Sphingomyelin(d35:1) as a novel predictor for lung adenocarcinoma recurrence after a radical surgery: a case-control study

Abstract Background: To improve the postoperative prognosis of patients with lung cancer, predicting the recurrence high-risk patients is needed for the efficient application of adjuvant chemotherapy. However, predicting lung cancer recurrence after a radical surgery is difficult even with conventional histopathological prognostic factors, thereby a novel predictor should be identified. As lipid metabolism alterations are known to contribute to cancer progression, we hypothesized that lung adenocarcinomas with high recurrence risk contain candidate lipid predictors. This study aimed to identify candidate lipid predictors for the recurrence of lung adenocarcinoma after a radical surgery.Methods: Frozen tissue samples of primary lung adenocarcinoma obtained from patients who underwent a radical surgery were retrospectively reviewed. Recurrent and non-recurrent cases were assigned to recurrent (n = 10) and non-recurrent (n = 10) groups, respectively. Extracted lipids from frozen tissue samples were subjected to liquid chromatography-tandem mass spectrometry analysis. The average total lipid levels of the non-recurrent and recurrent groups were compared. Candidate predictors were screened by comparing the folding change and P-value of t-test in each lipid species between the recurrent and non-recurrent groups.Results: The average total lipid level of the recurrent group was 1.65 times higher than that of the non-recurrent group (P < 0.05). A total of 203 lipid species were increased (folding change, ≥2; P < 0.05) and 4 lipid species were decreased (folding change, ≤0.5; P < 0.05) in the recurrent group. Among these candidates, increased sphingomyelin (SM)(d35:1) in the recurrent group was the most prominent candidate predictor, showing high performance of recurrence prediction (AUC, 9.1; sensitivity, 1.0; specificity, 0.8; accuracy, 0.9).Conclusion: We propose SM(d35:1) as a novel candidate predictor for lung adenocarcinoma recurrence. Our finding can contribute to precise recurrence prediction and qualified postoperative therapeutic strategy for lung adenocarcinomas.Abbreviations: AUC, area under the ROC curve; ROC, receiver operating characteristic.

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Sphingomyelin(d35:1) as a novel predictor for lung adenocarcinoma recurrence after a radical surgery: a case-control study

10.21203/rs.3.rs-29344/v3 ◽

2020 ◽

Author(s):

Yusuke Takanashi ◽

Kazuhito Funai ◽

Shumpei Sato ◽

Akikazu Kawase ◽

Hong Tao ◽

...

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Radical Surgery ◽

Tissue Samples ◽

Recurrent Group ◽

Recurrence Prediction ◽

Lipid Species ◽

Frozen Tissue ◽

Candidate Predictor ◽

Lung Adenocarcinomas

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Sphingomyelin(d35:1) as a novel predictor for lung adenocarcinoma recurrence after a radical surgery: a case control study

10.21203/rs.3.rs-29344/v1 ◽

2020 ◽

Author(s):

Yusuke Takanashi ◽

Kazuhito Funai ◽

Shumpei Sato ◽

Akikazu Kawase ◽

Hong Tao ◽

...

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Radical Surgery ◽

Tissue Samples ◽

Recurrent Group ◽

Recurrence Prediction ◽

Lipid Species ◽

Frozen Tissue ◽

Candidate Predictor ◽

Lung Adenocarcinomas

Abstract Background To improve the postoperative prognosis of patients with lung cancer, predicting the recurrence high-risk patients is needed for the efficient application of adjuvant chemotherapy. However, predicting lung cancer recurrence after a radical surgery is difficult even with conventional histopathological prognostic factors, thereby a novel predictor should be identified. As lipid metabolism alterations are known to contribute to cancer progression, we hypothesized that lung adenocarcinomas with high recurrence risk contain candidate lipid predictors. This study aimed to identify candidate lipid predictors for the recurrence of lung adenocarcinoma after a radical surgery. Methods Frozen tissue samples of primary lung adenocarcinoma obtained from patients who underwent a radical surgery were retrospectively reviewed. Recurrent and non-recurrent cases were assigned to recurrent (n = 10) and non-recurrent (n = 10) groups, respectively. Extracted lipids from frozen tissue samples were subjected to liquid chromatography-tandem mass spectrometry analysis. The average total lipid levels of the non-recurrent and recurrent groups were compared. Candidate predictors were screened by comparing the folding change and P-value of t-test in each lipid species between the recurrent and non-recurrent groups. Results The average total lipid level of the recurrent group was 1.65 times higher than that of the non-recurrent group (P < 0.05). A total of 203 lipid species were increased (folding change, ≥ 2; P < 0.05) and 4 lipid species were decreased (folding change, ≤ 0.5; P < 0.05) in the recurrent group. Among these candidates, increased sphingomyelin (SM)(d35:1) in the recurrent group was the most prominent candidate predictor, showing high performance of recurrence prediction (AUC, 9.1; sensitivity, 1.0; specificity, 0.8; accuracy, 0.9). Conclusion We propose SM(d35:1) as a novel candidate predictor for lung adenocarcinoma recurrence. Our finding can contribute to precise recurrence prediction and qualified postoperative therapeutic strategy for lung adenocarcinomas.

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Decreased sphingomyelin (t34:1) is a candidate predictor for lung squamous cell carcinoma recurrence after radical surgery: a case-control study

BMC Cancer ◽

10.1186/s12885-021-08948-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yusuke Takanashi ◽

Kazuhito Funai ◽

Fumihiro Eto ◽

Kiyomichi Mizuno ◽

Akikazu Kawase ◽

...

Keyword(s):

Prognostic Factors ◽

Adjuvant Chemotherapy ◽

Squamous Cell ◽

Radical Surgery ◽

Meta Analysis ◽

Lung Squamous Cell Carcinoma ◽

Fold Change ◽

Treatment Modalities ◽

Lipid Species ◽

Candidate Predictor

Abstract Background To reduce disease recurrence after radical surgery for lung squamous cell carcinomas (SQCCs), accurate prediction of recurrent high-risk patients is required for efficient patient selection for adjuvant chemotherapy. Because treatment modalities for recurrent lung SQCCs are scarce compared to lung adenocarcinomas (ADCs), accurately selecting lung SQCC patients for adjuvant chemotherapy after radical surgery is highly important. Predicting lung cancer recurrence with high objectivity is difficult with conventional histopathological prognostic factors; therefore, identification of a novel predictor is expected to be highly beneficial. Lipid metabolism alterations in cancers are known to contribute to cancer progression. Previously, we found that increased sphingomyelin (SM)(d35:1) in lung ADCs is a candidate for an objective recurrence predictor. However, no lipid predictors for lung SQCC recurrence have been identified to date. This study aims to identify candidate lipid predictors for lung SQCC recurrence after radical surgery. Methods Recurrent (n = 5) and non-recurrent (n = 6) cases of lung SQCC patients who underwent radical surgery were assigned to recurrent and non-recurrent groups, respectively. Extracted lipids from frozen tissue samples of primary lung SQCC were analyzed by liquid chromatography-tandem mass spectrometry. Candidate lipid predictors were screened by comparing the relative expression levels between the recurrent and non-recurrent groups. To compare lipidomic characteristics associated with recurrent SQCCs and ADCs, a meta-analysis combining SQCC (n = 11) and ADC (n = 20) cohorts was conducted. Results Among 1745 screened lipid species, five species were decreased (≤ 0.5 fold change; P < 0.05) and one was increased (≥ 2 fold change; P < 0.05) in the recurrent group. Among the six candidates, the top three final candidates (selected by AUC assessment) were all decreased SM(t34:1) species, showing strong performance in recurrence prediction that is equivalent to that of histopathological prognostic factors. Meta-analysis indicated that decreases in a limited number of SM species were observed in the SQCC cohort as a lipidomic characteristic associated with recurrence, in contrast, significant increases in a broad range of lipids (including SM species) were observed in the ADC cohort. Conclusion We identified decreased SM(t34:1) as a novel candidate predictor for lung SQCC recurrence. Lung SQCCs and ADCs have opposite lipidomic characteristics concerning for recurrence risk. Trial registration This retrospective study was registered at the UMIN Clinical Trial Registry (UMIN000039202) on January 21, 2020.

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The effectiveness of afatinib in patients with lung adenocarcinoma harboring complex epidermal growth factor receptor mutation

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920946156 ◽

2020 ◽

Vol 12 ◽

pp. 175883592094615

Author(s):

Shang-Gin Wu ◽

Chong-Jen Yu ◽

James Chih-Hsin Yang ◽

Jin-Yuan Shih

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Growth Factor Receptor ◽

Egfr Mutations ◽

Line Treatment ◽

First Line ◽

Tissue Samples ◽

Epidermal Growth ◽

Egfr Tkis ◽

First Line Treatment

Background and aims: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are effective against classical EGFR mutations in lung cancer. However, their effectiveness and the prognosis of lung cancer patients with complex EGFR mutations are not well delineated. Therefore, we aimed to investigate the treatment effectiveness of different EGFR TKIs in patients with complex EGFR mutations. Patients and methods: From 2005 to 2020, we collected lung adenocarcinoma tissue samples for EGFR mutation analysis using direct Sanger sequencing. Patients with EGFR mutations treated with EGFR TKIs as first-line treatment were enrolled. Clinical characteristics, EGFR mutation status, treatment response, progression-free survival (PFS), and overall survival (OS) were analyzed. Results: Among 2675 patients with EGFR mutations, 239 (8.9%) had complex EGFR mutations, of whom 125 received EGFR TKI treatment as first-line treatment. Multivariate analysis revealed that afatinib was a more favorable factor for PFS than gefitinib [hazard ratio (HR), 2.01; 95% confidence interval (CI), 1.11–3.62] and erlotinib (HR, 2.61; 95% CI, 1.31–5.22), especially in patients with uncommon mutation patterns. Afatinib treatment as first-line treatment was also associated with longer OS compared with erlotinib (HR, 2.48; 95% CI, 1.20–5.12). Classical mutation pattern was associated with longer PFS ( p = 0.001) and OS ( p = 0.020). Secondary T790M was detected in 22 of 52 (42.3%) patients who had re-biopsied tissue samples after acquiring resistance to EGFR TKIs. There was no significant difference in secondary T790M formation after acquired resistance to the three EGFR TKIs ( p = 0.261). Furthermore, three (5.8%) patients had small-cell lung cancer transformation. Conclusion: Afatinib is an effective first-line treatment for patients with lung adenocarcinoma harboring complex EGFR mutations, especially those with uncommon mutation patterns.

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Moesin as a prognostic indicator of lung adenocarcinoma improves prognosis by enhancing immune lymphocyte infiltration

World Journal of Surgical Oncology ◽

10.1186/s12957-021-02229-y ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Yan-Qi Li ◽

Zhi Zheng ◽

Quan-Xing Liu ◽

Xiao Lu ◽

Dong Zhou ◽

...

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Prognostic Indicator ◽

Pathological Feature ◽

Lymphocyte Infiltration ◽

Tissue Samples ◽

Immune Lymphocytes ◽

Immune Lymphocyte ◽

Detailed Statistical Analysis ◽

Cancer Tissues

Abstract Background Ezrin-radixin-moesin (ERM) have been explored in many cancer processes. Moesin, as its component, has also been found to play an important role in the prognosis of cancer patients, tumor metastasis, drug resistance, and others. Especially in regulating the immunity, but most results came from direct studies on immune cells, there is no clear conclusion on whether moesin has similar effects in tumor cells. And moesin has certain research results in many cancers in other aspects, but there are few about moesin in lung adenocarcinoma (LUAD). Methods We detect the expression of moesin in 82 LUAD and matched normal tissue samples by immunohistochemistry. Besides, for the pathological feature, we did a detailed statistical analysis. And with the help of various databases, we have done in-depth exploration of moesin’s ability to enhance the extent of immune lymphocyte infiltration. Results Moesin is a poor expression in lung cancer tissues than the corresponding normal samples. And this phenomenon had a strongly associated with the prognosis and TNM stage of these LUAD patients. Moesin can enhance the infiltration of multiple immune lymphocytes in lung cancer. And this may be related to the interaction between moesin and various inflammatory molecules. Conclusions Moesin is a newly index for the prognosis of LUAD and improves the prognosis of LUAD patients by regulating a variety of inflammation-related molecules to enhance immune lymphocytes infiltration.

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P43.03 Sphingomyelin Is a Candidate Predictor for Lung Adenocarcinoma Recurrence After Radical Surgery

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2021.01.837 ◽

2021 ◽

Vol 16 (3) ◽

pp. S483

Author(s):

Y. Takanashi ◽

S. Sato ◽

H. Tao ◽

T. Kahyo ◽

A. Kawase ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Radical Surgery ◽

Candidate Predictor

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CD26 is overexpressed in lung adenocarcinoma and qualifies as a therapeutic target against lung cancer

10.1055/s-0038-1668423 ◽

2018 ◽

Author(s):

N Enz ◽

F Janker ◽

F Ramírez Fragoso ◽

M Haberecker ◽

A Soltermann ◽

...

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Therapeutic Target

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Isoorientin Decreases Cell Migration via Decreasing Functional Activity and Molecular Expression of Proton-Linked Monocarboxylate Transporters in Human Lung Cancer Cells

The American Journal of Chinese Medicine ◽

10.1142/s0192415x20500111 ◽

2020 ◽

Vol 48 (01) ◽

pp. 201-222

Author(s):

Hsu-Kai Huang ◽

Shin-Yi Lee ◽

Shu-Fen Huang ◽

Yu-San Lin ◽

Shih-Chi Chao ◽

...

Keyword(s):

Lung Cancer ◽

Cell Migration ◽

Lung Adenocarcinoma ◽

Cell Viability ◽

Cancer Cells ◽

Functional Activity ◽

Human Lung ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Human Lung Cancer Cells

Aggressive tumor cells mainly rely on glycolysis, and further release vast amounts of lactate and protons by monocarboxylate transporter (MCT), which causes a higher intracellular pH (pHi) and acidic extracellular pH. Isoorientin, a principle flavonoid compound extracted from several plant species, shows various pharmacological activities. However, effects of isoorientin on anticancer and MCT await to explore in human lung cancer cells. Human lung cancer tissues were obtained from cancer patients undergoing surgery, while the human lung adenocarcinoma cells (A549) were bought commercially. Change of pHi was detected by microspectrofluorometry method with a pH-sensitive fluorescent dye, BCECF. MTT and wound-healing assay were used to detect the cell viability and migration, respectively. Western blot techniques and immunocytochemistry staining were used to detect the protein expression. Our results indicated that the expression of MCTs1/4 and CD147 were upregulated significantly in human lung tissues. In experiments of A549 cells, under HEPES-buffer, the resting pHi was 7.47, and isoorientin (1–300[Formula: see text][Formula: see text]M) inhibited functional activity of MCT concentration-dependently (up to [Formula: see text]%). Pretreatment with isoorientin (3–100[Formula: see text][Formula: see text]M) for 24[Formula: see text]h, MCT activity and cell migration were significantly inhibited ([Formula: see text]% and [Formula: see text]%, respectively), while the cell viability was not affected. Moreover, the expression of MCTs1/4, CD147, and matrix metalloproteinase (MMP) 2/9 were significantly down regulated. In summary, MCTs1/4 and CD147 are significantly upregulated in human lung adenocarcinoma tissues, and isoorientin inhibits cells-migration by inhibiting activity/expression of MCTs1/4 and MMPs2/9 in human lung cancer cells. These novel findings suggest that isoorientin could be a promising pharmacological agent for lung cancer.

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SFTPA1 is a potential prognostic biomarker correlated with immune cell infiltration and response to immunotherapy in lung adenocarcinoma

Cancer Immunology Immunotherapy ◽

10.1007/s00262-021-02995-4 ◽

2021 ◽

Author(s):

Lu Yuan ◽

Xixi Wu ◽

Longshan Zhang ◽

Mi Yang ◽

Xiaoqing Wang ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

Lung Adenocarcinoma ◽

Expression Profile ◽

Immune Cell ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Regulatory Pathways ◽

Chronic Lung Diseases ◽

Potential Biomarker

AbstractPulmonary surfactant protein A1 (SFTPA1) is a member of the C-type lectin subfamily that plays a critical role in maintaining lung tissue homeostasis and the innate immune response. SFTPA1 disruption can cause several acute or chronic lung diseases, including lung cancer. However, little research has been performed to associate SFTPA1 with immune cell infiltration and the response to immunotherapy in lung cancer. The findings of our study describe the SFTPA1 expression profile in multiple databases and was validated in BALB/c mice, human tumor tissues, and paired normal tissues using an immunohistochemistry assay. High SFTPA1 mRNA expression was associated with a favorable prognosis through a survival analysis in lung adenocarcinoma (LUAD) samples from TCGA. Further GeneOntology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that SFTPA1 was involved in the toll-like receptor signaling pathway. An immune infiltration analysis clarified that high SFTPA1 expression was associated with an increased number of M1 macrophages, CD8+ T cells, memory activated CD4+ T cells, regulatory T cells, as well as a reduced number of M2 macrophages. Our clinical data suggest that SFTPA1 may serve as a biomarker for predicting a favorable response to immunotherapy for patients with LUAD. Collectively, our study extends the expression profile and potential regulatory pathways of SFTPA1 and may provide a potential biomarker for establishing novel preventive and therapeutic strategies for lung adenocarcinoma.

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Immunogenomic Gene Signature of Cell-Death Associated Genes with Prognostic Implications in Lung Cancer

Cancers ◽

10.3390/cancers13010155 ◽

2021 ◽

Vol 13 (1) ◽

pp. 155

Author(s):

Pankaj Ahluwalia ◽

Meenakshi Ahluwalia ◽

Ashis K. Mondal ◽

Nikhil Sahajpal ◽

Vamsi Kota ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

Cell Death ◽

T Cell ◽

High Risk ◽

Lung Adenocarcinoma ◽

Risk Group ◽

High Risk Group ◽

Free Survival ◽

Cell Death Pathways

Lung cancer is one of the leading causes of death worldwide. Cell death pathways such as autophagy, apoptosis, and necrosis can provide useful clinical and immunological insights that can assist in the design of personalized therapeutics. In this study, variations in the expression of genes involved in cell death pathways and resulting infiltration of immune cells were explored in lung adenocarcinoma (The Cancer Genome Atlas: TCGA, lung adenocarcinoma (LUAD), 510 patients). Firstly, genes involved in autophagy (n = 34 genes), apoptosis (n = 66 genes), and necrosis (n = 32 genes) were analyzed to assess the prognostic significance in lung cancer. The significant genes were used to develop the cell death index (CDI) of 21 genes which clustered patients based on high risk (high CDI) and low risk (low CDI). The survival analysis using the Kaplan–Meier curve differentiated patients based on overall survival (40.4 months vs. 76.2 months), progression-free survival (26.2 months vs. 48.6 months), and disease-free survival (62.2 months vs. 158.2 months) (Log-rank test, p < 0.01). Cox proportional hazard model significantly associated patients in high CDI group with a higher risk of mortality (Hazard Ratio: H.R 1.75, 95% CI: 1.28–2.45, p < 0.001). Differential gene expression analysis using principal component analysis (PCA) identified genes with the highest fold change forming distinct clusters. To analyze the immune parameters in two risk groups, cytokines expression (n = 265 genes) analysis revealed the highest association of IL-15RA and IL 15 (> 1.5-fold, p < 0.01) with the high-risk group. The microenvironment cell-population (MCP)-counter algorithm identified the higher infiltration of CD8+ T cells, macrophages, and lower infiltration of neutrophils with the high-risk group. Interestingly, this group also showed a higher expression of immune checkpoint molecules CD-274 (PD-L1), CTLA-4, and T cell exhaustion genes (HAVCR2, TIGIT, LAG3, PDCD1, CXCL13, and LYN) (p < 0.01). Furthermore, functional enrichment analysis identified significant perturbations in immune pathways in the higher risk group. This study highlights the presence of an immunocompromised microenvironment indicated by the higher infiltration of cytotoxic T cells along with the presence of checkpoint molecules and T cell exhaustion genes. These patients at higher risk might be more suitable to benefit from PD-L1 blockade or other checkpoint blockade immunotherapies.

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