bims-meluca 2019-01-27 papers

Br J Radiol. 2019 Jan 23. 20180792

Impact of different image reconstructions on PET quantification in non-small cell lung cancer: a comparison of adenocarcinoma and squamous cell carcinoma.

Messerli M, Kotasidis F, Burger IA, Ferraro DA, Muehlematter UJ, Weyermann C, Kenkel D, von Schulthess GK, Kaufmann PA, Huellner MW.

OBJECTIVE:: Positron emission tomography (PET) using 18F-fluordeoxyglucose (18F-FDG) is an established imaging modality for tumor staging in patients with non-small cell lung cancer (NSCLC). There is a growing interest in using 18F-FDG PET for therapy response assessment in NSCLC which relies on quantitative PET parameters such as standardized uptake values (SUV). Different reconstruction algorithms in PET may affect SUV. We sought to determine the variation of SUV in patients with NSCLC when using ordered subset expectation maximization (OSEM) and block sequential regularized expectation maximization (BSREM) in latest-generation digital PET/CT, including a subanalysis for adenocarcinoma and squamous cell carcinoma.METHODS:: A total of 58 patients (34 = adenocarcinoma, 24 = squamous cell carcinoma) that underwent a clinically indicated 18F-FDG PET/CT for staging were reviewed. PET images were reconstructed with OSEM and BSREM reconstruction with noise penalty strength β-levels of 350, 450, 600, 800 and 1200. Lung tumors maximum standardized uptake value (SUVmax) were compared.
RESULTS:: Lung tumors SUVmax were significantly lower in adenocarcinomas compared to squamous cell carcinomas in all reconstructions evaluated (all p < 0.01). Comparing BSREM to OSEM, absolute SUVmax differences were highest in lower β-levels of BSREM with + 2.9 ± 1.6 in adenocarcinoma and + 4.0 ± 2.9 in squamous cell carcinoma, (difference between histology; p-values > 0.05). There was a statistically significant difference of the relative increase of SUVmax in adenocarcinoma (mean + 34.8%) and squamous cell carcinoma (mean 23.4%), when using BSREM350 instead of OSEMTOF (p < 0.05).
CONCLUSIONS:: In NSCLC the relative change of SUV when using BSREM instead of OSEM is significantly higher in adenocarcinoma as compared to squamous cell carcinoma.
ADVANCES IN KNOWLEDGE:: The impact of BSREM on SUV may vary in different histological subtypes of NSCLC. This highlights the importance for careful standardisation of β-value used for serial 18F-FDG PET scans when following-up NSCLC patients.

DOI: https://doi.org/10.1259/bjr.20180792

J Cell Physiol. 2019 Jan 24.

Blocking OLFM4/HIF-1α axis alleviates hypoxia-induced invasion, epithelial-mesenchymal transition, and chemotherapy resistance in non-small-cell lung cancer.

Gao XZ, Wang GN, Zhao WG, Han J, Diao CY, Wang XH, Li SL, Li WC.

Hypoxia is a common biological hallmark of solid cancers, which has been proposed to be associated with oncogenesis and chemotherapy resistance. The purpose of the present study was to investigate the role and underlying mechanisms of olfactomedin 4 (OLFM4) in the hypoxia-induced invasion, epithelial-mesenchymal transition (EMT), and chemotherapy resistance of non-small-cell lung cancer (NSCLC). We observed dramatically upregulated expression of OLFM4 in several NSCLC cell lines, and this effect was more pronounced in A549 and H1299 cells. In addition, our data revealed that OLFM4 expression was remarkably increased in both A549 and H1299 cells under hypoxic microenvironment, accompanied by enhanced levels of hypoxia-inducible factor (HIF)-1α protein. The HIF-1α level was elevated in response to hypoxia, resulting in the regulation of OLFM4. Interestingly, OLFM4 was a positive regulator of hypoxia-driven HIF-1α production. Moreover, depletion of OLFM4 modulated multiple EMT-associated proteins, as evidenced by the enhanced E-cadherin levels along with the diminished expression of N-cadherin and vimentin in response to hypoxia, and thus blocked invasion ability of A549 and H1299 cells following exposure to hypoxia. Furthermore, ablation of OLFM4 accelerated the sensitivity of A549 cells to cisplatin under hypoxic conditions, implying that OLFM4 serves as a key regulator in chemotherapeutic resistance under hypoxia. In conclusion, OLFM4/HIF-1α axis might be a potential therapeutic strategy for NSCLC.

Keywords: hypoxia-inducible factor; invasion; non-small-cell lung cancer; olfactomedin 4

DOI: https://doi.org/10.1002/jcp.28144

Sci Rep. 2019 Jan 23. 9(1): 402

The use of solid phase microextraction for metabolomic analysis of non-small cell lung carcinoma cell line (A549) after administration of combretastatin A4.

Jaroch K, Boyaci E, Pawliszyn J, Bojko B.

Use of solid phase microextraction (SPME) for cell culture metabolomic analysis allows for the attainment of more sophisticated data from in vitro cell cultures. Moreover, considering that SPME allows the implementation of multiple extractions from the same sample due to its non/low-depletive nature, time course studies using the same set of samples are thus facilitated via this method. Such an approach results in a reduction in the number of samples needed for analysis thus eliminates inter-batch variability related to biological variation occurring during cell culturing. The current work aims to demonstrate the capability of SPME for measurements of combretastatin A4 (CA4) effectiveness on non-small cell cancer cell line. A cultivation protocol was established in the 96-well plate, and a fiber format of SPME was selected for metabolite extraction. The extracellular metabolic pattern of cells was changed after administration of the tested drug. This suggests pharmacological activity of the administered compound towards the studied cell line model. Results support that the use of direct immersion SPME for analysis of cell cultures does not affect cells growth or contaminate sample. Consequently, SPME allows the attainment of accurate information regarding drug uptake, metabolism, and metabolomic changes in the studied cells induced by exposure to the drug simultaneously in a single experiment.

DOI: https://doi.org/10.1038/s41598-018-36481-2

Cancer Manag Res. 2019 ;11 681-689

Metformin induces apoptotic cytotoxicity depending on AMPK/PKA/GSK-3β-mediated c-FLIPL degradation in non-small cell lung cancer.

Luo Z, Zhu T, Luo W, Lv Y, Zhang L, Wang C, Li M, Wu W, Shi S.

Background: Metformin, a first-line antidiabetic drug, has recently been reported with anticancer activities in various cancers; however, the underlying mechanisms remain elusive. The aim of the present study was to investigate the role of cellular FADD-like IL-1β-converting enzyme (FLICE)-inhibitory protein large (c-FLIPL) in metformin-induced anticancer activity in non-small cell lung cancer (NSCLC) in vitro.Materials and methods: Cell viability was measured by MTT assay. Quantitative real-time PCR was carried out to detect the level of mRNA of related genes. The expression of related proteins was detected by Western blot. siRNA was used to silence the expression of targeted proteins.
Results: Metformin significantly suppressed proliferation of both A549 and H460 cells in a dose-dependent manner. Mechanistic studies suggested that metformin killed NSCLC cells by inducing apoptotic cell death. Moreover, metformin greatly inhibited c-FLIPL expression and then promoted its degradation. Furthermore, metformin significantly activated Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and its downstream glycogen synthase kinase 3beta (GSK-3β), block the expression of AMPK, and GSK-3β with siRNA partially reversed metformin-induced cytotoxicity and restored the expression of c-FLIPL in lung cancer cells. Metformin also suppressed the activity of AMPK downstream protein kinase A (PKA), PKA activators, both 8-Br-cAMP and forskolin, greatly increased c-FLIPL expression in NSCLC cells.
Conclusion: This study provided evidence that metformin killed NSCLC cells through AMPK/PKA/GSK-3β axis-mediated c-FLIPL degradation.

Keywords: AMPK; GSK-3β; PKA; c-FLIPL; non-small cell lung cancer

DOI: https://doi.org/10.2147/CMAR.S178688