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Cancer Research

Debra H Josephs, Heather J Bax, Tihomir Dodev, Mirella Georgouli, Mano Nakamura, Giulia Pellizzari, Louise Saul, Panagiotis Karagiannis, Anthony Cheung, Cecilia Herraiz, Kristina M Ilieva, Isabel Correa, Matthew Fittall, Silvia Crescioli, Patrycja Gazinska, Natalie Woodman, Silvia Mele, Giulia Chiaruttini, Amy E Gilbert, Alexander Koers, Marguerite Bracher, Christopher Selkirk, Heike Lentfer, Claire Barton, Elliott Lever, Gareth Muirhead, Sophia Tsoka, Silvana Canevari, Mariangela Figini, Ana Montes, Noel Downes, David Dombrowicz, Christopher Corrigan, Andrew J Beavil, Frank O Nestle, Paul S Jones, Hannah J Gould, Victoria Sanz-Moreno, Philip J Blower, James Spicer, Sophia N Karagiannis
IgE antibodies are key mediators of anti-parasitic immune responses, but their potential for cancer treatment via antibody-directed cell-mediated cytotoxicity (ADCC) has been little studied. Recently, tumor antigen-specific IgEs were reported to restrict cancer cell growth by engaging high-affinity Fc receptors on monocytes and macrophages, however, the underlying therapeutic mechanisms were undefined and in vivo proof-of-concept was limited. Here, an immunocompetent rat model was designed to recapitulate the human IgE-Fcε receptor system for cancer studies...
January 17, 2017: Cancer Research
Maeva Dufies, Sandy Giuliano, Damien Ambrosetti, Audrey Claren, Papa Diogop Ndiaye, Michalis Mastri, Walid Moghrabi, Lindsay S Cooley, Marc Ettaiche, Emmanuel Chamorey, Julien Parola, Valerie Vial, Marilena Lupu-Plesu, Jean-Christophe Bernhard, Alain Ravaud, Delphine Borchiellini, Jean Marc Ferrero, Andreas Bikfalvi, John M L Ebos, Khalid S A Khabar, Renaud Grepin, Gilles Pagès
Sunitinib is an antiangiogenic therapy given as a first-line treatment for renal cell carcinoma (RCC). While treatment improves progression-free survival, most patients relapse. We hypothesized that patient relapse can stem from the development of a lymphatic network driven by the production of the main growth factor for lymphatic endothelial cells, vascular endothelial growth factor C (VEGFC). In this study, we found that sunitinib can stimulate VEGFC gene transcription and increase VEGFC mRNA half-life. Additionally, sunitinib activated p38 MAP kinase, which resulted in the upregulation/activity of HuR and inactivation of tristetraprolin, two AU-rich-element binding proteins...
January 13, 2017: Cancer Research
Linjie Zhao, Gaili Ji, Xiaobing Le, Chenlu Wang, Lian Xu, Min Feng, Yaguang Zhang, Huiliang Yang, Yu Xuan, Yanfei Yang, Lingzi Lei, Qilian Yang, Wayne Bond Lau, Bonnie Lau, Yi Chen, Xiangbing Deng, Shaohua Yao, Tao Yi, Xia Zhao, Yuquan Wei, Shengtao Zhou
The majority of patients with epithelial ovarian cancer are diagnosed at a late stage when peritoneal metastases exist, however, there is little knowledge of the metastatic process in this disease setting. In this study, we report the identification of the long non-coding RNA LINC00092 as a nodal driver of metastatic progression mediated by cancer-associated fibroblasts (CAF). Pro-metastatic properties of CAF in vitro and in vivo were found to associate with elevated expression of the chemokine CXCL14. In clinical specimens, elevated levels of CXCL14 in CAF also correlated with poor prognosis...
January 13, 2017: Cancer Research
Rina Gendelman, Heming Xing, Olga K Mirzoeva, Preeti Sarde, Christina Curtis, Heidi Feiler, Paul McDonagh, Joe W Gray, Iya Khalil, W Michael Korn
Molecular networks governing cellular responses to targeted therapies are complex dynamic systems with non-intuitive behaviors. Here we applied a novel computational strategy to infer probabilistic causal relationships between network components based on gene expression. We constructed a model comprised of an ensemble of networks using multidimensional data from cell line models of cell cycle arrest caused by inhibition of MEK1/2. Through simulation of reverse-engineered Bayesian network modeling, we generated predictions of G1-S transition...
January 13, 2017: Cancer Research
Mia Niklasson, Gianluca Maddalo, Zuzana Sramkova, Ercan Mutlu, Shimei Wee, Petra Sekyrova, Linnéa Schmidt, Nicolas Fritz, Ivar Dehnisch, Gregorios Kyriatzis, Michaela Krafcikova, Brittany B Carson, Jennifer Feenstra, Voichita D Marinescu, Anna Segerman, Martin Haraldsson, Anna-Lena Gustavsson, Lars Gj Hammarström, Annika Jenmalm-Jensen, Lene Uhrbom, A F Maarten Altelaar, Sten Linnarsson, Per Uhlén, Lukas Trantirek, C Theresa Vincent, Sven Nelander, Per Øyvind Enger, Michael Andäng
Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca2+ and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown...
January 13, 2017: Cancer Research
Jin Kyung Rho, In Young Lee, Yun Jung Choi, Chang-Min Choi, Jae-Young Hur, Jong Sung Koh, Jaekyoo Lee, Byung-Chul Suh, Ho-Juhn Song, Paresh Salgaonkar, Jungmi Lee, Jaesang Lee, Dong Sik Jung, Sang-Yeob Kim, Dong-Cheol Woo, In-Jeoung Baek, Joo-Yong Lee, Chang Hoon Ha, Young Hoon Sung, Jeong Kon Kim, Woo Sung Kim, Joon Seon Song, Cheol Hyeon Kim, Trever G Bivona, Jae Cheol Lee
The clinical utility of approved EGFR small molecule kinase inhibitors is plagued both by toxicity against wild-type EGFR and by metastatic progression in the central nervous system (CNS), a disease sanctuary site. Here we report the discovery and preclinical efficacy of GNS-1486 and GNS-1481, two novel small molecule EGFR kinase inhibitors that are selective for T790M mutant isoforms of EGFR. Both agents were effective in multiple mouse xenograft models of human lung adenocarcinoma (T790M positive or negative), exhibiting less activity against wild-type EGFR than existing approved EGFR kinase inhibitors (including osimertinib)...
January 12, 2017: Cancer Research
Chunling Luo, Yuanming Cheng, Yuguo Liu, Linlin Chen, Lina Liu, Ning Wei, Zhiqin Xie, Wenwu Wu, Ying Feng
Aberrant RNA splicing is recognized to contribute to cancer pathogenesis but the underlying mechanisms remain mainly obscure. Here we report that the splicing factor SRSF2 is upregulated frequently in human hepatocellular carcinoma (HCC) where this event is associated with poor prognosis in patients. RNA-seq and other molecular analyses were used to identify SRSF2-regulated alternative splicing events. SRSF2 binding within an alternative exon was associated with its inclusion in the RNA, whereas SRSF2 binding in a flanking constitutive exon was associated with exclusion of the alternative exon...
January 12, 2017: Cancer Research
Sheeba Irshad, Fabian Flores-Borja, Katherine Lawler, James Monypenny, Rachel Evans, Victoria Male, Peter Gordon, Anthony Cheung, Patrycja Gazinska, Farzana Noor, Felix Wong, Anita Grigoriadis, Gilbert Fruhwirth, Paul R Barber, Natalie Woodman, Dominic Patel, Manuel Rodriguez-Justo, Julie Owen, Stewart G Martin, Sarah Pinder, Cheryl Gillett, Simon P Poland, Simon Ameer-Beg, Frank Mccaughan, Leo Carlin, Uzma Hasan, David R Withers, Peter Lane, Borivoj Vojnovic, Sergio A Quezada, Paul Ellis, Andrew N J Tutt, Tony Ng
Cancer cells tend to metastasize first to tumor-draining lymph nodes (LN), but the mechanisms mediating cancer cell invasion into the lymphatic vasculature remain little understood. Here we show that in the human breast tumor microenvironment (TME) the presence of increased numbers of RORγt+ group 3 innate lymphoid cells (ILC3) correlates with an increased likelihood of LN metastasis. In a preclinical mouse model of breast cancer, CCL21-mediated recruitment of ILC3 to tumors stimulated the production of the CXCL13 by TME stromal cells, which in turn promoted ILC3-stromal interactions and production of the cancer cell motile factor RANKL...
January 12, 2017: Cancer Research
Yanfang Song, Yu Gan, Qing Wang, Zihong Meng, Guohua Li, Yuling Shen, Yufeng Wu, Peiying Li, Ming Yao, Jianren Gu, Hong- Tu
Mice housed in an enriched environment (EE) display a tumor-resistant phenotype due to the eustress stimulation. However, the mechanisms underlying this EE-induced comprehensive protection against cancers remain largely unexplained. In this study, we observed a significant antitumor effect induced by EE in murine pancreatic cancer and lung cancer models. Intriguingly, while this effect remained intact in T/B lymphocyte-deficient Rag1-/- mice, it was nearly eliminated in natural killer (NK) cell-deficient Beige mice or in antibody-mediated NK cell-depleted mice, suggesting a predominant role of NK cells in mediating the tumor inhibition caused by EE...
January 12, 2017: Cancer Research
Sherly Mardiana, Liza B John, Melissa A Henderson, Clare Y Slaney, Bianca von Scheidt, Lauren Giuffrida, Alexander J Davenport, Joseph A Trapani, Paul J Neeson, Sherene Loi, Nicole M Haynes, Michael H Kershaw, Paul A Beavis, Phillip K Darcy
Adoptive immunotherapy utilizing chimeric antigen receptor (CAR) T cells has demonstrated high success rates in hematological cancers, but results against solid malignancies have been limited to date, due in part to the immunosuppressive tumor microenvironment. Activation of the 4-1BB (CD137) pathway using an agonistic α-4-1BB antibody is known to provide strong co-stimulatory signals for augmenting and diversifying T cell responses. We therefore hypothesized that a combination of α-4-1BB and CAR T cell therapy would result in improved anti-tumor responses...
January 12, 2017: Cancer Research
Tomasz B Owczarek, Takashi Kobayashi, Ricardo Ramirez, Lijie Rong, Anna M Puzio-Kuter, Gopa Iyer, Min Yuen Teo, Francisco Sanchez-Vega, Jingqiang Wang, Nikolaus Schultz, Tian Zheng, David B Solit, Hikmat A Al-Ahmadie, Cory Abate-Shen
Muscle invasive bladder cancer (MIBC) generally responds poorly to treatment and tends to exhibit significant mortality. Here we show that expression of the tumor suppressor p14ARF (ARF) is upregulated in aggressive subtypes of MIBC. Accumulation of ARF in the nucleolus is associated with poor outcome and attenuated response to chemotherapy. In both genetically-engineered mouse (GEM) models and murine xenograft models of human MIBC, we demonstrate that tumors expressing ARF failed to respond to treatment with the platinum-based chemotherapy agent cisplatin...
January 12, 2017: Cancer Research
Brett Schrand, Bhavna Verma, Agata Levay, Shradha Patel, Iris Castro, Ana Paula Benaduce, Randall Brenneman, Oliver Umland, Hideo Yagita, Eli Gilboa, Adrian S Ishkanian
Radiotherapy can elicit systemic immune control of local tumors and distant nonirradiated tumor lesions, known as the abscopal effect. While this effect is enhanced using checkpoint blockade or costimulatory antibodies, objective responses remain suboptimal. As radiotherapy can induce secretion of VEGF and other stress products in the tumor microenvironment, we hypothesized that targeting immune modulatory drugs to such products will not only reduce toxicity but also broaden the scope of tumor-targeted immunotherapy...
January 12, 2017: Cancer Research
Lawrence Fong, David Y Oh, Jason Cham, Li Zhang, Grant Fong, Serena S Kwek, Mark Klinger, Malek Faham
Immune checkpoint inhibitors can induce clinical responses with many cancers but also immune-related adverse events (IRAEs). Mechanisms driving IRAEs are unknown. Because CTLA-4 blockade leads to proliferation of circulating T cells, we examined whether ipilimumab leads to clonal expansion of tissue-reactive T cells. Rather than narrowing the T cell repertoire to a limited number of clones, ipilimumab induced greater repertoire diversification in IRAE patients compared to patients without IRAEs, with increases in the numbers of clonotypes, including newly detected clones, and declines in T cell clonality overall...
December 28, 2016: Cancer Research
Stacey A Ward, Nicole M Warrington, Sara Taylor, Najla Kfoury, Jingqin Luo, Joshua B Rubin
The CXCR4 chemokine and sonic hedgehog (SHH) morphogen pathways are validated therapeutic targets in many cancer types, including medulloblastoma. However, single agent treatments with SHH or CXCR4 antagonists have not proven efficacious in clinical trials to date. Here we show that dual inhibition of the SHH and CXCR4 pathways exerts potent antitumor effects in a murine model of SHH-subtype medulloblastoma. This therapeutic synergy resulted in suppression of tumor-propagating cell function and correlated with increased histone H3 lysine 27 trimethylation within the promoters of stem cell genes, resulting in their decreased expression...
December 28, 2016: Cancer Research
Friederike Braig, Malte Kriegs, Beate Habel, Minna Voigtlaender, Tobias Grob, Karina Biskup, Véronique Blanchard, Markus Sack, Anja Thalhammer, Isabel Ben Batalla, Ingke Braren, Simon Laban, Antje Danielczyk, Steffen Goletz, Elzbieta Jakubowicz, Bruno Märkl, Martin Trepel, Rainald Knecht, Kristoffer Riecken, Boris Fehse, Sonja Loges, Carsten Bokemeyer, Mascha Binder
Head and neck squamous cell carcinomas (HNSCC) exhibiting resistance to the EGFR targeting drug cetuximab poses a challenge to their effective clinical management. Here we report a specific mechanism of resistance in this setting based upon the presence of a single nucleotide polymorphism encoding EGFR-K521 (K-allele), which is expressed in >40% of HNSCC cases. Patients expressing the K-allele showed significantly shorter progression-free survival upon palliative treatment with cetuximab plus chemotherapy or radiation...
December 28, 2016: Cancer Research
Ting Li, Hanqing Guo, Xiaodi Zhao, Jiang Jin, Lifeng Zhang, Hong Li, Yuanyuan Lu, Yongzan Nie, Kaichun Wu, Yongquan Shi, Daiming Fan
Molecular links between inflammation and cancer remain obscure despite their great pathogenic significance. The JAK2/STAT3 pathway activated by IL-6 and other pro-inflammatory cytokines has garnered attention as a pivotal link in cancer pathogenesis, but the basis for its activation in cancer cells is not understood. Here we report that an IL-6-triggered feedback loop involving STAT3-mediated suppression of miR-520d-5p and its downstream target cyclophilin B (CypB) regulates the growth and survival of gastric cancer cells...
December 23, 2016: Cancer Research
Joshua N Sampson, Roni T Falk, Catherine Schairer, Steven C Moore, Barbara J Fuhrman, Cher M Dallal, Doug C Bauer, Joanne F Dorgan, Xiao-Ou Shu, Wei Zheng, Louise A Brinton, Mitchell H Gail, Regina G Ziegler, Xia Xu, Robert Hoover, Gretchen L Gierach
Endogenous estradiol and estrone are linked causally to increased risks of breast cancer. In this study, we evaluated multiple competing hypotheses for how metabolism of these parent estrogens may influence risk. Prediagnostic concentrations of estradiol, estrone, and 13 metabolites were measured in 1298 postmenopausal cases of breast cancer and 1524 matched controls in four separate patient cohorts. Median time between sample collection and diagnosis was 4.4-12.7 years across the cohorts. Estrogen analytes were measured in serum or urine by liquid chromatographic-tandem mass spectrometry...
December 23, 2016: Cancer Research
Joseph W Wragg, Victoria L Heath, Roy Bicknell
Anti-angiogenic therapies have failed to confer survival benefits in patients with metastatic breast cancer (mBC). However, to date there has not been an inquiry into roles for acquired versus innate drug resistance in this setting. In this study, we report roles for these distinct phenotypes in determining therapeutic response in a murine model of mBC resistance to the anti-angiogenic tyrosine kinase inhibitor sunitinib. Using tumor measurement and vascular patterning approaches, we differentiated tumors displaying innate versus acquired resistance...
December 23, 2016: Cancer Research
Rajdeep Das, Phillip A Gregory, Rayzel C Fernandes, Iza Denis, Qingqing Wang, Scott L Townley, Shuang G Zhao, Adrienne Hanson, Marie A Pickering, Heather K Armstrong, Noor A Lokman, Esmaeil Ebrahimie, Elai Davicioni, Robert B Jenkins, R Jeffrey Karnes, Ashley E Ross, Robert B Den, Eric A Klein, Kim N Chi, Hayley S Ramshaw, Elizabeth D Williams, Amina Zoubedi, Gregory J Goodall, Felix Y Feng, Lisa M Butler, Wayne D Tilley, Luke A Selth
Serum levels of microRNA-194 (miR-194) have been reported to predict prostate cancer recurrence after surgery, but its functional contributions to this disease have not been studied. Herein, it is demonstrated that miR-194 is a driver of prostate cancer metastasis. Prostate tissue levels of miR-194 were associated with disease aggressiveness and poor outcome. Ectopic delivery of miR-194 stimulated migration, invasion and epithelial-mesenchymal transition (EMT) in human prostate cancer cell lines, and stable overexpression of miR-194 enhanced metastasis of intravenous and intraprostatic tumor xenografts...
December 23, 2016: Cancer Research
Ioannis I Verginadis, Rahul Kanade, Brett Bell, Sravya Koduri, Edgar Ben-Josef, Constantinos Koumenis
Radiation is an important treatment modality for gastrointestinal tumors but intestinal injury is a common side effect. Here we describe a physiologically relevant model for studying the molecular determinants of radiation-induced intestinal damage and testing novel radioprotectors. The model employs a radiopaque marker implanted into the surface of the mouse jejunum, serving as a fiducial marker for precise radiation targeting. Mice were imaged with Cone-Beam CT (CBCT) and irradiated to the marked area using the Small Animal Radiation Research Platform (SARRP)...
December 23, 2016: Cancer Research
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