Intratumoural microbiota: a new frontier in cancer development and therapy.

Human microorganisms, including bacteria, fungi, and viruses, play key roles in several physiological and pathological processes. Some studies discovered that tumour tissues once considered sterile actually host a variety of microorganisms, which have been confirmed to be closely related to oncogenesis. The concept of intratumoural microbiota was subsequently proposed. Microbiota could colonise tumour tissues through mucosal destruction, adjacent tissue migration, and hematogenic invasion and affect the biological behaviour of tumours as an important part of the tumour microenvironment. Mechanistic studies have demonstrated that intratumoural microbiota potentially promote the initiation and progression of tumours by inducing genomic instability and mutations, affecting epigenetic modifications, promoting inflammation response, avoiding immune destruction, regulating metabolism, and activating invasion and metastasis. Since more comprehensive and profound insights about intratumoral microbiota are continuously emerging, new methods for the early diagnosis and prognostic assessment of cancer patients have been under examination. In addition, interventions based on intratumoural microbiota show great potential to open a new chapter in antitumour therapy, especially immunotherapy, although there are some inevitable challenges. Here, we aim to provide an extensive review of the concept, development history, potential sources, heterogeneity, and carcinogenic mechanisms of intratumoural microorganisms, explore the potential role of microorganisms in tumour prognosis, and discuss current antitumour treatment regimens that target intratumoural microorganisms and the research prospects and limitations in this field.

Fasudil Increased the Sensitivity to Gefitinib in NSCLC by Decreasing Intracellular Lipid Accumulation.

Tyrosine kinase inhibitors (TKIs) resistance is a challenge in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). Here, we examined the effect of Fasudil in reversing TKIs resistance. The results of CCK8 assay, clone formation assay, cell cycle arrest analysis, and apoptosis analysis show that Fasudil treatment effectively suppressed the growth and induced apoptosis of the EGFR-mutant NSCLC cells. Furthermore, Fasudil in combination with gefitinib showed a synergistic anti-tumor effect in gefitinib-resistant NSCLC cells. RNA-seq analysis and immunoblotting indicated that Fasudil treatment significantly inhibited intracellular lipid accumulation and EGFR/PI3K/AKT pathway activation. Mechanistic investigations showed that Fasudil regulated lipogenic gene expressions via AMPK signal pathway. In vivo, Fasudil and gefitinib co-administration significantly attenuated the growth of H1975 nude mouse xenograft models, suggesting that Fasudil treatment combined with gefitinib can be applied as a therapy for gefitinib-resistant NSCLC cells.

Identification of the Prognostic Significance of Somatic Mutation-Derived LncRNA Signatures of Genomic Instability in Lung Adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is a highly heterogeneous tumor with substantial somatic mutations and genome instability, which are emerging hallmarks of cancer. Long non-coding RNAs (lncRNAs) are promising cancer biomarkers that are reportedly involved in genomic instability. However, the identification of genome instability-related lncRNAs (GInLncRNAs) and their clinical significance has not been investigated in LUAD. Methods: We determined GInLncRNAs by combining somatic mutation and transcriptome data of 457 patients with LUAD and probed their potential function using co-expression network and Gene Ontology (GO) enrichment analyses. We then filtered GInLncRNAs by Cox regression and LASSO regression to construct a genome instability-related lncRNA signature (GInLncSig). We subsequently evaluated GInLncSig using correlation analyses with mutations, external validation, model comparisons, independent prognostic significance analyses, and clinical stratification analyses. Finally, we established a nomogram for prognosis prediction in patients with LUAD and validated it in the testing set and the entire TCGA dataset. Results: We identified 161 GInLncRNAs, of which seven were screened to develop a prognostic GInLncSig model (LINC01133, LINC01116, LINC01671, FAM83A-AS1, PLAC4, MIR223HG, and AL590226.1). GInLncSig independently predicted the overall survival of patients with LUAD and displayed an improved performance compared to other similar signatures. Furthermore, GInLncSig was related to somatic mutation patterns, suggesting its ability to reflect genome instability in LUAD. Finally, a nomogram comprising the GInLncSig and tumor stage exhibited improved robustness and clinical practicability for predicting patient prognosis. Conclusion: Our study identified a signature for prognostic prediction in LUAD comprising seven lncRNAs associated with genome instability, which may provide a useful indicator for clinical stratification management and treatment decisions for patients with LUAD.

Relationship between serum tumor markers and Anaplastic Lymphoma Kinase mutations in stage IV lung adenocarcinoma in Hubei province, Central China.

OBJECTIVE: The aim of this study was to explore the predictive value of carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCCAg), and neuron-specific enolase (NSE) in the prediction of anaplastic lymphoma kinase (ALK) mutations in advance stage non-small cell lung cancer (NSCLC). SUBJECTS AND METHODS: A total of 482 cases with untreated lung adenocarcinoma were retrospectively reviewed. Finally, 72 patients with stage IV were enrolled because of intact data of the detection of ALK rearrangement and serum tumor markers, as well they have not received any previous anticancer therapy. We used the one-way ANOVA analysis, correlation analysis, and multiple logistic regression analysis to evaluate the relationship between the level of serum tumor markers and ALK mutations. RESULTS: Fifteen cases with ALK mutations and 57 cases without mutations were identified. The result of the one-way ANOVA analysis showed only CEA was significantly associated with ALK mutations (95% CI:39.05-148.88; P = .001). The area under the ROC curve (AUC) of CEA was 0.705 (95%CI:0.567-0.843; P = .015). However, no significant association was observed between CEA and ALK mutations though the result of correlation analysis (P = .069) and multivariate logistic regression analysis (OR = 0.988, 95% CI: 0.972-1.003, P = .111). CONCLUSIONS: In our study, we performed on the patients with stage IV lung adenocarcinoma in our region and found preoperative serum levels of SCCAg, CYRF21-1, and NSE not suitable for the detection of ALK mutation. Although we observed a significant association between CEA and ALK mutations; however, it was not strong enough to distinguish ALK status for the patients in our region.

Value of serum tumor markers for predicting EGFR mutations and positive ALK expression in 1089 Chinese non-small-cell lung cancer patients: A retrospective analysis.

PURPOSE: The role of serum tumor markers (STMs) in the modern management of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations in lung cancer remains poorly described. In this study, we investigated whether STMs could be a valuable noninvasive tool to predict EGFR mutations and ALK positivity in non-small-cell lung cancer (NSCLC) patients. EXPERIMENTAL DESIGN: We retrospectively reviewed and included 1089 NSCLC patients who underwent EGFR or ALK mutation testing and STMs measurement prior to treatment. The differences in several clinical characteristics and STMs between the subgroups were analyzed. Multivariate logistic regression analysis was performed to identify predictors of EGFR mutations and ALK positivity. RESULTS: EGFR mutations were found more frequently in females (63.11%), never-smokers (59.69%), and those with lung adenocarcinoma (ADC) (53.87%). Negative carbohydrate antigen (CA) 125, ferritin (FERR), squamous cell carcinoma antigen (SCC), and soluble fragment of cytokeratin 19 (CYFRA 21-1) levels were significantly associated with EGFR mutations (p < 0.05). Multivariate analysis demonstrated that ADC, never-smoker status, and negative CA 125 and SCC results were predictors of EGFR mutations (p < 0.05). The receiver operating characteristic (ROC) curve yielded an area under the curve (AUC) of 0.715 (95% confidence interval [CI]: 0.673-0.758) for the combination of the four factors. Positive ALK expression was found more frequently in younger patients (median age: 49 years), females (8.40%), never-smokers (8.82%), and those negative for carcinoembryonic antigen (CEA) (8.02%). Multivariate analysis demonstrated that younger age and never-smoker status were the only independent predictors of ALK positivity (p < 0.05). The ROC curve yielded an AUC of 0.760 (95% CI: 0.677-0.844) for the combination of these two factors. CONCLUSION: STMs are associated with mutant EGFR status and could be integrated with other clinical factors to enhance the ability to distinguish EGFR mutation status among NSCLC patients. For ALK-positive patients, younger age and never-smoker status could predict the mutation status, whereas STMs could not.

Nanoparticles Targeting Macrophages as Potential Clinical Therapeutic Agents Against Cancer and Inflammation.

With the development of nanotechnology, significant progress has been made in the design, and manufacture of nanoparticles (NPs) for use in clinical treatments. Recent increases in our understanding of the central role of macrophages in the context of inflammation and cancer have reinvigorated interest in macrophages as drug targets. Macrophages play an integral role in maintaining the steady state of the immune system and are involved in cancer and inflammation processes. Thus, NPs tailored to accurately target macrophages have the potential to transform disease treatment. Herein, we first present a brief background information of NPs as drug carriers, including but not limited to the types of nanomaterials, their biological properties and their advantages in clinical application. Then, macrophage effector mechanisms and recent NPs-based strategies aimed at targeting macrophages by eliminating or re-educating macrophages in inflammation and cancer are summarized. Additionally, the development of nanocarriers targeting macrophages for disease diagnosis is also discussed. Finally, the significance of macrophage-targeting nanomedicine is highlighted, with the goal of facilitating future clinical translation.

Comprehensive genomic and prognostic analysis of the IL­17 family genes in lung cancer.

The six members of the interleukin (IL)­17 gene family (IL­17A­F) have been identified in various types of cancer. Although lung cancer is the leading cause of cancer­related death worldwide and IL­17A was found to play a critical role in lung cancer, there is little knowledge concerning the association between the other five members of the IL­17 family and lung cancer. The genetic mutations and expression of IL­17 family members were investigated using the Catalogue of Somatic Mutations in Cancer (COSMIC), Oncomine, and cBio Cancer Genomics Portal (cBioPortal) databases. Prognostic values and interaction networks of the members were assessed by the Kaplan­Meier plotter, Search Tool for the Retrieval of Interacting Genes (STRING) database and FunRich software. The results found that, across 5,238 lung cancer patients in the cBioPortal, the results of IL­17 family gene alteration frequencies and types showed that IL­17A, IL­25 and IL­17F exhibited higher alteration frequencies (2, 2.1 and 1.9%, respectively), and gene amplification accounted for the majority of changes. IL­17B, IL­17C and IL­17D exhibited lower alteration frequencies (0.8, 1.1 and 1.1%, respectively), and deep deletion accounted for the majority of changes. The rates of point mutations in IL­17A through IL­17F family genes in lung cancer were 0.66, 0.18, 0.13, 0.09, 0.27 and 0.44% in the COSMIC database. Within the Oncomine database, five datasets showed that IL­17D was significantly decreased in lung cancer, while no dataset showed a significant difference in the expression of IL­17A, IL­17B, IL­17C, IL­25 or IL17­F between lung cancer and normal controls. The frequencies of IL­17A, IL­17B and IL­17C mRNA upregulation in lung squamous cell carcinoma were lower than those in lung adenocarcinoma (2.7, 1.9 and 2.1%, respectively), whereas the frequencies of IL­17D, IL­25 and IL­17F mRNA upregulation were higher in lung squamous cell carcinoma than those in lung adenocarcinoma (3, 6 and 6%, respectively). IL­17A and IL­17B were unrelated to overall survival (p=0.11; P=0.17), whereas IL­17C, IL­17D, IL­25 and IL­17F influenced prognosis (P=0.0023, P=0.0059, P=0.039 and P=0.0017, respectively) according to the Kaplan­Meier plotter. Moreover, the expression level of IL­17C was the highest in lung tissues, and IL­17 family genes mainly participate in the 'IFN­Î³ pathway' according to the STRING database and Funrich software. In conclusion, we performed the first comprehensive investigation of the IL­17 gene family in lung cancer, including gene mutation, mRNA expression levels, prognostic values and network pathways. Our results revealed that IL­17 family gene mutation rates were in general low and that amplification and deep deletion were the main mutation type. The expression and function of IL­17A and IL­17B in lung cancer are still not fully elucidated and warrant research with larger sample sizes. IL­17D was significantly decreased in lung cancer and was correlated with better OS. Studies of IL­17C­F in lung cancer are limited. Further experimental studies on the association between IL­17D and lung cancer progression are needed to identify more effective therapeutic targets for lung cancer.

Autologous tumor cell-derived microparticle-based targeted chemotherapy in lung cancer patients with malignant pleural effusion.

Cell membrane-derived microparticles (MPs), the critical mediators of intercellular communication, have gained much interest for use as natural drug delivery systems. Here, we examined the therapeutic potential of tumor cell-derived MPs (TMPs) in the context of malignant pleural effusion (MPE). TMPs packaging the chemotherapeutic drug methotrexate (TMPs-MTX) markedly restricted MPE growth and provided a survival benefit in MPE models induced by murine Lewis lung carcinoma and colon adenocarcinoma cells. On the basis of the potential benefit and minimal toxicity of TMPs-MTX, we conducted a human study of intrapleural delivery of a single dose of autologous TMPs packaging methotrexate (ATMPs-MTX) to assess their safety, immunogenicity, and clinical activity. We report our findings on 11 advanced lung cancer patients with MPE. We found that manufacturing and infusing ATMPs-MTX were feasible and safe, without evidence of toxic effects of grade 3 or higher. Evaluation of the tumor microenvironment in MPE demonstrated notable reductions in tumor cells and CD163+ macrophages in MPE after ATMP-MTX infusion, which then translated into objective clinical responses. Moreover, ATMP-MTX treatment stimulated CD4+ T cells to release IL-2 and CD8+ cells to release IFN-γ. Our initial experience with ATMPs-MTX in advanced lung cancer with MPE suggests that ATMPs targeting malignant cells and the immunosuppressive microenvironment may be a promising therapeutic platform for treating malignancies.

The role of adrenergic receptors in lung cancer.

Adrenergic receptors (ARs), especially ß-ARs, are constitutively expressed in most mammalian cells and are associated with various malignancies including lung cancer. Epidemiologic studies have reported that activation of ß-AR signalling promotes the development and progression of lung cancer and that pharmacological interference by ß-AR blockers could partially reverse lung cancer progression. In this review, we mainly focus on the role of ß-ARs in lung cancer and then reveal the possible application of AR blockers in anti-tumour therapy for lung cancer.

Retinoic Acid Receptor-Related Orphan Receptors: Critical Roles in Tumorigenesis.

Retinoic acid receptor-related orphan receptors (RORs) include RORα (NR1F1), RORß (NR1F2), and RORγ (NR1F3). These receptors are reported to activate transcription through ligand-dependent interactions with co-regulators and are involved in the development of secondary lymphoid tissues, autoimmune diseases, inflammatory diseases, the circadian rhythm, and metabolism homeostasis. Researches on RORs contributing to cancer-related processes have been growing, and they provide evidence that RORs are likely to be considered as potential therapeutic targets in many cancers. RORα has been identified as a potential therapeutic target for breast cancer and has been investigated in melanoma, colorectal colon cancer, and gastric cancer. RORß is mainly expressed in the central nervous system, but it has also been studied in pharyngeal cancer, uterine leiomyosarcoma, and colorectal cancer, in addition to neuroblastoma, and recent studies suggest that RORγ is involved in various cancers, including lymphoma, melanoma, and lung cancer. Some studies found RORγ to be upregulated in cancer tissues compared with normal tissues, while others indicated the opposite results. With respect to the mechanisms of RORs in cancer, previous studies on the regulatory mechanisms of RORs in cancer were mostly focused on immune cells and cytokines, but lately there have been investigations concentrating on RORs themselves. Thus, this review summarizes reports on the regulation of RORs in cancer and highlights potential therapeutic targets in cancer.