ALDH1A1 in Cancers: Bidirectional Function, Drug Resistance, and Regulatory Mechanism

Yue, Hanxun; Hu, Zenan; Hu, Rui; Guo, Zeying; Zheng, Ya; Wang, Yuping; Zhou, Yongning

doi:10.3389/fonc.2022.918778

Cited by 36 publications

(25 citation statements)

References 98 publications

(132 reference statements)

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“…ALDH1A1 has frequently been described as a marker for stemness in human cancers ( 23 ), even though early investigations found it dispensable for stem cell function in murine hematopoietic and nervous systems ( 24 ). Studies on human glioblastoma cell lines suggested the enzyme as a mediator of TMZ resistance ( 25 ).…”

Section: Resultsmentioning

confidence: 99%

“…There are drugs already available broadly inhibiting aldehyde dehydrogenases (e.g., disulfiram), which unfortunately can show severe side effects and toxicity ( 45 ). Isoform-specific inhibitors are under development ( 23 ), but their safety profile remain to be elucidated under the premise that ALDH1A1 is also expressed during development and in the adult brain ( 27, 46 ). We therefore approached the alternative, provided by the marked upregulation of pAKT in the target cells.…”

Section: Discussionmentioning

confidence: 99%

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A Sequential Targeting Strategy Interrupts AKT-Driven Subclone-Mediated Progression in Glioblastoma

Kebir

Ullrich

Berger

et al. 2022

Clinical Cancer Research

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Purpose: Therapy resistance and fatal disease progression in glioblastoma are thought to result from the dynamics of intra-tumor heterogeneity. This study aimed at identifying and molecularly target tumor cells that can survive, adapt, and subclonally expand under primary therapy. Experimental Design: To identify candidate markers and to experimentally access dynamics of subclonal progression in glioblastoma, we established a discovery cohort of paired vital cell samples obtained before and after primary therapy. We further used two independent validation cohorts of paired clinical tissues to test our findings. Follow-up preclinical treatment strategies were evaluated in patient-derived xenografts. Results: We describe, in clinical samples, an archetype of rare ALDH1A1+ tumor cells that enrich and acquire AKT-mediated drug resistance in response to standard-of-care temozolomide. Importantly, we observe that drug resistance of ALDH1A1+ cells is not intrinsic, but rather an adaptive mechanism emerging exclusively after temozolomide treatment. In patient cells and xenograft models of disease, we recapitulate the enrichment of ALDH1A1+ cells under the influence of temozolomide. We demonstrate that their subclonal progression is AKT-driven and can be interfered with by well-timed sequential rather than simultaneous antitumor combination strategy. Conclusion: Drug-resistant ALDH1A1+/pAKT+ subclones accumulate in patient tissues upon adaptation to temozolomide therapy. These subclones may therefore represent a dynamic target in glioblastoma. Our study proposes the combination of temozolomide and AKT inhibitors in a sequential treatment schedule as a rationale for future clinical investigation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Sequential Targeting Strategy Interrupts AKT-Driven Subclone-Mediated Progression in Glioblastoma

Kebir

Ullrich

Berger

et al. 2022

Clinical Cancer Research

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“…ALDH1 is lowly expressed in normal tissues and highly expressed in cancer the expression level of ALDH1is a marker that distinguishes normal stem cells from cancer stem cells. Clinical research studies have found that the prognostic ratio of the ALDH1 gene family can be used as a robust poor predictor of various solid cancers, including breast cancer, colon cancer, esophageal squamous cell carcinoma, non-small cell lung cancer, ovarian cancer, and other cancers ( 18 , 19 ). As a strong predictor, ALDH1 is also involved in deriving drug resistance in solid cancers.…”

Section: Aldh1 and Mechanismmentioning

confidence: 99%

ALDH1: A potential therapeutic target for cancer stem cells in solid tumors

Wei

Chen

et al. 2022

Front. Oncol.

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Solid tumors can be divided into benign solid tumors and solid malignant tumors in the academic community, among which malignant solid tumors are called cancers. Cancer is the second leading cause of death in the world, and the global incidence of cancer is increasing yearly New cancer patients in China are always the first. After the concept of stem cells was introduced in the tumor community, the CSC markers represented by ALDH1 have been widely studied due to their strong CSC cell characteristics and potential to be the driving force of tumor metastasis. In the research results in the past five years, it has been found that ALDH1 is highly expressed in various solid cancers such as breast cancer, lung cancer, colorectal cancer, liver cancer, gastric cancer, cervical cancer, esophageal cancer, ovarian cancer, head,and neck cancer. ALDH1 can activate and transform various pathways (such as the USP28/MYC signaling pathway, ALDH1A1/HIF-1α/VEGF axis, wnt/β-catenin signaling pathway), as well as change the intracellular pH value to promote formation and maintenance, resulting in drug resistance in tumors. By targeting and inhibiting ALDH1 in tumor stem cells, it can enhance the sensitivity of drugs and inhibit the proliferation, differentiation, and metastasis of solid tumor stem cells to some extent. This review discusses the relationship and pathway of ALDH1 with various solid tumors. It proposes that ALDH1 may serve as a diagnosis and therapeutic target for CSC, providing new insights and new strategies for reliable tumor treatment.

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“…The ALDH1A subfamily is also known to play an important role in embryogenesis and development by mediating retinoic acid signaling [ 8 ]. The ALDH1A1 gene codes a cytoplasmic enzyme and exerts vital physiological and pathophysiological functions, playing important roles in various chronic diseases, including cancer [ 9 ]. ALDH1A1 can induce cancer development via the maintenance of cancer stem cell properties, the modification of the metabolism, and the promotion of DNA repair.…”

Section: Introductionmentioning

confidence: 99%

“…The expression of ALDH1A1, which acts as a tumor suppressor in certain cancers, is regulated by several epigenetic processes. Since the detoxification of ALDH1A1 often causes the failure of chemotherapy [ 9 ], ALDH1A1-targeted therapy has recently been widely used as a cancer chemotherapy [ 10 ], although the mechanism by which ALDH1A1 regulates carcinogenesis is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

A Case of Early-Stage Gallbladder Cancer, Positive for ALDH1A1, Which Arose from Adenomyomatosis of the Gallbladder

et al. 2022

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Adenomyomatosis (ADM) of the gallbladder is a condition characterized by the proliferation of Rokitansky–Aschoff sinus (RAS), in which the epithelium of the gallbladder extends into the muscular layer, causing a thickening of the gallbladder wall. Although ADM is generally considered not to be a precancerous lesion of gallbladder cancer, there are some reports of cases of gallbladder cancer from ADM. Therefore, the relationship between ADM and gallbladder cancer remains controversial. We herein report a case of early-stage gallbladder cancer, BilIN3 (high grade), arising from ADM that was positive for ALDH1A1, an important marker of stem cells and cancer stem cells.

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ALDH1A1 in Cancers: Bidirectional Function, Drug Resistance, and Regulatory Mechanism

Cited by 36 publications

References 98 publications

A Sequential Targeting Strategy Interrupts AKT-Driven Subclone-Mediated Progression in Glioblastoma

A Sequential Targeting Strategy Interrupts AKT-Driven Subclone-Mediated Progression in Glioblastoma

ALDH1: A potential therapeutic target for cancer stem cells in solid tumors

A Case of Early-Stage Gallbladder Cancer, Positive for ALDH1A1, Which Arose from Adenomyomatosis of the Gallbladder

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