bluuebunny/crossref_metadata_2025_split huggingface dataset:
αvβ6 Expression in Myoepithelial Cells: A Novel Marker for Predicting DCIS Progression with Therapeutic Potential
Authors: Allen Michael D. , Marshall John F. , Jones J. Louise 
Published: October 2014

Abstract
The tumor microenvironment dynamically regulates the progression of cancer. In the breast, a unique component of the microenvironment is the myoepithelial cell. Normal myoepithelial cells act as “natural tumor suppressors”; however, more recent evidence suggests that these cells develop phenotypic changes, which may contribute to loss of tumor suppressor activity. We have shown that myoepithelial cells in a subset of preinvasive ductal carcinoma in situ (DCIS) upregulate expression of the integrin αvβ6, switching on tumor promoter activity through activation of TGFβ and MMP9. This makes the tumor microenvironment more permissive to invasion, seen both in vitro and in vivo. In human tissue samples, increased myoepithelial αvβ6 expression correlated with increased risk of disease progression and recurrence. Current estimates suggest that as many as 50% of DCIS cases will never progress in the patient's lifetime, but there are no markers to predict the outcome of individual cases. The identification of αvβ6 in a subset of DCIS presents a unique way to stratify patients with DCIS into those who may or may not progress to more serious disease. As αvβ6 is not expressed on most normal adult tissues, this finding may also provide novel targets for therapy in this high-risk group. Cancer Res; 74(21); 5942–7. ©2014 AACR.
Chemoradiotherapy-Induced Upregulation of PD-1 Antagonizes Immunity to HPV-Related Oropharyngeal Cancer
Authors: Parikh Falguni , Duluc Dorothée , Imai Naoko , Clark Amelia , Misiukiewicz Krzys , Bonomi Marcello , Gupta Vishal , Patsias Alexis , Parides Michael , Demicco Elizabeth G. , Zhang David Y. , Kim-Schulze Seunghee , Kao Johnny , Gnjatic Sacha , Oh Sangkon , Posner Marshall R. , Sikora Andrew G. 
Published: October 2014

Abstract
While viral antigens in human papillomavirus (HPV)-related oropharyngeal cancer (HPVOPC) are attractive targets for immunotherapy, the effects of existing standard-of-care therapies on immune responses to HPV are poorly understood. We serially sampled blood from patients with stage III–IV oropharyngeal cancer undergoing concomitant chemoradiotherapy with or without induction chemotherapy. Circulating immunocytes including CD4+ and CD8+ T cells, regulatory T cells (Treg), and myeloid-derived suppressor cells (MDSC) were profiled by flow cytometry. Antigen-specific T-cell responses were measured in response to HPV16 E6 and E7 peptide pools. The role of PD-1 signaling in treatment-related immunosuppression was functionally defined by performing HPV-specific T-cell assays in the presence of blocking antibody. While HPV-specific T-cell responses were present in 13 of 18 patients before treatment, 10 of 13 patients lost these responses within 3 months after chemoradiotherapy. Chemoradiotherapy decreased circulating T cells and markedly elevated MDSCs. PD-1 expression on CD4+ T cells increased by nearly 2.5-fold after chemoradiotherapy, and ex vivo culture with PD-1–blocking antibody enhanced HPV-specific T-cell responses in 8 of 18 samples tested. Chemoradiotherapy suppresses circulating immune responses in patients with HPVOPC by unfavorably altering effector:suppressor immunocyte ratios and upregulating PD-1 expression on CD4+ T cells. These data strongly support testing of PD-1–blocking agents in combination with standard-of-care chemoradiotherapy for HPVOPC. Cancer Res; 74(24); 7205–16. ©2014 AACR.
RhoB Determines Tumor Aggressiveness in a Murine EGFRL858R-Induced Adenocarcinoma Model and Is a Potential Prognostic Biomarker for Lepidic Lung Cancer
Authors: Calvayrac Olivier , Pradines Anne , Raymond-Letron Isabelle , Rouquette Isabelle , Bousquet Emilie , Lauwers-Cances Valérie , Filleron Thomas , Cadranel Jacques , Beau-Faller Michèle , Casanova Anne , Milia Julie , Favre Gilles , Mazières Julien 
Published: October 2014

Abstract
Purpose: A crucial event in lung adenocarcinoma progression is the switch from an aerogenous spread toward an infiltrating tumor. Loss of RhoB expression has been suggested to be critical for lung cancer invasion. Here, we tested RhoB expression as a prognostic biomarker in non–small cell lung cancer (NSCLC) with a special focus on lepidic pattern.
Experimental Design: We analyzed RhoB expression using both IHC and RT-qPCR in two series of operated patients (n = 100 and 48, respectively) and in a series of advanced lepidic adenocarcinoma (n = 31) from different hospitals. Next, we examined the role of RhoB in lung cancer progression in transgenic mice that express inducible EGFRL858R crossed with Rhob null mice.
Results: We identified that loss of RhoB expression was strongly associated with worse survival (P = 0.0001) and progression-free survival (P &lt; 0.001) in the first series. We then confirmed these results after multivariate analyses of the second series. In the series of adenocarcinoma with lepidic features issued from a clinical trial (IFCT-0401), we showed that loss of RhoB expression was associated with higher aggressiveness of stage IV. Finally, we showed that EGFRL858R/Rhob+/+ mice developed mainly diffuse lung tumors with a lepidic pattern, whereas EGFRL858R/Rhob+/− and EGFRL858R/Rhob−/− developed a greater number of tumors, and aggressive adenocarcinomas with invasive properties.
Conclusions: We showed that RhoB is not only a strong prognostic factor in NSCLC but it is also critical for the acquisition of an aggressive phenotype of adenocarcinoma. Clin Cancer Res; 20(24); 6541–50. ©2014 AACR.
Combination of the mTOR Inhibitor Ridaforolimus and the Anti-IGF1R Monoclonal Antibody Dalotuzumab: Preclinical Characterization and Phase I Clinical Trial
Authors: Di Cosimo Serena , Sathyanarayanan Sriram , Bendell Johanna C. , Cervantes Andrés , Stein Mark N. , Braña Irene , Roda Desamparados , Haines Brian B. , Zhang Theresa , Winter Christopher G. , Jha Sharda , Xu Youyuan , Frazier Jason , Klinghoffer Richard A. , Leighton-Swayze Ann , Song Yang , Ebbinghaus Scot , Baselga José 
Published: October 2014

Abstract
Purpose: Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin–like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination.
Experimental Design: In vitro and in vivo models, and a phase I study in which patients with advanced cancer received ridaforolimus (10–40 mg/day every day × 5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg/every other week) were explored.
Results: Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main dose-limiting toxicities (DLT) of the combination were primarily mTOR-related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 patients with breast cancer); 10 of 23 patients with breast cancer and 6 of 11 patients with ER+/high-proliferative breast cancer showed antitumor activity.
Conclusions: Our study provides proof-of-concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER+/high-proliferative breast cancer (ClinicalTrials.gov identifier: NCT00730379). Clin Cancer Res; 21(1); 49–59. ©2014 AACR.
Development of T Cells Redirected to Glypican-3 for the Treatment of Hepatocellular Carcinoma
Authors: Gao Huiping , Li Kesang , Tu Hong , Pan Xiaorong , Jiang Hua , Shi Bizhi , Kong Juan , Wang Hongyang , Yang Shengli , Gu Jianren , Li Zonghai 
Published: October 2014

Abstract
Purpose: The aim of our study is to elucidate whether T cells expressing GPC3-targeted chimeric antigen receptor (CAR) can efficiently eliminate GPC3-positive HCC cells and their potential in the treatment of HCC.
Experimental Design: T cells expressing a first-generation and third-generation GPC3-targeted CAR were prepared using lentiviral vector transduction. The in vitro and in vivo cytotoxic activities of the genetically engineered CAR T cells were evaluated against various HCC cell lines.
Results: GPC3-targeted CAR T cells could efficiently kill GPC3-positive HCC cells but not GPC3-negative cells in vitro. These cytotoxic activities seemed to be positively correlated with GPC3 expression levels in the target cells. In addition, T cells expressing the third-generation GPC3-targeted CAR could eradicate HCC xenografts with high level of GPC3 expression and efficiently suppress the growth of HCC xenografts with low GPC3 expression level in vivo. The survival of the mice bearing established orthotopic Huh-7 xenografts was significantly prolonged by the treatment with the third-generation GPC3-targeted CAR T cells.
Conclusions: GPC3-targeted CAR T cells could potently eliminate GPC3-positive HCC cells, thereby providing a promising therapeutic intervention for GPC3-positive HCC. Clin Cancer Res; 20(24); 6418–28. ©2014 AACR.
Abiraterone Treatment in Castration-Resistant Prostate Cancer Selects for Progesterone Responsive Mutant Androgen Receptors
Authors: Chen Eddy J. , Sowalsky Adam G. , Gao Shuai , Cai Changmeng , Voznesensky Olga , Schaefer Rachel , Loda Massimo , True Lawrence D. , Ye Huihui , Troncoso Patricia , Lis Rosina L. , Kantoff Philip W. , Montgomery Robert B. , Nelson Peter S. , Bubley Glenn J. , Balk Steven P. , Taplin Mary-Ellen 
Published: October 2014

Abstract
Purpose: The CYP17A1 inhibitor abiraterone markedly reduces androgen precursors and is thereby effective in castration-resistant prostate cancer (CRPC). However, abiraterone increases progesterone, which can activate certain mutant androgen receptors (AR) identified previously in flutamide-resistant tumors. Therefore, we sought to determine if CYP17A1 inhibitor treatment selects for progesterone-activated mutant ARs.
Experimental Design: AR was examined by targeted sequencing in metastatic tumor biopsies from 18 patients with CRPC who were progressing on a CYP17A1 inhibitor (17 on abiraterone, 1 on ketoconazole), alone or in combination with dutasteride, and by whole-exome sequencing in residual tumor in one patient treated with neoadjuvant leuprolide plus abiraterone.
Results: The progesterone-activated T878A-mutant AR was present at high allele frequency in 3 of the 18 CRPC cases. It was also present in one focus of resistant tumor in the neoadjuvant-treated patient, but not in a second clonally related resistant focus that instead had lost one copy of PTEN and both copies of CHD1. The T878A mutation appeared to be less common in the subset of patients with CRPC treated with abiraterone plus dutasteride, and transfection studies showed that dutasteride was a more potent direct antagonist of the T878A versus the wild-type AR.
Conclusions: These findings indicate that selection for tumor cells expressing progesterone-activated mutant ARs is a mechanism of resistance to CYP17A1 inhibition. Clin Cancer Res; 21(6); 1273–80. ©2014 AACR.
See related commentary by Sharifi, p. 1240
Clever-1/Stabilin-1 Controls Cancer Growth and Metastasis
Authors: Karikoski Marika , Marttila-Ichihara Fumiko , Elima Kati , Rantakari Pia , Hollmén Maija , Kelkka Tiina , Gerke Heidi , Huovinen Ville , Irjala Heikki , Holmdahl Rikard , Salmi Marko , Jalkanen Sirpa 
Published: October 2014

Abstract
Purpose: Immunosuppressive leukocytes and vasculature are important host cell components regulating tumor progression. Clever-1/Stabilin-1, a multifunctional scavenger and adhesion receptor, is constitutively present on a subset of type II macrophages and lymphatic endothelium, but its functional role in cancer is unknown.
Experimental Design: Here, we generated full Clever-1 knockout mice and cell-specific ones lacking Clever-1 either on macrophages or endothelium. We also used anti-Clever-1 antibody therapy to treat B16 melanoma and EL-4 lymphoma.
Results: Clever-1–deficient mice had smaller primary and metastatic tumors than wild-type (WT) controls. Growth of primary tumors, but not of metastases, was attenuated also in mice lacking Clever-1 selectively in macrophages or in vascular endothelium. Anti-Clever-1 antibody treatment inhibited tumor progression in WT mice. Both genetically and therapeutically induced absence of functional Clever-1 led to diminished numbers of immunosuppressive leukocyte types in tumors. Functionally Clever-1 mediated binding of immunosuppressive leukocytes to the intratumoral blood vessels aberrantly expressing Clever-1, and tumor cell traffic via the lymphatics. The antibody therapy did not aggravate autoimmunity.
Conclusion: This work identifies Clever-1 in type II macrophages and in tumor vasculature as a new immunosuppressive molecule in cancer. Our finding that Clever-1 supports binding of tumor-infiltrating lymphocytes to tumor vasculature increases our understanding of leukocyte immigration to tumors. The ability of anti-Clever-1 antibody treatment to attenuate tumor progression in WT mice in vivo is therapeutically relevant. Thus, Clever-1 may be an emerging new target for modulating immune evasion and lymphatic spread in cancer. Clin Cancer Res; 20(24); 6452–64. ©2014 AACR.
Tadalafil Reduces Myeloid-Derived Suppressor Cells and Regulatory T Cells and Promotes Tumor Immunity in Patients with Head and Neck Squamous Cell Carcinoma
Authors: Weed Donald T. , Vella Jennifer L. , Reis Isildinha M. , De la fuente Adriana C. , Gomez Carmen , Sargi Zoukaa , Nazarian Ronen , Califano Joseph , Borrello Ivan , Serafini Paolo 
Published: October 2014

AbstractPurpose: Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) play a key role in the progression of head and neck squamous cell carcinoma (HNSCC). On the basis of our preclinical data demonstrating that phosphodiesterase-5 (PDE5) inhibition can modulate these cell populations, we evaluated whether the PDE5 inhibitor tadalafil can revert tumor-induced immunosuppression and promote tumor immunity in patients with HNSCC.Experimental Design: First, we functionally and phenotypically characterized MDSCs in HNSCCs and determined, retrospectively, whether their presence at the tumor site correlates with recurrence. Then, we performed a prospective single-center, double-blinded, randomized, three-arm study in which patients with HNSCC undergoing definitive surgical resection of oral and oropharyngeal tumors were treated with tadalafil 10 mg/day, 20 mg/day, or placebo for at least 20 days preoperatively. Blood and tumor MDSC and Treg presence and CD8+ T-cell reactivity to tumor antigens were evaluated before and after treatment.Results: MDSCs were characterized in HNSCC and their intratumoral presence significantly correlates with recurrence. Tadalafil treatment was well tolerated and significantly reduced both MDSCs and Treg concentrations in the blood and in the tumor (P &lt; 0.05). In addition, the concentration of blood CD8+ T cells reactive to autologous tumor antigens significantly increased after treatment (P &lt; 0.05). Tadalafil immunomodulatory activity was maximized at an intermediate dose but not at higher doses. Mechanistic analysis suggests a possible off-target effect on PDE11 at high dosages that, by increasing intracellular cAMP, may negatively affect antitumor immunity.Conclusions: Tadalafil seems to beneficially modulate the tumor micro- and macro-environment in patients with HNSCC by lowering MDSCs and Tregs and increasing tumor-specific CD8+ T cells in a dose-dependent fashion. Clin Cancer Res; 21(1); 39–48. ©2014 AACR.
Involvement of microRNA-24 and DNA Methylation in Resistance of Nasopharyngeal Carcinoma to Ionizing Radiation
Authors: Wang Sumei , Zhang Rong , Claret Francois X. , Yang Huiling 
Published: October 2014

Abstract
Nasopharyngeal carcinoma (NPC) is a malignant tumor originating in the epithelium. Radiotherapy is the standard therapy, but tumor resistance to this treatment reduces the 5-year patient survival rate dramatically. Studies are urgently needed to elucidate the mechanism of NPC radioresistance. Epigenetics—particularly microRNAs (miRNA) and DNA methylation—plays an important role in carcinogenesis and oncotherapy. We used qRT-PCR analysis and identified an miRNA signature from differentially expressed miRNAs. Our objectives were to identify the role of miR24 in NPC tumorigenesis and radioresistance and to identify the mechanisms by which miR24 is regulated. We found that miR24 inhibited NPC cell growth, promoted cell apoptosis, and suppressed the growth of NPC xenografts. We showed that miR24 was significantly downregulated in recurrent NPC tissues. When combined with irradiation, miR24 acted as a radiosensitizer in NPC cells. One of the miR24 precursors was embedded in a CpG island. Aberrant DNA methylation was involved in NPC response to radiotherapy, which linked inactivation of miR24 through hypermethylation of its precursor promoter with NPC radioresistance. Treating NPC cells with the DNA-hypomethylating agent 5-aza-2′-deoxycytidine compensated for the reduced miR24 expression. Together, our findings showed that miR24 was negatively regulated by hypermethylation of its precursor promoter in NPC radioresistance. Our findings defined a central role for miR24 as a tumor-suppressive miRNA in NPC and suggested its use in novel strategies for treatment of this cancer. Mol Cancer Ther; 13(12); 3163–74. ©2014 AACR.
Marine Sponge Cribrochalina vasculum Compounds Activate Intrinsic Apoptotic Signaling and Inhibit Growth Factor Signaling Cascades in Non–Small Cell Lung Carcinoma
Authors: Zovko Ana , Viktorsson Kristina , Hååg Petra , Kovalerchick Dimitry , Färnegårdh Katarina , Alimonti Andrea , Ilan Micha , Carmeli Shmuel , Lewensohn Rolf 
Published: October 2014

Abstract
Marine-derived compounds have been explored and considered as possible antitumor agents. In this study, we analyzed extracts of the sponge Cribrochalina vasculum for their ability to inhibit tumor cell proliferation. Screening identified two acetylenic compounds of similar structure that showed strong tumor-specific toxicity in non–small cell lung carcinoma (NSCLC) cells and small-cell lung carcinoma cells, and less prominent toxicity in ovarian carcinoma, while having no effect on normal cells. These acetylenic compounds were found to cause a time-dependent increase in activation of apoptotic signaling involving cleavage of caspase-9, caspase-3, and PARP, as well as apoptotic cell morphology in NSCLC cells, but not in normal fibroblasts. Further analysis demonstrated that these compounds caused conformational change in Bak and Bax, and resulted in loss of mitochondrial potential and cytochrome c release in NSCLC cells. Moreover, a decreased phosphorylation of the growth factor signaling kinases Akt, mTOR, and ERK was evident and an increased phosphorylation of JNK was observed. Thus, these acetylenic compounds hold potential as novel therapeutic agents that should be further explored for NSCLC and other tumor malignancies. Mol Cancer Ther; 13(12); 2941–54. ©2014 AACR.
Vorinostat Downregulates CD30 and Decreases Brentuximab Vedotin Efficacy in Human Lymphocytes
Authors: Hasanali Zainul S. , Epner Elliot M. , Feith David J. , Loughran Thomas P. , Sample Clare E. 
Published: October 2014

AbstractWith an increasing number of clinical trials looking at combination therapies in cancer, potential drug–drug interactions require particular attention. One such instance is the treatment of CD30+ tumors after previous vorinostat (SAHA; suberoylanilide hydroxyamic acid) failure with the anti-CD30 antibody–drug conjugate brentuximab vedotin. Using B-, T-, and natural killer (NK)–cell lines in vitro, we demonstrate that SAHA downregulates the expression of CD30 and lowers the efficacy of subsequent brentuximab vedotin treatment if baseline CD30 levels are reduced by 50% or more. Interestingly, low-dose SAHA treatment that maintained 50% or more of basal CD30 expression followed by subsequent treatment with brentuximab vedotin led to enhanced antitumor activity. The downregulation of CD30 was short lived upon SAHA removal, suggesting that allowing SAHA washout may circumvent any interactions with subsequent drug therapies. Our findings confirm the requirement of CD30 for brentuximab vedotin efficacy and suggest that combination treatment with SAHA in CD30dim tumors may decrease efficacy. Combination treatment in highly CD30+ tumors, however, increases efficacy and warrants further consideration as a new treatment paradigm. Mol Cancer Ther; 13(12); 2784–92. ©2014 AACR.
TGFβ1 Protects Cells from γ-IR by Enhancing the Activity of the NHEJ Repair Pathway
Authors: Kim Mi-Ra , Lee Jeeyong , An You Sun , Jin Yeung Bae , Park In-Chul , Chung Eunkyung , Shin Incheol , Barcellos-Hoff Mary Helen , Yi Jae Youn 
Published: October 2014

Abstract
Several groups have reported that TGFβ1 regulates cellular responses to γ-irradiation; however, the exact mechanism has not been fully elucidated. In the current study, the role of TGFβ1 in cellular responses to γ-irradiation was investigated in detail. The data indicate that TGFβ1 pretreatment decreased the aftermath of ionizing radiation (IR)-induced DNA damage in a SMAD-dependent manner. To determine the underlying mechanism for these effects, the extent of IR-induced DNA repair activity in the presence or absence of TGFβ1 was examined. Studies reveal that TGFβ1 upregulated DNA ligase IV (Lig4), augmented IR-induced nuclear retention of the DNA ligase, and enhanced nonhomologous end-joining (NHEJ) repair activity. In addition, knockdown of Lig4 reduced the TGFβ1-induced protection against IR. Overall, these data indicate that TGFβ1 facilitates the NHEJ repair process upon γ-irradiation and thereby enhances long-term survival.
Implications: These findings provide new insight and a possible approach to controlling genotoxic stress by the TGFβ signaling pathway. Mol Cancer Res; 13(2); 319–29. ©2014 AACR.
Prometastatic NEDD9 Regulates Individual Cell Migration via Caveolin-1–Dependent Trafficking of Integrins
Authors: Kozyulina Polina Y. , Loskutov Yuriy V. , Kozyreva Varvara K. , Rajulapati Anuradha , Ice Ryan J. , Jones Brandon C. , Pugacheva Elena N. 
Published: October 2014

Abstract
The dissemination of tumor cells relies on efficient cell adhesion and migration, which in turn depends upon endocytic trafficking of integrins. In the current work, it was found that depletion of the prometastatic protein, NEDD9, in breast cancer cells results in a significant decrease in individual cell migration due to impaired trafficking of ligand-bound integrins. NEDD9 deficiency does not affect the expression or internalization of integrins but heightens caveolae-dependent trafficking of ligand-bound integrins to early endosomes. Increase in mobility of ligand-bound integrins is concomitant with an increase in tyrosine phosphorylation of caveolin-1 (CAV1) and volume of CAV1-vesicles. NEDD9 directly binds to CAV1 and colocalizes within CAV1 vesicles. In the absence of NEDD9, the trafficking of ligand-bound integrins from early to late endosomes is impaired, resulting in a significant decrease in degradation of ligand–integrin complexes and an increase in recycling of ligand-bound integrins from early endosomes back to the plasma membrane without ligand disengagement, thus leading to low adhesion and migration. Reexpression of NEDD9 or decrease in the amount of active, tyrosine 14 phosphorylated (Tyr14) CAV1 in NEDD9-depleted cells rescues the integrin trafficking deficiency and restores cellular adhesion and migration capacity. Collectively, these findings indicate that NEDD9 orchestrates trafficking of ligand-bound integrins through the attenuation of CAV1 activity.
Implications: This study provides valuable new insight into the potential therapeutic benefit of NEDD9 depletion to reduce dissemination of tumor cells and discovers a new regulatory role of NEDD9 in promoting migration through modulation of CAV1-dependent trafficking of integrins. Mol Cancer Res; 13(3); 423–38. ©2014 AACR.