Targeting Gastric Cancer Stem Cells to Enhance Treatment Response

Rao, Xionghui; Zhang, Chaojun; Luo, Huixing; Zhang, Jianbao; Zhuang, Zhehong; Liang, Zhihao; Wu, Xiaobin

doi:10.3390/cells11182828

Cited by 30 publications

(13 citation statements)

References 181 publications

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“…Furthermore, gastric CSCs are involved in metastasis and recurrence in gastric cancer (Becerril-Rico et al, 2021;Yang et al, 2022). Therefore, targeting stemness is rising as a new therapeutic strategy in gastric cancer (Rao et al, 2022). HIF-1α is a key stimulator of stemness in gastric cancer.…”

Section: Hif-1α and Stemness In Gastric Cancermentioning

confidence: 99%

The hypoxia-inducible factor-1α in stemness and resistance to chemotherapy in gastric cancer: Future directions for therapeutic targeting

Özcan

2023

Front. Cell Dev. Biol.

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Hypoxia-inducible factor-1α (HIF-1α) is a crucial mediator of intra-tumoral heterogeneity, tumor progression, and unresponsiveness to therapy in tumors with hypoxia. Gastric tumors, one of the most aggressive tumors in the clinic, are highly enriched in hypoxic niches, and the degree of hypoxia is strongly correlated with poor survival in gastric cancer patients. Stemness and chemoresistance in gastric cancer are the two root causes of poor patient outcomes. Based on the pivotal role of HIF-1α in stemness and chemoresistance in gastric cancer, the interest in identifying critical molecular targets and strategies for surpassing the action of HIF-1α is expanding. Despite that, the understanding of HIF-1α induced signaling in gastric cancer is far from complete, and the development of efficacious HIF-1α inhibitors bears various challenges. Hence, here we review the molecular mechanisms by which HIF-1α signaling stimulates stemness and chemoresistance in gastric cancer, with the clinical efforts and challenges to translate anti-HIF-1α strategies into the clinic.

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Section: Hif-1α and Stemness In Gastric Cancermentioning

confidence: 99%

The hypoxia-inducible factor-1α in stemness and resistance to chemotherapy in gastric cancer: Future directions for therapeutic targeting

Özcan

2023

Front. Cell Dev. Biol.

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“…Several successes achieved in patients with HER2+ BC have not been reproduced in patients with HER2+ GC, mainly owing to several biological differences, including the higher degree of heterogeneity of HER2 expression in GC and the coexistence of other genomic drivers beyond HER2 itself [41]. Since altered HER2 signaling has a central role in the maintenance/survival of breast CSCs [12] and despite the availability of limited data on HER2+ GC stemness [15], the addition of GCSC-targeted therapies to current treatment options may be a key step for improving patient outcomes [6,42]. In this context, we found that the intrinsic sensitivity of the tested HER2+ GC cells to HER2 targeting is positively associated with the per se capability of anti-HER2 agents to impair gastrosphere formation; indeed, only low or no levels of GFE % inhibition were observed in T-resistant cell targets, confirming the existence of additional drivers supporting cancer stemness features.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, CSCs are able to continuously self-renew and differentiate into distinct lineages, being deeply implicated in tumor initiation, invasiveness, metastases, treatment resistance and in immune escape [7,8]. Thus, targeting molecular drivers involved in the CSC program, including the dysregulated expression/activation of HER2 and its splice variant d16HER2 in HER2+ breast [9][10][11][12] and gastric [13][14][15] cancers, may improve cancer patient outcomes, yielding long-lasting responses [16].…”

Section: Introductionmentioning

confidence: 99%

Fatty acid synthase as a new therapeutic target for HER2-positive gastric cancer

et al. 2023

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Purpose Trastuzumab is an HER2-specific agent approved as the gold-standard therapy for advanced HER2-positive (HER2+) gastric cancer (GC), but the high rate and rapid appearance of resistance limit its clinical efficacy, resulting in the need to identify new vulnerabilities. Defining the drivers influencing HER2+ cancer stem cell (CSC) maintenance/survival could represent a clinically useful strategy to counteract tumor growth and therapy resistance. Accumulating evidence show that targeting crucial metabolic hubs, as the fatty acid synthase (FASN), may be clinically relevant. Methods FASN protein and transcript expression were examined by WB and FACS and by qRT-PCR and GEP analyses, respectively, in trastuzumab-sensitive and trastuzumab-resistant HER2+ GC cell lines cultured in adherent (2D) or gastrosphere promoting (3D) conditions. Molecular data were analyzed in silico in public HER2+ GC datasets. The effectiveness of the FASN inhibitor TVB3166 to overcome anti-HER2 therapy resistance was tested in vitro in gastrospheres forming efficiency bioassays and in vivo in mice bearing trastuzumab-resistant GC cells. Results We compared the transcriptome profiles of HER2+ GC cells cultured in 2D versus 3D conditions finding a significant enrichment of FASN in 3D cultures. FASN upregulation significantly correlated with high stemness score and poor prognosis in HER2+ GC cases. TVB3166 treatment significantly decreased GCSCs in all cell targets. HER2 and FASN cotargeting significantly decreased the capability to form gastrospheres versus monotherapy and reduced the in vivo growth of trastuzumab-resistant GC cells. Conclusion Our findings indicate that cotargeting HER2 and FASN increase the benefit of anti-HER2 therapy representing a new opportunity for metabolically combating trastuzumab-resistant HER2+ GC.

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“…Gastric cancer (GC) remains one of the most incident neoplasms and the third leading cause of cancer-related death [ 1 ].The dysregulation of oncogenic and tumor suppressor genes and pathways result in the stepwise accumulation of numerous epigenetic alterations [ 2 ]. It has been reported that gastric cancer stem cells (GCSCs) function as vital contributors to tumor initiation, progression, metastasis and relapse, drug resistance [ 3 ].GCSCs possess the ability of unlimited self-renewal and heterogeneous differentiation, and they have been described highly resistant to currently available chemotherapy and targeted therapy in GC [ 4 , 5 ]. Therefore, understanding the molecular mechanisms that enhances the stemness of GC cells will provide new strategies to improve GC treatments.…”

Section: Introductionmentioning

confidence: 99%

Notum enhances gastric cancer stem-like cell properties through upregulation of Sox2 by PI3K/AKT signaling pathway

Liu,

Chen,

Xiao

et al. 2023

Cell Oncol.

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Purpose Considerable evidence suggests that tumor cells with stemness features contribute to initiation, progression, recurrence of gastric cancer (GC) and resistance to therapy, but involvement of underlying regulators and mechanisms remain largely unclear. However, the clinical significance and biological function of Notum in GC tumor sphere formation and tumorigenesis remain unclear. Methods Bioinformatics analysis, RT-qPCR, western blot and imunohistochemistry staining were applied to characterize Notum expression in GC specimens. The early diagnostic value of Notum was analyzed by logistic regression analysis method. Cancer stemness assays were used in Notum knockdown and overexpressing cells in vitro and in vivo. RNA-seq was employed to reveal the downstream effectors of Notum. Results Notum is highly expressed in early stage of GC patients and stem-like GC cells. For discriminating the early-stage and advanced GC patients, the joint analysis had a better diagnostic value. Overexpression of Notum markedly increased stemness features of GC cells to promote tumor sphere formation and tumorigenesis. Conversely, Notum knockdown attenuated the stem-like cell properties in vitro and in vivo. Mechanically, Notum upregulates Sox2 through activating the PI3K/AKT signaling pathway. Notum inhibitor Caffeine exhibited a potent inhibitory effect on stemness features by impairing the PI3K/AKT signaling pathway activity and targeting Sox2. Conclusion Our findings confer a comprehensive and mechanistic function of Notum in GC tumor sphere formation and tumorigenesis that may provide a novel and promising target for early diagnosis and clinical therapy of GC.

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Targeting Gastric Cancer Stem Cells to Enhance Treatment Response

Cited by 30 publications

References 181 publications

The hypoxia-inducible factor-1α in stemness and resistance to chemotherapy in gastric cancer: Future directions for therapeutic targeting

The hypoxia-inducible factor-1α in stemness and resistance to chemotherapy in gastric cancer: Future directions for therapeutic targeting

Fatty acid synthase as a new therapeutic target for HER2-positive gastric cancer

Notum enhances gastric cancer stem-like cell properties through upregulation of Sox2 by PI3K/AKT signaling pathway

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