The anti-cancer effect of retinoic acid signaling in CRC occurs via decreased growth of ALDH+ colon cancer stem cells and increased differentiation of stem cells

Modarai, Shirin; Gupta, Anindita; Opdenaker, Lynn M.; Kowash, Ryan; Masters, Gabriel; Viswanathan, Vignesh; Zhang, Tao; Fields, Jeremy Z.; Boman, Bruce M.

doi:10.18632/oncotarget.26157

Cited by 32 publications

(64 citation statements)

References 31 publications

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“…Similar findings were found in colon CSCs overexpressing ALDH. Indeed, the authors found that ATRA treatment inhibited colonic CSC proliferation, decreased the ALDH hi population size, induced differentiation of CSC, and reduced metastasis formation [265]. Moreover, the authors imputed the CSCs establishment due to dysregulation of ATRA signaling.…”

Section: Tumor Progression: Cscs and Invasionmentioning

confidence: 99%

Retinoic Acids in the Treatment of Most Lethal Solid Cancers

Costantini

Molinari

Farinon

et al. 2020

JCM

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Although the use of oral administration of pharmacological all-trans retinoic acid (ATRA) concentration in acute promyelocytic leukaemia (APL) patients was approved for over 20 years and used as standard therapy still to date, the same use in solid cancers is still controversial. In the present review the literature about the top five lethal solid cancers (lung, stomach, liver, breast, and colon cancer), as defined by The Global Cancer Observatory of World Health Organization, and retinoic acids (ATRA, 9-cis retinoic acid, and 13-cis retinoic acid, RA) was compared. The action of retinoic acids in inhibiting the cell proliferation was found in several cell pathways and compartments: from membrane and cytoplasmic signaling, to metabolic enzymes, to gene expression. However, in parallel in the most aggressive phenotypes several escape routes have evolved conferring retinoic acids-resistance. The comparison between different solid cancer types pointed out that for some cancer types several information are still lacking. Moreover, even though some pathways and escape routes are the same between the cancer types, sometimes they can differently respond to retinoic acid therapy, so that generalization cannot be made. Further studies on molecular pathways are needed to perform combinatorial trials that allow overcoming retinoic acids resistance.

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Section: Tumor Progression: Cscs and Invasionmentioning

confidence: 99%

Retinoic Acids in the Treatment of Most Lethal Solid Cancers

Costantini

Molinari

Farinon

et al. 2020

JCM

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“…And during CRC development, dysregulation of these kinetic mechanisms induces changes in crypt cell quiescence associated with the increased number of proliferative cells that occurs in colonic tumors. We also know that ALDH is a key component of the retinoid signaling pathway and ALDH-positive SCs directly differentiate into neuroendocrine cells [51]. Thus, we hypothesize that upregulated miRNA92a, by down-regulating LRIG1, decreases differentiation and increases proliferative potential of ALDH-positive CSCs.…”

Section: What Is the Role Of Mirna92a In The Stem Cell Origin Of Cancer?mentioning

confidence: 89%

“…ALDEFLUOR Assay, Propidium Iodide Staining and EpCAM Staining of Normal and Tumor cells. ALDEFLUOR-positive cells were isolated as described previously [5,17,51,56]. The dissociated cells from both normal and tumor were washed thrice in sterile HBSS and then subjected to the ALDELFUOR Assay following the manufacturer's protocol (STEMCELL Technologies Inc., BC, Canada).…”

Section: Methodsmentioning

confidence: 99%

MicroRNA Expression Profiling of Normal and Malignant Human Colonic Stem Cells Identifies miRNA92a as a Regulator of the LRIG1 Stem Cell Gene

Viswanathan

Opdenaker

Modarai

et al. 2020

IJMS

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MicroRNAs (miRNAs) have a critical role in regulating stem cells (SCs) during development, and because aberrant expression of miRNAs occurs in various cancers, our goal was to determine if dysregulation of miRNAs is involved in the SC origin of colorectal cancer (CRC). We previously reported that aldehyde dehydrogenase (ALDH) is a marker for normal and malignant human colonic SCs and tracks SC overpopulation during colon tumorigenesis. MicroRNA expression was studied in ALDH-positive SCs from normal and malignant human colon tissues by Nanostring miRNA profiling. Our findings show that: (1) A unique miRNA signature distinguishes ALDH-positive CRC cells from ALDH-positive normal colonic epithelial cells, (2) Expression of four miRNAs (miRNA200c, miRNA92a, miRNA20a, miRNA93) are significantly altered in CRC SCs compared to normal colonic SCs, (3) miRNA92a expression is also upregulated in ALDH-positive HT29 CRC SCs as compared to ALDH-negative SCs, (4) miRNA92a targets the 3′UTR of LRIG1 SC gene, and (5) miRNA92a modulates proliferation of HT29 CRC cells. Thus, our findings indicate that overexpression of miRNA92a contributes to the SC origin of CRC. Strategies designed to modulate miRNA expression, such as miRNA92a, may provide ways to target malignant SCs and to develop more effective therapies against CRC.

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“…ATRA is an active metabolite of vitamin A and involved in many crucial signaling pathways such as embryonic development, immune system function, reproduction, and epithelial integrity [124][125][126]. ATRA is commonly used as a differentiation agent in stem cell research [127,128], and several studies have reported the use of ATRA as a differentiation agent to inhibit cancer cell growth by altering the cell cycle progression [129][130][131] and to target CSCs tumorspheres in various malignancies both in vitro and in vivo [132][133][134][135][136]. In OC, ATRA reduced ALDH1 expression and suppressed in vitro tumorsphere formation, cell migration, and invasion and in vivo tumorigenesis [106] ( Table 2).…”

Section: All-trans Retinoic Acid (Atra)mentioning

confidence: 99%

Targeting Aldehyde Dehydrogenases to Eliminate Cancer Stem Cells in Gynecologic Malignancies

Muralikrishnan

Hurley

Nephew

2020

Cancers

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Gynecologic cancers cause over 600,000 deaths annually in women worldwide. The development of chemoresistance after initial rounds of chemotherapy contributes to tumor relapse and death due to gynecologic malignancies. In this regard, cancer stem cells (CSCs), a subpopulation of stem cells with the ability to undergo self-renewal and clonal evolution, play a key role in tumor progression and drug resistance. Aldehyde dehydrogenases (ALDH) are a group of enzymes shown to be robust CSC markers in gynecologic and other malignancies. These enzymes also play functional roles in CSCs, including detoxification of aldehydes, scavenging of reactive oxygen species (ROS), and retinoic acid (RA) signaling, making ALDH an attractive therapeutic target in various clinical scenarios. In this review, we discuss the critical roles of the ALDH in driving stemness in different gynecologic malignancies. We review inhibitors of ALDH, both general and isoform-specific, which have been used to target CSCs in gynecologic cancers. Many of these inhibitors have been shown to be effective in preclinical models of gynecologic malignancies, supporting further development in the clinic. Furthermore, ALDH inhibitors, including 673A and CM037, synergize with chemotherapy to reduce tumor growth. Thus, ALDH-targeted therapies hold promise for improving patient outcomes in gynecologic malignancies.

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The anti-cancer effect of retinoic acid signaling in CRC occurs via decreased growth of ALDH+ colon cancer stem cells and increased differentiation of stem cells

Cited by 32 publications

References 31 publications

Retinoic Acids in the Treatment of Most Lethal Solid Cancers

Retinoic Acids in the Treatment of Most Lethal Solid Cancers

MicroRNA Expression Profiling of Normal and Malignant Human Colonic Stem Cells Identifies miRNA92a as a Regulator of the LRIG1 Stem Cell Gene

Targeting Aldehyde Dehydrogenases to Eliminate Cancer Stem Cells in Gynecologic Malignancies

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