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      Drug Resistance in Non-Small Cell Lung Cancer: A Potential for NOTCH Targeting?

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          Abstract

          Drug resistance is a major cause for therapeutic failure in non-small cell lung cancer (NSCLC) leading to tumor recurrence and disease progression. Cell intrinsic mechanisms of resistance include changes in the expression of drug transporters, activation of pro-survival, and anti-apoptotic pathways, as well as non-intrinsic influences of the tumor microenvironment. It has become evident that tumors are composed of a heterogeneous population of cells with different genetic, epigenetic, and phenotypic characteristics that result in diverse responses to therapy, and underlies the emergence of resistant clones. This tumor heterogeneity is driven by subpopulations of tumor cells termed cancer stem cells (CSCs) that have tumor-initiating capabilities, are highly self-renewing, and retain the ability for multi-lineage differentiation. CSCs have been identified in NSCLC and have been associated with chemo- and radiotherapy resistance. Stem cell pathways are frequently deregulated in cancer and are implicated in recurrence after treatment. Here, we focus on the NOTCH signaling pathway, which has a role in stem cell maintenance in non-squamous non-small lung cancer, and we critically assess the potential for targeting the NOTCH pathway to overcome resistance to chemotherapeutic and targeted agents using both preclinical and clinical evidence.

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          Identification and expansion of the tumorigenic lung cancer stem cell population.

          Lung carcinoma is often incurable and remains the leading cancer killer in both men and women. Recent evidence indicates that tumors contain a small population of cancer stem cells that are responsible for tumor maintenance and spreading. The identification of the tumorigenic population that sustains lung cancer may contribute significantly to the development of effective therapies. Here, we found that the tumorigenic cells in small cell and non-small cell lung cancer are a rare population of undifferentiated cells expressing CD133, an antigen present in the cell membrane of normal and cancer-primitive cells of the hematopoietic, neural, endothelial and epithelial lineages. Lung cancer CD133(+) cells were able to grow indefinitely as tumor spheres in serum-free medium containing epidermal growth factor and basic fibroblast growth factor. The injection of 10(4) lung cancer CD133(+) cells in immunocompromised mice readily generated tumor xenografts phenotypically identical to the original tumor. Upon differentiation, lung cancer CD133(+) cells acquired the specific lineage markers, while loosing the tumorigenic potential together with CD133 expression. Thus, lung cancer contains a rare population of CD133(+) cancer stem-like cells able to self-renew and generates an unlimited progeny of non-tumorigenic cells. Molecular and functional characterization of such a tumorigenic population may provide valuable information to be exploited in the clinical setting.
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            Cancer. Addiction to oncogenes--the Achilles heal of cancer.

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              Characterizing the cancer genome in lung adenocarcinoma.

              Somatic alterations in cellular DNA underlie almost all human cancers. The prospect of targeted therapies and the development of high-resolution, genome-wide approaches are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in approximately 12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                24 July 2018
                2018
                : 8
                Affiliations
                Department of Radiation Oncology, GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC) , Maastricht, Netherlands
                Author notes

                Edited by: Ala-Eddin Al Moustafa, Qatar University, Qatar

                Reviewed by: Gabriele Multhoff, Technische Universität München, Germany; Lie-Fen Shyur, Agricultural Biotechnology Research Center, Academia Sinica, Taiwan

                *Correspondence: Marc Vooijs, marc.vooijs@ 123456maastrichtuniversity.nl

                These authors have contributed equally to this work.

                Specialty section: This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2018.00267
                6066509
                Copyright © 2018 Sosa Iglesias, Giuranno, Dubois, Theys and Vooijs.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 1, Tables: 7, Equations: 0, References: 209, Pages: 23, Words: 18457
                Funding
                Funded by: FP7 Ideas: European Research Council 10.13039/100011199
                Award ID: 617060
                Funded by: Association for International Cancer Research 10.13039/501100000391
                Award ID: 1311-97
                Funded by: H2020 Marie Skłodowska-Curie Actions 10.13039/100010665
                Award ID: 642623
                Categories
                Oncology
                Review

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