Cancer Biomarkers - Volume 41, issue 1

Authors: Fei, Xifeng | Wu, Jie | Tian, Haiyan | Jiang, Dongyi | Chen, Hanchun | Yan, Ke | Wang, Yuan | Zhao, Yaodong | Chen, Hua | Xie, Xiangtong | Wang, Zhimin | Zhu, Wenyu | Huang, Qiang

Article Type: Research Article

Abstract: Glioma is the most common primary tumor of the central nervous system (CNS). Glioblastoma (GBM) is incurable with current treatment strategies. Additionally, the treatment of recurrent GBM (rGBM) is often referred to as terminal treatment, necessitating hospice-level care and management. The presence of the blood-brain barrier (BBB) gives GBM a more challenging or “cold” tumor microenvironment (TME) than that of other cancers and gloma stem cells (GSCs) play an important role in the TME remodeling, occurrence, development and recurrence of giloma. In this review, our primary focus will be on discussing the following topics: niche-associated GSCs and macrophages, new theories …regarding GSC and TME involving pyroptosis and ferroptosis in GBM, metabolic adaptations of GSCs, the influence of the cold environment in GBM on immunotherapy, potential strategies to transform the cold GBM TME into a hot one, and the advancement of GBM immunotherapy and GBM models. Show more

Keywords: Glioma stem cells, niche, glioma cold environment, immunotherapy, GBM models

DOI: 10.3233/CBM-230486

Citation: Cancer Biomarkers, vol. 41, no. 1, pp. 1-24, 2024

Authors: An, Fangmei | Ge, Yan | Ye, Wei | Ji, Lin | Chen, Ke | Wang, Yunfei | Zhang, Xiaoxue | Dong, Shengrong | Shen, Yao | Zhao, Jiamin | Gao, Xiaojuan | Junankar, Simon | Chan, Robin Barry | Christodoulou, Dimitris | Wen, Wen | Lu, Peihua | Zhan, Qiang

Article Type: Research Article

Abstract: BACKGROUND: Chronic atrophy gastritis (CAG) is a high-risk pre-cancerous lesion for gastric cancer (GC). The early and accurate detection and discrimination of CAG from benign forms of gastritis (e.g. chronic superficial gastritis, CSG) is critical for optimal management of GC. However, accurate non-invasive methods for the diagnosis of CAG are currently lacking. Cytokines cause inflammation and drive cancer transformation in GC, but their utility as a diagnostic for CAG is poorly characterized. METHODS: Blood samples were collected, and 40 cytokines were quantified using a multiplexed immunoassay from 247 patients undergoing screening via endoscopy. Patients were divided …into discovery and validation sets. Each cytokine importance was ranked using the feature selection algorithm Boruta. The cytokines with the highest feature importance were selected for machine learning (ML), using the LightGBM algorithm. RESULTS: Five serum cytokines (IL-10, TNF-α , Eotaxin, IP-10 and SDF-1a) that could discriminate between CAG and CSG patients were identified and used for predictive model construction. This model was robust and could identify CAG patients with high performance (AUC = 0.88, Accuracy = 0.78). This compared favorably to the conventional approach using the PGI/PGII ratio (AUC = 0.59). CONCLUSION: Using state-of-the-art ML and a blood-based immunoassay, we developed an improved non-invasive screening method for the detection of precancerous GC lesions. FUNDING: Supported in part by grants from: Jiangsu Science and Technology Project (no. BK20211039); Top Talent Support Program for young and middle-aged people of Wuxi Health Committee (BJ2023008); Medical Key Discipline Program of Wuxi Health Commission (ZDXK2021010), Wuxi Science and Technology Bureau Project (no. N20201004); Scientific Research Program of Wuxi Health Commission (Z202208, J202104). Show more

Keywords: Chronic Atrophy Gastritis (CAG), Chronic Superficial Gastritis (CSG), Screening, Cytokines, Machine Learning (ML) Algorithms

DOI: 10.3233/CBM-240023

Citation: Cancer Biomarkers, vol. 41, no. 1, pp. 25-40, 2024

Authors: Chen, Wenjiao | Guo, Qin | Zhang, Huo | Du, Yiping | Zhou, Yan | Huang, Zebo | Zhang, Meiling | Qin, Songbing

Article Type: Research Article

Abstract: BACKGROUND: Gastric cancer (GC) is one of the most common tumors. There were several classifications of GC recently. The value of Lauren classification in evaluating the prognosis after radical gastrectomy was still unclear and the prognosis of gastric cancer remained relatively poor in the absence of prognostic biomarkers. This study aimed to explore microRNA (miRNA) in the prognosis of GC with different Lauren classification. METHODS: A retrospective study of 1144 patients was performed in this study. Quantificational reverse transcription-PCR (qRT-PCR) was used to examine the expression of miRNAs. Univariate and multivariate analysis were performed to evaluate prognosis …value of Lauren classification. RESULTS: Total 1144 GC patients were recruited in this cohort, including 302 diffuse type (26.4%), 436 intestinal type (38.1%) and 406 mixed type (35.5%) GC. Multivariate analysis showed that Lauren classification, patients’ age, tumor size, tumor infiltrating depth, vascular nerve infiltrating and metastatic lymph nodes ration were significantly correlated with GC patients’ OS and DFS. The miR-141-3p, miR-200b-3p and miR-133a-5p were significantly down-regulated in diffuse type compared to intestinal type GC tissues, the miR-105-5p had significant lower expression in diffuse type compared with intestinal type and mixed type GC tissues. As a consequence of univariate analysis, low miR-141-3p in diffuse type GC showed significant worse OS and DFS than high miR-141-3p. CONCLUSIONS: Lauren classification was an independent prognostic factor in GC. MiR-141-3p was an independent prognostic factor and a promising prognostic biomarker in Lauren classification GC. Show more

Keywords: Gastric cancer, Lauren classification, microRNA, prognosis

DOI: 10.3233/CBM-230303

Citation: Cancer Biomarkers, vol. 41, no. 1, pp. 41-54, 2024

Authors: Okabe*, Seiichi | Moriyama, Mitsuru | Arai, Yuya | Gotoh, Akihiko

Article Type: Research Article

Abstract: BACKGROUND: Myelodysplastic syndrome (MDS) features bone marrow failure and a heightened risk of evolving into acute myeloid leukemia (AML), increasing with age and reducing overall survival. Given the unfavorable outcomes of MDS, alternative treatments are necessary. Glutamine, the most abundant amino acid in the blood, is metabolized first by the enzyme glutaminase (GLS). OBJECTIVES: To investigate whether GLS is involved in the progression of MDS. The efficacy of GLS inhibitors (CB839 or IPN60090) and BCL2 inhibitor venetoclax was also examined. METHODS: We employed GLS inhibitors (CB839, IPN60090) and the BCL2 inhibitor venetoclax, prepared …as detailed. MDS and AML cell lines were cultured under standard and modified (hypoxic, glutamine-free) conditions. Viability, proliferation, and caspase activity were assessed with commercial kits. RT-PCR quantified gene expression post-shRNA transfection. Mitochondrial potential, ATP levels, proteasome activity, and metabolic functions were evaluated using specific assays. Statistical analyses (t-tests, ANOVA) validated the findings. RESULTS: The glutamine-free medium inhibited the growth of MDS cells. GLS1 expression was higher in AML cells than in normal control samples (GSE15061), whereas GLS2 expression was not. Treatment of MDS and AML cells for 72 h was inhibited in a dose-dependent manner by GLS inhibitors. Co-treatment with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax and GLS inhibitors increased potency. Cells transfected with GLS1 short hairpin RNA showed suppressed proliferation under hypoxic conditions and increased sensitivity to venetoclax. CONCLUSIONS: Targeting glutaminolysis and BCL2 inhibition enhances the therapeutic efficacy and has been proposed as a novel strategy for treating high-risk MDS and AML. Show more

Keywords: Glutaminolysis, GLS inhibitor, MDS, AML, BCL-2 inhibitor, hypoxia

DOI: 10.3233/CBM-230454

Citation: Cancer Biomarkers, vol. 41, no. 1, pp. 55-68, 2024

Authors: Deng, Yuxia | Patel, Nishant | Ding, Shuang | Zhang, Haijun

Article Type: Research Article

Abstract: OBJECTIVE: To investigate the impact and potential mechanisms of serum extracellular nano-vesicles (sEVs) miR-412-3p released from sub-centimeter lung nodules with a diameter of ⩽ 10 mm on the malignant biological function of micro-nodular lung cancer (mnLC). METHODS: A total of 87 participants were included and divided into a mnLC group (n = 30), a benign lung nodule (BLN) group (n = 27), and a healthy people control group (n = 30). Transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and …Western blot (WB) were used to measure the morphological characteristics and surface markers of sEVs. In vitro analysis, real-time quantitative polymerase chain reaction (RT-qPCR), CCK-8 cell proliferation assay, clone formation assay, Transwell, stem cell sphere-forming assay, and WB assay were conducted to verify the effect of miR-412-3p/TEAD1 signaling axis on the biological function of lung cancer cells through, respectively. Further validation was conducted using the serum sEVs of the participants. RESULTS: The expression level of sEVs-miR-412-3p in the mnLC group was significantly higher than that in the BLN and healthy groups (P < 0.01). In lung cancer cell lines, miR-412-3p can negatively regulate the targeted gene TEAD1. The miR-412-3p/TEAD1 signaling axis is involved in promoting the EMT signaling pathway and regulating the malignant biological functions of lung cancer cell proliferation, migration, and stemness (P < 0.05). In addition, sEVs in the mnLC group significantly promoted lung cancer cell proliferation, migration, and stemness compared to the BLN and healthy groups, inhibited the expression of E-cadherin and TEAD1 in lung cancer cells, and promoted the expression of N-cadherin and Vimentin (P < 0.05). CONCLUSION: sEVs-miR-412-3p could promote the biological process of EMT, and lead to the occurrence of malignant biological behavior in sub-centimeter lung nodules. This provides evidence for the miR-412-3p/TEAD1 signaling axis as a potential therapeutic target for mnLC. Show more

Keywords: Micro-nodular lung cancer, serum extracellular nano-vesicles, miR-412-3p, transcriptional enhancer associated domain 1, epithelial mesenchymal transition

DOI: 10.3233/CBM-240137

Citation: Cancer Biomarkers, vol. 41, no. 1, pp. 69-82, 2024

Authors: Mohamed, Yehia I. | Lee, Sunyoung S. | Demir, Tarik | Chamseddine, Shadi | Hu, Zishuo Ian | Xiao, Lianchun | Elsayes, Khaled | Morris, Jeffrey S. | Wolff, Robert A. | Hiatia, Rikita | Qayyum, Aliya | Rashid, Asif | Duda, Dan G. | Yao, James C. | LaPelusa, Michael | Koay, Eugene J. | Mahvash, Armeen | Al Azzam, Ahmed | Dumbrava, Ecaterina E. | Hassan, Manal | Amin, Hesham M. | Kaseb, Ahmed Omar

Article Type: Research Article

Abstract: BACKGROUND: Circulating tumor DNA (ctDNA) is a promising non-invasive marker for detection, diagnosis, treatment selection, and prognosis of hepatocellular carcinoma (HCC). OBJECTIVE: This study aimed to examine the utility of ctDNA as a prognostic and predictive tool in HCC patients treated with nivolumab. METHODS: We analyzed pre-treatment ctDNA from 44 HCC patients using comprehensive genomic testing on a commercially available platform. We utilized log rank test and univariate Cox models to correlate overall survival (OS) and progression-free survival (PFS) with ctDNA expressions. RESULTS: Of 44 patients, 77.3% were men with median …age of 67 years. All but 3 patients had at least one alteration identified, and TP53 was the most commonly altered gene (52.3%). Median OS was 17.5 months (95% CI: 12.7, NA). Mutations involving PIK3CA , BRCA1 , and CCND1 amplification were associated with shorter OS (P 0.0001, 0.0001 and 0.01, respectively). Median PFS time was 4.01 months (95% CI: 3.06, 9.33). Mutations involving KIT and PIK3CA were associated with shorter PFS (P 0.0001 and 0.0004, respectively), while mutation involving CTNNB1 were associated with longer PFS (p = 0.04). CONCLUSIONS: ctDNA profiling may provide a benefit for prediction of survival and progression of HCC patients treated with nivolumab. Future studies are needed for confirmation. Show more

Keywords: ctDNA, hepatocellular carcinoma, immunotherapy, nivolumab, biomarker

DOI: 10.3233/CBM-230431

Citation: Cancer Biomarkers, vol. 41, no. 1, pp. 83-91, 2024