bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types
Authors: Chartier Cecile , Raval Janak , Axelrod Fumiko , Bond Chris , Cain Jennifer , Dee-Hoskins Cristina , Ma Shirley , Fischer Marcus M. , Shah Jalpa , Wei Jie , Ji May , Lam Andrew , Stroud Michelle , Yen Wan-Ching , Yeung Pete , Cancilla Belinda , O'Young Gilbert , Wang Min , Kapoun Ann M. , Lewicki John , Hoey Timothy , Gurney Austin 
Published: January 2016

Abstract
Deregulation of the β-catenin signaling has long been associated with cancer. Intracellular components of this pathway, including axin, APC, and β-catenin, are frequently mutated in a range of human tumors, but the contribution of specific extracellular ligands that promote cancer development through this signaling axis remains unclear. We conducted a reporter-based screen in a panel of human tumors to identify secreted factors that stimulate β-catenin signaling. Through this screen and further molecular characterization, we found that R-spondin (RSPO) proteins collaborate with Wnt proteins to activate β-catenin. RSPO family members were expressed in several human tumors representing multiple malignancies, including ovarian, pancreatic, colon, breast, and lung cancer. We generated specific monoclonal antibody antagonists of RSPO family members and found that anti-RSPO treatment markedly inhibited tumor growth in human patient-derived tumor xenograft models, either as single agents or in combination with chemotherapy. Furthermore, blocking RSPO signaling reduced the tumorigenicity of cancer cells based on serial transplantation studies. Moreover, gene-expression analyses revealed that anti-RSPO treatment in responsive tumors strongly inhibited β-catenin target genes known to be associated with cancer and normal stem cells. Collectively, our results suggest that the RSPO family is an important stimulator of β-catenin activity in many human tumors and highlight a new effective approach for therapeutically modulating this fundamental signaling axis. Cancer Res; 76(3); 713–23. ©2015 AACR.
EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer
Authors: Amato Katherine R. , Wang Shan , Tan Li , Hastings Andrew K. , Song Wenqiang , Lovly Christine M. , Meador Catherine B. , Ye Fei , Lu Pengcheng , Balko Justin M. , Colvin Daniel C. , Cates Justin M. , Pao William , Gray Nathanael S. , Chen Jin 
Published: January 2016

Abstract
Despite the success of treating EGFR-mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKI), all patients eventually acquire resistance to these therapies. Although various resistance mechanisms have been described, there are currently no FDA-approved therapies that target alternative mechanisms to treat lung tumors with acquired resistance to first-line EGFR TKI agents. Here we found that EPHA2 is overexpressed in EGFR TKI-resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib-resistant tumor cells harboring EGFRT790M mutations in vitro and inhibited tumor growth and progression in an inducible EGFRL858R+T790M-mutant lung cancer model in vivo. Targeting EPHA2 in erlotinib-resistant cells decreased S6K1-mediated phosphorylation of cell death agonist BAD, resulting in reduced tumor cell proliferation and increased apoptosis. Furthermore, pharmacologic inhibition of EPHA2 by the small-molecule inhibitor ALW-II-41-27 decreased both survival and proliferation of erlotinib-resistant tumor cells and inhibited tumor growth in vivo. ALW-II-41-27 was also effective in decreasing viability of cells with acquired resistance to the third-generation EGFR TKI AZD9291. Collectively, these data define a role for EPHA2 in the maintenance of cell survival of TKI-resistant, EGFR-mutant lung cancer and indicate that EPHA2 may serve as a useful therapeutic target in TKI-resistant tumors. Cancer Res; 76(2); 305–18. ©2016 AACR.
JARID1D Is a Suppressor and Prognostic Marker of Prostate Cancer Invasion and Metastasis
Authors: Li Na , Dhar Shilpa S. , Chen Tsai-Yu , Kan Pu-Yeh , Wei Yongkun , Kim Jae-Hwan , Chan Chia-Hsin , Lin Hui-Kuan , Hung Mien-Chie , Lee Min Gyu 
Published: January 2016

Abstract
Entire or partial deletions of the male-specific Y chromosome are associated with tumorigenesis, but whether any male-specific genes located on this chromosome play a tumor-suppressive role is unknown. Here, we report that the histone H3 lysine 4 (H3K4) demethylase JARID1D (also called KDM5D and SMCY), a male-specific protein, represses gene expression programs associated with cell invasiveness and suppresses the invasion of prostate cancer cells in vitro and in vivo. We found that JARID1D specifically repressed the invasion-associated genes MMP1, MMP2, MMP3, MMP7, and Slug by demethylating trimethyl H3K4, a gene-activating mark, at their promoters. Our additional results demonstrated that JARID1D levels were highly downregulated in metastatic prostate tumors compared with normal prostate tissues and primary prostate tumors. Furthermore, the JARID1D gene was frequently deleted in metastatic prostate tumors, and low JARID1D levels were associated with poor prognosis in prostate cancer patients. Taken together, these findings provide the first evidence that an epigenetic modifier expressed on the Y chromosome functions as an anti-invasion factor to suppress the progression of prostate cancer. Our results also highlight a preclinical rationale for using JARID1D as a prognostic marker in advanced prostate cancer. Cancer Res; 76(4); 831–43. ©2016 AACR.
Interactions between Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive Src/Sox2/miR-302b–Mediated Malignant Progression
Authors: Picon-Ruiz Manuel , Pan Chendong , Drews-Elger Katherine , Jang Kibeom , Besser Alexandra H. , Zhao Dekuang , Morata-Tarifa Cynthia , Kim Minsoon , Ince Tan A. , Azzam Diana J. , Wander Seth A. , Wang Bin , Ergonul Burcu , Datar Ram H. , Cote Richard J. , Howard Guy A. , El-Ashry Dorraya , Torné-Poyatos Pablo , Marchal Juan A. , Slingerland Joyce M. 
Published: January 2016

Abstract
Consequences of the obesity epidemic on cancer morbidity and mortality are not fully appreciated. Obesity is a risk factor for many cancers, but the mechanisms by which it contributes to cancer development and patient outcome have yet to be fully elucidated. Here, we examined the effects of coculturing human-derived adipocytes with established and primary breast cancer cells on tumorigenic potential. We found that the interaction between adipocytes and cancer cells increased the secretion of proinflammatory cytokines. Prolonged culture of cancer cells with adipocytes or cytokines increased the proportion of mammosphere-forming cells and of cells expressing stem-like markers in vitro. Furthermore, contact with immature adipocytes increased the abundance of cancer cells with tumor-forming and metastatic potential in vivo. Mechanistic investigations demonstrated that cancer cells cultured with immature adipocytes or cytokines activated Src, thus promoting Sox2, c-Myc, and Nanog upregulation. Moreover, Sox2-dependent induction of miR-302b further stimulated cMYC and SOX2 expression and potentiated the cytokine-induced cancer stem cell–like properties. Finally, we found that Src inhibitors decreased cytokine production after coculture, indicating that Src is not only activated by adipocyte or cytokine exposures, but is also required to sustain cytokine induction. These data support a model in which cancer cell invasion into local fat would establish feed-forward loops to activate Src, maintain proinflammatory cytokine production, and increase tumor-initiating cell abundance and metastatic progression. Collectively, our findings reveal new insights underlying increased breast cancer mortality in obese individuals and provide a novel preclinical rationale to test the efficacy of Src inhibitors for breast cancer treatment. Cancer Res; 76(2); 491–504. ©2016 AACR.
Infiltrating Macrophages Induce ERα Expression through an IL17A-mediated Epigenetic Mechanism to Sensitize Endometrial Cancer Cells to Estrogen
Authors: Ning Chengcheng , Xie Bingying , Zhang Lin , Li Chunsheng , Shan Weiwei , Yang Bingyi , Luo Xuezhen , Gu Chao , He Qizhi , Jin Hongyan , Chen Xiaojun , Zhang Zhenbo , Feng Youji 
Published: January 2016

Abstract
Persistent unopposed estrogen stimulation is a central oncogenic mechanism driving the formation of type I endometrial cancer. Recent epidemiologic and clinical studies of endometrial cancer have also revealed a role for insulin resistance, clinically manifested by chronic inflammation. However, the role of inflammation in estrogen-driven endometrial cancer is not well characterized. In this study, we investigated the association between infiltrating macrophages and estrogen sensitivity in endometrial cancer. Evaluating tissue samples and serum from patients with precancerous lesions or endometrial cancer, we found that tissue macrophage infiltration, but not serum estradiol levels, correlated positively with endometrial cancer development. Furthermore, IL4/IL13-induced CD68+CD163+ macrophages enhanced the proliferative effects of estradiol in endometrial cancer cells by upregulating estrogen receptor alpha (ERα), but not ERβ. Mechanistic investigations revealed that CD68+CD163+ macrophages secreted cytokines, such as IL17A, that upregulated ERα expression through TET1-mediated epigenetic modulation of the ERα gene. Overall, our findings show how cytokines produced by infiltrating macrophages in the endometrial microenvironment can induce epigenetic upregulation of ERα expression, which in turn sensitizes endometrial cells to estrogen stimulation. The concept that inflammation-induced estrogen sensitivity in the endometrium acts as a driver of type I endometrial cancer has implications for infiltrating macrophages as a prognostic biomarker of progression in this disease setting. Cancer Res; 76(6); 1354–66. ©2016 AACR.
Spatial Modeling of Drug Delivery Routes for Treatment of Disseminated Ovarian Cancer
Authors: Winner Kimberly R. Kanigel , Steinkamp Mara P. , Lee Rebecca J. , Swat Maciej , Muller Carolyn Y. , Moses Melanie E. , Jiang Yi , Wilson Bridget S. 
Published: January 2016

Abstract
In ovarian cancer, metastasis is typically confined to the peritoneum. Surgical removal of the primary tumor and macroscopic secondary tumors is a common practice, but more effective strategies are needed to target microscopic spheroids persisting in the peritoneal fluid after debulking surgery. To treat this residual disease, therapeutic agents can be administered by either intravenous or intraperitoneal infusion. Here, we describe the use of a cellular Potts model to compare tumor penetration of two classes of drugs (cisplatin and pertuzumab) when delivered by these two alternative routes. The model considers the primary route when the drug is administered either intravenously or intraperitoneally, as well as the subsequent exchange into the other delivery volume as a secondary route. By accounting for these dynamics, the model revealed that intraperitoneal infusion is the markedly superior route for delivery of both small-molecule and antibody therapies into microscopic, avascular tumors typical of patients with ascites. Small tumors attached to peritoneal organs, with vascularity ranging from 2% to 10%, also show enhanced drug delivery via the intraperitoneal route, even though tumor vessels can act as sinks during the dissemination of small molecules. Furthermore, we assessed the ability of the antibody to enter the tumor by in silico and in vivo methods and suggest that optimization of antibody delivery is an important criterion underlying the efficacy of these and other biologics. The use of both delivery routes may provide the best total coverage of tumors, depending on their size and vascularity. Cancer Res; 76(6); 1320–34. ©2015 AACR.
miR-892b Silencing Activates NF-κB and Promotes Aggressiveness in Breast Cancer
Authors: Jiang Lili , Yu Liang , Zhang Xin , Lei Fangyong , Wang Lan , Liu Xiangxia , Wu Shu , Zhu Jinrong , Wu Geyan , Cao Lixue , Liu Aibin , Song Libing , Li Jun 
Published: January 2016

Abstract
The strength and duration of NF-κB signaling is tightly controlled at multiple levels under physiologic conditions, but the mechanism underlying constitutive activation of the NF-κB pathway in cancer remains unclear. In this study, we investigated miRNA-mediated regulation of the NF-κB cascade in breast cancer. We report that miR-892b expression was significantly downregulated in human breast cancer specimens and correlated with poor patient survival. Overexpression of miR-892b in breast cancer cells significantly decreased tumor growth, metastatic capacity, and the ability to induce angiogenesis, whereas miR-892b depletion enhanced these properties, in vitro and in vivo. Furthermore, we demonstrate that miR-892b attenuated NF-κB signaling by directly targeting and suppressing multiple mediators of NF-κB, including TRAF2, TAK1, and TAB3, and thus, miR-892b silencing in breast cancer cells sustains NF-κB activity. Moreover, miR-892b downregulation was attributed to aberrant hypermethylation of its promoter. Taken together, our results provide insight into a new mechanism by which NF-κB signaling becomes constitutively activated in breast cancer and suggest a tumor-suppressive role for miR-829b, prompting further investigation into miRNA mimics for cancer therapy. Cancer Res; 76(5); 1101–11. ©2016 AACR.
SOX4 Is Essential for Prostate Tumorigenesis Initiated by PTEN Ablation
Authors: Bilir Birdal , Osunkoya Adeboye O. , Wiles W. Guy , Sannigrahi Soma , Lefebvre Veronique , Metzger Daniel , Spyropoulos Demetri D. , Martin W. David , Moreno Carlos S. 
Published: January 2016

Abstract
Understanding remains incomplete of the mechanisms underlying initiation and progression of prostate cancer, the most commonly diagnosed cancer in American men. The transcription factor SOX4 is overexpressed in many human cancers, including prostate cancer, suggesting it may participate in prostate tumorigenesis. In this study, we investigated this possibility by genetically deleting Sox4 in a mouse model of prostate cancer initiated by loss of the tumor suppressor Pten. We found that specific homozygous deletion of Sox4 in the adult prostate epithelium strongly inhibited tumor progression initiated by homozygous loss of Pten. Mechanistically, Sox4 ablation reduced activation of AKT and β-catenin, leading to an attenuated invasive phenotype. Furthermore, SOX4 expression was induced by Pten loss as a result of the activation of PI3K–AKT–mTOR signaling, suggesting a positive feedback loop between SOX4 and PI3K–AKT–mTOR activity. Collectively, our findings establish that SOX4 is a critical component of the PTEN/PI3K/AKT pathway in prostate cancer, with potential implications for combination-targeted therapies against both primary and advanced prostate cancers. Cancer Res; 76(5); 1112–21. ©2015 AACR.
Anticancer Effects of Mesothelin-Targeted Immunotoxin Therapy Are Regulated by Tyrosine Kinase DDR1
Authors: Ali-Rahmani Fatima , FitzGerald David J. , Martin Scott , Patel Paresma , Prunotto Marco , Ormanoglu Pinar , Thomas Craig , Pastan Ira 
Published: January 2016

Abstract
Recombinant immunotoxins (RIT) have been highly successful in cancer therapy due, in part, to the high cancer-specific expression of cell surface antigens such as mesothelin, which is overexpressed in mesothelioma, ovarian, lung, breast, and pancreatic cancers, but is limited in normal cells. RG7787 is a clinically optimized RIT consisting of a humanized anti-mesothelin Fab fused to domain III of Pseudomonas exotoxin A, in which immunogenic B-cell epitopes are silenced. To enhance the therapeutic efficacy of RITs, we conducted a kinome RNAi sensitization screen, which identified discoidin domain receptor 1 (DDR1), a collagen-activated tyrosine kinase, as a potential target. The collagen/DDR1 axis is implicated in tumor–stromal interactions and potentially affects tumor response to therapy. Therefore, we investigated the effects of DDR1 on RIT. Knockdown of DDR1 by siRNA or treatment with inhibitor, 7rh, greatly enhanced the cytotoxic activity of RG7787 in several cancer cell lines. Investigation into the mechanism of action showed DDR1 silencing was associated with decreased expression of several ribosomal proteins and enhanced inhibition of protein synthesis. Conversely, induction of DDR1 expression or collagen-stimulated DDR1 activity protected cancer cells from RG7787 killing. Moreover, the combination of RG7787 and DDR1 inhibitor caused greater shrinkage of tumor xenografts than either agent alone. These data demonstrate that DDR1 is a key modulator of RIT activity and represents a novel therapeutic strategy to improve targeting of mesothelin-expressing cancers. Cancer Res; 76(6); 1560–8. ©2015 AACR.
Serum Endotoxins and Flagellin and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) Cohort
Authors: Kong So Yeon , Tran Hao Quang , Gewirtz Andrew T. , McKeown-Eyssen Gail , Fedirko Veronika , Romieu Isabelle , Tjønneland Anne , Olsen Anja , Overvad Kim , Boutron-Ruault Marie-Christine , Bastide Nadia , Affret Aurélie , Kühn Tilman , Kaaks Rudolf , Boeing Heiner , Aleksandrova Krasimira , Trichopoulou Antonia , Kritikou Maria , Vasilopoulou Effie , Palli Domenico , Krogh Vittorio , Mattiello Amalia , Tumino Rosario , Naccarati Alessio , Bueno-de-Mesquita H.B. , Peeters Petra H. , Weiderpass Elisabete , Quirós J. Ramón , Sala Núria , Sánchez María-José , Castaño José María Huerta , Barricarte Aurelio , Dorronsoro Miren , Werner Mårten , Wareham Nicholas J. , Khaw Kay-Tee , Bradbury Kathryn E. , Freisling Heinz , Stavropoulou Faidra , Ferrari Pietro , Gunter Marc J. , Cross Amanda J. , Riboli Elio , Bruce W. Robert , Jenab Mazda 
Published: January 2016

Abstract
Background: Chronic inflammation and oxidative stress are thought to be involved in colorectal cancer development. These processes may contribute to leakage of bacterial products, such as lipopolysaccharide (LPS) and flagellin, across the gut barrier. The objective of this study, nested within a prospective cohort, was to examine associations between circulating LPS and flagellin serum antibody levels and colorectal cancer risk.
Methods: A total of 1,065 incident colorectal cancer cases (colon, n = 667; rectal, n = 398) were matched (1:1) to control subjects. Serum flagellin- and LPS-specific IgA and IgG levels were quantitated by ELISA. Multivariable conditional logistic regression models were used to calculate ORs and 95% confidence intervals (CI), adjusting for multiple relevant confouding factors.
Results: Overall, elevated anti-LPS and anti-flagellin biomarker levels were not associated with colorectal cancer risk. After testing potential interactions by various factors relevant for colorectal cancer risk and anti-LPS and anti-flagellin, sex was identified as a statistically significant interaction factor (Pinteraction &lt; 0.05 for all the biomarkers). Analyses stratified by sex showed a statistically significant positive colorectal cancer risk association for men (fully-adjusted OR for highest vs. lowest quartile for total anti-LPS + flagellin, 1.66; 95% CI, 1.10–2.51; Ptrend, 0.049), whereas a borderline statistically significant inverse association was observed for women (fully-adjusted OR, 0.70; 95% CI, 0.47–1.02; Ptrend, 0.18).
Conclusion: In this prospective study on European populations, we found bacterial exposure levels to be positively associated to colorectal cancer risk among men, whereas in women, a possible inverse association may exist.
Impact: Further studies are warranted to better clarify these preliminary observations. Cancer Epidemiol Biomarkers Prev; 25(2); 291–301. ©2016 AACR.
Immunotherapy against Metastatic Melanoma with Human iPS Cell–Derived Myeloid Cell Lines Producing Type I Interferons
Authors: Miyashita Azusa , Fukushima Satoshi , Nakahara Satoshi , Kubo Yosuke , Tokuzumi Aki , Yamashita Junji , Aoi Jun , Haruta Miwa , Senju Satoru , Nishimura Yasuharu , Jinnin Masatoshi , Ihn Hironobu 
Published: January 2016

Abstract
In recent years, immunotherapy for advanced melanoma has been gaining increased attention. The efficacy of anti-cytotoxic T-lymphocyte antigen 4 antibodies, anti-programmed cell death 1 antibodies, and the BRAFV600E kinase inhibitor has been proven in metastatic melanoma. At the same time, adoptive cell transfer has significant effects against metastatic melanoma; however, it is difficult to apply on a broad scale because of the problems related to cell preparation. To overcome these problems, we developed immune cell therapy using induced pluripotent stem (iPS) cells. The benefit of our method is that a large number of cells can be readily obtained. We focused on macrophages for immune cell therapy because macrophage infiltration is frequently observed in solid cancers. In this study, the efficacy of human iPS cell–derived myeloid cell lines (iPS-ML) genetically modified to express type I IFNs against human melanoma cells was examined. The morphology, phagocytic ability, and surface markers of iPS-ML were similar to those of macrophages. The iPS-ML that express type I IFNs (iPS-ML-IFN) showed significant effects in inhibiting the growth of disseminated human melanoma cells in SCID mice. The infiltration of iPS-ML into the tumor nests was confirmed immunohistologically. The iPS-ML-IFNs increased the expression of CD169, a marker of M1 macrophages that can activate antitumor immunity. The iPS-ML-IFNs could infiltrate into tumor tissue and exert anticancer effects in the local tumor tissue. In conclusion, this method will provide a new therapeutic modality for metastatic melanoma. Cancer Immunol Res; 4(3); 248–58. ©2015 AACR.
Melanoma Brain Metastasis Pseudoprogression after Pembrolizumab Treatment
Authors: Cohen Justine V. , Alomari Ahmed K. , Vortmeyer Alexander O. , Jilaveanu Lucia B. , Goldberg Sarah B. , Mahajan Amit , Chiang Veronica L. , Kluger Harriet M. 
Published: January 2016

Abstract
The role of immunotherapy in treatment of brain metastases is unknown because most trials exclude patients with active brain lesions. As new immunomodulating agents gain approval for many malignancies, it is important to know if they have unique effects in the central nervous system (CNS). Here, we present a case of a patient with progressing brain metastases treated with a single cycle of pembrolizumab, who presented with mental status changes 11 days thereafter. MRI of the brain showed enlargement of CNS lesions with intense central enhancement and diffuse perilesional edema. Histologic evaluation of a resected lesion revealed isolated clusters of tumor cells surrounded by reactive astrocytosis, scattered inflammatory cells, and an abundance of microglial cells. Given the increasing use of immune checkpoint inhibitors in patients with brain metastases from melanoma and other diseases, recognition of pseudoprogression and management with immune suppression are essential. Cancer Immunol Res; 4(3); 179–82. ©2015 AACR.