High Expression Of Aldehyde Dehydrogenase Research Articles

PTEN overexpression and nuclear β-catenin stabilization promote morular differentiation through induction of epithelial–mesenchymal transition and cancer stem cell-like properties in endometrial carcinoma

BackgroundAlthough a lack of functional PTEN contributes to tumorigenesis in a wide spectrum of human malignancies, little is known about the functional role of its overexpression in the tumors. The current study focused on PTEN overexpression in endometrial carcinoma (Em Ca).MethodsThe functional impact of PTEN overexpression was assessed by Em Ca cell lines. Immunohistochemical analyses were also conducted using 38 Em Ca with morular lesions.ResultsEm Ca cell lines stably overexpressing PTEN (H6-PTEN) exhibited epithelial–mesenchymal transition (EMT)-like features, probably through β-catenin/Slug-meditated suppression of E-cadherin. PTEN overexpression also inhibited cell proliferation, accelerated cellular senescence, increased apoptotic features, and enhanced migration capability. Moreover, H6-PTEN cells exhibited cancer stem cell (CSC)-like properties, along with high expression of aldehyde dehydrogenase 1 and CD44s, a large ALDH 1high population, enriched spheroid formation, and β-catenin-mediated upregulation of cyclin D2, which is required for persistent CSC growth. In clinical samples, immunoreactivities for PTEN, as well as CSC-related molecules, were significantly higher in morular lesions as compared to the surrounding carcinomas. PTEN score was positively correlated with expression of nuclear β-catenin, cytoplasmic CD133, and CD44v6, and negatively with cell proliferation. Finally, estrogen receptor-α (ERα)-dependent expression of Ezrin-radixin-moesin-binding phophoprotein-50 (EBP50), a multifunctional scaffolding protein, acts as a negative regulator of morular formation by Em Ca cells through interacting with PTEN and β-catenin.ConclusionIn the abscess of ERα/EBP50 expression, PTEN overexpression and nuclear β-catenin stabilization promote the establishment and maintenance of morular phenotype associated with EMT/CSC-like features in Em Ca cells.BZqz53M46AEhaXf_YNaSmyVideo

Abstract 6063: FOXK2 promotes stemness in ovarian cancer by regulating unfolded protein response signaling

Abstract Introduction: Cancer stem cells (CSCs), a rare cell population within tumors that possesses self-renewal and tumor initiation capacity, have been implicated in cancer relapse and resistance to chemotherapy. In ovarian cancer (OC), CSCs are characterized by a high expression of aldehyde dehydrogenase (ALDH). Understanding the regulatory programs promoting stemness could identify new treatments. We identified FOXK2 as a key transcription factor (TF) that promotes stemness in OC. Methods: We generated FOXK2 knockdown OC models by stable transduction of shRNA targeting this TF and measured the population of ALDH+ CSCs, expression of stemness-associated genes, and in vivo tumor initiation capacities. Transcriptomic and ChIP-seq analyses were used to identify key FOXK2 targets. CRISPR-dCas9 genome editing was used to verify the regulatory function of FOXK2. Rescue experiments validated the roles of a newly discovered target gene of FOXK2. Results: Through gene expression analyses in CSCs vs. non-CSCs, we identified FOXK2 as a highly expressed stemness-specific TF in OC. Genetic depletion of FOXK2 diminished stemness features and reduced in vivo tumor initiation capacity. Through ChIP-sequencing we discovered that FOXK2 directly regulates IRE1α (ERN1 gene) expression, a key sensor for the unfolded protein response (UPR). ChIP-sequencing analysis further revealed that FOXK2 binds to an intronic regulatory element of ERN1. Blocking FOXK2 from binding to this enhancer by using a CRISPR/dCas9 diminished IRE1α transcription. At the molecular level, FOXK2-driven upregulation of IRE1α led to alternative XBP1 mRNA splicing and activation of stemness pathways, while genetic or pharmacological blockade of IRE1α inhibited CSCs in OC models. Conclusion: Our data establish a new function for FOXK2 as a key transcriptional regulator of CSCs and a mediator of the UPR, providing insight into potentially targetable new pathways in ovarian CSCs. Citation Format: Yaqi Zhang, Yinu Wang, Guangyuan Zhao, Edward J. Tanner, Mazhar Adli, Daniela E. Matei. FOXK2 promotes stemness in ovarian cancer by regulating unfolded protein response signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6063.

Epithelial membrane protein 3 regulates lung cancer stem cells via the TGF‑β signaling pathway.

Epithelial membrane protein 3 (EMP3) is a transmembrane glycoprotein that contains a peripheral myelin protein22 domain. EMP3 first received attention as a tumor suppressor, but accumulating evidence has since suggested that it may exhibit a tumor‑promoting function. Nonetheless, the biological function of EMP3 remains largely unclear with regards to its role in cancer. Herein, it was shown that EMP3 expression is upregulated in non‑small cell lung cancer (NSCLC) cells overexpressing aldehyde dehydrogenase1(ALDH1). EMP3 was shown to be involved in cell proliferation, the formation of cancer stem cells (CSCs) and in epithelial‑mesenchymal transition (EMT). The ability to resist irradiation, one of the characteristics of CSCs, decreased when the EMP3 mRNA expression was knocked down using small interfering RNA. In addition, when EMP3 knockdown reduced the migratory ability of cells, a characteristic of EMT. Additionally, it was shown that the TGF‑β/Smad signaling axis was a target of EMP3. EMP3 was found to interact with TGF‑β receptor type2 (TGFBR2) upon TGF‑β stimulation in lung CSCs (LCSC). As a result, binding of EMP3‑TGFBR2 regulates TGF‑β/Smad signaling activation and consequently affects CSCs and EMT. Kaplan‑Meier analysis results confirmed that patients with high expression of EMP3 had poor survival rates. Taken together, these findings showed that EMP3 may be a potential target for management of LCSCs with high expression of ALDH1, and that EMP3 is involved in TGF‑β/Smad signaling activation where it promotes acquisition of cancerous properties in tumors.

ALDH1 & CD133 in invasive cervical carcinoma & their association with the outcome of chemoradiation therapy.

Background & objectives:Chemoradiation is the standard therapy for locally advanced invasive cervical cancer and response to treatment determines the outcome. Cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT) play a role in response to treatment and hence the aim of this study was to evaluate if their levels in pre-treatment biopsies by immunohistochemistry (IHC) could predict response to treatment and outcome.Methods:The study comprised 60 patients with FIGO Stage IIB/III invasive cervical carcinoma treated by chemoradiation. They were divided into two groups based on their clinical outcome: group 1, 30 patients who had no evidence of disease at 48 month follow up and group 2, 30 patients who had disease relapse within 6-12 months of treatment completion. IHC was performed for CSC markers (ALDH1, CD133, Nanog and Oct-4), EMT markers (E-cadherin and vimentin) and squamocolumnar junction (KRT7) markers and H-scores determined. Intergroup comparison was performed. The expression of these markers was also evaluated in histological sections of cervical pre-cancer (CIN1 and CIN3) in comparison to normal cervix.Results:Cervical Intraepithelial Neoplasia grade 3 (CIN3) showed high expression of ALDH1 and KRT7 as compared to normal cervical epithelium. Aldehyde dehydrogenase 1 (ALDH1) and CD133 were overexpressed in 70 and 24 per cent cervical carcinoma cases whereas E-cadherin showed reduced expression in invasive carcinoma as compared to normal controls. ALDH1 overexpression was significantly associated with disease relapse in invasive cervical carcinoma treated by chemoradiation (P<0.01).Interpretation & conclusions:Determination of ALDH1 levels in pre-treatment cervical biopsies of invasive cervical carcinoma may be useful for prediction of response to chemoradiation, with high levels predicting for a poor response.

Expression pattern of ALDH1, E-cadherin, Vimentin and Twist in early and late onset sporadic colorectal cancer.

Aim: To evaluate the expression pattern of ALDH1 (aldehyde dehydrogenase 1), E-cadherin, Vimentin and Twist in early and late onset sporadic colorectal cancer (CRC) and to study association of their expression with the occurrence of CRC at a young age. Materials & methods: Immunohistochemistry of ALDH1, E-cadherin, Vimentin and Twist was performed on 103 pretreated CRC biopsy samples. Results: ALDH1 expression was found to have strong correlation with early onset CRC (p < 0.0001). Conclusion: High ALDH1 expression correlates with the early onset of CRC. ALDH1 over-expression correlates with poor overall survival in colon cancer.

Prognostic Value of PET/CT and ALDH1 in Pancreatic Cancer and Correlation of Standardized Uptake Values with Clinical Characteristics and Survival

Abstract Background: Pancreatic malignancy is a rapidly growing cause of death in the world. Its survival rate is months even if discovered early. Aim of Study: We evaluated the correlations between PET/SUVs (Standard Uptake Values), clinical characteristics and cancer stem-like cells named aldehyde dehydrogenase 1 (ALDH1) in pancreatic cancer. We evaluated the diagnostic performance of SUV and its correlation with overall survival. Patients and Methods: Thirty-nine patients with pancreatic cancer were evaluated by PET/CT. The expression of ALDH1 was detected immunohistochemically in their cancer speci-mens. Results of PET/SUV were correlated with clinic-pathological character, ALDH1 and overall survival. Results: PET/SUV was associated significantly with tumor size (p=0.027). No significant correlation with other clinical-pathological characteristics. PET/CT showed sensitivity= 81%, specificity=78% and accuracy=82%. PET/SUV reflected the expression level of ALDH1 with significant correlation (p=0.001). Patients with high SUV and high expression of ALDH1 had a worse median overall. Conclusion: PET-CT was a non-invasive imaging modality that helped in pancreatic cancer especially in doubtful tumors. PET/CT was helpful tool to detect lymph nodes invasion and distant metastasis. It was associated with the expression level of ALDH1. High SUV and high expression of ALDH1were significantly correlated with a worse clinical outcome. PET/SUV and Cancer stem cells may serve as significant prognostic factors in predicting outcomes in pancreatic cancer patients.

Disulfiram potentiates the anticancer effect of cisplatin in atypical teratoid/rhabdoid tumors (AT/RT).

Atypical teratoid/rhabdoid tumor (AT/RT) is the most malignant tumor of the central nervous system that generally occurs in young children. Despite the use of intensive multimodal therapy for AT/RT, the prognosis is still poor. The brain tumor initiating cells in AT/RT cells has been suggested as one of the challenges in AT/RT treatment. These cells have high expression of aldehyde dehydrogenase (ALDH). We investigated the combination effect of the ALDH inhibitor, disulfiram and cisplatin in the treatment of AT/RT cells. Isobologram analysis revealed that the combination therapy synergistically increases AT/RT cell death. The enzyme activity of ALDH AT/RT cells was effectively reduced by the combination therapy. We proposed that the synergistic augmentation occurs, at least partially through an increase in cleaved Poly (ADP-ribose) polymerase (PARP)-dependent apoptosis mediated by activating transcription factor 3 (ATF3). In the AT/RT mouse model, the combination therapy decreased tumor volume and prolonged survival. Immunofluorescence assay in mouse brain tissues were consistent with the expression of ATF3 and cleaved PARP. Our study demonstrates enhanced anti-cancer effect of combination therapy of disulfiram and cisplatin. This combination might provide a viable therapeutic strategy for AT/RT patients.

Disulfiram/cytarabine eradicates a subset of acute myeloid leukemia stem cells with high aldehyde dehydrogenase expression

Most patients with acute myeloid leukemia (AML) achieve complete remission (CR) after induction chemotherapy, however, in some patients, the disease subsequently relapses and may lead to death. Leukemia stem cells (LSC) have been identified as the main cause for recurrence. Increased aldehyde dehydrogenase (ALDHhigh) activity in a variety of cancer stem cells prevents effective action of chemotherapeutic drugs. In this study, we found that approximately 50.7% of AML patients had ALDHhigh, and the presence of ALDHhigh stem cells was associated with poor cytogenetic prognosis. Lentiviral vector transduced ALDHhigh leukemia cell lines are insensitive to the conventional chemotherapy drug cytarabine, and inhibition of ALDH activity by disulfiram (DSF) can increase the sensitivity of ALDHhigh leukemia cells to cytarabine. Unlike traditional chemotherapy drugs, DSF is not toxic to healthy umbilical cord blood stem cells. An ALDHhigh leukemia cell xenograft model was established using immunodeficient mice to mimic the disease environment, and DSF and cytarabine were found to eliminate the ALDHhigh leukemia cells in transplanted mice while not affecting the healthy blood cells of mice. These findings suggest that DSF may have therapeutic potential by inhibiting ALDH activity and thereby increasing chemosensitivity.

Isolation and Identification of Cancer Stem-Like Cells in Adenocarcinoma and Squamous Cell Carcinoma of the Lung: A Pilot Study.

Background: Lung cancer stem cells (CSCs) share many characteristics with normal stem cells, such as self-renewal and multipotentiality. High expression of aldehyde dehydrogenase (ALDH) has been detected in many tumors, particularly in the CSC compartment, and it plays an important role in tumor proliferation, metastasis, and drug resistance. CD44 is commonly used as a cell surface marker of cancer stem-like cells in epithelial tumors. The aim of this study was to isolate and analyze cancer stem-like cells from surgically removed specimens to compare lung adenocarcinoma (ADENO) and squamous (SQUAMO) cell carcinoma.Methods: The ALDEFLUOR assay was used to identify and sort ALDHhigh and ALDHlow human lung cancer cells following tissue digestion. Fluorescence-activated cell sorting analysis for CD44 was performed with tumor cells. Quantitative real-time PCR was performed to assess the expression of SOX2 and NANOG as stemness markers. ALDH1A1 expression was additionally determined by immunohistochemistry. Anchorage-independent ALDHhigh cell growth was also evaluated. ALDHhigh ADENO and SQUAMO cells were cultured to analyze spheroid formation.Results: All specimens contained 0.5–12.5% ALDHhigh cells with 3.8–18.9% CD44-positive cells. SOX2 and NANOG relative expression in ALDHhigh compared to ALDHlow cells in ADENO and SQUAMO was analyzed and compared between the histotypes. Immunohistochemistry confirmed the presence of ALDH1A1 in the sections. SOX2 and NANOG were expressed at higher levels in the ALDHhigh subpopulation than in the ALDHlow subpopulation only in ADENO cells, and the opposite result was seen in SQUAMO cells. In vitro functional assays demonstrated that ALDHhigh cells exhibited migration capacity with distinct behaviors between ALDHhigh spheres in ADENO vs. SQUAMO samples.Conclusions: Our results highlight the importance of a better characterization of cancer stem-like cells in ADENO and SQUAMO histotypes. This may suggest new differential approaches for prognostic and therapeutic purposes in patients with non-small-cell lung cancer.

Abstract 4924: High ALDH1 expression in colorectal carcinoma could predict early onset of the disease

Abstract Background: Worldwide there is an increase in the trend of early onset of colorectal carcinoma in individuals who are less than 45 years of age. The composition of young age colorectal cases ranges from 35% to 40% in India. Currently, we do not have the access to any molecular marker that could predict early onset of the disease and its clinical course. Aldehyde dehydrogenase 1 (ALDH1), Twist, E Cadherin and Vimentin are markers for cancer stem cells and epithelial mesenchymal transition. However, there is paucity of data on their clinical significance in terms of their impact on early onset of colorectal carcinoma. This lack of data prompted us to investigate their role in the early onset of the colorectal cancer. Methods: Immunohistochemisty of ALDH1, Twist, E Cadherin and Vimentin was performed in pre treatment biopsy samples collected from 103 colorectal patients who were further divided into 2 groups: viz, less than or equal to 45 years and more than 46 years. Results: Over expression of ALDH1, Twist, E Cadherin and Vimentin was observed in 75.7%, 90.3%, 92.2% and 2.9% of pre treatment colorectal carcinoma tissue specimens respectively. ALDH1 expression was found to have strong correlation with early onset of the disease (patients who were less than or equal to 45 years of age (P=0.003). Women patients were found predominantly non smokers (P=0.001) and non tobacco chewers (P=0.004) with respect to men. Conclusion: High ALDH1 expression correlates with the early onset of colorectal cancer. None of other markers could reach statistical significance with the early or late onset of colorectal cancer. Note: This abstract was not presented at the meeting. Citation Format: Litika Vermani, N Senthil Kumar, Anuradha Talukdar, Monoj Deka, Ravi Kannan, Rajeev Kumar. High ALDH1 expression in colorectal carcinoma could predict early onset of the disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4924.

Serum deprivation-response protein regulates aldehyde dehydrogenase 1 through integrin-linked kinase signaling in endometrioid carcinoma cells.

Endometrioid carcinoma (EC) is one of the most common malignancies of the female genital system. We reported previously that aldehyde dehydrogenase 1 (ALDH1), a predominant isoform of the ALDH family in mammals and a potential marker of normal and malignant stem cells, is related to the tumorigenic potential of EC. We compared the levels of various proteins in human EC cells with high and low ALDH1 expression using shotgun proteomics and found that serum deprivation‐response protein (SDPR) was preferentially expressed in cells with high ALDH1 expression. Also known as cavin‐2, SDPR is a member of the cavin protein family, which is required for the formation of caveolae. Using SDPR‐knockout EC cells generated using the CRISPR/Cas9 system, we revealed that SDPR was correlated with invasion, migration, epithelial‐mesenchymal transition, and colony formation, as well as the expression of ALDH1. RNA sequencing showed that integrin‐linked kinase (ILK) signaling is involved in the effect of SDPR on ALDH1. Immunohistochemical analysis revealed that the localization of ILK at the cell cortex was disrupted by SDPR knockout, potentially interfering with ILK signaling. Moreover, immunohistochemical analysis of clinical samples showed that SDPR is related to histological characteristics associated with invasiveness, such as poor differentiation, lymphatic invasion, and the microcystic, elongated, and fragmented histopathological pattern. This is, to our knowledge, the first report that SDPR is related to tumor progression.

High expression of aldehyde dehydrogenase 1 and tissue necrosis factor alpha may relate to chronic infection of buffalo mammary gland

Aldehyde dehydrogenase 1 (ALDH1) and hepatocyte nuclear factor 4A (HNF4A) are the putative mammary stem cell markers. Tissue necrosis factor alpha (TNFA) is involved in inflammation-associated carcinogenesis and cell proliferation. In this study, the gene expression profile of ALDH1, HNF4A and TNFA of buffalo mammary tissue using real-time quantitative PCR (RT-qPCR). Analysis of RT-qPCR data revealed that the relative expression (log2 fold change) of ALDH1 and TNFA during mastitis (vs. lactation) was increased (P < .05) by 2.98 and 4.71, respectively. The relative expression (log2 fold change; −7.39) of stem cell marker, HNF4A was decreased (P < .05) during mastitis. Histological analysis of mammary tissue during mastitis showed thickening of stroma and occasionally hyperplasia, predominantly in prepubertal and non-lactating animals. Although, the level of expression of these genes may vary, depending upon the physiological stage of the animals, however expression of ALDH1 and TNFA was high during mastitis. A systematic study on large samples of buffalo mammary tissue with appropriate comparisons needs to be evaluated with these markers for prognosis of buffalo mammary health.

Aldehyde dehydrogenase serves as a biomarker for worse survival profiles in ovarian cancer patients: an updated meta-analysis

BackgroundThe purpose of this comprehensive meta-analysis was to assess the association of aldehyde dehydrogenase (ALDH) expression with overall survival (OS) and disease-free survival (DFS)/progression-free survival (PFS) in ovarian cancer patients.MethodsSystematic searches of Pubmed databases was performed to identify relevant literature published before February 28, 2018. A total of 14 studies (13 articles) with 2210 ovarian cancer patients were pooled. All included studies were performed by using Immunohistochemistry (IHC) for detection of ALDH expression. Hazard ratio (HR) and 95% confidence interval (CI) were extracted from included studies to evaluate the correlation of ALDH expression with OS and DFS/PFS.ResultsHigh expression of ALDH was associated with worse OS (HR: 1.43; 95% CI: 1.18–1.73) and poor DFS/PFS (HR: 1.55, 95% CI: 1.12–2.14). No evidence of publication bias was observed in OS (Begg’s test, P = 0.113; Egger’s test, P = 0.355) and DFS/PFS (Begg’s test, P = 0.655; Egger’s test, P = 0.189) in ovarian cancer patients. The subgroup of studies with cut-off value of low expression showed that high expression of ALDH was correlated with poor OS (HR: 1.36; 95% CI: 1.14–1.62) and DFS/PFS (HR: 1.79; 95% CI: 1.45–2.20) in ovarian cancer patients, with no observed heterogeneity (OS: I2 = 0%, P = 0.45; DFS/PFS: I2 = 0%, P = 0.55).ConclusionIn conclusion, high expression of ALDH is correlated with worse survival profiles in ovarian cancer patients, indicating that ALDH might act as a potential molecular biomarker for prognosis of ovarian cancer.

Aldehyde dehydrogenase 1 as a predictor of the neoadjuvant chemotherapy response in breast cancer: A meta-analysis.

Many reports suggest that aldehyde dehydrogenase 1 (ALDH1) expression is associated with poorer neoadjuvant chemotherapy (NAC) response in patients with breast cancer; however, the prognostic value of this enzyme in cancer has yet to be confirmed. Therefore, we conducted a meta-analysis of related studies to investigate the relationship between ALDH1 expression and the NAC response in breast cancer patients. PubMed, Web of Science, ScienceDirect, Cochrane Library, and EMBASE were searched for potentially eligible literature. The study characteristics and relevant data were extracted. Odds ratios (ORs) with 95% confidence intervals (CIs) were pooled to estimate the prognostic role of ALDH1 in the NAC response in patients with breast cancer. The robustness of our results was confirmed by sensitivity and publication bias analyses. Pooled meta-analysis of 10 eligible studies including 1081 patients indicated an association between high ALDH1 expression and poor NAC responses (pooled OR = 0.44, 95% CI: 0.25-0.77, P = .004) with low significant heterogeneity (I = 55.1%, P = .018). During subgroup analyses, we found that the recipient sample size presents a potential source of heterogeneity. Begg funnel plot and Egger test showed no possible publication bias. Sensitivity analysis suggested that the pooled OR was robust. Our results suggested that higher ALDH1 expression is associated with poorer NAC responses in patients with breast cancer. However, given the limited number of studies analyzed in this work, more studies are necessary to verify our results.

ALDH1 as a prognostic marker for lymph node metastasis in OSCC

Long-term survival in cases of head and neck squamous cell carcinoma, particularly oral squamous cell carcinoma (OSCC), remains a rare achievement in the field of clinical oncology. In recent years, the theory of cancer stem cells (CSCs) has emerged and been used to offer explanations for tumour recurrence and metastasis. The present aim was to investigate the role of aldehyde dehydrogenase 1 (ALDH1) as a CSC-marker for OSCC and to determine the role of p16ink4a, which is also a surrogate marker of human papilloma virus (HPV), in the expression of ALDH1. The study cohort comprised of 186 surgically-treated cases of OSCC. The primaries were located in the oral cavity. The expression of the CSC marker (CSCM) ALDH1 was evaluated via immunohistochemistry (IHC) of a tissue microarray. HPV detection was performed by polymerase chain reaction and an HPV Array kit. Furthermore, the IHC expression of p16ink4a was also analysed. Risk regression models as the Kruskal Wallis test was used to assess the association of CSCM and p16ink4a expression with tumour size and lymph node metastasis, and cox proportional hazards were analysed. Additionally, coexpression of the markers ALDH1 and p16ink4a was analysed with regard to associations with tumour classification. Overall, high expression of ALDH1 in lymph nodes was significantly associated with Union for International Cancer Control (UICC) stage IV (P=0.044) and T4 stage cancer (P=0.03). p16ink4a positivity, in cases of HPV negativity, was associated with worse survival rate compared with that of the total cohort (P=0.048). Collectively the data indicate that ALDH1 expression may be suitable for detection of unfavourable prognosis in OSCC patients, based in part on its apparent role as a marker of metastasis. HPV status was not statistically predictive of patient outcome or CSCM expression; however, p16ink4a remains a potential marker in HNSCC Further in vitro studies with ALDH1 and p16ink4a should be performed to evaluate the expression of ALDH1 and HPV in cell culture and to clarify the role of ALDH1 as a marker for increased invasiveness of OSCC cells.

Clinicopathological characteristics and prognostic value of the cancer stem cell marker ALDH1 in ovarian cancer: a meta-analysis.

BackgroundThe clinicopathological and prognostic values of the cancer stem cell marker aldehyde dehydrogenase 1 (ALDH1) in ovarian cancer (OC) remain unknown. The aim of our meta-analysis was to evaluate ALDH1’s association with clinicopathological characteristics and its prognostic significance in patients with OC.Materials and methodsPubMed, Embase, and China Biology Medicine were systematically searched for eligible studies (up to October 2017). Pooled odds ratios (ORs) or hazard ratios (HRs) with 95% CIs were used to evaluate the association of ALDH1 expression with clinicopathological features and survival outcomes.ResultsA total of 17 papers (18 studies) that included 2,531 patients with OC were analyzed. The results showed a significant association between increasing ALDH1 expression and International Federation of Gynecology and Obstetrics stage (OR 2.02, 95% CI 1.16–3.52), lymph node metastasis (OR 1.91, 95% CI 1.01–3.61), and distant metastasis (OR 5.43, 95% CI 1.44–20.42) in OC. However, no significant correlation was found between increasing ALDH1 expression and age (OR 0.90, 95% CI 0.25–3.28), tumor size (OR 1.13, 95% CI 0.75–1.71), tumor location (OR 0.69, 95% CI 0.22–2.13), ascite status (OR 0.74, 95% CI 0.49–1.11), resistance status (OR 0.70, 95% CI 0.14–3.51), or clinicopathological type (OR 1.14, 95% CI 0.69–1.86). Moreover, a high ALDH1 expression was significantly associated with overall survival (HR 1.56, 95% CI 1.21–2.02) but not with disease-free survival (HR 1.38, 95% CI 0.99–1.93).ConclusionThe meta-analysis indicates that increasing ALDH1 predicts poor prognosis and clinicopathological characteristics in OC. Future studies are needed to explore tailored treatments that directly target ALDH1 for the improvement of survival in OC.

Aldehyde dehydrogenase 1 expression has prognostic significance in patients with glioma

As a cancer stem cell marker associated with tumorigenesis, aldehyde dehydrogenase 1 (ALDH1) has recently been identified in gliomas. However, an insufficient number of clinical studies have been published to demonstrate its prognostic significance in glioma. In the present study, a systematic meta-analysis was performed to comprehensively evaluate the correlation of ALDH1 with age, sex, the World Health Organization (WHO) grade, and overall survival (OS) in patients with glioma. A search of relevant publications was conducted to select eligible studies on this subject, and the pooled hazard ratios (HRs) and related risks (RRs) with 95% confidence intervals (95% CIs) were assessed. Publication bias was also evaluated using Begg's funnel plots. A total of 6 articles were identified that included a total of 1,057 patients. OS analysis revealed that a high expression of ALDH1 was significantly associated with poor 5-year OS (n=6; HR, 2.10; 95% CI, 1.13-3.91; P<0.0001), and a high WHO grade (III+IV; n=4; RR, 2.28; 95% CI, 1.31-3.99; P=0.001). In conclusion, a high expression of ALDH1 is associated with a high WHO grade of gliomas and a worse prognosis in patients with glioma. Further, well-designed clinical studies are required to confirm its role in the process of selecting a suitable therapeutic approach in glioma.

Abstract 2788: High ALDH1, S phase fraction, p16INK4A in esophageal squamous cell carcinoma could predict response to neoadjuvant chemotherapy

Abstract Background: The prevalence of locally advanced esophageal squamous cell carcinoma (ESCC) remains high despite technological advancements in its diagnosis. This leads to prolonged multimodality treatment often resulting in poor response eventually leading to poor prognosis. Currently, there are no biomarkers available to predict response to neoadjuvant chemotherpy. Aldehyde dehydrogenase 1 (ALDH1), human epidermal growth factor receptor-2 (HER2), p16INK4A, ploidy and S phase fraction are considered significant biomarkers in various solid malignancies. However, there is paucity of data on their clinical significance in ESCC. In the present study, we investigated their significance in predicting the response to neoadjuvant chemotherapy (NACT) in ESCC patients. Methods: Immunohistochemisty of ALDH1, HER2, p16INK4A and propidium iodide based cell cycle analysis through flow cytometer was performed in pre treatment biopsy sample collected from 108 ESCC patients who were presented at a comprehensive cancer centre in northeast India and all of them subsequently received neo adjuvant chemotherapy. Results: ALDH 1, HER2 and p16INK4A were found positive in 65.7%, 7.4% and 22% of pre treatment ESCC specimens respectively. ALDH1 expression correlates with poor response to neo adjuvant chemotherapy (P&amp;lt;0.001). A significant proportion of poor responders were found to be smokers (P=0.004). Poor responders also tends to correlate with increased mortality (P=0.009). HER2 couldn’t predict response to NACT. However, all HER2 positive cases were associated with high ALDH1 expression (P=0.034). 50% of those with pathologically complete response were p16 positive on the contrary only 15% non responders were positive for p16 (P&amp;lt;0.001). 84% of the ESCC patients reported aneuploid tumor status and responder's were found having high S phase fraction (P=0.041). Conclusion: High ALDH1 expression can predict poor response whereas high p16 and S phase fraction can indicate good response to neoadjuvant chemotherapy in ESCC patients. HER2 seems having no clinical significance in the response assessment of neo adjuvant chemotherapy in ESCC. Citation Format: Rajeev Kumar, R. Ravi Kannan, Akalesh Kumar Verma, Anuradha Talukdar, Monoj Kumar Deka, Ritesh Tapkire, Litika Vermani, Sankar Kumar Ghosh. High ALDH1, S phase fraction, p16INK4A in esophageal squamous cell carcinoma could predict response to neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2788. doi:10.1158/1538-7445.AM2017-2788

High ALDH1 expression correlates with better prognosis in tumorigenic malignant melanoma

Aldehyde dehydrogenase 1 (ALDH1) has been proposed as biomarker of stem cells for certain human cancers. ALDH1 expression has been correlated with poor patient outcomes in a variety of malignancies but better patient outcomes in others, and its prognostic significance in malignant melanoma is unclear. Thus, 68 melanoma patients with comprehensive clinical and pathologic follow-up data were used to construct a tissue microarray. A modified histological score (H-score) with a maximum score of 300 was used to quantify immunohistochemical staining for ALDH1. Survival time was defined as the time between diagnosis and melanoma-specific death. Using univariate logistic regression, a low (<80 H-score) ALDH1 score showed 3.7-fold increase in risk for melanoma-specific death within 10 years when compared with high (>80) ALDH1 levels (P=0.017). Odds of MSD were lower by a factor of ~0.9 for each 10-point increase in H-Score. Median survival time was 44.1 months and 180.9 months for patients with low and high ALDH1 expression, respectively. Using multivariate analysis, ALDH1 H-score was found to be an independent prognostic factor. These findings suggest that ALDH1 expression in malignant melanoma has a favorable effect on patient survival. Further study is needed elucidate the function of this enzymatic protein in melanoma progression.

Abstract 2946: Increased ALDH7A1 expression enhances the resistance to the anticancer drugs and colony formation in lung cancer cell lines

Abstract Background: Aldehyde dehydrogenase (ALDH) forms a superfamily of enzymes that catalyze conversion of aldehydes into carboxylic acids, and they are categorized into 19 families in human. Increased ALDH activity was reported to be a potential marker of cancer stem cell (CSC) in various solid tumors including lung cancer. Furthermore, High ALDH expression has been shown to be involved in drug resistance to conventional cytotoxic drugs. Recent studies revealed that ALDH7A1 is highly expressed in prostate cancer and associated with recurrence in patients with surgically resected non-small-cell lung cancer. However, there is not a fundamental link between ALDH7A1 expression and malignant phenotype, including drug resistance and colony formation. Material and methods: Anticancer drug resistant cell lines were established from lung cancer cell lines (PC-6, DMS53, PC-14, PC-9, NCI-H23 and NCI-H2228 cells) by exposure to various anticancer drug, including 7-ethyl-10-hydroxycamptothesin (SN-38), gemcitabine (GEM), cisplatin (CDDP), etoposide, paclitaxel (TXL), pemetrexed, amrubicin, erlotinib and crizotinib. Protein expression was determined by western blotting and gene expression was examined by RT-PCR. ALDH enzyme activity was measured by ALDEFLOUR TM assay. Proliferation was measured using MTS assay. ALDH7A1encoding plasmid was stably transfected into PC-14 cell. These transfected cells displayed sphere formation on ultralow binding plates and survived for more than 3 weeks. Results: We found that the levels of ALDH7A1 expression were higher in various anticancer drug-resistant lung cancer cell lines compared with the parental cells. ALDH enzyme activity was about 4-9 fold higher in SN-38, TXL, CDDP and GEM resistant cell lines (PC6/SN38, PC6/TXL, PC14/CDDP and PC14/GEM) than the parents cells. Up-regulation of ALDH7A1 expression by using a forced expression vector in PC14 cell altered cytotoxicity to SN-38 and TXL. Furthermore, overexpression of ALDH7A1in PC-14 cells enhanced sphere formation relative to the cells transfected with control vector. Conclusion: These results suggested that increased ALDH7A1 expression in lung cancer cell lines might be one of the mechanisms of acquired resistance to anticancer agents and enhance colony formation. Citation Format: Yuichi Sakamori, Hiroaki Ozasa, Eiji Kunii, Yoshitaka Yagi, Takahiro Tsuji, Takeshi Nomizo, Hiroki Nagai, Young Hak Kim, Ken Maeno, Tetsuya Oguri, Michiaki Mishima. Increased ALDH7A1 expression enhances the resistance to the anticancer drugs and colony formation in lung cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2946.