HuR Small-Molecule Inhibitor Elicits Differential Effects in Adenomatosis Polyposis and Colorectal Carcinogenesis
In this study, we evaluated HuR as a small-molecule target for preventing colorectal cancer in high-risk groups such as those with familial adenomatosis polyposis (FAP) or inflammatory bowel disease (IBD). In human specimens, levels of cytoplasmic HuR were increased in colonic epithelial cells from patients with IBD, IBD-cancer, FAP-adenoma, and colorectal cancer, but not in patients with IBD-dysplasia. Intraperitoneal injection of the HuR small-molecule inhibitor MS-444 in AOM/DSS mice, a model of IBD and inflammatory colon cancer, augmented DSS-induced weight loss and increased tumor multiplicity, size, and invasiveness....
Source: Cancer Research - April 30, 2017 Category: Cancer & Oncology Authors: Michaela Lang, David Berry, Katharina Passecker, Ildiko Mesteri, Sabin Bhuju, Florian Ebner, Vitaly Sedlyarov, Rayko Evstatiev, Kyle Dammann, Alexander Loy, Orest Kuzyk, Pavel Kovarik, Vineeta Khare, Martin Beibel, Guglielmo Roma, Nicole Meisner-Kober, Ch Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
Endothelin Promotes Colorectal Tumorigenesis by Activating YAP/TAZ
In this study, we demonstrate that ETAR stimulates colon cell proliferation, migration, and tumorigenesis through the activation of YAP/TAZ, two transcription coactivators of the Hippo tumor suppressor pathway. Endothelin-1 treatment induced YAP/TAZ dephosphorylation, nuclear accumulation, and transcriptional activation in multiple colon cancer cells. ETAR stimulation acted via downstream G-protein Gαq/11 and Rho GTPase to suppress the Hippo pathway, thus leading to YAP/TAZ activation, which was required for ETAR-induced tumorigenesis. Overall, these results indicate a critical role of the YAP/TAZ axis in ETAR signaling. ...
Source: Cancer Research - April 30, 2017 Category: Cancer & Oncology Authors: Zhen Wang, Peng Liu, Xin Zhou, Tianxiang Wang, Xu Feng, Yi-Ping Sun, Yue Xiong, Hai-Xin Yuan, Kun-Liang Guan Tags: Molecular and Cellular Pathobiology Source Type: research
Genetic Manipulation of Helicobacter pylori Virulence Function by Host Carcinogenic Phenotypes
Helicobacter pylori is the strongest risk factor for gastric adenocarcinoma, yet only a minority of infected persons ever develop this malignancy. One cancer-linked locus is the cag type 4 secretion system (cagT4SS), which translocates an oncoprotein into host cells. A structural component of the cagT4SS is CagY, which becomes rapidly altered during in vivo adaptation in mice and rhesus monkeys, rendering the cagT4SS nonfunctional; however, these models rarely develop gastric cancer. We previously demonstrated that the H. pylori cag+ strain 7.13 rapidly induces gastric cancer in Mongolian gerbils. We now use this model, in...
Source: Cancer Research - April 30, 2017 Category: Cancer & Oncology Authors: Giovanni Suarez, Judith Romero-Gallo, Johanna C. Sierra, M. Blanca Piazuelo, Uma S. Krishna, Martin A. Gomez, Keith T. Wilson, Richard M. Peek, Jr Tags: Molecular and Cellular Pathobiology Source Type: research
Kruppel-like Transcription Factor KLF10 Suppresses TGF{beta}-Induced Epithelial-to-Mesenchymal Transition via a Negative Feedback Mechanism
In this study, we show how KLF10 opposes the prometastatic effects of TGFβ by limiting its ability to induce epithelial-to-mesenchymal transition (EMT). KLF10 depletion accentuated induction of EMT as assessed by multiple metrics. KLF10 occupied GC-rich sequences in the promoter region of the EMT-promoting transcription factor SLUG/SNAI2, repressing its transcription by recruiting HDAC1 and licensing the removal of activating histone acetylation marks. In clinical specimens of lung adenocarcinoma, low KLF10 expression associated with decreased patient survival, consistent with a pivotal role for KLF10 in distinguishing th...
Source: Cancer Research - April 30, 2017 Category: Cancer & Oncology Authors: Vivek Kumar Mishra, Malayannan Subramaniam, Vijayalakshmi Kari, Kevin S. Pitel, Simon J. Baumgart, Ryan M. Naylor, Sankari Nagarajan, Florian Wegwitz, Volker Ellenrieder, John R. Hawse, Steven A. Johnsen Tags: Molecular and Cellular Pathobiology Source Type: research
NR4A3 Suppresses Lymphomagenesis through Induction of Proapoptotic Genes
In this study, we investigated the hypothesized contribution of the related NR4A family member NR4A3 to lymphomagenesis. In aggressive lymphoma patients, low expression of NR4A3 was associated with poor survival. Ectopic expression or pharmacological activation of NR4A3 in lymphoma cell lines led to a significantly higher proportion of apoptotic cells. In a mouse NSG xenograft model of lymphoma (stably transduced SuDHL4 cells), NR4A3 expression abrogated tumor growth, compared with vector control and uninduced cells that formed massive tumors. Transcript analysis of four different aggressive lymphoma cell lines overexpress...
Source: Cancer Research - April 30, 2017 Category: Cancer & Oncology Authors: Alexander J.A. Deutsch, Beate Rinner, Martin Pichler, Katharina Prochazka, Katrin Pansy, Marco Bischof, Karoline Fechter, Stefan Hatzl, Julia Feichtinger, Kerstin Wenzl, Marie-Therese Frisch, Verena Stiegelbauer, Andreas Prokesch, Anne Krogsdam, Heinz Sil Tags: Molecular and Cellular Pathobiology Source Type: research
Loss of NDRG2 Expression Confers Oral Squamous Cell Carcinoma with Enhanced Metastatic Potential
Loss of the tumor suppressor NDRG2 has been implicated in the development of oral squamous cell carcinoma (OSCC), acting by modulating PI3K/AKT-mediated dephosphorylation of PTEN at S380/S382/T383 (STT). Here, we show that the majority of OSCC tumors with lymph node metastasis, a major prognostic factor, exhibit high levels of phosphorylated AKT-S473 and PTEN-STT and low levels of NDRG2 expression. In Ndrg2-deficient mice, which develop a wide range of tumors, we developed a model of OSCC by treatment with the tobacco surrogate 4-nitroquinoline-1-oxide (4-NQO). In this model, both the number and size of OSCC tumors were in...
Source: Cancer Research - April 30, 2017 Category: Cancer & Oncology Authors: Tomohiro Tamura, Tomonaga Ichikawa, Shingo Nakahata, Yudai Kondo, Yuri Tagawa, Koji Yamamoto, Kentaro Nagai, Takashi Baba, Ryoji Yamaguchi, Mitsuru Futakuchi, Yoshihiro Yamashita, Kazuhiro Morishita Tags: Molecular and Cellular Pathobiology Source Type: research
Hypercholesterolemia Increases Colorectal Cancer Incidence by Reducing Production of NKT and {gamma}{delta} T Cells from Hematopoietic Stem Cells
In this study, we show that hypercholesterolemia increases the incidence and pathologic severity of colorectal neoplasia in two independent mouse models. Hypocholesterolemia induced an oxidant stress–dependent increase in miR101c, which downregulated Tet1 in hematopoietic stem cells (HSC), resulting in reduced expression of genes critical to natural killer T cell (NKT) and γδ T-cell differentiation. These effects reduced the number and function of terminally differentiated NKT and γδ T cells in the thymus, the colon submucosa, and during early tumorigenesis. These results suggest a novel mechanism by which a metaboli...
Source: Cancer Research - April 30, 2017 Category: Cancer & Oncology Authors: Guodong Tie, Jinglian Yan, Lyne Khair, Julia A. Messina, April Deng, Joonsoo Kang, Thomas Fazzio, Louis M. Messina Tags: Molecular and Cellular Pathobiology Source Type: research
Noncoding Effects of Circular RNA CCDC66 Promote Colon Cancer Growth and Metastasis
Circular RNA (circRNA) is a class of noncoding RNA whose functions remain mostly unknown. Recent studies indicate circRNA may be involved in disease pathogenesis, but direct evidence is scarce. Here, we characterize the functional role of a novel circRNA, circCCDC66, in colorectal cancer. RNA-Seq data from matched normal and tumor colon tissue samples identified numerous circRNAs specifically elevated in cancer cells, several of which were verified by quantitative RT-PCR. CircCCDC66 expression was elevated in polyps and colon cancer and was associated with poor prognosis. Gain-of-function and loss-of-function studies in co...
Source: Cancer Research - April 30, 2017 Category: Cancer & Oncology Authors: Kuei-Yang Hsiao, Ya-Chi Lin, Sachin Kumar Gupta, Ning Chang, Laising Yen, H. Sunny Sun, Shaw-Jenq Tsai Tags: Molecular and Cellular Pathobiology Source Type: research
Tankyrase-Binding Protein TNKS1BP1 Regulates Actin Cytoskeleton Rearrangement and Cancer Cell Invasion
Tankyrase, a PARP that promotes telomere elongation and Wnt/β-catenin signaling, has various binding partners, suggesting that it has as-yet unidentified functions. Here, we report that the tankyrase-binding protein TNKS1BP1 regulates actin cytoskeleton and cancer cell invasion, which is closely associated with cancer progression. TNKS1BP1 colocalized with actin filaments and negatively regulated cell invasion. In TNKS1BP1-depleted cells, actin filament dynamics, focal adhesion, and lamellipodia ruffling were increased with activation of the ROCK/LIMK/cofilin pathway. TNKS1BP1 bound the actin-capping protein CapZA2. TNKS1...
Source: Cancer Research - April 30, 2017 Category: Cancer & Oncology Authors: Tomokazu Ohishi, Haruka Yoshida, Masamichi Katori, Toshiro Migita, Yukiko Muramatsu, Mao Miyake, Yuichi Ishikawa, Akio Saiura, Shun-ichiro Iemura, Tohru Natsume, Hiroyuki Seimiya Tags: Molecular and Cellular Pathobiology Source Type: research
Granzyme B PET Imaging as a Predictive Biomarker of Immunotherapy Response
While cancer immunotherapy can produce dramatic responses, only a minority of patients respond to treatment. Reliable response biomarkers are needed to identify responders, and conventional imaging modalities have not proved adequate. Here, we provide a preclinical proof of concept for the use of granzyme B, a downstream effector of tumoral cytotoxic T cells, as an early biomarker for tumors responding to immunotherapy. We designed novel PET imaging probes for the murine and human granzyme B isoforms that specifically and quantitatively bind granzyme B. Immunotherapy-treated mice were imaged prior to therapy-induced tumor ...
Source: Cancer Research - April 30, 2017 Category: Cancer & Oncology Authors: Benjamin M. Larimer, Eric Wehrenberg-Klee, Frank Dubois, Anila Mehta, Taylor Kalomeris, Keith Flaherty, Genevieve Boland, Umar Mahmood Tags: Microenvironment and Immunology Source Type: research
MYC Mediates Large Oncosome-Induced Fibroblast Reprogramming in Prostate Cancer
Communication between cancer cells and the tumor microenvironment results in the modulation of complex signaling networks that facilitate tumor progression. Here, we describe a new mechanism of intercellular communication originating from large oncosomes (LO), which are cancer cell–derived, atypically large (1–10 μm) extracellular vesicles (EV). We demonstrate that, in the context of prostate cancer, LO harbor sustained AKT1 kinase activity, nominating them as active signaling platforms. Active AKT1 was detected in circulating EV from the plasma of metastatic prostate cancer patients and was LO specific. LO internaliz...
Source: Cancer Research - April 30, 2017 Category: Cancer & Oncology Authors: Valentina R. Minciacchi, Cristiana Spinelli, Mariana Reis-Sobreiro, Lorenzo Cavallini, Sungyong You, Mandana Zandian, Xiaohong Li, Rajeev Mishra, Paola Chiarugi, Rosalyn M. Adam, Edwin M. Posadas, Giuseppe Viglietto, Michael R. Freeman, Emanuele Cocucci, Tags: Microenvironment and Immunology Source Type: research
Local Activation of p53 in the Tumor Microenvironment Overcomes Immune Suppression and Enhances Antitumor Immunity
Mutations in tumor suppressor p53 remain a vital mechanism of tumor escape from apoptosis and senescence. Emerging evidence suggests that p53 dysfunction also fuels inflammation and supports tumor immune evasion, thereby serving as an immunological driver of tumorigenesis. Therefore, targeting p53 in the tumor microenvironment (TME) also represents an immunologically desirable strategy for reversing immunosuppression and enhancing antitumor immunity. Using a pharmacological p53 activator nutlin-3a, we show that local p53 activation in TME comprising overt tumor-infiltrating leukocytes (TILeus) induces systemic antitumor im...
Source: Cancer Research - April 30, 2017 Category: Cancer & Oncology Authors: Gang Guo, Miao Yu, Wei Xiao, Esteban Celis, Yan Cui Tags: Microenvironment and Immunology Source Type: research
Soluble IL6R Expressed by Myeloid Cells Reduces Tumor-Specific Th1 Differentiation and Drives Tumor Progression
In this study, we focused on the impact of IL6 trans-signaling mediated by soluble IL6 receptors (sIL6R) expressed in tumor-bearing hosts. Higher levels of sIL6R circulating in blood were observed in tumor-bearing mice, whereas the systemic increase of sIL6R was not prominent in tumor-bearing mice with myeloid cell–specific conditional deletion of IL6R even when tumor cells produced sIL6R. Abundant sIL6R was released by CD11b+ cells from tumor-bearing mice but not tumor-free mice. Notably, IL6-mediated defects in Th1 differentiation, T-cell helper activity for tumor-specific CD8+ T cells, and downstream antitumor effects...
Source: Cancer Research - April 30, 2017 Category: Cancer & Oncology Authors: Hirotake Tsukamoto, Koji Fujieda, Masatoshi Hirayama, Tokunori Ikeda, Akira Yuno, Keiko Matsumura, Daiki Fukuma, Kimi Araki, Hiroshi Mizuta, Hideki Nakayama, Satoru Senju, Yasuharu Nishimura Tags: Microenvironment and Immunology Source Type: research
Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma
In glioblastoma (GBM), tumor-associated macrophages (TAM) represent up to one half of the cells of the tumor mass, including both infiltrating macrophages and resident brain microglia. In an effort to delineate the temporal and spatial dynamics of TAM composition during gliomagenesis, we used genetically engineered and GL261-induced mouse models in combination with CX3CR1GFP/WT;CCR2RFP/WT double knock-in mice. Using this approach, we demonstrated that CX3CR1LoCCR2Hi monocytes were recruited to the GBM, where they transitioned to CX3CR1HiCCR2Lo macrophages and CX3CR1HiCCR2− microglia-like cells. Infiltrating macrophages/m...
Source: Cancer Research - April 30, 2017 Category: Cancer & Oncology Authors: Zhihong Chen, Xi Feng, Cameron J. Herting, Virginia Alvarez Garcia, Kai Nie, Winnie W. Pong, Rikke Rasmussen, Bhakti Dwivedi, Sandra Seby, Susanne A. Wolf, David H. Gutmann, Dolores Hambardzumyan Tags: Microenvironment and Immunology Source Type: research
Genomic and Epigenomic Heterogeneity of Hepatocellular Carcinoma
Understanding the intratumoral heterogeneity of hepatocellular carcinoma is instructive for developing personalized therapy and identifying molecular biomarkers. Here we applied whole-exome sequencing to 69 samples from 11 patients to resolve the genetic architecture of subclonal diversification. Spatial genomic diversity was found in all 11 hepatocellular carcinoma cases, with 29% of driver mutations being heterogeneous, including TERT, ARID1A, NOTCH2, and STAG2. Similar with other cancer types, TP53 mutations were always shared between all tumor regions, that is, located on the “trunk” of the evolutionary tree. In ad...
Source: Cancer Research - April 30, 2017 Category: Cancer & Oncology Authors: De-Chen Lin, Anand Mayakonda, Huy Q. Dinh, Pinbo Huang, Lehang Lin, Xiaoping Liu, Ling-wen Ding, Jie Wang, Benjamin P. Berman, Er-Wei Song, Dong Yin, H. Phillip Koeffler Tags: Integrated Systems and Technologies Source Type: research
