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Cancer Research

Jinyou Liu, Gangadhara R Sareddy, Mei Zhou, Suryavathi Viswanadhapalli, Xiaonan Li, Zhao Lai, Rajeshwar R Tekmal, Andrew J Brenner, Ratna K Vadlamudi
The estrogen receptor beta (ERβ) functions as a tumor suppressor in glioblastoma cells (GBM). However, the in vivo significance of endogenous ERβ and the roles of its isoforms in GBM are incompletely understood. Using ERβ isoform-specific PCR screening, we found that GBM cells predominantly express ERβ1 and ERβ5, along with low levels of ERβ2 and ERβ4. We observed greater ERβ5 expression in higher grades of glioma than in lower grades. In CRISPR-based ERβ knockout (KO) cells and ERβ KO cells uniquely expressing ERβ1, ERβ1 significantly reduced proliferation...
April 16, 2018: Cancer Research
Julie K Allen, Guillermo N Armaiz-Pena, Archana S Nagaraja, Nouara C Sadaoui, Tatiana Ortiz, Robert Dood, Merve Ozcan, Danielle M Herder, Monika Haemerrle, Kshipra M Gharpure, Rajesha Rupaimoole, Rebecca Previs, Sherry Y Wu, Sunila Pradeep, Xiaoyun Xu, Hee Dong Han, Behrouz Zand, Heather J Dalton, Morgan Taylor, Wei Hu, Justin Bottsford-Miller, Myrthala Moreno-Smith, Yu Kang, Lingegowda S Mangala, Cristian Rodriguez-Aguayo, Vasudha Sehgal, Erika L Spaeth, Prahlad T Ram, Stephen Tc Wong, Frank C Marini, Gabriel Lopez-Berestein, Steve W Cole, Susan K Lutgendorf, Mariella diBiasi, Anil K Sood
Mounting clinical and preclinical evidence supports a key role for sustained adrenergic signaling in the tumor microenvironment as a driver of tumor growth and progression. However, the mechanisms by which adrenergic neurotransmitters are delivered to the tumor microenvironment are not well understood. Here we present evidence for a feedforward loop whereby adrenergic signaling leads to increased tumoral innervation. In response to catecholamines, tumor cells produced brain-derived neurotrophic factor (BDNF) in an ADRB3/cAMP/Epac/JNK-dependent manner...
April 16, 2018: Cancer Research
Sara García-Alonso, Alberto Ocaña, Atanasio Pandiella
Antibody-drug conjugates (ADC) are multicomponent molecules constituted by an antibody covalently linked to a potent cytotoxic agent. ADCs combine high target specificity provided by the antibody together with strong antitumoral properties provided by the attached cytotoxic agent. At present, four ADCs have been approved and over 60 are being explored in clinical trials. Despite their effectiveness, resistance to these drugs unfortunately occurs. Efforts to understand the bases underlying such resistance are being carried out with the final purpose of counteracting them...
April 13, 2018: Cancer Research
C Bryce Johnson, Bennett R May, Brian P Riesenberg, Samantha Suriano, Shikhar Mehrotra, Elizabeth Garret-Mayer, Mohamed L Salem, Emily K Jeng, Hing C Wong, Chrystal M Paulos, John Wrangle, David J Cole, Mark P Rubinstein
Effector CD8+ T cells conditioned with IL-12 during activation mediate enhanced antitumor efficacy after adoptive transfer into lymphodepleted hosts; this is due in part to improved IL-7 responsiveness. Therefore, we hypothesized that increasing the intensity or type of lymphodepletion would deplete more IL-7-consuming host cells and improve the persistence and antitumor activity of IL-12-conditioned CD8+ T cells. Using cyclophosphamide (CTX), fludarabine (FLU), and total body irradiation (TBI, 6 Gy) either individually or in combination, we found that combined lymphodepletion best enhanced T cell engraftment in mice...
April 10, 2018: Cancer Research
Kyle P Feeley, Mick D Edmonds
At the time of its construction in the 1950s, the central dogma of molecular biology was a useful model that represented the current state of knowledge for the flow of genetic information after a period of prolific scientific discovery. Unknowingly, it also biased many of our assumptions going forward. Whether intentional or not, genomic elements not fitting into this paradigm were deemed unimportant and emphasis on the study of protein-coding genes prevailed for decades. The phrase "Junk DNA," first popularized in the 1960s, is still used with alarming frequency to describe the entirety of noncoding DNA...
April 9, 2018: Cancer Research
Linda Resar, Lionel Chia, Lingling Xian
High mobility group A1 (HMGA1) chromatin remodeling proteins are enriched in aggressive cancers and stem cells, although their common function in these settings has remained elusive until now. Recent work in murine intestinal stem cells (ISC) revealed a novel role for Hmga1 in enhancing self-renewal by amplifying Wnt signaling, both by inducing genes expressing Wnt agonist receptors and Wnt effectors. Surprisingly, Hmga1 also "builds" a stem cell niche by upregulating Sox9 , a factor required for differentiation to Paneth cells; these cells constitute an epithelial niche by secreting Wnt and other factors to support ISCs...
April 4, 2018: Cancer Research
Willemijne Ame Schrijver, Pier Selenica, Ju Youn Lee, Charlotte K Y Ng, Kathleen Burke, Salvatore Piscuoglio, Samuel H Berman, Jorge S Reis-Filho, Britta Weigelt, Paul J Van Diest, Cathy B Moelans
Although the repertoire of somatic genetic alterations of primary breast cancers has been extensively catalogued, the genetic differences between primary and metastatic tumors have been less studied. In this study, we compared somatic mutations and gene copy number alterations of primary breast cancers and their matched metastases from patients with estrogen receptor (ER)-negative disease, with higher incidence of brain metastases than ER-positive/HER2-negative cancers. DNA samples obtained from formalin-fixed paraffin-embedded ER-negative/HER2-positive (n=9) and ER-, progesterone receptor (PR-), HER2-negative (n=8) primary breast cancers and from paired brain or skin metastases and normal tissue were subjected to a hybridization capture-based massively parallel sequencing assay, targeting 341 key cancer genes...
April 3, 2018: Cancer Research
Domenico Orlando, Evelina Miele, Biagio De Angelis, Marika Guercio, Iolanda Boffa, Matilde Sinibaldi, Agnese Po, Ignazio Caruana, Luana Abballe, Andrea Carai, Simona Caruso, Antonio Camera, Annemarie Moseley, Renate S Hagedoorn, Mirjam H M Heemskerk, Felice Giangaspero, Angela Mastronuzzi, Elisabetta Ferretti, Franco Locatelli, Concetta Quintarelli
Medulloblastoma is the most frequent malignant childhood brain tumor with a high morbidity. Identification of new therapeutic targets would be instrumental in improving patient outcomes. We evaluated the expression of the tumor-associated antigen PRAME in biopsies from 60 medulloblastoma patients. PRAME expression was detectable in 82% of tissues independent of molecular and histopathologic subgroups. High PRAME expression also correlated with worse overall survival. We next investigated the relevance of PRAME as a target for immunotherapy...
April 3, 2018: Cancer Research
Daisuke Shiraishi, Yukio Fujiwara, Hasita Horlad, Yoichi Saito, Toyohisa Iriki, Junko Tsuboki, Pan Cheng, Naomi Nakagata, Hiroshi Mizuta, Hirofumi Bekki, Yasuharu Nakashima, Yoshinao Oda, Motohiro Takeya, Yoshihiro Komohara
Recent findings have shown the significance of CD163-positive macrophages in tumor progression, yet there have been few studies on the function of CD163 in macrophages. Here we uncover the role of CD163 in macrophage activation using CD163-deficient mice and human samples. We detected CD163 in 62 undifferentiated pleomorphic sarcoma samples, in which a high percentage of CD163-positive macrophages was associated with decreased overall survival and higher histological grade. We observed macrophage-induced tumor cell proliferation in co-cultures of human monocyte-derived macrophages and leiomyosarcoma (TYLMS-1) and myxofibrosarcoma (NMFH-1) cell lines, which was abrogated by silencing of CD163...
April 2, 2018: Cancer Research
Chi Yan Ooi, Daniel R Carter, Bing Liu, Chelsea Mayoh, Anneleen Beckers, Amit Lalwani, Zsuzsanna Nagy, Sara De Brouwer, Bieke Decaesteker, Tzong-Tyng Hung, Murray D Norris, Michelle Haber, Tao Liu, Katleen De Preter, Frank Speleman, Belamy B Cheung, Glenn M Marshall
Neuroblastoma is a pediatric cancer of the sympathetic nervous system where MYCN amplification is a key indicator of poor prognosis. However, mechanisms by which MYCN promotes neuroblastoma tumorigenesis are not fully understood. In this study, we analyzed global miRNA and mRNA expression profiles of tissues at different stages of tumorigenesis from TH-MYCN transgenic mice, a model of MYCN-driven neuroblastoma. Based on a Bayesian learning network model in which we compared pre-tumor ganglia from TH-MYCN+/+ mice to age-matched wild-type controls, we devised a predicted miRNA-mRNA interaction network...
April 2, 2018: Cancer Research
Lu-Hai Wang, Chien-Wei Tseng, Wen-Hung Kuo, Shih-Hsuan Chan, Hong-Lin Chan, King-Jen Chang
Although metabolic reprogramming is recognized as a hallmark of tumorigenesis and progression, little is known about metabolic enzymes and oncometabolites that regulate breast cancer metastasis, and very few metabolic molecules have been identified as potential therapeutic targets. In this study, the transketolase (TKT) expression correlated with tumor size in the 4T1/BALB/c syngeneic model. In addition, TKT expression was higher in lymph node metastases compared with primary tumor or normal tissues of patients, and high TKT levels were associated with poor survival...
March 29, 2018: Cancer Research
Chao Mao, Xiang Wang, Yating Liu, Min Wang, Bin Yan, Yiqun Jiang, Ying Shi, Yi Shen, Xiaoli Liu, Weiwei Liai, Rui Yang, Desheng Xiao, Yan Cheng, Shuang Liu, Hu Zhou, Ya Cao, Weishi Yu, Kathrin Muegge, Herbert Yu, Yongguang Tao
Long non-coding RNAs (lncRNA) have been associated with various types of cancer, however, the precise role of many lncRNAs in tumorigenesis remains elusive. Here we demonstrate that the cytosolic lncRNA P53RRA is downregulated in cancers and functions as a tumor suppressor by inhibiting cancer progression. Chromatin remodeling proteins LSH and Cfp1 silenced or increased P53RRA expression respectively. P53RRA bound Ras GTPase-activating protein-binding protein 1 (G3BP1) using nucleotides 1 and 871 of P53RRA and the RRM interaction domain of G3BP1 (aa 177-466)...
March 27, 2018: Cancer Research
Mantang Qiu, Wenjia Xia, Rui Chen, Siwei Wang, Youtao Xu, Zhifei Ma, Weizhang Xu, Erbao Zhang, Jie Wang, Tian Fang, Jingwen Hu, Gaochao Dong, Rong Yin, Jun Wang, Lin Xu
Somatic copy-number variations (CNV) may drive cancer progression through both coding and noncoding transcripts. However, noncoding transcripts resulting from CNV are largely unknown, especially for circular RNAs. By integrating bioinformatics analyses of alerted circRNAs and focal CNV in lung adenocarcinoma (LAC), we identify a proto-oncogenic circular RNA (circPRKCI) from the 3q26.2 amplicon, one of the most frequent genomic aberrations in multiple cancers. circPRKCI was overexpressed in LAC tissues, in part due to amplification of the 3q26...
March 27, 2018: Cancer Research
Malamati Vreka, Ioannis Lilis, Maria Papageorgopoulou, Georgia A Giotopoulou, Marina Lianou, Ioanna Giopanou, Nikolaos I Kanellakis, Magda Spella, Theodora Agalioti, Vasileios Armenis, Torsten Goldmann, Sebastian Marwitz, Fiona E Yull, Timothy S Blackwell, Manolis Pasparakis, Antonia Marazioti, Georgios T Stathopoulos
Although oncogenic activation of nuclear factor (NF)-κΒ has been identified in various tumors, the NF-κΒ-activating kinases (inhibitor of NF-κΒ kinases, IKK) responsible for this are elusive. In this study, we determined the role of IKKα and IKKβ in KRAS-mutant lung adenocarcinomas induced by the carcinogen urethane and by respiratory epithelial expression of oncogenic KRASG12D. Using NF-κB reporter mice and conditional deletions of IKKα and IKKβ, we identified two distinct early and late activation phases of NF-κΒ during chemical and genetic lung adenocarcinoma development, which were characterized by nuclear translocation of RelB, ΙκΒβ, and IKKα in tumor-initiated cells...
March 27, 2018: Cancer Research
Marion Humbert, Leslie Guery, Dale Brighouse, Sylvain Lemeille, Stephanie Hugues
Cancer immunotherapies utilize distinct mechanisms to harness the power of the immune system to eradicate cancer cells. Therapeutic vaccines, aimed at inducing active immune responses against an existing cancer, are highly dependent on the immunological microenvironment, where many immune cell types display high levels of plasticity and, depending on the context, promote very different immunological outcomes. Among them, plasmacytoid dendritic cells (pDC), known to be highly immunogenic upon inflammation, are maintained in a tolerogenic state by the tumor microenvironment...
March 27, 2018: Cancer Research
Swadesh K Das, Anjan K Pradhan, Praveen Bhoopathi, Sarmistha Talukdar, Xue-Ning Shen, Devanand Sarkar, Luni Emdad, Paul B Fisher
Although prostate cancer (PCa) is clinically manageable during several stages of progression, survival is severely compromised once cells invade and metastasize to distant organs. Comprehending the pathobiology of invasion is required for developing efficacious targeted therapies against metastasis. Based on bioinformatics data, we predicted an association of melanoma differentiation associated gene-9 (syntenin, or syndecan binding protein (SDCBP)) in PCa progression. Using tissue samples from various Gleason stage PCa patients with adjacent normal tissue, a series of normal prostate and PCa cell lines (with differing tumorigenic/metastatic properties), mda-9/syntenin manipulated variants (including loss-of-function and gain-of-function cell lines), and CRISPR/Cas9 stable MDA-9/syntenin knockout cells, we now confirm the relevance of and dependence on MDA-9/syntenin in PCa invasion...
March 23, 2018: Cancer Research
Francis Jacob, Shahidul Alam, Martina Konantz, Ching-Yeu Liang, Reto S Kohler, Arun V Everest-Dass, Yen-Lin Huang, Natalie Rimmer, André Fedier, Andreas Schötzau, Mónica Núñez López, Nicolle Packer, Claudia Lengerke, Viola Heinzelmann-Schwarz
The reversible transitions of cancer cells between epithelial and mesenchymal states comprise cellular and molecular processes essential for local tumor growth and respective dissemination. We report here that globoside glycosphingolipid (GSL) glycosyltransferase-encoding genes are elevated in epithelial cells and correlate with characteristic EMT signatures predictive of disease outcome. Depletion of globosides through CRISPR-Cas9-mediated deletion of the key enzyme A4GALT induces EMT, enhances chemoresistance, and increased CD24low/CD44high cells...
March 23, 2018: Cancer Research
Ping Zhu, Yong Zhang Liu, Fenglin Zhang, Xiu Feng Bai, Zilei Chen, Fugen Shangguan, Bo Zhang, Lingyun Zhang, Qian Qian Chen, Deyao Xie, Linhua Lan, Xiangdong Xue, Xing-Jie Liang, Bin Lu, Taotao Wei, Yan Qin
Mitochondria regulate cellular bioenergetics and redox states and influence multiple signaling pathways required for tumorigenesis. In this study, we determined that the mitochondrial translation elongation factor 4 (EF4) is a critical component of tumor progression. EF4 was ubiquitous in human tissues with localization to the mitochondria (mtEF4) and performed quality control on respiratory chain biogenesis. Knockout of mtEF4 induced respiratory chain complex defects and apoptosis, while its overexpression stimulated cancer development...
March 23, 2018: Cancer Research
Bo Zhang, Men-Yun Chen, Yu-Jun Sheng, Xian-Bo Zhuo, Ping Gao, Fu-Sheng Zhou, Bo Liang, Jun Zu, Qin Zhang, Sufyan Suleman, Yi-Hui Xu, Min-Gui Xu, Jin-Kai Xu, Chen-Cheng Liu, Nikolaos Giannareas, Ji-Han Xia, Yuan Zhao, Zhong-Lian Huang, Zhen Yang, Huaidong Cheng, Na Li, Yan-Yan Hong, Wei Li, Min-Jun Zhang, Ke-Da Yu, Guoliang Li, Meng-Hong Sun, Zhen-Dong Chen, Gong-Hong Wei, Zhi-Ming Shao
Genome-wide association studies have identified more than 90 susceptibility loci for breast cancer. However, the missing heritability is evident, and the contributions of coding variants to breast cancer susceptibility have not yet been systematically evaluated. Here we present a large-scale whole-exome association study for breast cancer consisting of 24,162 individuals (10,055 cases and 14,107 controls). In addition to replicating known susceptibility loci (e.g. ESR1, FGFR2 and TOX3), we identify two novel missense variants in C21orf58 (rs13047478, Pmeta = 4...
March 23, 2018: Cancer Research
Remi Adelaiye-Ogala, Nur P Damayanti, Ashley R Orillion, Sreevani Arisa, Sreenivasulu Chintala, Mark A Titus, Chinghai Kao, Roberto Pili
Androgen receptor (AR) plays a crucial role in the development and progression of prostate cancer. AR expression has also been reported in other solid tumors, including renal cell carcinoma (RCC), but its biological role here remains unclear. Through integrative analysis of a reverse phase protein array (RPPA), we discovered increased expression of AR in an RCC patient-derived xenograft model of acquired resistance to the receptor tyrosine kinase inhibitor (RTKi) sunitinib. AR expression was increased in RCC cell lines with either acquired or intrinsic sunitinib resistance in vitro...
March 23, 2018: Cancer Research
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