bims-meluca 2020-03-08 papers

Adv Exp Med Biol. 2020 ;1219 311-333

The Metabolic Remodelling in Lung Cancer and Its Putative Consequence in Therapy Response.

Lung cancer is the leading cause of cancer-related deaths worldwide in both men and women. Conventional chemotherapy has failed to provide long-term benefits for many patients and in the past decade, important advances were made to understand the underlying molecular/genetic mechanisms of lung cancer, allowing the unfolding of several other pathological entities. Considering these molecular subtypes, and the appearance of promising targeted therapies, an effective personalized control of the disease has emerged, nonetheless benefiting a small proportion of patients. Although immunotherapy has also appeared as a new hope, it is still not accessible to the majority of patients with lung cancer.The metabolism of energy and biomass is the basis of cellular survival. This is true for normal cells under physiological conditions and it is also true for pathophysiologically altered cells, such as cancer cells. Thus, knowledge of the metabolic remodelling that occurs in cancer cells in the sense of, on one hand, surviving in the microenvironment of the organ in which the tumour develops and, on the other hand, escaping from drugs conditioned microenvironment, is essential to understand the disease and to develop new therapeutic approaches.

Keywords: Lung cancer; Metabolic remodelling; New therapeutic approaches; Targeted therapy; Tumor microenvironment

DOI: https://doi.org/10.1007/978-3-030-34025-4_16

Anticancer Res. 2020 Mar;40(3): 1451-1458

Hedgehog Pathway Activation Might Mediate Pemetrexed Resistance in NSCLC Cells.

Liu Y, Huber RM, Kiefl R, Tufman A, Kauffmann-Guerrero D.

BACKGROUND/AIM: Resistance to chemotherapeutic agents is the main cause of reduced survival in non-small cell lung cancer (NSCLC) patients. The Hedgehog (HH) pathway has been shown to be crucial in cell development and survival. Activated in several types of cancer it might be a potent bypass mechanism mediating chemotherapy resistance.MATERIALS AND METHODS: HCC827 NSCLC cells were treated with sub-lethal doses of pemetrexed to produce pemetrexed resistance. RT-qPCR was performed to measure gene expression of HH pathway proteins. A cell growth assay was used to measure the impact of the HH-inhibitor Gant61 in naïve and chemoresistant cell lines.
RESULTS: Pemetrexed resistant cells showed significantly increased expression of HH signaling genes (GLI1, GLI2, GLI3, PTCH1, SHH). Supporting these results, pemetrexed resistant cells treated with the HH inhibitor Gant61 showed reduced proliferation compared to naïve cells.
CONCLUSION: HH pathway may play an important role in mediating pemetrexed resistance in NSCLC cells. Blocking the HH pathway may be a potential option to overcome this resistance.

Keywords: Gant61; Hedgehog pathway; NSCLC; chemo resistance; pemetrexed

DOI: https://doi.org/10.21873/anticanres.14087

J Pathol Transl Med. 2020 Mar 04.

Gene variant profiles and tumor metabolic activity as measured by FOXM1 expression and glucose uptake in lung adenocarcinoma.

Goodman A, Mahmud W, Buckingham L.

Background: Cancer cells displaying aberrant metabolism switch energy production from oxidative phosphorylation to glycolysis. Measure of glucose standardized uptake value (SUV) by positron emission tomography (PET), used for staging of adenocarcinoma in high-risk patients, can reflect cellular use of the glycolysis pathway. The transcription factor, FOXM1 plays a role in regulation of glycolytic genes. Cancer cell transformation is driven by mutations in tumor suppressor genes such as TP53 and STK11 and oncogenes such as KRAS and EGFR. In this study, SUV and FOXM1 gene expression were compared in the background of selected cancer gene mutations.Materials and Methods: Archival tumor tissue from cases of lung adenocarcinoma were analyzed. SUV was collected from patient records. FOXM1 gene expression was assessed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Gene mutations were detected by allele-specific PCR and gene sequencing.
Results: SUV and FOXM1 gene expression patterns differed in the presence of single and coexisting gene mutations. Gene mutations affected SUV and FOXM1 differently. EGFR mutations were found in tumors with lower FOXM1 expression but did not affect SUV. Tumors with TP53 mutations had increased SUV (p = .029). FOXM1 expression was significantly higher in tumors with STK11 mutations alone (p < .001) and in combination with KRAS or TP53 mutations (p < .001 and p = .002, respectively).
Conclusion: Cancer gene mutations may affect tumor metabolic activity. These observations support consideration of tumor cell metabolic state in the presence of gene mutations for optimal prognosis and treatment strategy.

Keywords: Forkhead Box protein M1; KRAS protein, human; Lung neoplasms; Treatment outcome

DOI: https://doi.org/10.4132/jptm.2020.02.08

EBioMedicine. 2020 Mar 03. pii: S2352-3964(20)30071-2. [Epub ahead of print]53 102696

Enhanced monoacylglycerol lipolysis by ABHD6 promotes NSCLC pathogenesis.

Tang Z, Xie H, Heier C, Huang J, Zheng Q, Eichmann TO, Schoiswohl G, Ni J, Zechner R, Ni S, Hao H.

BACKGROUND: Tumor cells display metabolic changes that correlate with malignancy, including an elevated hydrolysis of monoacylglycerol (MAG) in various cancer types. However, evidence is absent for the relationship between MAG lipolysis and NSCLC.METHODS: MAG hydrolase activity assay, migration, invasion, proliferation, lipids quantification, and transactivation assays were performed in vitro. Tumor xenograft studies and lung metastasis assays were examined in vivo. The correlations of MAGL/ABHD6 expression in cancerous tissues with the clinicopathological characteristics and survival of NSCLC patients were validated.
FINDINGS: ABHD6 functions as the primary MAG lipase and an oncogene in NSCLC. MAG hydrolase activities were more than 11-fold higher in cancerous lung tissues than in paired non-cancerous tissues derived from NSCLC patients. ABHD6, instead of MAGL, was significantly associated with advanced tumor node metastasis (TNM) stage (HR, 1.382; P = 0.004) and had a negative impact on the overall survival of NSCLC patients (P = 0.001). ABHD6 silencing reduced migration and invasion of NSCLC cells in vitro as well as metastatic seeding and tumor growth in vivo. Conversely, ectopic overexpression of ABHD6 provoked the pathogenic potential. ABHD6 blockade significantly induced intracellular MAG accumulation which activated PPARα/γ signaling and inhibited cancer pathophysiology.
INTERPRETATION: The present study provide evidence for a previously uncovered pro-oncogenic function of ABHD6 in NSCLC, with the outlined metabolic mechanisms shedding light on new potential strategies for anticancer therapy. FUND: This work was supported by the Project for Major New Drug Innovation and Development (2015ZX09501010 and 2018ZX09711001-002-003).

Keywords: ABHD6; Aggressiveness; MAG; NSCLC

DOI: https://doi.org/10.1016/j.ebiom.2020.102696

Biochem Biophys Res Commun. 2020 Feb 26. pii: S0006-291X(20)30412-5. [Epub ahead of print]

Role of plasminogen activator inhibitor-1 in methotrexate-induced epithelial-mesenchymal transition in alveolar epithelial A549 cells.

Yamagami Y, Kawami M, Ojima T, Futatsugi S, Yumoto R, Takano M.

There is increasing evidence that epithelial-mesenchymal transition (EMT) contributes to the development of organ fibrosis. We demonstrated that methotrexate (MTX) clearly induced EMT through the transforming growth factor (TGF)-β-related signaling pathway in human alveolar epithelial cell line, A549. However, critical factors associated with MTX-induced EMT have not yet been identified. In our study, we attempted to identify factors playing a crucial role in MTX-induced EMT in A549 cells. We focused on plasminogen activator inhibitor-1 (PAI-1) as the possible target for the prevention of MTX-induced EMT-related lung injury. Comprehensive gene expression analysis by microarray revealed that mRNA expression level of PAI-1 was clearly increased by MTX treatment. In addition, using several cloned A549 cells, we found a good correlation between MTX-induced increase in mRNA expression levels of α-smooth muscle actin (SMA), a representative EMT marker, and PAI-1. Furthermore, MTX upregulated mRNA and protein expression levels of PAI-1 in A549 cells; this upregulation was canceled by co-treatment with SB431542, a TGF-β-related signaling pathway inhibitor. Notably, tiplaxtinin, a PAI-1 inhibitor, and knockdown of urokinase-type plasminogen activator receptor (uPAR) prevented MTX-induced EMT in A549 cells. These findings indicate that MTX may induce EMT via upregulation of PAI-1 expression and interaction of PAI-1 with uPAR in A549 cells.

Keywords: Epithelial-mesenchymal transition; Methotrexate; Plasminogen activator inhibitor-1; Pulmonary fibrosis; Urokinase-type plasminogen activator receptor

DOI: https://doi.org/10.1016/j.bbrc.2020.02.131

Exerc Immunol Rev. 2020 ;26 100-115

Benefits of exercise and immunotherapy in a murine model of human non-small-cell lung carcinoma.

Martín-Ruiz A, Fiuza-Luces C, Rincón-Castanedo C, Fernández-Moreno D, Gálvez BG, Martínez-Martínez E, Martín-Acosta P, Coronado MJ, Franco-Luzón L, González-Murillo Á, Ramírez M, Provencio M, Lucia A.

BACKGROUND: Lung cancer has the highest incidence and mortality rate in the world. One of the most promising new cancer therapies in recent years is immunotherapy, which is based on the blockade of immune checkpoints such as programmed cell death protein 1 (PD-1). Exercise training is beneficial to maintain and improve the quality of life of cancer patients, and it might also modulate the anti-tumoral efficiency of some chemotherapeutic agents. However, the potential of exercise combined with immunotherapy as a cancer therapy remains to be elucidated. Here, we examined the effects of exercise on tumor growth and its possible adjuvant effects when combined with anti-PD-1 immunotherapy (nivolumab) in a patient derived xenograft (PDX) model of non-small-cell lung carcinoma (NSCLC).METHODS: We generated a PDX model using NOD-SCID gamma mice with subcutaneous grafts from tumor tissue of a patient with NSCLC. Animals were randomly assigned to one of four groups: non-exercise + isotype control (n=5), exercise + isotype control (n=5), non-exercise + nivolumab (n=6) or exercise + nivolumab (n=6). The animals undertook an 8- week moderate-intensity training regimen (treadmill aerobic exercise and strength training). Immunotherapy (nivolumab) or an isotype control was administered 2 days/week, for 6 weeks. Several tumor growth and microenvironment parameters were measured after the intervention.
RESULTS: Improvements in aerobic capacity and muscle strength (p=0.027 and p=0.005) were noted in exercised animals. Exercise alone reduced the tumor growth rate with respect to non-exercised mice (p=0.050). The double intervention (exercise + nivolumab) increased tumor necrosis and reduced apoptosis with respect to controls (p=0.026; p=0.030). All interventions achieved a reduction in proliferation compared with the control group (p=0.015, p=0.011, and p=0.011). Exercise alone increased myeloid tumor infiltrates (mostly neutrophils) with respect to the nivolumab only group (p=0.018). Finally, Vegf-a expression was higher in the nivolumab groups (in combination or not with exercise) than in exercise + isotype control group (p=0.045 and p=0.047, respectively). No other significant effects were found.
CONCLUSIONS: Our results would suggest that aerobic and strength training should be studied as an adjuvant to cancer immunotherapy treatment.

Keywords: cancer immunotherapy; exercise; immune checkpoints; lung cancer; patient-derived xenografts; training