IL33 Promotes Colon Cancer Cell Stemness via JNK Activation and Macrophage Recruitment
In this study, we show that IL33 is expressed by vascular endothelial cells and tumor cells in the human colon cancer microenvironment. Administration of human IL33 and overexpression of murine IL33 enhanced human and murine colon cancer cell growth in vivo, respectively. IL33 stimulated cell sphere formation and prevented chemotherapy-induced tumor apoptosis. Mechanistically, IL33 activated core stem cell genes NANOG, NOTCH3, and OCT3/4 via the ST2 signaling pathway, and induced phosphorylation of c-Jun N terminal kinase (JNK) activation and enhanced binding of c-Jun to the promoters of the core stem cell genes. Moreover,...
Source: Cancer Research - May 14, 2017 Category: Cancer & Oncology Authors: Min Fang, Yongkui Li, Kai Huang, Shanshan Qi, Jian Zhang, Witold Zgodzinski, Marek Majewski, Grzegorz Wallner, Stanislaw Gozdz, Pawel Macek, Artur Kowalik, Marcin Pasiarski, Ewelina Grywalska, Linda Vatan, Nisha Nagarsheth, Wei Li, Lili Zhao, Ilona Krycze Tags: Tumor and Stem Cell Biology Source Type: research
Cell-Cycle Regulation Accounts for Variability in Ki-67 Expression Levels
The cell proliferation antigen Ki-67 is widely used in cancer histopathology, but estimations of Ki-67 expression levels are inconsistent and understanding of its regulation is limited. Here we show that cell-cycle regulation underlies variable Ki-67 expression in all situations analyzed, including nontransformed human cells, normal mouse intestinal epithelia and adenomas, human cancer cell lines with or without drug treatments, and human breast and colon cancers. In normal cells, Ki-67 was a late marker of cell-cycle entry; Ki-67 mRNA oscillated with highest levels in G2 while protein levels increased throughout the cell ...
Source: Cancer Research - May 14, 2017 Category: Cancer & Oncology Authors: Michal Sobecki, Karim Mrouȷ, Jacques Colinge, Francois Gerbe, Philippe Jay, Liliana Krasinska, Vȷekoslav Dulic, Daniel Fisher Tags: Tumor and Stem Cell Biology Source Type: research
Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors
In this study, we investigated the effects of specific EGFR and HER2 exon 20 insertion mutations from NSCLC patients that had clinically achieved a partial response after dacomitinib treatment. We identified Gly770 as a common feature among the drug-sensitive mutations. Structural modeling suggested that this mutation may facilitate inhibitor binding to EGFR. Introduction of Gly770 into two dacomitinib-resistant EGFR exon 20 insertion mutants restored sensitivity to dacomitinib. Based on these findings, we used afatinib to treat an NSCLC patient whose tumor harbored the HER2 V777_G778insGSP mutation and achieved a durable ...
Source: Cancer Research - May 14, 2017 Category: Cancer & Oncology Authors: Takayuki Kosaka, Junko Tanizaki, Raymond M. Paranal, Hideki Endoh, Christine Lydon, Marzia Capelletti, Claire E. Repellin, Jihyun Choi, Atsuko Ogino, Antonio Calles, Dalia Ercan, Amanda J. Redig, Magda Bahcall, Geoffrey R. Oxnard, Michael J. Eck, Pasi A. Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
Development of a T-cell Receptor Mimic Antibody against Wild-Type p53 for Cancer Immunotherapy
The tumor suppressor p53 is widely dysregulated in cancer and represents an attractive target for immunotherapy. Because of its intracellular localization, p53 is inaccessible to classical therapeutic monoclonal antibodies, an increasingly successful class of anticancer drugs. However, peptides derived from intracellular antigens are presented on the cell surface in the context of MHC I and can be bound by T-cell receptors (TCR). Here, we report the development of a novel antibody, T1-116C, that acts as a TCR mimic to recognize an HLA-A*0201–presented wild-type p53 T-cell epitope, p5365–73(RMPEAAPPV). The antibody reco...
Source: Cancer Research - May 14, 2017 Category: Cancer & Oncology Authors: Demin Li, Carol Bentley, Amanda Anderson, Sarah Wiblin, Kirstie L.S. Cleary, Sofia Koustoulidou, Tasneem Hassanali, Jenna Yates, Jenny Greig, Marloes Olde Nordkamp, Iva Trenevska, Nicola Ternette, Benedikt M. Kessler, Bart Cornelissen, Mark S. Cragg, Alis Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
Antibody-Drug Conȷugates Bearing Pyrrolobenzodiazepine or Tubulysin Payloads Are Immunomodulatory and Synergize with Multiple Immunotherapies
In this study, we investigated whether antibody–drug conjugates (ADCS) conjugated with pyrrolobenzodiazepine dimer (PBD) or tubulysin payloads induce ICD, modulate the immune microenvironment, and could combine with immuno-oncology drugs to enhance antitumor activity. We show that these payloads on their own induced an immune response that prevented the growth of tumors following subsequent tumor cell challenge. ADCs had greater antitumor activity in immunocompetent versus immunodeficient mice, demonstrating a contribution of the immune system to the antitumor activity of these ADCs. ADCs also induced immunologic memory....
Source: Cancer Research - May 14, 2017 Category: Cancer & Oncology Authors: Jonathan Rios-Doria, Jay Harper, Raymond Rothstein, Leslie Wetzel, Jon Chesebrough, Allison Marrero, Cui Chen, Patrick Strout, Kathy Mulgrew, Kelly McGlinchey, Ryan Fleming, Binyam Bezabeh, John Meekin, David Stewart, Maureen Kennedy, Philip Martin, Andre Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
SSRP1 Cooperates with PARP and XRCC1 to Facilitate Single-Strand DNA Break Repair by Chromatin Priming
In this study, we show that SSRP1, but not SPT16, is critical for cell survival after ionizing radiation or methyl methanesulfonate–induced single-strand DNA damage. SSRP1 is recruited to SSB in a PARP-dependent manner and retained at DNA damage sites by N-terminal interactions with the DNA repair protein XRCC1. Mutational analyses showed how SSRP1 function is essential for chromatin decondensation and histone H2B exchange at sites of DNA strand breaks, which are both critical to prime chromatin for efficient SSB repair and cell survival. By establishing how SSRP1 facilitates SSB repair, our findings provide a mechanisti...
Source: Cancer Research - May 14, 2017 Category: Cancer & Oncology Authors: Ying Gao, Changling Li, Leizhen Wei, Yaqun Teng, Satoshi Nakajima, Xiukai Chen, Jianquan Xu, Brittany Legar, Hongqiang Ma, Stephen T. Spagnol, Yong Wan, Kris Noel Dahl, Yang Liu, Arthur S. Levine, Li Lan Tags: Molecular and Cellular Pathobiology Source Type: research
Pancreatic Cancer Progression Relies upon Mutant p53-Induced Oncogenic Signaling Mediated by NOP14
In this study, we report that NOP14 nucleolar protein (NOP14) expression is upregulated in PDAC tumors and metastatic tissue specimens. NOP14 overexpression promoted cell motility, whereas NOP14 inhibition decreased invasive capacity of PDAC cells. In vivo invasion assays conducted on established subcutaneously, orthotopically, and intravenously injected tumor mouse models also indicated NOP14 as a promoter of PDAC metastasis. Mechanistically, mutp53 was validated as a functional target of NOP14; NOP14 primed tumor invasion and metastasis by increasing the stability of mutp53 mRNA. The NOP14/mutp53 axis suppressed p21 expr...
Source: Cancer Research - May 14, 2017 Category: Cancer & Oncology Authors: Yongxing Du, Ziwen Liu, Lei You, Pengjiao Hou, Xiaoxia Ren, Tao Jiao, Wenjing Zhao, Zongze Li, Hong Shu, Changzheng Liu, Yupei Zhao Tags: Molecular and Cellular Pathobiology Source Type: research
Lipocalin-2 Promotes Pancreatic Ductal Adenocarcinoma by Regulating Inflammation in the Tumor Microenvironment
In this study, we investigated the effects of Lcn2 depletion on diet-induced obesity, inflammation, and PDAC development. Mice with acinar cell–specific expression of KrasG12D were crossed with Lcn2-depleted animals and fed isocaloric diets with varying amounts of fat content. Pancreas were collected and analyzed for inflammation, pancreatic intraepithelial neoplasia (PanIN), and PDAC. We also used a syngeneic orthotopic PDAC mouse model to study tumor growth in the presence or absence of Lcn2 expression. In addition, to understand the mechanistic role of how LCN2 could be mediating PDAC, we studied LCN2 and its specific...
Source: Cancer Research - May 14, 2017 Category: Cancer & Oncology Authors: Sobeyda B. Gomez-Chou, Agnieszka Katarzyna Swidnicka-Siergiejko, Niharika Badi, Myrriah Chavez-Tomar, Gregory B. Lesinski, Tanios Bekaii-Saab, Matthew R. Farren, Thomas A. Mace, Carl Schmidt, Yan Liu, Defeng Deng, Rosa F. Hwang, Liran Zhou, Todd Moore, De Tags: Molecular and Cellular Pathobiology Source Type: research
Differential Expression of VEGFA Isoforms Regulates Metastasis and Response to Anti-VEGFA Therapy in Sarcoma
Elevated plasma concentrations of soluble VEGFA isoforms are associated with poor prognosis in parallel with improved response to treatment with the anti-VEGFA antibody bevacizumab. To uncover the underlying mechanism to these observations, we administered anti-VEGFA therapy to mice bearing luminescent mouse fibrosarcomas expressing single VEGFA isoforms or their wild-type counterparts expressing all isoforms (fs120, fs164, fs188, or fsWT). Expression of the more soluble isoforms conferred an advantage for lung metastasis from subcutaneous tumors (fs120/164 vs. fs188/WT); fs120 cells also produced more lung colonies than f...
Source: Cancer Research - May 14, 2017 Category: Cancer & Oncology Authors: William R. English, Sarah Jane Lunt, Matthew Fisher, Diane V. Lefley, Mohit Dhingra, Yu-Chin Lee, Karina Bingham, Jack E. Hurrell, Scott K. Lyons, Chryso Kanthou, Gillian M. Tozer Tags: Molecular and Cellular Pathobiology Source Type: research
Locoregional Effects of Microbiota in a Preclinical Model of Colon Carcinogenesis
Inflammation and microbiota are critical components of intestinal tumorigenesis. To dissect how the microbiota contributes to tumor distribution, we generated germ-free (GF) ApcMin/+and ApcMin/+;Il10−/− mice and exposed them to specific-pathogen-free (SPF) or colorectal cancer-associated bacteria. We found that colon tumorigenesis significantly correlated with inflammation in SPF-housed ApcMin/+;Il10−/−, but not in ApcMin/+mice. In contrast, small intestinal neoplasia development significantly correlated with age in both ApcMin/+;Il10−/− and ApcMin/+ mice. GF ApcMin/+;Il10−/− mice conventionalized by an SPF...
Source: Cancer Research - May 14, 2017 Category: Cancer & Oncology Authors: Sarah Tomkovich, Ye Yang, Kathryn Winglee, Josee Gauthier, Marcus Muhlbauer, Xiaolun Sun, Mansour Mohamadzadeh, Xiuli Liu, Patricia Martin, Gary P. Wang, Eric Oswald, Anthony A. Fodor, Christian Jobin Tags: Microenvironment and Immunology Source Type: research
Anti-PD-L1 Efficacy Can Be Enhanced by Inhibition of Myeloid-Derived Suppressor Cells with a Selective Inhibitor of PI3K{delta}/{gamma}
Checkpoint inhibitors are relatively inefficacious in head and neck cancers, despite an abundance of genetic alterations and a T-cell–inflamed phenotype. One significant barrier to efficacy may be the recruitment of myeloid-derived suppressor cells (MDSC) into the tumor microenvironment. Here we demonstrate functional inhibition of MDSC with IPI-145, an inhibitor of PI3Kδ and PI3Kγ isoforms, which enhances responses to PD-L1 blockade. Combination therapy induced CD8+ T lymphocyte–dependent primary tumor growth delay and prolonged survival only in T-cell–inflamed tumor models of head and neck cancers. However, highe...
Source: Cancer Research - May 14, 2017 Category: Cancer & Oncology Authors: Ruth J. Davis, Ellen C. Moore, Paul E. Clavijo, Jay Friedman, Harrison Cash, Zhong Chen, Chris Silvin, Carter Van Waes, Clint Allen Tags: Microenvironment and Immunology Source Type: research
HDAC Inhibitor Panobinostat Engages Host Innate Immune Defenses to Promote the Tumoricidal Effects of Trastuzumab in HER2+ Tumors
Histone deacetylase inhibitors (HDACi) may engage host immunity as one basis for their antitumor effects. Herein, we demonstrate an application of this concept using the HDACi panobinostat to augment the antitumor efficacy of trastuzumab (anti-HER2) therapy, through both tumor cell autonomous and nonautonomous mechanisms. In HER2+ tumors that are inherently sensitive to the cytostatic effects of trastuzumab, cotreatment with panobinostat abrogated AKT signaling and triggered tumor regression in mice that lacked innate and/or adaptive immune effector cells. However, the cooperative ability of panobinostat and trastuzumab to...
Source: Cancer Research - May 14, 2017 Category: Cancer & Oncology Authors: Mikolaj Medon, Eva Vidacs, Stephin J Vervoort, Jason Li, Misty R. Jenkins, Kelly M. Ramsbottom, Joseph A. Trapani, Mark J. Smyth, Phillip K. Darcy, Peter W. Atadja, Michael A. Henderson, Ricky W. Johnstone, Nicole M. Haynes Tags: Microenvironment and Immunology Source Type: research
Morphoproteomic Characterization of Lung Squamous Cell Carcinoma Fragmentation, a Histological Marker of Increased Tumor Invasiveness
In this study, we used an image-based computational method on pan-cytokeratin IHC stainings to quantify tumor fragmentation (TF), a measure of tumor invasiveness of lung squamous cell carcinoma (LSCC). In two independent clinical cohorts from tissue microarrays (TMA: n = 208 patients) and whole sections (WS: n = 99 patients), TF was associated with poor prognosis and increased risk of blood vessel infiltration. A third cohort from The Cancer Genome Atlas (TCGA: n = 335 patients) confirmed the poor prognostic value of TF using a similar human-based score on hematoxylin-eosin staining. Integration of RNA-seq data from TCGA a...
Source: Cancer Research - May 14, 2017 Category: Cancer & Oncology Authors: Ruben Casanova, Daniel Xia, Undine Rulle, Paolo Nanni, Jonas Grossmann, Bart Vrugt, Reto Wettstein, Rafael Ballester, Alberto Astolfo, Walter Weder, Holger Moch, Marco Stampanoni, Andrew H. Beck, Alex Soltermann Tags: Integrated Systems and Technologies Source Type: research
A Model-Based Personalized Cancer Screening Strategy for Detecting Early-Stage Tumors Using Blood-Borne Biomarkers
An effective cancer blood biomarker screening strategy must distinguish aggressive from nonaggressive tumors at an early, intervenable time. However, for blood-based strategies to be useful, the quantity of biomarker shed into the blood and its relationship to tumor growth or progression must be validated. To study how blood biomarker levels correlate with early-stage viable tumor growth in a mouse model of human cancer, we monitored early tumor growth of engineered human ovarian cancer cells (A2780) implanted orthotopically into nude mice. Biomarker shedding was monitored by serial blood sampling, whereas tumor viability ...
Source: Cancer Research - May 14, 2017 Category: Cancer & Oncology Authors: Sharon Seiko Hori, Amelie M. Lutz, Ramasamy Paulmurugan, Sanjiv Sam Gambhir Tags: Integrated Systems and Technologies Source Type: research
Tumor Dormancy and Relapse: From a Natural Byproduct of Evolution to a Disease State
This article reviews growing evidence about tumor dormancy and suggests that (i) cellular malignancy is a natural byproduct of evolutionary mechanisms, such as gene mutations and epigenetic modifications, which is manifested in the form of tumor dormancy in healthy individuals as well as in cancer survivors; (ii) cancer metastasis could be an early dissemination event that could occur during malignant dormancy even before primary cancer is clinically detectable; and (iii) chronic inflammation is a key factor in awakening dormant malignant cells at the primary site, leading to primary cancer development, and at distant site...
Source: Cancer Research - May 14, 2017 Category: Cancer & Oncology Authors: Masoud H. Manjili Tags: Reviews Source Type: research
