MicroRNAs: a new key in lung cancer.
Zhang Yunlong,Yang Qian,Wang Siwang
Cancer chemotherapy and pharmacology
Lung cancer as a malignance has been killing numerous patients around the world annually, and small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) are the two major types, the later accounting for nearly 80 % of lung cancer. There are multiple causes for lung cancer, and more researches have been carried out to prevent, anticipate, and diagnose the cancer. MicroRNAs (miRNAs) are small non-coding RNA molecules capable of regulating expression of over 50 % of protein-coding genes. The RNA molecules are stable in tissues and blood, so it can tend to be a biomarker in anti-lung cancer. Here, this is a review on the roles of miRNAs for possible ways to prevent lung cancer in clinical trials.
10.1007/s00280-014-2559-9
Identification and imaging of miR-155 in the early screening of lung cancer by targeted delivery of octreotide-conjugated chitosan-molecular beacon nanoparticles.
Zhu Hai-Zhen,Hou Jing,Guo Yi,Liu Xin,Jiang Fei-Long,Chen Guang-Peng,Pang Xiu-Feng,Sun Jian-Guo,Chen Zheng-Tang
Drug delivery
Lung cancer is still the most common cancer globally. Early screening remains the key to improve the prognosis of patients. There is currently a lack of specific and sensitive methods for early screening of lung cancer. In recent years, studies have found that microRNA plays an important role in the occurrence and development of lung cancer and become a biological target in the early diagnosis of lung cancer. In this study, lung cancer cells, subcutaneous xenografts of lung cancer in nude mice, and Lox-Stop-lox K-ras G12D transgenic mice were used as models. The transgenic mice displayed the dynamic processes from normal lung tissue to atypical hyperplasia, adenomas, carcinoma in situ and lung adenocarcinoma. It was found that miR-155 and somatostatin receptor 2 (SSTR2) were expressed in all the disease stages of transgenic mice. Through molecular beacon (MB) technology and nanotechnology, chitosan-molecular beacon (CS-MB) nanoparticles and targeted octreotide (OCT) were conjugated and synthesized. The octreotide-conjugated chitosan-molecular beacon nanoparticles (CS-MB-OCT) can specifically bind to SSTR2 expressed by the lung cancer cells to achieve the goal of identification of lung cancer cells and imaging miR-155 in vivo and in vitro. Fluorescence imaging at different disease stages of lung cancer in Lox-Stop-lox K-ras G12D transgenic mice was performed, and could dynamically monitor the occurrence and development of lung cancer by different fluorescence intensity ranges. The current research, in turn, provides new idea, new method, and new technology for the early screening of lung cancer.
10.1080/10717544.2018.1516003
Novel molecular beacons to monitor microRNAs in non-small-cell lung cancer.
Yao Quan,Zhang An-mei,Ma Hu,Lin Sheng,Wang Xin-xin,Sun Jian-guo,Chen Zheng-tang
Molecular and cellular probes
Lung cancer is the leading cause of cancer death worldwide. There is no effective early diagnostic technology for lung cancer. microRNAs (miRNAs) are noncoding RNA molecules which regulate the process of cell growth and differentiation in human cancers. Hsa-miR-155 (miR-155), highly expressed in non-small-cell lung cancer (NSCLC), can be used as a diagnostic marker for NSCLC. Dynamic observation of miR-155 is critical to diagnose NSCLC. A novel molecular beacon (MB) of miR-155 was designed to image the expression of miR-155 in NSCLC. Then miR-155 was detected in vitro by laser confocal microscopy and in vivo by stereomicroscope imaging system, respectively. The present study demonstrated that intracellular miR-155 could be successfully and quickly detected by novel miR-155 MBs. As a noninvasive monitoring approach, MBs could be used to diagnose lung cancer at early stage through molecular imaging.
10.1016/j.mcp.2012.07.001
Detection of miR-155-5p and imaging lung cancer for early diagnosis: in vitro and in vivo study.
Zhu Hai-Zhen,Fang Chun-Ju,Guo Yi,Zhang Qi,Huang Li-Min,Qiu Dong,Chen Guang-Peng,Pang Xiu-Feng,Hu Jian-Jun,Sun Jian-Guo,Chen Zheng-Tang
Journal of cancer research and clinical oncology
PURPOSE:Currently, the routine screening program has insufficient capacity for the early diagnosis of lung cancer. Therefore, a type of chitosan-molecular beacon (CS-MB) probe was developed to recognize the miR-155-5p and image the lung cancer cells for the early diagnosis. METHODS:Based on the molecular beacon (MB) technology and nanotechnology, the CS-MB probe was synthesized self-assembly. There are four types of cells-three kinds of animal models and one type of histopathological sections of human lung cancer were utilized as models, including A549, SPC-A1, H446 lung cancer cells, tumor-initiating cells (TICs), subcutaneous and lung xenografts mice, and lox-stop-lox(LSL) K-ras G12D transgenic mice. The transgenic mice dynamically displayed the process from normal lung tissues to atypical hyperplasia, adenoma, carcinoma in situ, and adenocarcinoma. The different miR-155-5p expression levels in these cells and models were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The CS-MB probe was used to recognize the miR-155-5p and image the lung cancer cells by confocal microscopy in vitro and by living imaging system in vivo. RESULTS:The CS-MB probe could be used to recognize the miR-155-5p and image the lung cancer cells significantly in these cells and models. The fluorescence intensity trends detected by the CS-MB probe were similar to the expression levels trends of miR-155 tested by qRT-PCR. Moreover, the fluorescence intensity showed an increasing trend with the tumor progression in the transgenic mice model, and the occurrence and development of lung cancer were dynamically monitored by the differen fluorescence intensity. In addition, the miR-155-5p in human lung cancer tissues could be detected by the miR-155-5p MB. CONCLUSION:Both in vivo and in vitro experiments demonstrated that the CS-MB probe could be utilized to recognize the miR-155-5p and image the lung cancer cells. It provided a novel experimental and theoretical basis for the early diagnosis of the disease. Also, the histopathological sections of human lung cancer research laid the foundation for subsequent preclinical studies. In addition, different MBs could be designed to detect other miRNAs for the early diagnosis of other tumors.
10.1007/s00432-020-03246-2
Biomarkers for immune checkpoint inhibition in non-small cell lung cancer (NSCLC).
Cancer
The emergence of immunotherapy has dramatically changed how non-small cell lung cancer is treated, and longer survival is now possible for some patients, even those with advanced disease. Although some patients achieve durable responses to checkpoint blockade, not all experience such benefits, and some suffer from significant immunotoxicities. Given this, biomarkers that predict response to therapy are essential, and testing for tumor programmed death ligand 1(PD-L1) expression is the current standard. The extent of PD-L1 expression determined by immunohistochemistry (IHC) has demonstrated a correlation with treatment response, although limitations with this marker exist. Recently, tumor mutational burden has emerged as an alternative biomarker, and studies have demonstrated its utility, irrespective of the PD-L1 level of a tumor. Gene expression signatures, tumor genotype (such as the presence of an oncogenic driver mutation), as well as the density of tumor-infiltrating lymphocytes in the tumor microenvironment also seem to affect response to immunotherapy and are being researched. Peripheral serum markers are being studied, and some have demonstrated predictive ability, although most are still investigational and need prospective validation. In the current article, the authors review the biomarker PD-L1 as well as other emerging and investigational tissue-based and serum-based markers that have potential to better predict responders to immunotherapy.
10.1002/cncr.32468
Orally available tubulin inhibitor VERU-111 enhances antitumor efficacy in paclitaxel-resistant lung cancer.
Cancer letters
Lung cancer is the most common cause of cancer associated mortality. Chemotherapeutic agents, such as paclitaxel, are important treatment options but drug resistance often develops upon prolonged use. We report here the preclinical evaluation of a new orally available tubulin inhibitor, VERU-111, which can overcome several ABC-transporters mediated multi-drug resistance associated with taxane treatment. In vitro, VERU-111 prevents cell proliferation, invasion, migration and colony formation in both paclitaxel-sensitive and paclitaxel-resistant A549 lung cancer cells. VERU-111 effectively inhibits tubulin polymerization, arrests cells in G2/M phase, and induces cancer cell apoptosis. Further evaluation of various apoptotic proteins revealed that treatment of VERU-111 increases the expression of cleaved-PARP, cleaved-caspase-3 and p-histone H3 proteins. In vivo, orally administered VERU-111 in a paclitaxel-sensitive A549 xenograft model strongly inhibits tumor growth in a dose-dependent manner and is equally potent with paclitaxel. When tested in a highly paclitaxel-resistant A549/TxR tumor model, VERU-111 is as effective as the parental A549 model in significantly reducing the tumor volume, whereas paclitaxel is essentially ineffective. Collectively, this study showed that VERU-111 is a promising new generation of anti-tubulin agent for the treatment of taxane-resistant lung cancer.
10.1016/j.canlet.2020.09.004
Integrating genomic features for non-invasive early lung cancer detection.
Nature
Radiologic screening of high-risk adults reduces lung-cancer-related mortality; however, a small minority of eligible individuals undergo such screening in the United States. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq), a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.
10.1038/s41586-020-2140-0
Inhibition of tumor metastasis by targeted daunorubicin and dioscin codelivery liposomes modified with PFV for the treatment of non-small-cell lung cancer.
International journal of nanomedicine
Chemotherapy for non-small-cell lung cancer (NSCLC) still leads to unsatisfactory clinical prognosis because of poor active targeting and tumor metastasis. The objective of this study was to construct a kind of PFV peptide modified targeted daunorubicin and dioscin codelivery liposomes, which could enhance tumor targeting and inhibit tumor cell metastasis. Targeted daunorubicin and dioscin codelivery liposomes were prepared by film dispersion and the ammonium sulfate gradient method. With the ideal physicochemical properties, targeted daunorubicin and dioscin codelivery liposomes exhibited enhanced cellular uptake and showed strong cytotoxicity to tumor cells. The encapsulation of dioscin increased the inhibitory effects of daunorubicin on A549 cells, vasculogenic mimicry (VM) channels and tumor metastasis. The enhanced antimetastatic mechanism of the targeted liposomes was attributed to the downregulation of matrix metalloproteinase-2 (MMP-2), vascular endothelial cadherin (VE-Cad), transforming growth factor-β1 (TGF-β1) and hypoxia inducible factor-1α (HIF-1α). Meanwhile, the targeted daunorubicin and dioscin codelivery liposomes exhibited significant antitumor effects in tumor-bearing mice. H&E staining, immunohistochemistry with Ki-67 and TUNEL assay also showed the promoted antitumor activity of the targeted liposomes. Targeted daunorubicin and dioscin codelivery liposomes may provide an effective strategy for the treatment of NSCLC.
10.2147/IJN.S194304
Vasculature surrounding a nodule: A novel lung cancer biomarker.
Wang Xiaohua,Leader Joseph K,Wang Renwei,Wilson David,Herman James,Yuan Jian-Min,Pu Jiantao
Lung cancer (Amsterdam, Netherlands)
PURPOSE:To investigate whether the vessels surrounding a nodule depicted on non-contrast, low-dose computed tomography (LDCT) can discriminate benign and malignant screen detected nodules. MATERIALS AND METHODS:We collected a dataset consisting of LDCT scans acquired on 100 subjects from the Pittsburgh Lung Screening study (PLuSS). Fifty subjects were diagnosed with lung cancer and 50 subjects had suspicious nodules later proven benign. For the lung cancer cases, the location of the malignant nodule in the LDCT scans was known; while for the benign cases, the largest nodule in the LDCT scan was used in the analysis. A computer algorithm was developed to identify surrounding vessels and quantify the number and volume of vessels that were connected or near the nodule. A nonparametric receiver operating characteristic (ROC) analysis was performed based on a single nodule per subject to assess the discriminability of the surrounding vessels to provide a lung cancer diagnosis. Odds ratio (OR) were computed to determine the probability of a nodule being lung cancer based on the vessel features. RESULTS:The areas under the ROC curves (AUCs) for vessel count and vessel volume were 0.722 (95% CI=0.616-0.811, p<0.01) and 0.676 (95% CI=0.565-0.772), respectively. The number of vessels attached to a nodule was significantly higher in the lung cancer group 9.7 (±9.6) compared to the non-lung cancer group 4.0 (±4.3) CONCLUSION: Our preliminary results showed that malignant nodules are often surrounded by more vessels compared to benign nodules, suggesting that the surrounding vessel characteristics could serve as lung cancer biomarker for indeterminate nodules detected during LDCT lung cancer screening using only the information collected during the initial visit.
10.1016/j.lungcan.2017.10.008
Management of co-existent tuberculosis and lung cancer.
Ho James Chung-Man,Leung Chi-Chiu
Lung cancer (Amsterdam, Netherlands)
Tuberculosis (TB) and lung cancer are important global health threats, each accounting for 1.6 million deaths yearly. The incidence of both conditions remains high in many developing countries, especially in East Asia. There is now epidemiologic evidence that pre-existing TB poses an increased lung cancer risk. The clinical diagnosis of co-existent TB and lung cancer relies on symptoms of infection, typical radiological features and microbiological confirmation, and remains a challenge in both early and late stage lung cancer. The presence of histological granulomatous inflammation in resected lung specimens is not exclusively indicative of TB. The widely accepted systemic chemotherapy and immunotherapy for treating lung cancer are highly relevant to the occurrence of TB and its management. This review addresses the clinical approach to the diagnosis and treatment of TB that co-exists with lung cancer.
10.1016/j.lungcan.2018.05.030