bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Early Detection of Tumor Cells by Innate Immune Cells Leads to Treg Recruitment through CCL22 Production by Tumor Cells
Authors: Faget Julien , Biota Cathy , Bachelot Thomas , Gobert Michael , Treilleux Isabelle , Goutagny Nadège , Durand Isabelle , Léon-Goddard Sophie , Blay Jean Yves , Caux Christophe , Ménétrier-Caux Christine
Published: March 2023

Abstract
In breast carcinomas, patient survival seems to be negatively affected by the recruitment of regulatory T cells (Treg) within lymphoid aggregates by CCL22. However, the mechanisms underpinning this process, which may be of broader significance in solid tumors, have yet to be described. In this study, we determined how CCL22 production is controlled in tumor cells. In human breast carcinoma cell lines, CCL22 was secreted at low basal levels that were strongly increased in response to inflammatory signals [TNF-α, IFN-γ, and interleukin (IL)-1β], contrasting with CCL17. Primary breast tumors and CD45+ infiltrating immune cells appeared to cooperate in driving CCL22 secretion, as shown clearly in cocultures of breast tumor cell lines and peripheral blood mononuclear cells (PBMC) or their supernatants. We determined that monocyte-derived IL-1β and TNF-α are key players as monocyte depletion or neutralization of these cytokines attenuated secretion of CCL22. However, when purified monocytes were used, exogenous human IFN-γ was also required to generate this response suggesting a role for IFN-γ–producing cells within PBMCs. In this setting, we found that human IFN-γ could be replaced by the addition of (i) IL-2 or K562-activated natural killer (NK) cells or (ii) resting NK cells in the presence of anti-MHC class I antibody. Taken together, our results show a dialogue between NK and tumor cells leading to IFN-γ secretion, which in turn associates with monocyte-derived IL-1β and TNF-α to drive production of CCL22 by tumor cells and subsequent recruitment of Treg. As one validation of this conclusion in primary breast tumors, we showed that NK cells and macrophages tend to colocalize within tumors. In summary, our findings suggest that at early times during tumorigenesis, the detection of tumor cells by innate effectors (monocytes and NK cells) imposes a selection for CCL22 secretion that recruits Treg to evade this early antitumor immune response. Cancer Res; 71(19); 6143–52. ©2011 AACR.
Data from IKKβ and NF-κB Transcription Govern Lymphoma Cell Survival through AKT-Induced Plasma Membrane Trafficking of GLUT1
Authors: Sommermann Thomas G. , O'Neill Kathleen , Plas David R. , Cahir-McFarland Ellen
Published: March 2023

Abstract
All cancer cells require increased nutrient uptake to support proliferation. In this study, we investigated the signals that govern glucose uptake in B-cell lymphomas and determined that the inhibitor of NF-κB-kinase β (IKKβ) induced glucose transporter-1 (GLUT1) membrane trafficking in both viral and spontaneous B-cell lymphomas. IKKβ induced AKT activity, whereas IKKβ-driven NF-κB transcription was required for GLUT1 surface localization downstream of AKT. Activated NF-κB promoted AKT-mediated phosphorylation of the GLUT1 regulator, AKT substrate of 160kD (AS160), but was not required for AKT phosphorylation of the mTOR regulator Tuberous Sclerosis 2 (TSC2). In Epstein-Barr virus–transformed B cells, NF-κB inhibition repressed glucose uptake and induced caspase-independent cell death associated with autophagy. After NF-κB inhibition, an alternate carbon source ameliorated both autophagy and cell death, whereas autophagy inhibitors specifically accelerated cell death. Taken together, the results indicate that NF-κB signaling establishes a metabolic program supporting proliferation and apoptosis resistance by driving glucose import. Cancer Res; 71(23); 7291–300. ©2011 AACR.
Data from Itraconazole Inhibits Angiogenesis and Tumor Growth in Non–Small Cell Lung Cancer
Authors: Aftab Blake T. , Dobromilskaya Irina , Liu Jun O. , Rudin Charles M.
Published: March 2023

Abstract
The antiangiogenic agent bevacizumab has been approved for the treatment of non–small cell lung cancer (NSCLC), although the survival benefit associated with this agent is marginal, and toxicities and cost are substantial. A recent screen for selective inhibitors of endothelial cell proliferation identified the oral antifungal drug itraconazole as a novel agent with potential antiangiogenic activity. In this article, we define and characterize the antiangiogenic and anticancer activities of itraconazole in relevant preclinical models of angiogenesis and lung cancer. Itraconazole consistently showed potent, specific, and dose-dependent inhibition of endothelial cell proliferation, migration, and tube formation in response to both VEGF- and basic fibroblast growth factor–mediated angiogenic stimulation. In vivo, using primary xenograft models of human NSCLC, oral itraconazole showed single-agent growth-inhibitory activity associated with induction of tumor hypoxia-inducible factor 1 alpha expression and marked inhibition of tumor vascularity. Itraconazole significantly enhanced the antitumor efficacy of the chemotherapeutic agent cisplatin in the same model systems. Taken together, these data suggest that itraconazole has potent and selective inhibitory activity against multiple key aspects of tumor-associated angiogenesis in vitro and in vivo, and strongly support clinical translation of its use. Based on these observations, we have initiated a randomized phase II study comparing the efficacy of standard cytotoxic therapy with or without daily oral itraconazole in patients with recurrent metastatic NSCLC. Cancer Res; 71(21); 6764–72. ©2011 AACR.
Data from Apoptosis Inhibitor ARC Promotes Breast Tumorigenesis, Metastasis, and Chemoresistance
Authors: Medina-Ramirez Christina M. , Goswami Sumanta , Smirnova Tatiana , Bamira Daniel , Benson Benjamin , Ferrick Neal , Segall Jeffrey , Pollard Jeffrey W. , Kitsis Richard N.
Published: March 2023

Abstract
Apoptosis repressor with caspase recruitment domain (ARC) inhibits both death receptor- and mitochondrial/ER-mediated pathways of apoptosis. Although expressed mainly in terminally differentiated cells, ARC is markedly upregulated in a variety of human cancers, where its potential contributions have not yet been defined. In this study, we provide evidence of multiple critical pathophysiologic functions for ARC in breast carcinogenesis. In the polyoma middle T-antigen (PyMT) transgenic mouse model of breast cancer, in which endogenous ARC is strongly upregulated, deletion of the ARC-encoding gene nol3 decreased primary tumor burden without affecting tumor onset or multiplicity. More notably, ARC deficiency also limited tumor cell invasion and the number of circulating cancer cells, markedly reducing the number of lung metastases. Conversely, ectopic overexpression of ARC in a PyMT-derived metastatic breast cancer cell line increased invasion in vitro and lung metastasis in vivo. We confirmed these results in a humanized orthotopic model based on MDA-MB-231-derived LM2 metastatic breast cancer cells, in which RNAi-mediated knockdown of ARC levels was shown to reduce tumor volume, local invasion, and lung metastases. Lastly, we found that endogenous levels of ARC conferred chemoresistance in primary tumors and invading cell populations. Our results establish that ARC promotes breast carcinogenesis by driving primary tumor growth, invasion, and metastasis as well as by promoting chemoresistance in invasive cells. Cancer Res; 71(24); 7705–15. ©2011 AACR.
Data from Induction of the RNA Regulator LIN28A Is Required for the Growth and Pathogenesis of RESTless Breast Tumors
Authors: Gunsalus Kearney T.W. , Wagoner Matthew P. , Meyer Kassondra , Potter Wyatt B. , Schoenike Barry , Kim Soyoung , Alexander Caroline M. , Friedl Andreas , Roopra Avtar
Published: March 2023

Abstract
The transcription factor RE1 silencing transcription factor (REST) is lost in approximately 20% of breast cancers. Although it is known that these RESTless tumors are highly aggressive and include all tumor subtypes, the underlying tumorigenic mechanisms remain unknown. In this study, we show that loss of REST results in upregulation of LIN28A, a known promoter of tumor development, in breast cancer cell lines and human breast tumors. We found that LIN28A was a direct transcriptional target of REST in cancer cells and that loss of REST resulted in increased LIN28A expression and enhanced tumor growth both in vitro and in vivo, effects that were dependent on heightened LIN28A expression. Tumors lacking REST expression were locally invasive, consistent with the increased lymph node involvement observed in human RESTless tumors. Clinically, human RESTless breast tumors also displayed significantly enhanced LIN28A expression when compared with non-RESTless tumors. Our findings therefore show a critical role for the REST-LIN28A axis in tumor aggression and suggest a causative relationship between REST loss and tumorigenicity in vivo. Cancer Res; 72(13); 3207–16. ©2012 AACR.
Data from Wnt/Snail Signaling Regulates Cytochrome c Oxidase and Glucose Metabolism
Authors: Lee Su Yeon , Jeon Hyun Min , Ju Min Kyung , Kim Cho Hee , Yoon Gyesoon , Han Song Iy , Park Hye Gyeong , Kang Ho Sung
Published: March 2023

Abstract
Wnt signaling plays a critical role in embryonic development, and its deregulation is closely linked to the occurrence of a number of malignant tumors, including breast and colon cancer. The pathway also induces Snail-dependent epithelial-to-mesenchymal transition (EMT), which is responsible for tumor invasion and metastasis. In this study, we show that Wnt suppresses mitochondrial respiration and cytochrome C oxidase (COX) activity by inhibiting the expression of 3 COX subunits, namely, COXVIc, COXVIIa, and COXVIIc. We found that Wnt induced a glycolytic switch via increased glucose consumption and lactate production, with induction of pyruvate carboxylase (PC), a key enzyme of anaplerosis. In addition, Wnt-induced mitochondrial repression and glycolytic switching occurred through the canonical β-catenin/T-cell factor 4/Snail pathway. Short hairpin RNA–mediated knockdown of E-cadherin, a regulator of EMT, repressed mitochondrial respiration and induced a glycolytic switch via Snail activation, indicating that EMT may contribute to Wnt/Snail regulation of mitochondrial respiration and glucose metabolism. Together, our findings provide a new function for Wnt/Snail signaling in the regulation of mitochondrial respiration (via COX gene expression) and glucose metabolism (via PC gene expression) in tumor growth and progression. Cancer Res; 72(14); 3607–17. ©2012 AACR.
Data from Breast Cancer Subtype-Specific Interactions with the Microenvironment Dictate Mechanisms of Invasion
Authors: Dang Tuyen T. , Prechtl Amanda M. , Pearson Gray W.
Published: March 2023

Abstract
Most ductal breast carcinoma cells are weakly invasive in vitro and in vivo, suggesting that components of their microenvironment may facilitate a transition from in situ to invasive stages during progression. Here, we report that coculture of mammary fibroblasts specifically triggers invasive behavior in basal-type breast cancer cells through a ligand independent mechanism. When cultured alone in organotypic culture, both basal- and luminal-type breast cancer cells formed noninvasive spheroids with characteristics of ductal carcinoma in situ (DCIS). In contrast, when cocultured with mammary fibroblasts, basal-type spheroids exhibited invasive character whereas the luminal-type spheroids retained a benign and noninvasive duct-like architecture. Real-time imaging and functional studies revealed that the specificity of invasion was linked to a unique capacity of basal-type breast cancer cells to move within spheroids. Mammary fibroblasts induced invasion by triggering basal-type breast cancer cells to convert from a noninvasive program of mammary epithelial morphogenesis to an invasive program of sprouting endothelial angiogenesis. Contrary to the existing invasion models, soluble ligands produced by the fibroblasts were not sufficient to trigger invasion. Instead, basal-type invasion relied upon a Cdc42-dependent reorganization of collagen fibers in the extracellular matrix by fibroblasts. Inhibiting basal-type cell movement with clinically relevant drugs blocked invasion both in organotypic culture and in animals, suggesting a new treatment strategy for early-stage patients. Together our findings establish that fibroblast recruitment by basal-type breast cancer cells into early-stage tumors is sufficient to trigger their conversion from a benign, noninvasive DCIS-like stage to a malignant invasive stage. Furthermore, our findings suggest that different subtypes of breast cancer may require distinct types of contributions from the microenvironment to undergo malignant progression. Cancer Res; 71(21); 6857–66. ©2011 AACR.
Data from Activation of the Glucocorticoid Receptor Is Associated with Poor Prognosis in Estrogen Receptor-Negative Breast Cancer
Authors: Pan Deng , Kocherginsky Masha , Conzen Suzanne D.
Published: March 2023

Abstract
Estrogen receptor–negative (ER−) breast cancers have limited treatment options and are associated with earlier relapses. Because glucocorticoid receptor (GR) signaling initiates antiapoptotic pathways in ER− breast cancer cells, we hypothesized that activation of these pathways might be associated with poor prognosis in ER− disease. Here we report findings from a genome-wide study of GR transcriptional targets in a premalignant ER− cell line model of early breast cancer (MCF10A-Myc) and in primary early-stage ER− human tumors. Chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq) coupled to time-course expression profiling led us to identify epithelial-to-mesenchymal transition (EMT) pathways as an important aspect associated with GR activation. We validated these findings by carrying out a meta-analysis of primary breast tumor gene expression from 1,378 early-stage breast cancer patients with long-term clinical follow-up, confirming that high levels of GR expression significantly correlated with shorter relapse-free survival in ER− patients who were treated or untreated with adjuvant chemotherapy. Notably, in ER+ breast cancer patients, high levels of GR expression in tumors were significantly associated with better outcome relative to low levels of GR expression. Gene expression analysis revealed that ER− tumors expressing high GR levels exhibited differential activation of EMT, cell adhesion, and inflammation pathways. Our findings suggest a direct transcriptional role for GR in determining the outcome of poor-prognosis ER− breast cancers. Cancer Res; 71(20); 6360–70. ©2011 AACR.
Data from Human Papillomavirus E7 Enhances Hypoxia-Inducible Factor 1–Mediated Transcription by Inhibiting Binding of Histone Deacetylases
Authors: Bodily Jason M. , Mehta Kavi P.M. , Laimins Laimonis A.
Published: March 2023

Abstract
Infection by human papillomaviruses (HPV) leads to the formation of benign lesions, warts, and in some cases, cervical cancer. The formation of these lesions is dependent upon increased expression of proangiogenic factors. Angiogenesis is linked to tissue hypoxia through the activity of the oxygen-sensitive hypoxia-inducible factor 1α (HIF-1α). Our studies indicate that the HPV E7 protein enhances HIF-1 transcriptional activity whereas E6 functions to counteract the repressive effects of p53. Both high- and low-risk HPV E7 proteins were found to bind to HIF-1α through a domain located in the N-terminus. Importantly, the ability of E7 to enhance HIF-1 activity mapped to the C-terminus and correlated with the displacement of the histone deacetylases HDAC1, HDAC4, and HDAC7 from HIF-1α by E7. Our findings describe a novel role of the E7 oncoprotein in activating the function of a key transcription factor mediating hypoxic responses by blocking the binding of HDACs. Cancer Res; 71(3); 1187–95. ©2010 AACR.
Data from Analysis of Mitosis and Antimitotic Drug Responses in Tumors by In Vivo Microscopy and Single-Cell Pharmacodynamics
Authors: Orth James D. , Kohler Rainer H. , Foijer Floris , Sorger Peter K. , Weissleder Ralph , Mitchison Timothy J.
Published: March 2023

Abstract
Cancer relies upon frequent or abnormal cell division, but how the tumor microenvironment affects mitotic processes in vivo remains unclear, largely due to the technical challenges of optical access, spatial resolution, and motion. We developed high-resolution in vivo microscopy methods to visualize mitosis in a murine xenograft model of human cancer. Using these methods, we determined whether the single-cell response to the antimitotic drug paclitaxel (Ptx) was the same in tumors as in cell culture, observed the impact of Ptx on the tumor response as a whole, and evaluated the single-cell pharmacodynamics (PD) of Ptx (by in vivo PD microscopy). Mitotic initiation was generally less frequent in tumors than in cell culture, but subsequently it proceeded normally. Ptx treatment caused spindle assembly defects and mitotic arrest, followed by slippage from mitotic arrest, multinucleation, and apoptosis. Compared with cell culture, the peak mitotic index in tumors exposed to Ptx was lower and the tumor cells survived longer after mitotic arrest, becoming multinucleated rather than dying directly from mitotic arrest. Thus, the tumor microenvironment was much less proapoptotic than cell culture. The morphologies associated with mitotic arrest were dose and time dependent, thereby providing a semiquantitative, single-cell measure of PD. Although many tumor cells did not progress through Ptx-induced mitotic arrest, tumor significantly regressed in the model. Our findings show that in vivo microscopy offers a useful tool to visualize mitosis during tumor progression, drug responses, and cell fate at the single-cell level. Cancer Res; 71(13); 4608–16. ©2011 AACR.
Data from Prediction and Genetic Demonstration of a Role for Activator E2Fs in Myc-Induced Tumors
Authors: Fujiwara Kenichiro , Yuwanita Inez , Hollern Daniel P. , Andrechek Eran R.
Published: March 2023

Abstract
Advances in genomic signatures have begun to dissect breast cancer heterogeneity and application of these signatures will allow the prediction of which pathways are important in tumor development. Here we used genomic signatures to predict involvement of specific E2F transcription factors in Myc-induced tumors. We genetically tested this prediction by interbreeding Myc transgenics with mice lacking various activator E2F alleles. Tumor latency decreased in the E2F1 mutant background and significantly increased in both the E2F2 and E2F3 mutants. Investigating the mechanism behind these changes revealed a reduction in apoptosis in the E2F1 knockout strain. E2F2 and E2F3 mutant backgrounds alleviated Myc proliferative effects on the pregnant mammary gland, reducing the susceptible tumor target population. Gene expression data from tumors revealed that the E2F2 knockout background resulted in fewer tumors with EMT, corresponding with a reduction in probability of Ras activation. In human breast cancer we found that a low probability of E2F2 pathway activation was associated with increased relapse-free survival time. Together these data illustrate the predictive utility of genomic signatures in deciphering the heterogeneity within breast cancer and illustrate the unique genetic requirements for individual E2Fs in mediating tumorigenesis in both mouse models and human breast cancer. Cancer Res; 71(5); 1924–32. ©2011 AACR.
Data from LPA Receptor Heterodimerizes with CD97 to Amplify LPA-Initiated RHO-Dependent Signaling and Invasion in Prostate Cancer Cells
Authors: Ward Yvona , Lake Ross , Yin Juan Juan , Heger Christopher D. , Raffeld Mark , Goldsmith Paul K. , Merino Maria , Kelly Kathleen
Published: March 2023

Abstract
CD97, an adhesion-linked G-protein–coupled receptor (GPCR), is induced in multiple epithelial cancer lineages. We address here the signaling properties and the functional significance of CD97 expression in prostate cancer. Our findings show that CD97 signals through Gα12/13 to increase RHO-GTP levels. CD97 functioned to mediate invasion in prostate cancer cells, at least in part, by associating with lysophosphatidic acid receptor 1 (LPAR1), leading to enhanced LPA-dependent RHO and extracellular signal–regulated kinase activation. Consistent with its role in invasion, depletion of CD97 in PC3 cells resulted in decreased bone metastasis without affecting subcutaneous tumor growth. Furthermore, CD97 heterodimerized and functionally synergized with LPAR1, a GPCR implicated in cancer progression. We also found that CD97 and LPAR expression were significantly correlated in clinical prostate cancer specimens. Taken together, these findings support the investigation of CD97 as a potential therapeutic cancer target. Cancer Res; 71(23); 7301–11. ©2011 AACR.
Data from Adjuvant Combination and Antigen Targeting as a Strategy to Induce Polyfunctional and High-Avidity T-Cell Responses against Poorly Immunogenic Tumors
Authors: Aranda Fernando , Llopiz Diana , Díaz-Valdés Nancy , Riezu-Boj José Ignacio , Bezunartea Jaione , Ruiz Marta , Martínez Marta , Durantez Maika , Mansilla Cristina , Prieto Jesús , Lasarte Juan José , Borrás-Cuesta Francisco , Sarobe Pablo
Published: March 2023

Abstract
Low antigen expression and an absence of coimmunostimulatory signals may be partly responsible for the low immunogenicity of many tumors. It may be possible to overcome this situation by defining a combination of adjuvants and antigens that can activate a high-avidity antitumor response. Using the poorly immunogenic B16-OVA melanoma cells as tumor model, we tested different combinations of adjuvants and antigens to treat established tumors. In the absence of exogenous antigens, repeated administration of the TLR7 ligand Imiquimod together with anti-CD40 agonistic antibodies activated only innate immunity, which was insufficient to reject intradermal tumors. Administering this adjuvant combination together with OVA as a tumor antigen induced T-cell responses that delayed tumor growth. However, administering a combination of anti-CD40 plus TLR3 and TLR7 ligands, together with antigen targeting to dendritic cells through TLR4, was sufficient to induce tumor rejection in 50% of mice. This response was associated with a greater activation of innate immunity and induction of high-avidity polyfunctional CD8+ T-cell responses, which each contributed to tumor rejection. This therapy activated T-cell responses not only against OVA, which conferred protection against a rechallenge with B16-OVA cells, but also activated T-cell responses against other melanoma-associated antigens. Our findings support the concept that multiple adjuvant combination and antigen targeting may be a useful immunotherapeutic strategy against poorly immunogenic tumors. Cancer Res; 71(9); 3214–24. ©2011 AACR.
Data from Pharmacokinetic Modeling of Tumor Bioluminescence Implicates Efflux, and Not Influx, as the Bigger Hurdle in Cancer Drug Therapy
Authors: Sim Hoon , Bibee Kristin , Wickline Samuel , Sept David
Published: March 2023

Abstract
In vivo bioluminescence imaging is a powerful tool for assessing tumor burden and quantifying therapeutic response in xenograft models. However, this technique exhibits significant variability as a consequence of differences in substrate administration, as well as the tumor size, type, and location. Here, we present a novel pharmacokinetic (PK) approach that utilizes bioluminescence image data. The sample data are taken from mice implanted with a melanoma tumor cell line that was transfected to express the firefly (Photinus pyralis) luciferase gene. At 5, 7, and 10 days postimplant, intraperitoneal injections of D-luciferin were given to monitor the uptake into the tumor, and the tumor volume was measured using ultrasound. A multicompartment PK model was used to simultaneously fit all experiments for each mouse. We observed that the rates of luciferin transport in and out of the tumor exhibited a clear dependence on the tumor volume. Also, the rate of tumor influx increased faster than did the efflux, resulting in a shortening of the time to peak-luciferin concentration as the tumor grows. The time of the peak concentration correlated poorly with the tumor volume, but the peak bioluminescence signal and the area under the curve both exhibited a dependence on the tumor surface area. These results agree with Starling's hypothesis relating the higher interstitial fluid pressure in the tumor with flux across the boundary, and suggest that drug transport may depend more strongly on the surface area of the tumor than its volume. These observations provide a quantitative physical rationale for molecular targeting of therapeutics that enhance trapping and overcome the accelerated efflux kinetics. Cancer Res; 71(3); 686–92. ©2010 AACR.
Data from HER3 Is Required for HER2-Induced Preneoplastic Changes to the Breast Epithelium and Tumor Formation
Authors: Vaught David B. , Stanford Jamie C. , Young Christian , Hicks Donna J. , Wheeler Frank , Rinehart Cammie , Sánchez Violeta , Koland John , Muller William J. , Arteaga Carlos L. , Cook Rebecca S.
Published: March 2023

Abstract
Increasing evidence suggests that HER2-amplified breast cancer cells use HER3/ErbB3 to drive therapeutic resistance to HER2 inhibitors. However, the role of ErbB3 in the earliest events of breast epithelial transformation remains unknown. Using mouse mammary specific models of Cre-mediated ErbB3 ablation, we show that ErbB3 loss prevents the progressive transformation of HER2-overexpressing mammary epithelium. Decreased proliferation and increased apoptosis were seen in MMTV-HER2 and MMTV-Neu mammary glands lacking ErbB3, thus inhibiting premalignant HER2-induced hyperplasia. Using a transgenic model in which HER2 and Cre are expressed from a single polycistronic transcript, we showed that palpable tumor penetrance decreased from 93.3% to 6.7% upon ErbB3 ablation. Penetrance of ductal carcinomas in situ was also decreased. In addition, loss of ErbB3 impaired Akt and p44/42 phosphorylation in preneoplastic HER2-overexpressing mammary glands and in tumors, decreased growth of preexisting HER2-overexpressing tumors, and improved tumor response to the HER2 tyrosine kinase inhibitor lapatinib. These events were rescued by reexpression of ErbB3, but were only partially rescued by ErbB36F, an ErbB3 mutant harboring six tyrosine-to-phenylalanine mutations that block its interaction with phosphatidyl inositol 3-kinase. Taken together, our findings suggest that ErbB3 promotes HER2-induced changes in the breast epithelium before, during, and after tumor formation. These results may have important translational implications for the treatment and prevention of HER2-amplified breast tumors through ErbB3 inhibition. Cancer Res; 72(10); 2672–82. ©2012 AACR.
Data from Thrombospondin-1 Triggers Cell Migration and Development of Advanced Prostate Tumors
Authors: Firlej Virginie , Mathieu Jacques R.R. , Gilbert Cristèle , Lemonnier Loïc , Nakhlé Jessica , Gallou-Kabani Catherine , Guarmit Basma , Morin Aurélie , Prevarskaya Natalia , Delongchamps Nicolas Barry , Cabon Florence
Published: March 2023

Abstract
The antitumor effects of pharmacologic inhibitors of angiogenesis are hampered in patients by the rapid development of tumor resistance, notably through increased invasiveness and accelerated metastasis. Here, we reevaluated the role of the endogenous antiangiogenic thrombospondin 1 (TSP1) in prostate carcinomas in which angiogenesis is an active process. In xenografted tumors, we observed that TSP1 altogether inhibited angiogenesis and fostered tumor development. Our results show that TSP1 is a potent stimulator of prostate tumor cell migration. This effect required CD36, which also mediates TSP1 antiangiogenic activity, and was mimicked by an antiangiogenic TSP1-derived peptide. As suspected for pharmacologic inhibitors of angiogenesis, the TSP1 capacities to increase hypoxia and to trigger cell migration are thus inherently linked. Importantly, although antiangiogenic TSP1 increases hypoxia in vivo, our data show that, in turn, hypoxia induced TSP1, thus generating a vicious circle in prostate tumors. In radical prostatectomy specimens, we found TSP1 expression significantly associated with invasive tumors and with tumors which eventually recurred. TSP1 may thus help select patients at risk of prostate-specific antigen relapse. Together, the data suggest that intratumor disruption of the hypoxic cycle through TSP1 silencing will limit tumor invasion. Cancer Res; 71(24); 7649–58. ©2011 AACR.
Data from Aberrant Lipid Metabolism in Hepatocellular Carcinoma Revealed by Plasma Metabolomics and Lipid Profiling
Authors: Patterson Andrew D. , Maurhofer Olivier , Beyoğlu Diren , Lanz Christian , Krausz Kristopher W. , Pabst Thomas , Gonzalez Frank J. , Dufour Jean-François , Idle Jeffrey R.
Published: March 2023

Abstract
There has been limited analysis of the effects of hepatocellular carcinoma (HCC) on liver metabolism and circulating endogenous metabolites. Here, we report the findings of a plasma metabolomic investigation of HCC patients by ultraperformance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS), random forests machine learning algorithm, and multivariate data analysis. Control subjects included healthy individuals as well as patients with liver cirrhosis or acute myeloid leukemia. We found that HCC was associated with increased plasma levels of glycodeoxycholate, deoxycholate 3-sulfate, and bilirubin. Accurate mass measurement also indicated upregulation of biliverdin and the fetal bile acids 7α-hydroxy-3-oxochol-4-en-24-oic acid and 3-oxochol-4,6-dien-24-oic acid in HCC patients. A quantitative lipid profiling of patient plasma was also conducted by ultraperformance liquid chromatography-electrospray ionization-triple quadrupole mass spectrometry (UPLC-ESI-TQMS). By this method, we found that HCC was also associated with reduced levels of lysophosphocholines and in 4 of 20 patients with increased levels of lysophosphatidic acid [LPA(16:0)], where it correlated with plasma α-fetoprotein levels. Interestingly, when fatty acids were quantitatively profiled by gas chromatography-mass spectrometry (GC-MS), we found that lignoceric acid (24:0) and nervonic acid (24:1) were virtually absent from HCC plasma. Overall, this investigation illustrates the power of the new discovery technologies represented in the UPLC-ESI-QTOFMS platform combined with the targeted, quantitative platforms of UPLC-ESI-TQMS and GC-MS for conducting metabolomic investigations that can engender new insights into cancer pathobiology. Cancer Res; 71(21); 6590–600. ©2011 AACR.
Data from Identification of N-Terminally Truncated Stable Nuclear Isoforms of CDC25B That Are Specifically Involved in G2/M Checkpoint Recovery
Authors: Jullien Denis , Bugler Beatrix , Dozier Christine , Cazales Martine , Ducommun Bernard
Published: March 2023

Abstract
CDC25B phosphatases must activate cyclin B-CDK1 complexes to restart the cell cycle after an arrest in G2 phase caused by DNA damage. However, little is known about the precise mechanisms involved in this process, which may exert considerable impact on cancer susceptibility and therapeutic responses. Here we report the discovery of novel N-terminally truncated CDC25B isoforms, referred to as ΔN-CDC25B, with an exclusively nuclear and nonredundant function in cell cycle re-initiation after DNA damage. ΔN-CDC25B isoforms are expressed from a distinct promoter not involved in expression of canonical full-length isoforms. Remarkably, in contrast to the high lability and spatial dynamism of the full-length isoforms, ΔN-CDC25B isoforms are highly stable and exclusively nuclear, strongly suggesting the existence of two pools of CDC25B phosphatases in the cell that have functionally distinct properties. Using isoform-specific siRNA, we found that depleting full-length isoforms, but not ΔN-CDC25B isoforms, delays entry into mitosis. Thus, in an unperturbed cell cycle, the full-length isoforms are exclusively responsible for activating cyclin B-CDK1. Strikingly, in the late response to DNA damage, we found a CHK1-dependent shift in accumulation of CDC25B isoforms toward the ΔN-CDC25B species. Under this physiological stress condition, the ΔN-CDC25B isoform was found to play a crucial, nonredundant function in restarting the cell cycle after DNA damage-induced G2 phase arrest. Our findings reveal the existence of a previously unrecognized CDC25B isoform that operates specifically in the nucleus to reinitiate G2/M transition after DNA damage. Cancer Res; 71(5); 1968–77. ©2011 AACR.
Data from Identification of Tumorigenic Cells in KrasG12D-Induced Lung Adenocarcinoma
Authors: Cho Huan-Chieh , Lai Chao-Yang , Shao Li-En , Yu John
Published: March 2023

Abstract
We established an inducible KrasG12D-driven lung adenocarcinoma in CCSP-rtTA/TetO-Cre/LSL-KrasG12D mice that enable pursuits of the cellular and molecular processes involved in Kras-induced tumorigenesis. To investigate the cellular origin of this cancer, we first report a strategy using fluorescence-activated cell sorting fractionation that could highly enrich bronchiolar Clara and alveolar type II cells, respectively. The EpCAM+MHCII− cells (bronchiolar origin) were more enriched with tumorigenic cells in generating secondary tumors than EpCAM+MHCII+ cells (alveolar origin) in primary tumors that had been already initiated with oncogenic Kras activation. In addition, secondary tumors derived from EpCAM+MHCII− cells showed diversity of tumor locations compared with those derived from EpCAM+MHCII+ cells. In the alveolar region, secondary tumors from EpCAM+MHCII− cells expressed not only bronchiolar epithelial marker, panCK, but also differentiation marker, proSPC, consistent with the notion that cancer-initiating cells display not only the abilities for self-renewal but also the features of differentiation to generate heterogeneous tumors with phenotypic diversity. Furthermore, high level of ERK1/2 activation and colony-forming ability as well as lack of Sprouty-2 expression were also observed in EpCAM+MHCII− cells. Therefore, these results suggest that bronchiolar Clara cells are the origin of cells and tumorigenesis for KrasG12D-induced neoplasia in the lungs. Cancer Res; 71(23); 7250–8. ©2011 AACR.
Data from Differentiation of NUT Midline Carcinoma by Epigenomic Reprogramming
Authors: Schwartz Brian E. , Hofer Matthias D. , Lemieux Madeleine E. , Bauer Daniel E. , Cameron Michael J. , West Nathan H. , Agoston Elin S. , Reynoird Nicolas , Khochbin Saadi , Ince Tan A. , Christie Amanda , Janeway Katherine A. , Vargas Sara O. , Perez-Atayde Antonio R. , Aster Jon C. , Sallan Stephen E. , Kung Andrew L. , Bradner James E. , French Christopher A.
Published: March 2023

Abstract
NUT midline carcinoma (NMC) is a lethal pediatric tumor defined by the presence of BRD-NUT fusion proteins that arrest differentiation. Here we explore the mechanisms underlying the ability of BRD4-NUT to prevent squamous differentiation. In both gain-of and loss-of-expression assays, we find that expression of BRD4-NUT is associated with globally decreased histone acetylation and transcriptional repression. Bulk chromatin acetylation can be restored by treatment of NMC cells with histone deacetylase inhibitors (HDACi), engaging a program of squamous differentiation and arrested growth in vitro that closely mimics the effects of siRNA-mediated attenuation of BRD4-NUT expression. The potential therapeutic utility of HDACi differentiation therapy was established in three different NMC xenograft models, where it produced significant growth inhibition and a survival benefit. Based on these results and translational studies performed with patient-derived primary tumor cells, a child with NMC was treated with the FDA-approved HDAC inhibitor, vorinostat. An objective response was obtained after five weeks of therapy, as determined by positron emission tomography. These findings provide preclinical support for trials of HDACi in patients with NMC. Cancer Res; 71(7); 2686–96. ©2011 AACR.
Data from Cancer Causes Cardiac Atrophy and Autophagy in a Sexually Dimorphic Manner
Authors: Cosper Pippa F. , Leinwand Leslie A.
Published: March 2023

Abstract
Approximately one-third of cancer deaths are caused by cachexia, a severe form of skeletal muscle and adipose tissue wasting that affects men more than women. The heart also undergoes atrophy in cancer patients, but the mechanisms and the basis for apparent sex differences are unclear. In a mouse colon-adenocarcinoma model, cancer causes a loss of cardiac mass due to a decrease in cardiac myocyte size that is associated with reduced levels of all sarcomeric proteins. Unlike skeletal muscle cachexia, atrophic hearts do not upregulate the ubiquitin-proteasome system or its activity but increase autophagy. Thus, cancer causes cardiac atrophy by a mechanism distinct from that in skeletal muscle. Male tumor-bearing mice have a more severe phenotype than females, including greater cardiac mass loss and mortality, a more robust pro-inflammatory response to the tumor, and greater cardiac autophagy. In females, estrogen protects against cancer-induced cardiac atrophy and body weight loss by signaling through its receptor. Sex differences in cardiac atrophy need to be considered during the treatment of patients suffering from chemotherapy-induced cardiomyopathy to prevent exacerbation of cardiac dysfunction. Cancer Res; 71(5); 1710–20. ©2010 AACR.
Data from Loss of Cell-Surface Laminin Anchoring Promotes Tumor Growth and Is Associated with Poor Clinical Outcomes
Authors: Akhavan Armin , Griffith Obi L. , Soroceanu Liliana , Leonoudakis Dmitri , Luciani-Torres Maria Gloria , Daemen Anneleen , Gray Joe W. , Muschler John L.
Published: March 2023

Abstract
Perturbations in the composition and assembly of extracellular matrices (ECM) contribute to progression of numerous diseases, including cancers. Anchoring of laminins at the cell surface enables assembly and signaling of many ECMs, but the possible contributions of altered laminin anchoring to cancer progression remain undetermined. In this study, we investigated the prominence and origins of defective laminin anchoring in cancer cells and its association with cancer subtypes and clinical outcomes. We found loss of laminin anchoring to be widespread in cancer cells. Perturbation of laminin anchoring originated from several distinct defects, which all led to dysfunctional glycosylation of the ECM receptor dystroglycan. In aggressive breast and brain cancers, defective laminin anchoring was often due to suppressed expression of the glycosyltransferase LARGE. Reduced expression of LARGE characterized a broad array of human tumors in which it was associated with aggressive cancer subtypes and poor clinical outcomes. Notably, this defect robustly predicted poor survival in patients with brain cancers. Restoring LARGE expression repaired anchoring of exogenous and endogenous laminin and modulated cell proliferation and tumor growth. Together, our findings suggest that defects in laminin anchoring occur commonly in cancer cells, are characteristic of aggressive cancer subtypes, and are important drivers of disease progression. Cancer Res; 72(10); 2578–88. ©2012 AACR.
Data from Sorcin Induces a Drug-Resistant Phenotype in Human Colorectal Cancer by Modulating Ca2+ Homeostasis
Authors: Maddalena Francesca , Laudiero Gabriella , Piscazzi Annamaria , Secondo Agnese , Scorziello Antonella , Lombardi Valentina , Matassa Danilo Swann , Fersini Alberto , Neri Vincenzo , Esposito Franca , Landriscina Matteo
Published: March 2023

Abstract
The Ca2+-binding protein sorcin regulates intracellular calcium homeostasis and plays a role in the induction of drug resistance in human cancers. Recently, an 18 kDa mitochondrial isoform of sorcin was reported to participate in antiapoptosis in human colorectal cancer (CRC), but information remains lacking about the functional role of the more abundant 22 kDa isoform of sorcin expressed in CRC. We found the 22 kDa isoform to be widely expressed in human CRC cells, whether or not they were drug resistant. Its upregulation in drug-sensitive cells induced resistance to 5-fluorouracil, oxaliplatin, and irinotecan, whereas its downregulation sensitized CRC cells to these chemotherapeutic agents. Sorcin enhances the accumulation of Ca2+ in the endoplasmic reticulum (ER), preventing ER stress, and, in support of this function, we found that the 22 kDa isoform of sorcin was upregulated under conditions of ER stress. In contrast, RNAi-mediated silencing of sorcin activated caspase-3, caspase-12, and GRP78/BiP, triggering apoptosis through the mitochondrial pathway. Our findings establish that CRC cells overexpress sorcin as an adaptive mechanism to prevent ER stress and escape apoptosis triggered by chemotherapeutic agents, prompting its further investigation as a novel molecular target to overcome MDR. Cancer Res; 71(24); 7659–69. ©2011 AACR.
Data from Oncogene-Mediated Human Lung Epithelial Cell Transformation Produces Adenocarcinoma Phenotypes In Vivo
Authors: Sasai Ken , Sukezane Taiko , Yanagita Emmy , Nakagawa Harumi , Hotta Azusa , Itoh Tomoo , Akagi Tsuyoshi
Published: March 2023

Abstract
It has been challenging to engineer lung adenocarcinoma models via oncogene-mediated transformation of primary cultured normal human cells. Although viral oncoprotein-mediated malignant transformation has been reported, xenografts derived from such transformed cells generally represent poorly differentiated cancers. Here, we demonstrate that the combined expression of multiple cellular factors induces malignant transformation in normal human lung epithelial cells. Although a combination of four genetic alterations, including hTERT overexpression, inactivation of the pRB and p53 pathways, and KRAS activation, is insufficient for normal human small airway epithelial cells to be fully transformed, expression of one additional oncogene induces malignant transformation. Notably, we have succeeded in reproducing human lung adenocarcinoma phenotypes in the flanks of nude mice by introducing an active form of PIK3CA, CYCLIN-D1, or a dominant-negative form of LKB1 in combination with the four genetic alterations above. Besides differentiated lung cancer, poorly differentiated cancer models can also be engineered by employing c-MYC as one of the genetic elements, indicating that histologic features and degree of differentiation of xenografts are controllable to some extent by changing the combination of genetic elements introduced. This is the first study reporting malignant transformation of normal lung epithelial cells in the absence of viral oncoproteins. We propose that our model system would be useful to identify the minimal and most crucial set of changes required for lung tumorigenesis, and that it would provide a broadly applicable approach for discovering attractive therapeutic targets. Cancer Res; 71(7); 2541–9. ©2011 AACR.
Data from Use of Multifunctional Sigma-2 Receptor Ligand Conjugates to Trigger Cancer-Selective Cell Death Signaling
Authors: Spitzer Dirk , Simon Peter O. , Kashiwagi Hiroyuki , Xu Jinbin , Zeng Chenbo , Vangveravong Suwanna , Zhou Dong , Chang Katherine , McDunn Jonathan E. , Hornick John R. , Goedegebuure Peter , Hotchkiss Richard S. , Mach Robert H. , Hawkins William G.
Published: March 2023

Abstract
One major challenge in the development of cancer therapeutics is the selective delivery of the drugs to their cellular targets. In the case of pancreatic cancer, the σ-2 receptor is a unique target that triggers apoptosis upon activation. We have previously developed a series of chemical compounds with high affinity for the σ-2 receptor and showed rapid internalization of the ligands. One particular specific ligand of the σ-2 receptor, SV119, binds to pancreatic cancer cells and induces target cell death in vitro and in vivo. In this study, we characterized the ability of SV119 to selectively deliver other death-inducing cargos to augment the cytotoxic properties of SV119 itself. When conjugated to SV119, small molecules that are known to interfere with intracellular prosurvival pathways retained their ability to induce cell death, the efficiency of which was enhanced by the combinatorial effect of SV119 delivered with its small molecule cargo. Our findings define a simple platform technology to increase the tumor-selective delivery of small molecule therapeutics via σ-2 ligands, permitting chemotherapeutic synergy that can optimize efficacy and patient benefit. Cancer Res; 72(1); 201–9. ©2011 AACR.
Data from Suppression of Colonic Polyposis by Homeoprotein CDX2 through its Nontranscriptional Function that Stabilizes p27Kip1
Authors: Aoki Koji , Kakizaki Fumihiko , Sakashita Hiromi , Manabe Toshiaki , Aoki Masahiro , Taketo Makoto M.
Published: March 2023

Abstract
Caudal-related homeoprotein CDX2 is expressed in intestinal epithelial cells, in which it is essential for their development and differentiation. A tumor suppressor function is suggested by evidence that CDX2 levels are decreased in human colon cancer specimens and that an inactivating mutation of Cdx2 in ApcΔ716 mice markedly increases the incidence of colonic polyps. In this study, we investigated roles for transcriptional and nontranscriptional functions of CDX2 in suppression of colonic tumorigenesis. Mutagenic analysis of CDX2 revealed that loss of function stabilizes CDK inhibitor p27Kip1 by a nontranscriptional but homeodomain-dependent mechanism that inhibits cyclin E-CDK2 activity and blocks G0/G1-S progression in colon cancer cells. p27Kip1 stabilization was mediated by an inhibition of ubiquitylation-dependent proteolysis associated with decreased phosphorylation of Thr187 in p27Kip1. siRNA-mediated knockdown of p27Kip1 relieved the decrease in cyclin E-CDK2 activity and S-phase cell fraction elicited by CDX2 expression. Together, these results implicate a nontranscriptional function of CDX2 in tumor suppression mediated by p27Kip1 stabilization. Up to approximately 75% of low-CDX2 human colon cancer lesions show reduced levels of p27Kip1, whereas approximately 68% of high-CDX2 lesions retain expression of p27Kip1. These results show that low levels of CDX2 accelerate colon tumorigenesis by reducing p27Kip1 levels. Cancer Res; 71(2); 593–602. ©2011 AACR.
Data from Targeting PI3K/mTOR Signaling in Cancer
Authors: Emerling Brooke M. , Akcakanat Argun
Published: March 2023

Abstract
The American Association for Cancer Research (AACR) Special Conference on Targeting PI3K/mTOR Signaling in Cancer was held in San Francisco, California from February 24 to 27, 2011. The meeting was cochaired by Drs. Lewis C. Cantley, David M. Sabatini, and Funda Meric-Bernstam. The main focus of this event was the therapeutic potential of drugs targeting the PI3K/mTOR signaling pathway for the treatment of cancer. This article summarizes the recent discoveries in the field, with particular emphasis on the major themes of the conference. Cancer Res; 71(24); 7351–9. ©2011 AACR.