ALDH2 dysfunction and alcohol cooperate in cancer stem cell enrichment
Abstract The alcohol metabolite acetaldehyde is a potent human carcinogen linked to esophageal squamous cell carcinoma (ESCC) initiation and development. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme that detoxifies acetaldehyde in the mitochondria. Acetaldehyde accumulation causes genotoxi...
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| Veröffentlicht in: | Carcinogenesis (New York) 2024-02, Vol.45 (1-2), p.95-106 |
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| creator | Flashner, Samuel Shimonosono, Masataka Tomita, Yasuto Matsuura, Norihiro Ohashi, Shinya Muto, Manabu Klein-Szanto, Andres J Alan Diehl, J Chen, Che-Hong Mochly-Rosen, Daria Weinberg, Kenneth I Nakagawa, Hiroshi |
| description | Abstract
The alcohol metabolite acetaldehyde is a potent human carcinogen linked to esophageal squamous cell carcinoma (ESCC) initiation and development. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme that detoxifies acetaldehyde in the mitochondria. Acetaldehyde accumulation causes genotoxic stress in cells expressing the dysfunctional ALDH2E487K dominant negative mutant protein linked to ALDH2*2, the single nucleotide polymorphism highly prevalent among East Asians. Heterozygous ALDH2*2 increases the risk for the development of ESCC and other alcohol-related cancers. Despite its prevalence and link to malignant transformation, how ALDH2 dysfunction influences ESCC pathobiology is incompletely understood. Herein, we characterize how ESCC and preneoplastic cells respond to alcohol exposure using cell lines, three-dimensional organoids and xenograft models. We find that alcohol exposure and ALDH2*2 cooperate to increase putative ESCC cancer stem cells with high CD44 expression (CD44H cells) linked to tumor initiation, repopulation and therapy resistance. Concurrently, ALHD2*2 augmented alcohol-induced reactive oxygen species and DNA damage to promote apoptosis in the non-CD44H cell population. Pharmacological activation of ALDH2 by Alda-1 inhibits this phenotype, suggesting that acetaldehyde is the primary driver of these changes. Additionally, we find that Aldh2 dysfunction affects the response to cisplatin, a chemotherapeutic commonly used for the treatment of ESCC. Aldh2 dysfunction facilitated enrichment of CD44H cells following cisplatin-induced oxidative stress and cell death in murine organoids, highlighting a potential mechanism driving cisplatin resistance. Together, these data provide evidence that ALDH2 dysfunction accelerates ESCC pathogenesis through enrichment of CD44H cells in response to genotoxic stressors such as environmental carcinogens and chemotherapeutic agents.
The carcinogenic alcohol metabolite acetaldehyde drives ESCC. Acetaldehyde is detoxified by ALDH2 which is suppressed by its common polymorphism. Here, we demonstrate that ALDH2 dysfunction and alcohol exposure cooperate in ESCC progression through cancer stem cell enrichment.
Graphical Abstract
Graphical Abstract |
| doi_str_mv | 10.1093/carcin/bgad085 |
| format | Article |
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The alcohol metabolite acetaldehyde is a potent human carcinogen linked to esophageal squamous cell carcinoma (ESCC) initiation and development. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme that detoxifies acetaldehyde in the mitochondria. Acetaldehyde accumulation causes genotoxic stress in cells expressing the dysfunctional ALDH2E487K dominant negative mutant protein linked to ALDH2*2, the single nucleotide polymorphism highly prevalent among East Asians. Heterozygous ALDH2*2 increases the risk for the development of ESCC and other alcohol-related cancers. Despite its prevalence and link to malignant transformation, how ALDH2 dysfunction influences ESCC pathobiology is incompletely understood. Herein, we characterize how ESCC and preneoplastic cells respond to alcohol exposure using cell lines, three-dimensional organoids and xenograft models. We find that alcohol exposure and ALDH2*2 cooperate to increase putative ESCC cancer stem cells with high CD44 expression (CD44H cells) linked to tumor initiation, repopulation and therapy resistance. Concurrently, ALHD2*2 augmented alcohol-induced reactive oxygen species and DNA damage to promote apoptosis in the non-CD44H cell population. Pharmacological activation of ALDH2 by Alda-1 inhibits this phenotype, suggesting that acetaldehyde is the primary driver of these changes. Additionally, we find that Aldh2 dysfunction affects the response to cisplatin, a chemotherapeutic commonly used for the treatment of ESCC. Aldh2 dysfunction facilitated enrichment of CD44H cells following cisplatin-induced oxidative stress and cell death in murine organoids, highlighting a potential mechanism driving cisplatin resistance. Together, these data provide evidence that ALDH2 dysfunction accelerates ESCC pathogenesis through enrichment of CD44H cells in response to genotoxic stressors such as environmental carcinogens and chemotherapeutic agents.
The carcinogenic alcohol metabolite acetaldehyde drives ESCC. Acetaldehyde is detoxified by ALDH2 which is suppressed by its common polymorphism. Here, we demonstrate that ALDH2 dysfunction and alcohol exposure cooperate in ESCC progression through cancer stem cell enrichment.
Graphical Abstract
Graphical Abstract</description><identifier>ISSN: 0143-3334</identifier><identifier>ISSN: 1460-2180</identifier><identifier>EISSN: 1460-2180</identifier><identifier>DOI: 10.1093/carcin/bgad085</identifier><identifier>PMID: 37978873</identifier><language>eng</language><publisher>UK: Oxford University Press</publisher><subject>Acetaldehyde - metabolism ; Alcohol Dehydrogenase - genetics ; Alcohol Drinking - genetics ; Aldehyde Dehydrogenase - genetics ; Aldehyde Dehydrogenase - metabolism ; Aldehyde Dehydrogenase, Mitochondrial - genetics ; Animals ; Carcinogenesis ; Cell Transformation, Neoplastic ; Cisplatin - pharmacology ; Editor's Choice ; Esophageal Neoplasms - pathology ; Esophageal Squamous Cell Carcinoma - genetics ; Ethanol - metabolism ; Humans ; Mice ; Neoplastic Stem Cells - pathology ; Risk Factors</subject><ispartof>Carcinogenesis (New York), 2024-02, Vol.45 (1-2), p.95-106</ispartof><rights>The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. 2023</rights><rights>The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c340t-234ef82bfd6763d779db8b0f82f9e43034a76b1eeabfa47a9dfdadb07a6b4d573</cites><orcidid>0000-0002-6691-8733 ; 0000-0001-9796-0515</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,1578,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37978873$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Flashner, Samuel</creatorcontrib><creatorcontrib>Shimonosono, Masataka</creatorcontrib><creatorcontrib>Tomita, Yasuto</creatorcontrib><creatorcontrib>Matsuura, Norihiro</creatorcontrib><creatorcontrib>Ohashi, Shinya</creatorcontrib><creatorcontrib>Muto, Manabu</creatorcontrib><creatorcontrib>Klein-Szanto, Andres J</creatorcontrib><creatorcontrib>Alan Diehl, J</creatorcontrib><creatorcontrib>Chen, Che-Hong</creatorcontrib><creatorcontrib>Mochly-Rosen, Daria</creatorcontrib><creatorcontrib>Weinberg, Kenneth I</creatorcontrib><creatorcontrib>Nakagawa, Hiroshi</creatorcontrib><title>ALDH2 dysfunction and alcohol cooperate in cancer stem cell enrichment</title><title>Carcinogenesis (New York)</title><addtitle>Carcinogenesis</addtitle><description>Abstract
The alcohol metabolite acetaldehyde is a potent human carcinogen linked to esophageal squamous cell carcinoma (ESCC) initiation and development. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme that detoxifies acetaldehyde in the mitochondria. Acetaldehyde accumulation causes genotoxic stress in cells expressing the dysfunctional ALDH2E487K dominant negative mutant protein linked to ALDH2*2, the single nucleotide polymorphism highly prevalent among East Asians. Heterozygous ALDH2*2 increases the risk for the development of ESCC and other alcohol-related cancers. Despite its prevalence and link to malignant transformation, how ALDH2 dysfunction influences ESCC pathobiology is incompletely understood. Herein, we characterize how ESCC and preneoplastic cells respond to alcohol exposure using cell lines, three-dimensional organoids and xenograft models. We find that alcohol exposure and ALDH2*2 cooperate to increase putative ESCC cancer stem cells with high CD44 expression (CD44H cells) linked to tumor initiation, repopulation and therapy resistance. Concurrently, ALHD2*2 augmented alcohol-induced reactive oxygen species and DNA damage to promote apoptosis in the non-CD44H cell population. Pharmacological activation of ALDH2 by Alda-1 inhibits this phenotype, suggesting that acetaldehyde is the primary driver of these changes. Additionally, we find that Aldh2 dysfunction affects the response to cisplatin, a chemotherapeutic commonly used for the treatment of ESCC. Aldh2 dysfunction facilitated enrichment of CD44H cells following cisplatin-induced oxidative stress and cell death in murine organoids, highlighting a potential mechanism driving cisplatin resistance. Together, these data provide evidence that ALDH2 dysfunction accelerates ESCC pathogenesis through enrichment of CD44H cells in response to genotoxic stressors such as environmental carcinogens and chemotherapeutic agents.
The carcinogenic alcohol metabolite acetaldehyde drives ESCC. Acetaldehyde is detoxified by ALDH2 which is suppressed by its common polymorphism. Here, we demonstrate that ALDH2 dysfunction and alcohol exposure cooperate in ESCC progression through cancer stem cell enrichment.
Graphical Abstract
Graphical Abstract</description><subject>Acetaldehyde - metabolism</subject><subject>Alcohol Dehydrogenase - genetics</subject><subject>Alcohol Drinking - genetics</subject><subject>Aldehyde Dehydrogenase - genetics</subject><subject>Aldehyde Dehydrogenase - metabolism</subject><subject>Aldehyde Dehydrogenase, Mitochondrial - genetics</subject><subject>Animals</subject><subject>Carcinogenesis</subject><subject>Cell Transformation, Neoplastic</subject><subject>Cisplatin - pharmacology</subject><subject>Editor's Choice</subject><subject>Esophageal Neoplasms - pathology</subject><subject>Esophageal Squamous Cell Carcinoma - genetics</subject><subject>Ethanol - metabolism</subject><subject>Humans</subject><subject>Mice</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Risk Factors</subject><issn>0143-3334</issn><issn>1460-2180</issn><issn>1460-2180</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkD1PwzAURS0EoqWwMiKPMKS1YzdOJlQVSpEqscBsPX-kDUrsYidI_fekakEwMVmyj-997yB0TcmYkoJNNARduYlagyH59AQNKc9IktKcnKIhoZwljDE-QBcxvhNCMzYtztGAiULkuWBDtJitHpYpNrtYdk63lXcYnMFQa7_xNdbeb22A1uLKYQ1O24BjaxusbV1j60KlN4117SU6K6GO9up4jtDb4vF1vkxWL0_P89kq0YyTNkkZt2WeqtJkImNGiMKoXJH-qiwsZ4RxEJmi1oIqgQsoTGnAKCIgU9xMBRuh-0PutlONNbqvDlDLbagaCDvpoZJ_X1y1kWv_KWlvpxCM9gm3x4TgPzobW9lUcb8NOOu7KNO8oGIqBGc9Oj6gOvgYgy1_eiiRe_vyYF8e7fcfbn5P94N_6-6BuwPgu-1_YV9luJK5</recordid><startdate>20240212</startdate><enddate>20240212</enddate><creator>Flashner, Samuel</creator><creator>Shimonosono, Masataka</creator><creator>Tomita, Yasuto</creator><creator>Matsuura, Norihiro</creator><creator>Ohashi, Shinya</creator><creator>Muto, Manabu</creator><creator>Klein-Szanto, Andres J</creator><creator>Alan Diehl, J</creator><creator>Chen, Che-Hong</creator><creator>Mochly-Rosen, Daria</creator><creator>Weinberg, Kenneth I</creator><creator>Nakagawa, Hiroshi</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6691-8733</orcidid><orcidid>https://orcid.org/0000-0001-9796-0515</orcidid></search><sort><creationdate>20240212</creationdate><title>ALDH2 dysfunction and alcohol cooperate in cancer stem cell enrichment</title><author>Flashner, Samuel ; Shimonosono, Masataka ; Tomita, Yasuto ; Matsuura, Norihiro ; Ohashi, Shinya ; Muto, Manabu ; Klein-Szanto, Andres J ; Alan Diehl, J ; Chen, Che-Hong ; Mochly-Rosen, Daria ; Weinberg, Kenneth I ; Nakagawa, Hiroshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c340t-234ef82bfd6763d779db8b0f82f9e43034a76b1eeabfa47a9dfdadb07a6b4d573</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Acetaldehyde - metabolism</topic><topic>Alcohol Dehydrogenase - genetics</topic><topic>Alcohol Drinking - genetics</topic><topic>Aldehyde Dehydrogenase - genetics</topic><topic>Aldehyde Dehydrogenase - metabolism</topic><topic>Aldehyde Dehydrogenase, Mitochondrial - genetics</topic><topic>Animals</topic><topic>Carcinogenesis</topic><topic>Cell Transformation, Neoplastic</topic><topic>Cisplatin - pharmacology</topic><topic>Editor's Choice</topic><topic>Esophageal Neoplasms - pathology</topic><topic>Esophageal Squamous Cell Carcinoma - genetics</topic><topic>Ethanol - metabolism</topic><topic>Humans</topic><topic>Mice</topic><topic>Neoplastic Stem Cells - pathology</topic><topic>Risk Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Flashner, Samuel</creatorcontrib><creatorcontrib>Shimonosono, Masataka</creatorcontrib><creatorcontrib>Tomita, Yasuto</creatorcontrib><creatorcontrib>Matsuura, Norihiro</creatorcontrib><creatorcontrib>Ohashi, Shinya</creatorcontrib><creatorcontrib>Muto, Manabu</creatorcontrib><creatorcontrib>Klein-Szanto, Andres J</creatorcontrib><creatorcontrib>Alan Diehl, J</creatorcontrib><creatorcontrib>Chen, Che-Hong</creatorcontrib><creatorcontrib>Mochly-Rosen, Daria</creatorcontrib><creatorcontrib>Weinberg, Kenneth I</creatorcontrib><creatorcontrib>Nakagawa, Hiroshi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Carcinogenesis (New York)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Flashner, Samuel</au><au>Shimonosono, Masataka</au><au>Tomita, Yasuto</au><au>Matsuura, Norihiro</au><au>Ohashi, Shinya</au><au>Muto, Manabu</au><au>Klein-Szanto, Andres J</au><au>Alan Diehl, J</au><au>Chen, Che-Hong</au><au>Mochly-Rosen, Daria</au><au>Weinberg, Kenneth I</au><au>Nakagawa, Hiroshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ALDH2 dysfunction and alcohol cooperate in cancer stem cell enrichment</atitle><jtitle>Carcinogenesis (New York)</jtitle><addtitle>Carcinogenesis</addtitle><date>2024-02-12</date><risdate>2024</risdate><volume>45</volume><issue>1-2</issue><spage>95</spage><epage>106</epage><pages>95-106</pages><issn>0143-3334</issn><issn>1460-2180</issn><eissn>1460-2180</eissn><abstract>Abstract
The alcohol metabolite acetaldehyde is a potent human carcinogen linked to esophageal squamous cell carcinoma (ESCC) initiation and development. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme that detoxifies acetaldehyde in the mitochondria. Acetaldehyde accumulation causes genotoxic stress in cells expressing the dysfunctional ALDH2E487K dominant negative mutant protein linked to ALDH2*2, the single nucleotide polymorphism highly prevalent among East Asians. Heterozygous ALDH2*2 increases the risk for the development of ESCC and other alcohol-related cancers. Despite its prevalence and link to malignant transformation, how ALDH2 dysfunction influences ESCC pathobiology is incompletely understood. Herein, we characterize how ESCC and preneoplastic cells respond to alcohol exposure using cell lines, three-dimensional organoids and xenograft models. We find that alcohol exposure and ALDH2*2 cooperate to increase putative ESCC cancer stem cells with high CD44 expression (CD44H cells) linked to tumor initiation, repopulation and therapy resistance. Concurrently, ALHD2*2 augmented alcohol-induced reactive oxygen species and DNA damage to promote apoptosis in the non-CD44H cell population. Pharmacological activation of ALDH2 by Alda-1 inhibits this phenotype, suggesting that acetaldehyde is the primary driver of these changes. Additionally, we find that Aldh2 dysfunction affects the response to cisplatin, a chemotherapeutic commonly used for the treatment of ESCC. Aldh2 dysfunction facilitated enrichment of CD44H cells following cisplatin-induced oxidative stress and cell death in murine organoids, highlighting a potential mechanism driving cisplatin resistance. Together, these data provide evidence that ALDH2 dysfunction accelerates ESCC pathogenesis through enrichment of CD44H cells in response to genotoxic stressors such as environmental carcinogens and chemotherapeutic agents.
The carcinogenic alcohol metabolite acetaldehyde drives ESCC. Acetaldehyde is detoxified by ALDH2 which is suppressed by its common polymorphism. Here, we demonstrate that ALDH2 dysfunction and alcohol exposure cooperate in ESCC progression through cancer stem cell enrichment.
Graphical Abstract
Graphical Abstract</abstract><cop>UK</cop><pub>Oxford University Press</pub><pmid>37978873</pmid><doi>10.1093/carcin/bgad085</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-6691-8733</orcidid><orcidid>https://orcid.org/0000-0001-9796-0515</orcidid></addata></record> |
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| ispartof | Carcinogenesis (New York), 2024-02, Vol.45 (1-2), p.95-106 |
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| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE |
| subjects | Acetaldehyde - metabolism Alcohol Dehydrogenase - genetics Alcohol Drinking - genetics Aldehyde Dehydrogenase - genetics Aldehyde Dehydrogenase - metabolism Aldehyde Dehydrogenase, Mitochondrial - genetics Animals Carcinogenesis Cell Transformation, Neoplastic Cisplatin - pharmacology Editor's Choice Esophageal Neoplasms - pathology Esophageal Squamous Cell Carcinoma - genetics Ethanol - metabolism Humans Mice Neoplastic Stem Cells - pathology Risk Factors |
| title | ALDH2 dysfunction and alcohol cooperate in cancer stem cell enrichment |
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