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      Cancer germline gene activation : Friend or foe?

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          Abstract

          The human male germ line is passed on via the production of haploid sperm, which, upon fusion with the female gamete, the ovum, will form a diploid zygote that will ultimately become a genetically unique individual. Male gametogenesis occurs throughout the lifespan of adult males. Sperm production is restricted to the seminiferous tubules of the testis, and this process is continually fed by the mitotic proliferation of germline stem cells (GSCs). The GSCs are a sub-group of spermatagonial cells, which are found at the basal layer of the seminiferous tubules. Upon receipt of differentiation signals, spermatagonial cells will undergo differentiation, first maturing to primary spermatocytes and then ultimately through to fully differentiated spermatozoa. During this cellular differentiation, meiosis occurs, reducing the chromosomal content from diploid to haploid status and driving genetic variation. Spermatagonial stem cell maintenance, spermatogenic cellular differentiation, and the reductional chromosome segregation of meiosis requires an array of molecular orchestrators that are unique to the germline, and there are a large number of genes that are specifically activated to regulate distinct processes within the spermatogenic program. These genes are regulated in a highly restricted tissue-specific fashion, and many are tightly silenced in somatic tissues. Male germline genes have been reported to be activated in cancers and can encode antigens known as the cancer/testis antigens (CTAs). 1 CTAs have garnered much interest, as their tight cancer-restricted profile makes them important potential targets for cancer immunotherapies and as diagnostic and prognostic markers; 1 indeed, recent seminal work has also demonstrated that specific assessment of germline gene expression profiles in tumors can be used for highly accurate prognostic stratification in cancer patients. 2 Most of the originally identified CTA genes (also referred to as CT genes if an associated antigen has not yet been demonstrated) are encoded by large paralogous gene families located on the X chromosome. The X chromosome becomes inactivated on entry into meiosis, however, leading Feichtinger and coworkers 3 , 4 to speculate that there may be a substantial number of additional genes encoding meiosis-specific proteins that could potentially serve as clinically and functionally important factors. Through the meta-analysis of clinical cancer gene expression data sets performed by this group, the CT gene family has now been extended to encompass many more single-copy, autosomally encoded genes. 3 , 4 Aside from the unquestionably important potential for clinical application as biomarkers and immunotherapeutic targets, CTA/meiosis-associated genes and their products pose a bigger question that could ultimately reveal a previously unidentified weakness of cancer cells that may provide new therapeutic opportunities. There is increasing evidence supporting the view that CT genes are not simply passively activated as a byproduct of the oncogenic process, and there is a growing consensus that CT genes can actually drive oncogenesis and tumor drug resistance. This is illustrated by 2 additional seminal studies. First Janic and coworkers 5 demonstrated that germline genes were activated in l(3)mbt tumors in Drosophila melanogaster, and that some of these were required to promote tumor formation; subsequent meta-analysis of human cancer gene expression data sets by Feichtinger and colleagues 6 indicated that the human orthologs of the these germline genes were also extensively activated in a wide range of human tumors, inferring that an oncogenic soma-to-germline transition could be a feature of many human cancers. Second, in a distinct seminal study by Whitehurst and coworkers 7 that aimed to identify genes that de-sensitized lung cancer cells to the microtubule-stabilizing chemotherapeutic agent paclitaxel, a number of CTA genes were found to be capable of driving chemoresistance, indicating germline genes contribute to therapeutic resistance. Not only do these studies demonstrate that germline genes are important in driving the oncogenic process, it also reveals a new class of therapeutically targetable molecules, the extent and potential of which remains very poorly explored. The proposal that a soma-to-germline transition is occurring in human cancers to drive oncogenic mitotic proliferation of cells in the soma may infer that activation of a multitude of germline genes is required. However, the evidence to support an extensive co-activation remains weak. It is possible, even likely, that the activation of one or a few key regulatory CT genes can contribute to oncogenesis in the absence of extensive germline program activation. Moreover, it is likely that distinct germline gene functions serve to contribute to distinct features of tumor progression and survival. While there are now many detailed questions to be addressed, it is clear that oncogenesis involves the loosening of the constraints on expression of not only X encoded germline genes, but also of the large cohort of meiosis-associated genes identified by Feichtinger and coworkers 3 , 4 that are autosomally encoded. Activation of meiotic functions, including programmed inter-homolog recombination and reductional chromosome segregation pathways mediated by centromeric monopolarity, in somatic cells clearly has the potential to disturb somatic cellular genetic homeostasis and provide the factors to drive the genetic instability and tumor heterogeneity that is required for oncogenic progression and therapeutic resistance.

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          Most cited references7

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          Ectopic activation of germline and placental genes identifies aggressive metastasis-prone lung cancers.

          Activation of normally silent tissue-specific genes and the resulting cell "identity crisis" are the unexplored consequences of malignant epigenetic reprogramming. We designed a strategy for investigating this reprogramming, which consisted of identifying a large number of tissue-restricted genes that are epigenetically silenced in normal somatic cells and then detecting their expression in cancer. This approach led to the demonstration that large-scale "off-context" gene activations systematically occur in a variety of cancer types. In our series of 293 lung tumors, we identified an ectopic gene expression signature associated with a subset of highly aggressive tumors, which predicted poor prognosis independently of the TNM (tumor size, node positivity, and metastasis) stage or histological subtype. The ability to isolate these tumors allowed us to reveal their common molecular features characterized by the acquisition of embryonic stem cell/germ cell gene expression profiles and the down-regulation of immune response genes. The methodical recognition of ectopic gene activations in cancer cells could serve as a basis for gene signature-guided tumor stratification, as well as for the discovery of oncogenic mechanisms, and expand the understanding of the biology of very aggressive tumors.
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            Synthetic lethal screen identification of chemosensitizer loci in cancer cells.

            Abundant evidence suggests that a unifying principle governing the molecular pathology of cancer is the co-dependent aberrant regulation of core machinery driving proliferation and suppressing apoptosis. Anomalous proteins engaged in support of this tumorigenic regulatory environment most probably represent optimal intervention targets in a heterogeneous population of cancer cells. The advent of RNA-mediated interference (RNAi)-based functional genomics provides the opportunity to derive unbiased comprehensive collections of validated gene targets supporting critical biological systems outside the framework of preconceived notions of mechanistic relationships. We have combined a high-throughput cell-based one-well/one-gene screening platform with a genome-wide synthetic library of chemically synthesized small interfering RNAs for systematic interrogation of the molecular underpinnings of cancer cell chemoresponsiveness. NCI-H1155, a human non-small-cell lung cancer line, was employed in a paclitaxel-dependent synthetic lethal screen designed to identify gene targets that specifically reduce cell viability in the presence of otherwise sublethal concentrations of paclitaxel. Using a stringent objective statistical algorithm to reduce false discovery rates below 5%, we isolated a panel of 87 genes that represent major focal points of the autonomous response of cancer cells to the abrogation of microtubule dynamics. Here we show that several of these targets sensitize lung cancer cells to paclitaxel concentrations 1,000-fold lower than otherwise required for a significant response, and we identify mechanistic relationships between cancer-associated aberrant gene expression programmes and the basic cellular machinery required for robust mitotic progression.
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              Ectopic expression of germline genes drives malignant brain tumor growth in Drosophila.

              Model organisms such as the fruit fly Drosophila melanogaster can help to elucidate the molecular basis of complex diseases such as cancer. Mutations in the Drosophila gene lethal (3) malignant brain tumor cause malignant growth in the larval brain. Here we show that l(3)mbt tumors exhibited a soma-to-germline transformation through the ectopic expression of genes normally required for germline stemness, fitness, or longevity. Orthologs of some of these genes were also expressed in human somatic tumors. In addition, inactivation of any of the germline genes nanos, vasa, piwi, or aubergine suppressed l(3)mbt malignant growth. Our results demonstrate that germline traits are necessary for tumor growth in this Drosophila model and suggest that inactivation of germline genes might have tumor-suppressing effects in other species.
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                Author and article information

                Journal
                Cell Cycle
                Cell Cycle
                CC
                Cell Cycle
                Landes Bioscience
                1538-4101
                1551-4005
                15 July 2014
                23 June 2014
                15 July 2015
                : 13
                : 14
                : 2151-2152
                Affiliations
                [1 ]North West Cancer Research Institute; Bangor University; Bangor, UK
                [2 ]Institute for Knowledge Discovery; Graz University of Technology; Graz, Austria
                [3 ]Core Facility Bioinformatics; Austrian Centre of Industrial Biotechnology; Graz, Austria
                [4 ]MRC Functional Genomics Unit; Department of Physiology, Anatomy and Genetics; University of Oxford; Oxford; UK
                Author notes
                [* ]Correspondence to: Ramsay J McFarlane, Email: r.macfarlane@ 123456bangor.ac.uk
                Article
                2014FT1206 29661
                10.4161/cc.29661
                4111666
                25111983
                b31b27d4-f335-487c-85c5-16131c088b01
                Copyright © 2014 Landes Bioscience

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                : 18 June 2014
                : 19 June 2014
                Categories
                Editorials: Cell Cycle Features

                Cell biology
                cancer/testis antigen,meiosis,germline,oncogenesis,drug resistance
                Cell biology
                cancer/testis antigen, meiosis, germline, oncogenesis, drug resistance

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