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Gulyas, M., Mattsson, J. S., Lindgren, A., Ek, L., Lamberg Lundström, K., Behndig, A., . . . Bergman, B. (2018). COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer.. Acta Oncologica, 57(2), 244-250
Open this publication in new window or tab >>COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer.
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2018 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 244-250Article in journal (Refereed) Published
Abstract [en]

Aim: Inhibition of cyclooxygenase-2 (COX-2) is proposed as a treatment option in several cancer types. However, in non-small cell lung cancer (NSCLC), phase III trials have failed to demonstrate a benefit of adding COX-2 inhibitors to standard chemotherapy. The aim of this study was to analyze COX-2 expression in tumor and stromal cells as predictive biomarker for COX-2 inhibition.

Methods: In a multicenter phase III trial, 316 patients with advanced NSCLC were randomized to receive celecoxib (400 mg b.i.d.) or placebo up to one year in addition to a two-drug platinum-based chemotherapy combination. In a subset of 122 patients, archived tumor tissue was available for immunohistochemical analysis of COX-2 expression in tumor and stromal cells. For each compartment, COX-2 expression was graded as high or low, based on a product score of extension and intensity of positively stained cells.

Results: An updated analysis of all 316 patients included in the original trial, and of the 122 patients with available tumor tissue, showed no survival differences between the celecoxib and placebo arms (HR 1.01; 95% CI 0.81–1.27 and HR 1.12; 95% CI 0.78–1.61, respectively). High COX-2 scores in tumor (n = 71) or stromal cells (n = 55) was not associated with a superior survival outcome with celecoxib vs. placebo (HR =0.96, 95% CI 0.60–1.54; and HR =1.51; 95% CI 0.86–2.66), and no significant interaction effect between COX-2 score in tumor or stromal cells and celecoxib effect on survival was detected (p = .48 and .25, respectively).

Conclusions: In this subgroup analysis of patients with advanced NSCLC treated within the context of a randomized trial, we could not detect any interaction effect of COX-2 expression in tumor or stromal cells and the outcome of celecoxib treatment in addition to standard chemotherapy.

National Category
Clinical Medicine Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-343645 (URN)10.1080/0284186X.2017.1400685 (DOI)000423473200011 ()29140138 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-03-09Bibliographically approved
Mezheyeuski, A., Bergsland, C. H., Backman, M., Djureinovic, D., Sjöblom, T., Bruun, J. & Micke, P. (2018). Multispectral imaging for quantitative and compartment-specific immune infiltrates reveals distinct immune profiles that classify lung cancer patients.. Journal of Pathology, 244(4), 421-431
Open this publication in new window or tab >>Multispectral imaging for quantitative and compartment-specific immune infiltrates reveals distinct immune profiles that classify lung cancer patients.
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2018 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 244, no 4, p. 421-431Article in journal (Refereed) Published
Abstract [en]

Semiquantitative assessment of immune markers by immunohistochemistry (IHC) has significant limitations for describing the diversity of the immune response in cancer. Therefore, we evaluated a fluorescence-based multiplexed immunohistochemical method in combination with a multispectral imaging system to quantify immune infiltrates in situ in the environment of non-small-cell lung cancer (NSCLC). A tissue microarray including 57 NSCLC cases was stained with antibodies against CD8, CD20, CD4, FOXP3, CD45RO, and pan-cytokeratin, and immune cells were quantified in epithelial and stromal compartments. The results were compared with those of conventional IHC, and related to corresponding RNA-sequencing (RNAseq) expression values. We found a strong correlation between the visual and digital quantification of lymphocytes for CD45RO (correlation coefficient: r = 0.52), FOXP3 (r = 0.87), CD4 (r = 0.79), CD20 (r = 0.81) and CD8 (r = 0.90) cells. The correlation with RNAseq data for digital quantification (0.35-0.65) was comparable to or better than that for visual quantification (0.38-0.58). Combination of the signals of the five immune markers enabled further subpopulations of lymphocytes to be identified and localized. The specific pattern of immune cell infiltration based either on the spatial distribution (distance between regulatory CD8(+) T and cancer cells) or the relationships of lymphocyte subclasses with each other (e.g. cytotoxic/regulatory cell ratio) were associated with patient prognosis. In conclusion, the fluorescence multiplexed immunohistochemical method, based on only one tissue section, provided reliable quantification and localization of immune cells in cancer tissue. The application of this technique to clinical biopsies can provide a basic characterization of immune infiltrates to guide clinical decisions in the era of immunotherapy.

Keywords
PD-L1, checkpoint therapy, deep-learning microscopy, digital pathology, prognosis, tumour microenvironment
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-343644 (URN)10.1002/path.5026 (DOI)000428213800006 ()29282718 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-06-20Bibliographically approved
Uhlen, M., Zhang, C., Lee, S., Sjöstedt, E., Fagerberg, L., Bidkhori, G., . . . Ponten, F. (2017). A pathology atlas of the human cancer transcriptome. Science, 357(6352), Article ID eaan2507.
Open this publication in new window or tab >>A pathology atlas of the human cancer transcriptome
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2017 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 357, no 6352, article id eaan2507Article in journal (Refereed) Published
Abstract [en]

Cancer is one of the leading causes of death, and there is great interest in understanding the underlying molecular mechanisms involved in the pathogenesis and progression of individual tumors. We used systems-level approaches to analyze the genome-wide transcriptome of the protein-coding genes of 17 major cancer types with respect to clinical outcome. A general pattern emerged: Shorter patient survival was associated with up-regulation of genes involved in cell growth and with down-regulation of genes involved in cellular differentiation. Using genome-scale metabolic models, we show that cancer patients have widespread metabolic heterogeneity, highlighting the need for precise and personalized medicine for cancer treatment. All data are presented in an interactive open-access database (www.proteinatlas.org/pathology) to allow genome-wide exploration of the impact of individual proteins on clinical outcomes.

Place, publisher, year, edition, pages
AMER ASSOC ADVANCEMENT SCIENCE, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-334302 (URN)10.1126/science.aan2507 (DOI)000407793600028 ()
Funder
Swedish Cancer SocietyScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceKnut and Alice Wallenberg FoundationSwedish Research Council
Available from: 2017-11-22 Created: 2017-11-22 Last updated: 2018-02-01Bibliographically approved
Sandelin, M., Gruden, S., Räsänen, V., Micke, P., Hedeland, M., Axen, N. & Jeansson, M. (2017). Antitumoral effect and reduced systemic toxicity in mice after intra-tumoral injection of an in vivo solidifying calcium sulfate formulation with docetaxel. Paper presented at European Lung Cancer Conference (ELCC), MAY 05-08, 2017, Geneva, SWITZERLAND. Annals of Oncology, 28(S2), Article ID 40P.
Open this publication in new window or tab >>Antitumoral effect and reduced systemic toxicity in mice after intra-tumoral injection of an in vivo solidifying calcium sulfate formulation with docetaxel
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2017 (English)In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 28, no S2, article id 40PArticle in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-333343 (URN)10.1093/annonc/mdx089.011 (DOI)000405512800049 ()
Conference
European Lung Cancer Conference (ELCC), MAY 05-08, 2017, Geneva, SWITZERLAND
Funder
Swedish Research Council, 521-2012-865Åke Wiberg Foundation, 738866289Magnus Bergvall Foundation, 24942-1-2013, 2014-00055
Available from: 2017-11-14 Created: 2017-11-14 Last updated: 2018-02-01Bibliographically approved
Grudén, S., Sandelin, M., Rasanen, V., Micke, P., Hedeland, M., Axén, N. & Jeansson, M. (2017). Antitumoral effect and reduced systemic toxicity in mice after intra-tumoral injection of an in vivo solidifying calcium sulfate formulation with docetaxel. European journal of pharmaceutics and biopharmaceutics, 114, 186-193
Open this publication in new window or tab >>Antitumoral effect and reduced systemic toxicity in mice after intra-tumoral injection of an in vivo solidifying calcium sulfate formulation with docetaxel
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2017 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 114, p. 186-193Article in journal (Refereed) Published
Abstract [en]

Background

Docetaxel is a cytostatic agent approved for treatment of non-small cell lung cancer as well as other cancers. Although docetaxel is an effective cytostatic agent, its effectiveness in clinical practice is associated with a variety of acute and long term side-effects. To overcome systemic side-effects, a slow release formulation based on calcium sulfate with docetaxel for intra-tumoral administration was developed.

Methods

Two formulations with the calcium sulfate NanoZolid technology were generated with a twofold difference in docetaxel drug load. The formulations were injected intra-tumorally as a paste which solidified within the tumor. The effects of the two intra-tumoral injection formulations were tested in female mice (n = 60) inoculated with subcutaneous Lewis lung carcinoma cells. The two formulations were compared to systemic intraperitoneal injection of docetaxel and a placebo formulation without docetaxel. Tumor volumes were measured and systemic side-effects were evaluated using body weight and cell counts from whole blood as well as plasma concentrations.

Results

Both docetaxel formulations showed a significantly higher antitumor efficacy compared to placebo, which was comparable to that of systemic administration of docetaxel. Moreover, the intra-tumoral formulations with docetaxel showed reduced systemic toxicity compared to systemic treatment, including less weight loss and no decrease in blood cell counts.

Conclusions

The results suggest that intra-tumoral slow release calcium sulfate based formulations with docetaxel can be an alternative strategy as an efficient local antitumoral treatment with reduced systemic toxicity.

Keywords
Bioresorbable, Calcium sulfate, Docetaxel, Intratumoral, Lewis lung carcinoma, Non-small cell lung cancer, Slow release formulation
National Category
Cancer and Oncology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-316552 (URN)10.1016/j.ejpb.2017.01.018 (DOI)000399268900019 ()28161551 (PubMedID)
Funder
Magnus Bergvall Foundation, 24942-1-2013Magnus Bergvall Foundation, 214-00055Swedish Research Council, 521-2012-865Åke Wiberg Foundation, 738866289
Available from: 2017-03-02 Created: 2017-03-02 Last updated: 2018-02-01Bibliographically approved
Karlsson, A., Brunnström, H., Micke, P., Veerla, S., Mattsson, J. S., La Fleur, L., . . . Staaf, J. (2017). Gene Expression Profiling of Large Cell Lung Cancer Links Transcriptional Phenotypes to the New Histological WHO 2015 Classification. Journal of Thoracic Oncology, 12(8), 1257-1267
Open this publication in new window or tab >>Gene Expression Profiling of Large Cell Lung Cancer Links Transcriptional Phenotypes to the New Histological WHO 2015 Classification
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2017 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 12, no 8, p. 1257-1267Article in journal (Refereed) Published
Abstract [en]

Introduction: Large cell lung cancer (LCLC) and large cell neuroendocrine carcinoma (LCNEC) constitute a small proportion of NSCLC. The WHO 2015 classification guidelines changed the definition of the debated histological subtype LCLC to be based on immunomarkers for adenocarcinoma and squamous cancer. We sought to determine whether these new guidelines also translate into the transcriptional landscape of lung cancer, and LCLC specifically.

Methods: Gene expression profiling was performed by using Illumina V4 HT12 microarrays (Illumina, San Diego, CA) on samples from 159 cases (comprising all histological subtypes, including 10 classified as LCLC WHO 2015 and 14 classified as LCNEC according to the WHO 2015 guidelines), with complimentary mutational and immunohistochemical data. Derived transcriptional phenotypes were validated in 199 independent tumors, including six WHO 2015 LCLCs and five LCNECs.

Results: Unsupervised analysis of gene expression data identified a phenotype comprising 90% of WHO 2015 LCLC tumors, with characteristics of poorly differentiated proliferatiVe cancer, a 90% tumor protein p53 gene (TP53) mutation rate, and lack of well-known NSCLC oncogene driver alterations. Validation in independent data confirmed aggregation of WHO 2015 LCLCs in the specific phenotype. For LCNEC tumors, the unsupervised gene expression analysis suggested two different transcriptional patterns corresponding to a proposed genetic division of LCNEC tumors into SCLC-like and NSCLC-like cancer on the basis of TP53 and retinoblastoma 1 gene (RB1) alteration patterns.

Conclusions: Refined classification of LCLC has implications for diagnosis, prognostics, and therapy decisions. Our molecular analyses support the WHO 2015 classification of LCLC and LCNEC tumors, which herein follow different tumorigenic paths and can accordingly be stratified into different transcriptional subgroups, thus linking diagnostic immunohistochemical staining driven classification with the transcriptional landscape of lung cancer.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC, 2017
Keywords
Lung cancer, Large cell lung carcinoma, LCNEC, Mutation, Gene expression, WHO classification
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-333713 (URN)10.1016/j.jtho.2017.05.008 (DOI)000407187400009 ()28535939 (PubMedID)
Funder
Swedish Cancer SocietyGunnar Nilsson Cancer FoundationThe Crafoord FoundationKing Gustaf V Jubilee Fund
Available from: 2017-11-21 Created: 2017-11-21 Last updated: 2018-02-01Bibliographically approved
Jabs, V., Edlund, K., Koenig, H., Grinberg, M., Madjar, K., Rahnenfuehrer, J., . . . Micke, P. (2017). Integrative analysis of genome-wide gene copy number changes and gene expression in non-small cell lung cancer. PLoS ONE, 12(11), Article ID e0187246.
Open this publication in new window or tab >>Integrative analysis of genome-wide gene copy number changes and gene expression in non-small cell lung cancer
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 11, article id e0187246Article in journal (Refereed) Published
Abstract [en]

Non-small cell lung cancer (NSCLC) represents a genomically unstable cancer type with extensive copy number aberrations. The relationship of gene copy number alterations and subsequent mRNA levels has only fragmentarily been described. The aim of this study was to conduct a genome-wide analysis of gene copy number gains and corresponding gene expression levels in a clinically well annotated NSCLC patient cohort (n = 190) and their association with survival. While more than half of all analyzed gene copy number-gene expression pairs showed statistically significant correlations (10,296 of 18,756 genes), high correlations, with a correlation coefficient >0.7, were obtained only in a subset of 301 genes (1.6%), including KRAS, EGFR and MDM2. Higher correlation coefficients were associated with higher copy number and expression levels. Strong correlations were frequently based on few tumors with high copy number gains and correspondingly increased mRNA expression. Among the highly correlating genes, GO groups associated with posttranslational protein modifications were particularly frequent, including ubiquitination and neddylation. In a meta-analysis including 1,779 patients we found that survival associated genes were overrepresented among highly correlating genes (61 of the 301 highly correlating genes, FDR adjusted p<0.05). Among them are the chaperone CCT2, the core complex protein NUP107 and the ubiquitination and neddylation associated protein CAND1. In conclusion, in a comprehensive analysis we described a distinct set of highly correlating genes. These genes were found to be overrepresented among survival-associated genes based on gene expression in a large collection of publicly available datasets.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-341934 (URN)10.1371/journal.pone.0187246 (DOI)000414572100012 ()29112949 (PubMedID)
Available from: 2018-02-16 Created: 2018-02-16 Last updated: 2018-02-16Bibliographically approved
Horie, M., Kaczkowski, B., Ohshima, M., Matsuzaki, H., Noguchi, S., Mikami, Y., . . . Nagase, T. (2017). Integrative CAGE and DNA Methylation Profiling Identify Epigenetically Regulated Genes in NSCLC. Molecular Cancer Research, 15(10), 1354-1365
Open this publication in new window or tab >>Integrative CAGE and DNA Methylation Profiling Identify Epigenetically Regulated Genes in NSCLC
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2017 (English)In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 15, no 10, p. 1354-1365Article in journal (Refereed) Published
Abstract [en]

Lung cancer is the leading cause of cancer-related deaths worldwide. The majority of cancer driver mutations have been identified; however, relevant epigenetic regulation involved in tumorigenesis has only been fragmentarily analyzed. Epigenetically regulated genes have a great theranostic potential, especially in tumors with no apparent driver mutations. Here, epigenetically regulated genes were identified in lung cancer by an integrative analysis of promoter-level expression profiles from Cap Analysis of Gene Expression (CAGE) of 16 nonsmall cell lung cancer (NSCLC) cell lines and 16 normal lung primary cell specimens with DNA methylation data of 69 NSCLC cell lines and 6 normal lung epithelial cells. A core set of 49 coding genes and 10 long noncoding RNAs (lncRNA), which are upregulated in NSCLC cell lines due to promoter hypomethylation, was uncovered. Twenty-two epigenetically regulated genes were validated (upregulated genes with hypomethylated promoters) in the adenocarcinoma and squamous cell cancer subtypes of lung cancer using The Cancer Genome Atlas data. Furthermore, it was demonstrated that multiple copies of the REP522 DNA repeat family are prominently upregulated due to hypomethylation in NSCLC cell lines, which leads to cancer-specific expression of lncRNAs, such as RP1-90G24.10, AL022344.4, and PCAT7. Finally, Myeloma Overexpressed (MYEOV) was identified as the most promising candidate. Functional studies demonstrated that MYEOV promotes cell proliferation, survival, and invasion. Moreover, high MYEOV expression levels were associated with poor prognosis. (C) 2017 AACR.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 2017
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-337081 (URN)10.1158/1541-7786.MCR-17-0191 (DOI)000412161400006 ()28698358 (PubMedID)
Available from: 2018-02-01 Created: 2018-02-01 Last updated: 2018-02-01Bibliographically approved
Brunnstrom, H., Johansson, A., Westbom-Fremer, S., Backman, M., Djureinovic, D., Patthey, A., . . . Micke, P. (2017). PD-L1 immunohistochemistry in clinical diagnostics of lung cancer: inter-pathologist variability is higher than assay variability. Modern Pathology, 30(10), 1411-1421
Open this publication in new window or tab >>PD-L1 immunohistochemistry in clinical diagnostics of lung cancer: inter-pathologist variability is higher than assay variability
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2017 (English)In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 30, no 10, p. 1411-1421Article in journal (Refereed) Published
Abstract [en]

Assessment of programmed cell death ligand 1 (PD-L1) immunohistochemical staining is used for decision on treatment with programmed cell death 1 and PD-L1 checkpoint inhibitors in lung adenocarcinomas and squamous cell carcinomas. This study aimed to compare the staining properties of tumor cells between the antibody clones 28-8, 22C3, SP142, and SP263 and investigate interrater variation between pathologists to see if these stainings can be safely evaluated in the clinical setting. Using consecutive sections from a tissue microarray with tumor tissue from 55 resected lung cancer cases, staining with five PD-L1 assays (28-8 from two different vendors, 22C3, SP142, and SP263) was performed. Seven pathologists individually evaluated the percentage of positive tumor cells, scoring each sample applying cutoff levels used in clinical studies: < 1% positive tumor cells (score 0), 1-4% (score 1), 5-9% (score 2), 10-24% (score 3), 25-49% (score 4), and > 50% positive tumor cells (score 5). Pairwise analysis of antibody clones showed weighted kappa values in the range of 0.45-0.91 with the highest values for comparisons with 22C3 and 28-8 and the lowest involving SP142. Excluding SP142 resulted in kappa 0.75-0.91. Weighted kappa for interobserver variation between pathologists was 0.71-0.96. Up to 20% of the cases were differently classified as positive or negative by any pathologist compared with consensus score using >= 1% positive tumor cells as cutoff. A significantly better agreement between pathologists was seen using >= 50% as cutoff (0-5% of cases). In conclusion, the concordance between the PD-L1 antibodies 22C3, 28-8 and SP263 is relatively good when evaluating lung cancers and suggests that any one of these assays may be sufficient as basis for decision on treatment with nivolumab, pembrolizumab, and durvalumab. The scoring of the pathologist presents an intrinsic source of error that should be considered especially at low PD-L1 scores.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-337074 (URN)10.1038/modpathol.2017.59 (DOI)000412100400007 ()28664936 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2018-02-02 Created: 2018-02-02 Last updated: 2018-02-02Bibliographically approved
Rao, S., Sigl, V., Wimmer, R. A., Novatchkova, M., Jais, A., Wagner, G., . . . Penninger, J. (2017). RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer. Genes & Development, 31(20), 2099-2112
Open this publication in new window or tab >>RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer
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2017 (English)In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 31, no 20, p. 2099-2112Article in journal (Refereed) Published
Abstract [en]

Lung cancer is the leading cause of cancer deaths. Besides smoking, epidemiological studies have linked female sex hormones to lung cancer in women; however, the underlying mechanisms remain unclear. Here we report that the receptor activator of nuclear factor-kB (RANK), the key regulator of osteoclastogenesis, is frequently expressed in primary lung tumors, an active RANK pathway correlates with decreased survival, and pharmacologic RANK inhibition reduces tumor growth in patient-derived lung cancer xenografts. Clonal genetic inactivation of KRas(G12D) in mouse lung epithelial cells markedly impairs the progression of KRas(G12D)-driven lung cancer, resulting in a significant survival advantage. Mechanistically, RANK rewires energy homeostasis in human and murine lung cancer cells and promotes expansion of lung cancer stem-like cells, which is blocked by inhibiting mitochondrial respiration. Our data also indicate survival differences in KRas(G12D)-driven lung cancer between male and female mice, and we show that female sex hormones can promote lung cancer progression via the RANK pathway. These data uncover a direct role for RANK in lung cancer and may explain why female sex hormones accelerate lung cancer development. Inhibition of RANK using the approved drug denosumab may be a therapeutic drug candidate for primary lung cancer.

Keywords
RANK, energy homeostasis, lung cancer, lung cancer stem-like cells
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-342920 (URN)10.1101/gad.304162.117 (DOI)000415923700007 ()29118048 (PubMedID)
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-02-26Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-1210-5961

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