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Section: Resultsmentioning

confidence: 99%

Targeting Metabolic Vulnerability by Combining NAMPT Inhibitors and Disulfiram for Treatment of Recurrent Ovarian Cancer

Lipkowitz,

Kudo,

Crooks

et al. 2024

Preprint

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“…In CRC, markers such as CD133, CD44, Oct-4, and Nanog are commonly used to identify and isolate cancer stem cells [ 49 , 50 ]. In addition, CD133, CD44, and Nanog may have clinical roles in predicting pathological stages, cancer recurrence, and therapy resistance in CRC [ 51 , 52 ]. In this study, the tumor sphere formation assay showed that the expression level of BAP31 was positively correlated with the cancer stemness of CRC.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of BAP31 Downregulates Galectin-3 to Inhibit the Wnt/β-Catenin Signaling Pathway to Modulate 5-FU Chemosensitivity and Cancer Stemness in Colorectal Cancer

Liu,

Zhang,

Wang

et al. 2023

IJMS

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Increased stemness is causally linked to the development of chemoresistance in cancers. B-cell receptor-associated protein 31 (BAP31) has been identified to play an oncogenic role in many types of cancer. However, the role of BAP31 in 5-fluorouracil (5-FU) chemosensitivity and stemness of colorectal cancer (CRC) is still unknown. The aim of this study was to investigate the biological function and molecular mechanism of BAP31 in regulating 5-FU chemosensitivity and stemness. The correlation between BAP31 expression and 5-FU chemosensitivity was examined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide and colony formation assays. Cancer stemness was analyzed using tumor sphere formation and Western blot assays. Western blot and immunofluorescence analyses of the knockdown cell lines were performed to explore the possible mechanisms. Finally, we investigated the function of BAP31 by constructing xenograft nude mouse models in vivo. In this study, we demonstrated that BAP31 was increased in CRC cells, and knockdown of BAP31 reduced the half maximal inhibitory concentration (IC50) of 5-FU, while this effect was reversed by overexpression of BAP31. In addition, knockdown of BAP31 substantially reduced the stemness of CRC cells in vitro. Consistently, knockdown of BAP31 significantly suppressed the tumorigenicity and stemness of CRC in vivo. The functional study further suggested that knockdown of BAP31 downregulated galectin-3 to inhibit the accumulation of β-catenin, which in turn repressed the transcription of downstream target genes (c-MYC, SOX2) of the Wnt/β-catenin signaling pathway. Knockdown of BAP31 reduced stemness by inhibiting the Wnt/β-catenin signaling pathway to increase 5-FU chemosensitivity. Importantly, intrabodies against BAP31 suppressed tumor growth and enhanced the antitumor effects of 5-FU in vivo. Therefore, using intrabodies against BAP31 may be a strategy for improving the antitumor effect of 5-FU in CRC.

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“…CSCs appear to be related to the resistance of cancer to therapy. 31 CD133 and CD44 are the most used markers for CSCs analysis in CRC, [32][33][34][35] been associated with cancer progression, 36 poor prognosis 37 and resistance to therapy. 38 Then, we investigated a possible enrichment of CSCs after single treatments or co-treatment (Figure 1H and Figure S3E,F).…”

Section: -Fu and Oxa Co-treatment Exert An Additive Cytotoxic Effect ...mentioning

confidence: 99%

The rational modulation of autophagy sensitizes colorectal cancer cells to 5‐fluouracil and oxaliplatin

Baldasso‐Zanon,

Silva,

Franco

et al. 2024

J of Cellular Biochemistry

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Colorectal cancer (CRC) is the third most common and deadliest cancer globally. Regimens using 5‐fluorouracil (5FU) and Oxaliplatin (OXA) are the first‐line treatment for CRC, but tumor recurrence is frequent. It is plausible to hypothesize that differential cellular responses are triggered after treatments depending on the genetic background of CRC cells and that the rational modulation of cell tolerance mechanisms like autophagy may reduce the regrowth of CRC cells. This study proposes investigating the cellular mechanisms triggered by CRC cells exposed to 5FU and OXA using a preclinical experimental design mimicking one cycle of the clinical regimen (i.e., 48 h of treatment repeated every 2 weeks). To test this, we treated CRC human cell lines HCT116 and HT29 with the 5FU and OXA, combined or not, for 48 h, followed by analysis for two additional weeks. Compared to single‐drug treatments, the co‐treatment reduced tumor cell regrowth, clonogenicity and stemness, phenotypes associated with tumor aggressiveness and poor prognosis in clinics. This effect was exerted by the induction of apoptosis and senescence only in the co‐treatment. However, a week after treatment, cells that tolerated the treatment had high levels of autophagy features and restored the proliferative phenotype, resembling tumor recurrence. The pharmacologic suppression of early autophagy during its peak of occurrence, but not concomitant with chemotherapeutics, strongly reduced cell regrowth. Overall, our experimental model provides new insights into the cellular mechanisms that underlie the response and tolerance of CRC cells to 5FU and OXA, suggesting optimized, time‐specific autophagy inhibition as a new avenue for improving the efficacy of current treatments.

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The Potential Role of CD44 and CD133 in Colorectal Stem Cell Cancer

Cited by 10 publications

References 43 publications

Targeting Metabolic Vulnerability by Combining NAMPT Inhibitors and Disulfiram for Treatment of Recurrent Ovarian Cancer

Targeting Metabolic Vulnerability by Combining NAMPT Inhibitors and Disulfiram for Treatment of Recurrent Ovarian Cancer

Knockdown of BAP31 Downregulates Galectin-3 to Inhibit the Wnt/β-Catenin Signaling Pathway to Modulate 5-FU Chemosensitivity and Cancer Stemness in Colorectal Cancer

The rational modulation of autophagy sensitizes colorectal cancer cells to 5‐fluouracil and oxaliplatin

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