Oncoscience最新文献

{"title":"Kinetochore-microtube attachments in cancer therapy","authors":"D. Del Bufalo, F. Degrassi","doi":"10.18632/ONCOSCIENCE.265","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.265","url":null,"abstract":"The process of cell division represents an extraordinary target to develop antitumor therapies. Indeed, a large number of clinically relevant anti-cancer drugs, such as taxanes and vinca alkaloids, target mitosis by stimulating or inhibiting microtubule (MT) polymerization. During the past decades anti-tubulin drugs have proven very effective against a wide range of tumors. However, collateral effects, such as myelosuppression and MT disruption in non-dividing tissues, including brain, are common. Recently, the increased understanding of the cell division process and the identification of several signaling pathways controlling mitosis have provided novel opportunities for cancer drug discovery. Consequently, mitotic proteins have become attractive targets to develop molecular cancer therapeutics. In this scenario, kinetochores (KTs) represent an attractive therapeutic target in light of their fundamental role in driving chromosome segregation and controlling chromosome segregation errors. Indeed, cells require a fine regulation of the kinetochore-microtubule (KT-MT) attachment stability to prevent chromosome instability, and KT-MT attachment dynamics is often deregulated in tumour cells [2]. Chromosome instability is commonly accepted as a driving force in the development of cancer, but more recent work has demonstrated that extensive chromosome missegregation may be detrimental to cancer cells and act as a tumor suppression mechanism [3]. In light of this double role of chromosome instability in cancer, we have explored the hypothesis that interfering with KT-MT attachment dynamics could drive massive chromosome missegregation and kill tumor cells. Highly Expressed in Cancer protein 1 (Hec1) is a constituent of the evolutionary conserved Ndc80 complex, the molecular connector between KTs and MTs. Among the subunits of the Ndc80 complex, Hec1 directly interacts with MTs and regulates KT-MT dynamics and attachment stability [3]. Importantly, Hec1 is frequently overexpressed in cancer. We previously demonstrated that expression of Hec1 fused with the enhanced green fluorescent protein (EGFP) tag at its N-terminus (EGFP-Hec1), the protein domain that regulates MT attachment dynamics, led to a strong accumulation of this modified protein, which acted as a dominant negative mutant over the endogenous Hec1. Mitotic cells expressing a N-terminus tagged Hec1 accumulated lateral KT-MT attachments and underwent a spindle assembly checkpoint (SAC) dependent mitotic arrest associated with the formation of multipolar spindles [4]. We further showed that expression of an inducible N-terminus modified Hec1 completely abolished in vitro growth of EGFP-Hec1 expressing HeLa cells but had no effects on untransformed human fibroblasts or epithelial cells [5]. These in vitro cell-based data were validated in vivo by showing that inducible EGFP-Hec1 expression strongly inhibited tumor growth in a HeLa xenograft mouse model [5]. Strikingly, in both in vitro and in vivo","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"43 1","pages":"902 - 903"},"PeriodicalIF":0.0,"publicationDate":"2015-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82653381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Snail1 controls cooperative cell plasticity during metastasis","authors":"J. Baulida","doi":"10.18632/ONCOSCIENCE.262","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.262","url":null,"abstract":"Mortality in cancer is strongly associated with the capacity of tumor cells to spread and critically affect other tissues and organs. Genetic mutations accumulated by tumor cells and cross-signaling between tumor and host cells underlie the formation of metastasis. Cancer-activated fibroblasts (CAFs), which are host fibroblasts activated by tumor signaling, can alter tumor cell behavior by both paracrine signaling (secreting diffusible molecules) and mechanical signaling (modifying the composition and organization of the stroma). These fibroblasts resemble myofibroblasts (MFs) of the granulation tissue generated during wound healing, which produce a rigid desmoplastic stroma rich in signaling molecules and cross-linked extracellular fibers. Desmoplasia favors malignant tumor cell properties such as mobility, stemness, and even resistance to pharmacological insults [1].","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"33 1","pages":"898 - 899"},"PeriodicalIF":0.0,"publicationDate":"2015-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73297482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NETosis in cancer","authors":"J. Cedervall, A. Olsson","doi":"10.18632/ONCOSCIENCE.264","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.264","url":null,"abstract":"A large proportion of cancer-related deaths are caused by thrombosis and general organ failure. Although the awareness of tumor-induced systemic effects has increased significantly in recent years, current knowledge is still mainly restricted to metastatic sites. Surprisingly little is known about the situation in organs that are not targets for metastasis or directly affected by the primary tumor. We therefore decided to look deeper into this relatively unexplored field of cancer research. For obvious reasons human biopsy material from tissues not affected by tumor cells, in an individual with cancer, are rare and mouse models therefore become important tools for such investigations. Using two different orthotopic and spontaneously metastasizing tumor models - the RIP1-Tag2 model for insulinoma with metastasis to the liver and the MMTV-PyMT model for mammary carcinoma with lung metastasis - we analyzed the presence of hematopoietic cells in organs which do not represent sites for primary tumor growth. There was a significant increase in the number of neutrophils in heart and kidneys of tumor-bearing mice compared to healthy individuals [1]. In mice with cancer, peripheral organs displayed systemic inflammation and impaired vascular function, which was restored upon neutrophil depletion. Platelet/neutrophil complexes, indicative of neutrophil extracellular traps (NETs), were found in kidney and heart from tumor-bearing mice, while these complexes were completely absent in the corresponding tissues from healthy mice. Indeed, analysis of peripheral blood confirmed the presence of neutrophils with extracellular DNA-tails in tumor-bearing mice.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"4 1","pages":"900 - 901"},"PeriodicalIF":0.0,"publicationDate":"2015-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90189648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A pivotal role for HOXB7 protein in endocrine resistant breast cancer","authors":"Kideok Jin, S. Sukumar","doi":"10.18632/ONCOSCIENCE.263","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.263","url":null,"abstract":"HOXB7 is a homeodomain containing transcription factor which plays a pivotal role in tamoxifen resistant breast cancer. Our work has shown that overexpression of HOXB7 renders cells tamoxifen resistant by mobilizing a number of receptor tyrosine kinase pathways. EGFR expression is upregulated by direct binding of HOXB7 to the EGFR promoter, while HOXB7 functions as a cofactor with ERα to cause overexpression of multiple ER-target genes, including HER2, in tamoxifen resistant breast cancer cells. Probing the pathway further, we found that miR-196a and MYC are upstream regulators of HOXB7 expression. Mechanistically, HOXB7 and ERα jointly upregulate HER2 which phosphorylates MYC. Thus stabilized, MYC in turn suppresses miR-196a. Loss of miR-196a results lifts the quelling influence of miR-196a on HOXB7 expression. Besides shedding light on the intricate interplay of events occurring in tamoxifen resistant breast cancer, the work identifies a number of new therapeutic targets capable of restoring sensitivity of breast cancer cells to tamoxifen.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"1 1","pages":"917 - 919"},"PeriodicalIF":0.0,"publicationDate":"2015-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89546764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New alternative splicing BCR/ABL-OOF shows an oncogenic role by lack of inhibition of BCR GTPase activity and an increased of persistence of Rac activation in chronic myeloid leukemia","authors":"C. Panuzzo, G. Volpe, E. C. Rocchietti, C. Casnici, K. Crotta, S. Crivellaro, Giovanna Carrá, Roberta Lorenzatti, Barbara Peracino, Davide Torti, A. Morotti, M. P. Camacho-Leal, P. Defilippi, O. Marelli, G. Saglio","doi":"10.18632/ONCOSCIENCE.260","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.260","url":null,"abstract":"In Chronic Myeloid Leukemia 80% of patients present alternative splice variants involving BCR exons 1, 13 or 14 and ABL exon 4, with a consequent impairment in the reading frame of the ABL gene. Therefore BCR/ABL fusion proteins (BCR/ABL-OOF) are characterized by an in-frame BCR portion followed by an amino acids sequence arising from the out of frame (OOF) reading of the ABL gene. The product of this new transcript contains the characteristic BCR domains while lacking the COOH-terminal Rho GTPase GAP domain. The present work aims to characterize the protein functionality in terms of cytoskeleton (re-)modelling, adhesion and activation of canonical oncogenic signalling pathways. Here, we show that BCR/ABL-OOF has a peculiar endosomal localization which affects EGF receptor activation and turnover. Moreover, we demonstrate that BCR/ABL-OOF expression leads to aberrant cellular adhesion due to the activation of Rac GTPase, increase in cellular proliferation, migration and survival. When overexpressed in a BCR/ABL positive cell line, BCR/ABL-OOF induces hyperactivation of Rac signaling axis offering a therapeutic window for Rac-targeted therapy. Our data support a critical role of BCR/ABL-OOF in leukemogenesis and identify a subset of patients that may benefit from Rac-targeted therapies.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"124 1","pages":"880 - 891"},"PeriodicalIF":0.0,"publicationDate":"2015-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76223000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A ceRNA approach may unveil unexpected contributors to deletion syndromes, the model of 5q- syndrome","authors":"W. Arancio, S. Genovese, L. Bongiovanni, C. Tripodo","doi":"10.18632/ONCOSCIENCE.261","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.261","url":null,"abstract":"In genomic deletions, gene haploinsufficiency might directly configure a specific disease phenotype. Nevertheless, in some cases no functional association can be identified between haploinsufficient genes and the deletion-associated phenotype. Transcripts can act as microRNA sponges. The reduction of transcripts from the hemizygous region may increase the availability of specific microRNAs, which in turn may exert in-trans regulation of target genes outside the deleted region, eventually contributing to the phenotype. Here we prospect a competing endogenous RNA (ceRNA) approach for the identification of candidate genes target of epigenetic regulation in deletion syndromes. As a model, we analyzed the 5q- myelodysplastic syndrome. Genes in haploinsufficiency within the common 5q deleted region in CD34+ blasts were identified in silico. Using the miRWalk 2.0 platform, we predicted microRNAs whose availability, and thus activity, could be enhanced by the deletion, and performed a genomewide analysis of the genes outside the 5q deleted region that could be targeted by the predicted miRNAs. The analysis pointed to two genes with altered expression in 5q- transcriptome, which have never been related with 5q- before. The prospected approach allows investigating the global transcriptional effect of genomic deletions, possibly prompting discovery of unsuspected contributors in the deletion-associated phenotype. Moreover, it may help in functionally characterizing previously reported unexpected interactions.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"129 1","pages":"872 - 879"},"PeriodicalIF":0.0,"publicationDate":"2015-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76938055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective amino acid restriction therapy (SAART): a non-pharmacological strategy against all types of cancer cells","authors":"M. López-Lázaro","doi":"10.18632/ONCOSCIENCE.258","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.258","url":null,"abstract":"Metastasis will continue to be an incurable disease for most patients until we develop highly selective anticancer therapies. The development of these therapies requires finding and exploiting major differences between cancer cells and normal cells. Although the sum of the many DNA alterations of cancer cells makes up such a major difference, there is currently no way of exploiting these alterations as a whole. Here I propose a non-pharmacological strategy to selectively kill any type of cancer cell, including cancer stem cells, by exploiting their complete set of DNA alterations. It is based on creating challenging environmental conditions that only cells with undamaged DNAs can overcome. Cell survival requires continuous protein synthesis, which in turn requires adequate levels of 20 amino acids (AAs). If we temporarily restrict specific AAs and keep high levels of others whose deficit triggers proteolysis, we will force cells to activate a variety of genetic programs to obtain adequate levels of each of the 20 proteinogenic AAs. Because cancer cells have an extremely altered DNA that has evolved under particular environmental conditions, they may be unable to activate the genetic programs required to adapt to and survive the new environment. Cancer patients may be successfully treated with a protein-free artificial diet in which the levels of specific AAs are manipulated. Practical considerations for testing and implementing this cheap and universal anticancer strategy are discussed.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"33 1","pages":"857 - 866"},"PeriodicalIF":0.0,"publicationDate":"2015-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86821104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conserved E2F mediated metastasis in mouse models of breast cancer and HER2 positive patients","authors":"J. Rennhack, E. Andrechek","doi":"10.18632/ONCOSCIENCE.259","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.259","url":null,"abstract":"To improve breast cancer patient outcome work must be done to understand and block tumor metastasis. This study leverages bioinformatics techniques and traditional genetic screens to create a novel method of discovering potential contributors of tumor progression with a focus on tumor metastasis. A database of 1172 of expression data from a variety of mouse models of breast cancer was assembled and queried using previously defined oncogenic activity signatures. This analysis revealed high activity of the E2F family of transcription factors in the MMTV-Neu mouse model. A genetic cross of MMTV-Neu mice into an E2F1 null, E2F2 null, or E2F3 heterozygous background revealed significant changes in tumor progression specifically reductions in tumor latency and metastasis with E2F1 or E2F2 loss. These findings were found to be conserved in human HER2 positive patients. Patients with high E2F1 activity were shown to have worse outcomes such as relapse free survival and distant metastasis free survival. This study shows conserved mechanisms of tumor progression in human breast cancer subtypes and analogous mouse models and underlies the importance of increased research into the characterization of and comparisons between mouse and human tumors to identify which mouse models resemble each subtype of human breast cancer.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"246 1","pages":"867 - 871"},"PeriodicalIF":0.0,"publicationDate":"2015-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72759541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding why aspirin prevents cancer and why consuming very hot beverages and foods increases esophageal cancer risk. Controlling the division rates of stem cells is an important strategy to prevent cancer","authors":"M. López-Lázaro","doi":"10.18632/ONCOSCIENCE.257","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.257","url":null,"abstract":"Cancer is, in essence, a stem cell disease. The main biological cause of cancer is that stem cells acquire DNA alterations during cell division. The more stem cell divisions a tissue accumulates over a lifetime, the higher is the risk of cancer in that tissue. This explains why cancer is diagnosed millions of times more often in some tissues than in others, and why cancer incidence increases so dramatically with age. It may also explain why taking a daily low-dose aspirin for several years reduces the risk of developing and dying from cancer. Since aspirin use reduces PGE2 levels and PGE2 fuels stem cell proliferation, aspirin may prevent cancer by restricting the division rates of stem cells. The stem cell division model of cancer may also explain why regular consumption of very hot foods and beverages increases the risk of developing esophageal cancer. Given that tissue injury activates stem cell division for repair, the thermal injury associated with this dietary habit will increase esophageal cancer risk by inducing the accumulation of stem cell divisions in the esophagus. Using these two examples, here I propose that controlling the division rates of stem cells is an essential approach to preventing cancer.","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"28 1","pages":"849 - 856"},"PeriodicalIF":0.0,"publicationDate":"2015-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85203408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDK4/6 inhibitor: from quiescence to senescence","authors":"A. Yoshida, J. Diehl","doi":"10.18632/ONCOSCIENCE.256","DOIUrl":"https://doi.org/10.18632/ONCOSCIENCE.256","url":null,"abstract":"The CDK4 and CDK6 kinases (CDK4/6) are the first cyclin dependent kinases to be activated and initiate transition through G1 phase of the cell cycle. In response to mitogenic growth factors, the CDK4/6 kinase together with one of three D-type cyclins (D1, D2, D3) initiates G1 progression by virtue of its capacity to phosphorylate the retinoblastoma protein (RB), a bona fide tumor suppressor and Gate Keeper of cell division. Phosphorylation of RB in turn results in de-repression of E2F transcription factors thereby triggering expression of genes whose products drive S-phase entry and progression (1). Cyclin D1 dysregulation occurs in a majority of human cancers, a direct result of gene amplification or mutations that disrupt its protein degradation. CDK4 amplification or activating point mutations are also observed in select malignancies. The end result of such aberrations is elevated CDK4 catalytic function, increased cell division and decreased dependence on extracellular mitogenic growth factors for cell proliferation. These observations have contributed to significant efforts to develop selective small molecule CDK4/6 inhibitors with the hope that such entities would have significant anti-cancer benefit. PD0332991 (Palbociclib), a highly selective inhibitor of CDK4 (IC50: 0.011 μM) and CDK6 (IC50: 0.016 μM), has been shown to be highly efficacious in a variety of cell culture models with regard to its capacity to suppress cell cycle progression through inhibition of CDK4/6 kinase activity in an RB-dependent manner and it is currently being tested in clinical trials for malignancies such as mantle cell lymphoma, breast cancer, and colorectal cancer (2). \u0000 \u0000While acute inhibition of CDK4/6 is associated with reversible cell cycle withdraw or quiescence, some recent investigations have provided provocative evidence that Palbociclib treatment can in fact trigger irreversible withdraw, a state referred to as senescence (3, 4, 5). However the mechanisms that determine whether Palbociclib evokes quiescence versus senescence are yet to be established. In work described by Kovatcheva et al a new molecular mechanism wherein MDM2 and ATRX determine cell fate following CDK4/6 inhibition in cancer cells derived from several distinct cancer etiologies such as well-differentiated and dedifferentiated liposarcoma (WD/DDLS), lung cancer, and glioma (6). In this work, WD/DDLS cell lines were classified based upon cell fate following Palbociclib exposure: quiescence (non-responders) versus senescence (responders). While both groups had the expected reduction in RB phosphorylation, the responders also exhibited a significant decrease in MDM2 levels after prolonged CDK4 inhibition. Importantly, the phenotype is RB dependent, but is p53 and p16INK4a-independent. The capacity of MDM2 knock down to trigger senescence from quiescent phase in a combination with Palbociclib in non-responders, provides evidence that the reduction of MDM2 is in fact causative in the respo","PeriodicalId":94164,"journal":{"name":"Oncoscience","volume":"11 1","pages":"896 - 897"},"PeriodicalIF":0.0,"publicationDate":"2015-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89915379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}