The STAT3-miRNA-92-Wnt Signaling Pathway Regulates Spheroid Formation and Malignant Progression in Ovarian Cancer
In this study, we show that STAT3 is hyperactivated in ovarian cancer spheroids and that STAT3 disruption in this setting is sufficient to relieve chemoresistance. In an NSG murine model of human ovarian cancer, STAT3 signaling regulated spheroid formation and self-renewal properties, whereas STAT3 attenuation reduced tumorigenicity. Mechanistic investigations revealed that Wnt signaling was required for STAT3-mediated spheroid formation. Notably, the Wnt antagonist DKK1 was the most strikingly upregulated gene in response to STAT3 attenuation in ovarian cancer cells. STAT3 signaling maintained stemness and interconnected ...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Min-Wei Chen, Shu-Ting Yang, Ming-Hsien Chien, Kuo-Tai Hua, Chin-Jui Wu, S.M. Hsiao, Hao Lin, Michael Hsiao, Jen-Liang Su, Lin-Hung Wei Tags: Molecular and Cellular Pathobiology Source Type: research
Role of Megakaryocytes in Breast Cancer Metastasis to Bone
In this study, we explored the functional implications of megakaryocyte accumulation in the femurs of mice after injection of metastatic or non-metastatic breast cancer cells in 4T1.2 BALB/cJ and MDA-MB-231 nude mouse models. At bone metastatic sites, but not primary growth sites, tumor growth was associated with increased megakaryopoiesis in both model systems. In the orthotopic BALB/cJ model, extramedullary hematopoiesis occurred in the spleen, resulting in a four-fold increase in megakaryocytes. In support of the hypothesis that reducing megakaryocytes may reduce metastasis, we found that thrombopoietin-deficient mice e...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Walter Jackson III, Donna M. Sosnoski, Sara E. Ohanessian, Paige Chandler, Adam Mobley, Kacey D. Meisel, Andrea M. Mastro Tags: Molecular and Cellular Pathobiology Source Type: research
Evolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles
The hypothesis that microvesicle-mediated miRNA transfer converts noncancer stem cells into cancer stem cells (CSC) leading to therapy resistance remains poorly investigated. Here we provide direct evidence supporting this hypothesis, by demonstrating how microvesicles derived from cancer-associated fibroblasts (CAF) transfer miR-221 to promote hormonal therapy resistance (HTR) in models of luminal breast cancer. We determined that CAF-derived microvesicles horizontally transferred miR-221 to tumor cells and, in combination with hormone therapy, activated an ERlo/Notchhi feed-forward loop responsible for the generation of ...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Pasquale Sansone, Marȷan Berishaȷ, Vinagolu K. Raȷasekhar, Claudio Ceccarelli, Qing Chang, Antonio Strillacci, Claudia Savini, Lauren Shapiro, Robert L. Bowman, Chiara Mastroleo, Sabrina De Carolis, Laura Daly, Alberto Benito–Ma Tags: Microenvironment and Immunology Source Type: research
CD40 Signaling Drives Potent Cellular Immune Responses in Heterologous Cancer Vaccinations
Antagonistic antibodies targeting coinhibitory receptors have revolutionized the treatment of cancer by inducing durable immune responses and clinical remissions in patients. In contrast, success of agonistic costimulatory antibodies has thus far been limited because of the insufficient induction of adaptive immune responses. Here, we describe a novel vaccination method consisting of a primary dendritic cell (DC) immunization followed by a composite vaccination, including an agonistic CD40 antibody, soluble antigen, and a TLR3 agonist, referred to as CoAT. In mice, DC/CoAT prime-boost vaccinations targeting either MHC clas...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Supot Nimanong, Dmitriȷ Ostroumov, Jessica Wingerath, Sarah Knocke, Norman Woller, Engin Gurlevik, Christine S. Falk, Michael P. Manns, Florian Kuhnel, Thomas C. Wirth Tags: Microenvironment and Immunology Source Type: research
Extracellular Matrix Receptor Expression in Subtypes of Lung Adenocarcinoma Potentiates Outgrowth of Micrometastases
In this study, we show how differential expression of a network of extracellular matrix (ECM) molecules and their interacting proteins contributes to risk of relapse in distinct LUAD subtypes. Overexpression of the hyaluronan receptor HMMR in primary LUAD was associated with an inflammatory molecular signature and poor prognosis. Attenuating HMMR in LUAD cells diminished their ability to initiate lung tumors and distant metastases. HMMR upregulation was not required for dissemination in vivo, but enhanced ECM-mediated signaling, LUAD cell survival, and micrometastasis expansion in hyaluronan-rich microenvironments in the l...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Laura E. Stevens, William K.C. Cheung, Sally J. Adua, Anna Arnal–Estape, Minghui Zhao, Zongzhi Liu, Kelly Brewer, Roy S. Herbst, Don X. Nguyen Tags: Microenvironment and Immunology Source Type: research
Differential PI3K{delta} Signaling in CD4+ T-cell Subsets Enables Selective Targeting of T Regulatory Cells to Enhance Cancer Immunotherapy
In this study, we show how a functional dichotomy in Class IA PI3K isoforms in these two subsets of CD4+ T cells can be exploited to target Treg while leaving Tconv intact. Studies employing isoform-specific PI3K inhibitors and a PI3Kδ-deficient mouse strain revealed that PI3Kα and PI3Kβ were functionally redundant with PI3Kδ in Tconv. Conversely, PI3Kδ was functionally critical in Treg, acting there to control T-cell receptor signaling, cell proliferation, and survival. Notably, in a murine model of lung cancer, coadministration of a PI3Kδ-specific inhibitor with a tumor-specific vaccine decreased numbers of suppres...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Shamim Ahmad, Rasha Abu-Eid, Rajeev Shrimali, Mason Webb, Vivek Verma, Atbin Doroodchi, Zuzana Berrong, Raed Samara, Paulo C. Rodriguez, Mikayel Mkrtichyan, Samir N. Khleif Tags: Microenvironment and Immunology Source Type: research
LIGHT Elevation Enhances Immune Eradication of Colon Cancer Metastases
In conclusion, increasing LIGHT expression increased T-cell proliferation, activation, and infiltration, resulting in enhanced tumor-specific immune-mediated tumor regressions in primary tumors and colorectal liver metastases. Mechanisms to increase LIGHT in the colon cancer microenvironment warrant further investigation and hold promise as an immunotherapeutic strategy. Cancer Res; 77(8); 1880–91. ©2017 AACR. (Source: Cancer Research)
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Guilin Qiao, Jianzhong Qin, Nicholas Kunda, Jed F. Calata, Dolores L. Mahmud, Peter Gann, Yang-Xin Fu, Steven A. Rosenberg, Bellur S. Prabhakar, Ajay V. Maker Tags: Microenvironment and Immunology Source Type: research
PanIN Neuroendocrine Cells Promote Tumorigenesis via Neuronal Cross-talk
Nerves are a notable feature of the tumor microenvironment in some epithelial tumors, but their role in the malignant progression of pancreatic ductal adenocarcinoma (PDAC) is uncertain. Here, we identify dense innervation in the microenvironment of precancerous pancreatic lesions, known as pancreatic intraepithelial neoplasms (PanIN), and describe a unique subpopulation of neuroendocrine PanIN cells that express the neuropeptide substance P (SP) receptor neurokinin 1-R (NK1-R). Using organoid culture, we demonstrated that sensory neurons promoted the proliferation of PanIN organoids via SP-NK1-R signaling and STAT3 activa...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Smrita Sinha, Ya-Yuan Fu, Adrien Grimont, Maren Ketcham, Kelly Lafaro, Joseph A. Saglimbeni, Gokce Askan, Jennifer M. Bailey, Jerry P. Melchor, Yi Zhong, Min Geol Joo, Olivera Grbovic-Huezo, In-Hong Yang, Olca Basturk, Lindsey Baker, Young Park, Robert C. Tags: Microenvironment and Immunology Source Type: research
Cellular Model of Colon Cancer Progression Reveals Signatures of mRNAs, miRNA, lncRNAs, and Epigenetic Modifications Associated with Metastasis
Here, we developed and comprehensively characterized a cellular model of colon cancer progression consisting of four defined derivatives of a colon cancer cell line that resulted from consecutive epithelial–mesenchymal and mesenchymal–epithelial transitions (EMT/MET) and phenotypically recapitulate the metastatic cascade. Initial EMT was induced by prolonged exposure to IL6, a cytokine also generated by the tumor-stroma. Genome-wide characterization of transcriptional (mRNA, miRNA, and lncRNA) and epigenetic (DNA methylation, H3K4me3, H3K79me3, and H3K27me3 histone modifications) profiles of the cell derivatives, combi...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Matjaz Rokavec, David Horst, Heiko Hermeking Tags: Integrated Systems and Technologies Source Type: research
Lapatinib Resistance in Breast Cancer Cells Is Accompanied by Phosphorylation-Mediated Reprogramming of Glycolysis
In this study, we employed explorative mass spectrometry to profile proteome, kinome, and phosphoproteome changes in an established model of lapatinib resistance to systematically investigate initial inhibitor response and subsequent reprogramming in resistance. The resulting dataset, which collectively contains quantitative data for>7,800 proteins,>300 protein kinases, and>15,000 phosphopeptides, enabled deep insight into signaling recovery and molecular reprogramming upon resistance. Our data-driven approach confirmed previously described mechanisms of resistance (e.g., AXL overexpression and PIK3 reactivation), revealed...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Benjamin Ruprecht, Esther A. Zaal, Jana Zecha, Wei Wu, Celia R. Berkers, Bernhard Kuster, Simone Lemeer Tags: Integrated Systems and Technologies Source Type: research
Combined PET Imaging of the Inflammatory Tumor Microenvironment Identifies Margins of Unique Radiotracer Uptake
In this study, noninvasive imaging by PET with [18F]DPA-714 (TSPO) and [18F]BR-351 (MMP) was used for the assessment of localization and quantification of the expression of TSPO and MMP. Imaging was performed in addition to established clinical imaging biomarker of active tumor volume ([18F]FET) in conjunction with MRI. We hypothesized that each imaging biomarker revealed distinct areas of the heterogeneous glioma tissue in a mouse model of human glioma. Tracers were found to be increased 1.4- to 1.7-fold, with [18F]FET showing the biggest volume as depicted by a thresholding-based, volumes of interest analysis. Tumor area...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Bastian Zinnhardt, Hayet Pigeon, Benoit Theze, Thomas Viel, Lydia Wachsmuth, Inga B. Fricke, Sonȷa Schelhaas, Lisa Honold, Katrin Schwegmann, Stefan Wagner, Andreas Faust, Cornelius Faber, Michael T. Kuhlmann, Sven Hermann, Michael Schafers, Alexan Tags: Integrated Systems and Technologies Source Type: research
Effective Combination Therapies for B-cell Lymphoma Predicted by a Virtual Disease Model
In this study, we used chronic active B-cell receptor (BCR) signaling in diffuse large B-cell lymphoma as a model system to establish a computational framework to optimize combinatorial therapy in silico. We constructed a detailed kinetic model of the BCR signaling network, which captured the known complex cross-talk between the NFκB, ERK, and AKT pathways and multiple feedback loops. Combining this signaling model with a data-derived tumor growth model, we predicted viability responses of many single drug and drug combinations in agreement with experimental data. Under this framework, we exhaustively predicted and ranked...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Wei Du, Rebecca Goldstein, Yanwen Jiang, Omar Aly, Leandro Cerchietti, Ari Melnick, Olivier Elemento Tags: Integrated Systems and Technologies Source Type: research
Behind the Scenes: Endo/Exocytosis in the Acquisition of Metastatic Traits
Alterations of endo/exocytic proteins have long been associated with malignant transformation, and genes encoding membrane trafficking proteins have been identified as bona fide drivers of tumorigenesis. Focusing on the mechanisms underlying the impact of endo/exocytic proteins in cancer, a scenario emerges in which altered trafficking routes/networks appear to be preferentially involved in the acquisition of prometastatic traits. This involvement in metastasis frequently occurs through the integration of programs leading to migratory/invasive phenotypes, survival and resistance to environmental stresses, epithelial-to-mes...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Letizia Lanzetti, Pier Paolo Di Fiore Tags: Reviews Source Type: research
The Host Microbiome Regulates and Maintains Human Health: A Primer and Perspective for Non-Microbiologists
Humans consider themselves discrete autonomous organisms, but recent research is rapidly strengthening the appreciation that associated microorganisms make essential contributions to human health and well being. Each person is inhabited and also surrounded by his/her own signature microbial cloud. A low diversity of microorganisms is associated with a plethora of diseases, including allergy, diabetes, obesity, arthritis, inflammatory bowel diseases, and even neuropsychiatric disorders. Thus, an interaction of microorganisms with the host immune system is required for a healthy body. Exposure to microorganisms from the mome...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Sunil Thomas, Jacques Izard, Emily Walsh, Kristen Batich, Pakawat Chongsathidkiet, Gerard Clarke, David A. Sela, Alexander J. Muller, James M. Mullin, Korin Albert, John P. Gilligan, Katherine DiGuilio, Rima Dilbarova, Walker Alexander, George C. Prenderg Tags: Reviews Source Type: research
Highlights from Recent Cancer Literature
(Source: Cancer Research)
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Tags: Breaking Advances Source Type: research
