bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4244: The role of hypoxia on the tumor-stromal interaction in pancreatic ductal adenocarcinoma
Authors: Heuchel Rainer L. , Longati Paola , Jia Xiaohui , Wagman Annika , Jesenofsky Ralf , Witt Michael R. , Löhr Matthias 
Published: August 2012

Abstract
INTRODUCTION: Pancreatic cancer is characterized by extraordinary fibrosis and pancreatic stellate cells (PSCs) are the major player in synthesizing extracellular matrix (ECM) upon activation. The interaction/communication between PSCs and pancreatic ductal adenocarcinoma (PDAC) cells is essential for inducing stroma/ECM production, pancreatic cancer progression and general therapy resistance. Compared to traditional 2D cell culture, cells in a three-dimensional context demonstrate different behavior and functions as reflected by building up a microenvironment that more closely mimics the one observed in the native tissue. This feature is especially critical for testing drug efficiency as cellular response to drugs is profoundly affected by environmental cues. AIMS & METHODS: Our aim was to build up a more reliable and predictive drug screening system. To this end we set up and compared 2D and 3D cell cultures containing either human PSC and PDAC cells alone or in combination. RESULTS: Among PDAC cells, panc-1 cells are the most commonly used which are also able to form spheres in vitro. We generated mono-spheres from panc-1 cells and compared them to conventional 2D culture. The efficiency of different drugs on viability of cells in panc-1 sphere resulted to be much lower than on viability in 2D cultures. Cells in 3D compared to the 2D culture show higher gene expression for ECM proteins as collagen and fibronectin, for growth factors as PDGF and VEGF, as well as for protein like Cox2, Glut1. We co-cultured panc-1 and PSCs, allowing them to interact and form hetero-spheres in which PSCs localized in the cortical area and were identified e.g. by expression of asma, a marker for PSCs activation. These avascular mini-tumors were further characterized at different levels. CONCLUSION: 3D cultures are more resistant to chemotherapy compared to their 2D counterpart offering a more predictive platform for drug screening before proceeding to more expensive in vivo models and clinical trials. The avascular mini-tumors can be considered as an alternative in vitro cell model for studying pancreatic cancer development and fibrosis from a more complete perspective.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4244. doi:1538-7445.AM2012-4244
Abstract 4371: RRx-001 modulates intratumor blood flow in SCCVII and U87 tumors
Authors: Scicinski Jan , Oronsky Bryan , Ning Shoucheng , Minchinton Andrew , Knox Susan 
Published: August 2012

Abstract
The tumor-specific provascular effects of the anti-cancer agent RRx-001, a novel nitrogen oxide donor and allosteric hemoglobin modifier in Phase 1 clinical trials were investigated using contrast enhanced ultrasound (CEUS) and whole tissue section quantitative immunohistological staining. Changes in tumor blood flow by CEUS in SCCVII tumor bearing mice following RRx-001 (3, 6, 12 mg/kg) were dose and time dependent, reaching maximum perfusion 6 h after treatment, returning to baseline within 72 h. Microregional effects of RRx-001 (15 mg/kg) on tumor blood flow and oxygenation by immunohistological staining were studied in mouse SCCVII and human U87 tumors. SCCVII tumors exhibited regions of intermittent perfusion exemplified by co-localization of vessels with the hypoxia marker pimonidazole commonly occurring throughout the tissue. Only 21% of vessels showed perfusion after a bolus dose of the perivascular stain DiOC7. This increased to 28% 12 h post RRx-001. Paradoxically, an increase in tissue oxygenation was not seen while modestly increased pimonidazole binding was observed. However, preliminary radiobiological assessment suggested tumors were radiosensitized when irradiated 10 min after 12 mg/kg RRx-001. In the U87 tumor a decrease in vessel perfusion at 90 min post RRx-001 administration was observed. Blood flow over large areas of treated tumors was completely shut down. These areas stained positive for CD31 and tissue did not appear necrotic. Analysis indicated 25% reduction in the fraction of perfused vessels and un-perfused tissue by area at 90 min returning to near normal levels at 12 h. There was no significant increase in the fraction of necrosis at 12 h suggesting that the large un-perfused regions seen at 90 min had recovered rather than become necrotic. No significant change in tumor hypoxia was seen at 90 min or 12 h. For both tumor types, RRx-001 appeared to cause the loss of perfusion in large regions of the tumor however, at the 12 h time point, both tumor types showed increase in vessel perfusion but no significant decrease in hypoxia. These data suggest a redistribution of blood flow in both tumor types while differences between the tumors were related to tumor architecture and distribution of α-SMA. RRx-001 shows promise for short-term blood flow redistribution in tumors with a pericyte-rich vasculature with contractile proteins such as α-SMA. Expression of α-SMA in tumor vasculature could therefore be useful for predicting tumor response to RRx-001.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4371. doi:1538-7445.AM2012-4371
Abstract 4372: Chronic myeloid leukemia (CML) exosomes promote angiogenesis in a Src-dependent fashion in vitro and in vivo
Authors: Mineo Marco , Taverna Simona , Flugy Anna , Leo Giacomo De , Alessandro Riccardo , Kohn Elise C. 
Published: August 2012

Abstract
CML is an uncontrolled proliferation of bone marrow myeloid cells driven by the constitutively active fusion product tyrosine kinase BCR/ABL. Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is newly recognized as a factor in CML progression. Exosomes, released by a broad spectrum of cells, are microvesicles that play an important role in cell-to-cell communication both in physiological and pathological conditions. The role of exosomes released by CML cells in angiogenesis is emerging; however, little is known about the mechanisms involved in this process. We first isolated and characterized exosomes released by K562 CML cells and we demonstrated their ability to stimulate human vascular endothelial cells (HUVECs) tube differentiation on Matrigel. K562 exosomes induced an increase of the cumulative tube length in a dose-dependent manner, with a maximum effect at 10ug/ml (p=0.003). Next, we evaluated the effect on exosome behavior of imatinib and dasatinib, two tyrosine kinase inhibitors in use in CML treatment. K562 CML cell treatment with either imatinib or dasatinib reduced exosome release by 58% and 56%, respectively (p&lt;0.01). Equivalent exosome concentrations isolated from imatinib or dasatinib treated K562 cells maintained their ability to stimulate HUVEC tube formation, compared to those isolated from untreated cells. Dasatinib treatment of HUVECs strongly reduced exosome-induced vascular differentiation (p=0.0002). On the contrary, little effect was observed following treatment with imatinib. K562 exosomes stimulated vascularization when added to Matrigel plug in vivo; angiogenesis was markedly inhibited by oral administration of dasatinib (p&lt;0.01), but not imatinib. Consistent with the differential effects of dasatinib and imatinib, exosome-induced HUVEC Src and FAK phosphorylation was only inhibited by dasatinib. Confocal images showed that both FAK and Src phosphorylation were increased at points of membrane-matrix contact. Immunoblot analysis confirmed that K562 exosomes induced a dasatinib-sensitive phosphorylation of Src and FAK and their downstream effectors, Erk and Akt. Again, imatinib was minimally active against exosome stimulation of HUVEC cell signaling. Thus, K562 CML exosomes stimulate angiogenesis in vitro and in vivo in a dasatinib-sensitive fashion. This credentials exosomes and angiogenesis as molecular targets in CML via activation of Src both in leukemia and its microenvironment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4372. doi:1538-7445.AM2012-4372
Abstract 4378: Pericyte coverage of differentiated vessels inside tumor vasculature is an independent unfavorable prognostic factor for patients with clear cell renal cell carcinoma
Authors: Cao Yun , Zhang Zhi-Ling , Zhou Ming , Elson Paul , Rini Brian , Aydin Hakan , Feenstra Kristin , Tan Min-Han , Berghuis Bree , Tabbey Rebeka , Resau James , Zhou Fang-Jian , Teh Bin Tean , Qian Chao-Nan 
Published: August 2012

Abstract
Background: The clinical significance of pericyte coverage (PC) surrounding differentiated vessels in clear cell renal cell carcinoma (CCRCC) is unclear. Objective: To evaluate the effect of PC on the prognosis of patients with CCRCC. Methods: Samples from two cohorts of CCRCC patients (Asian, 101 cases; U.S., 542 cases) were immunohistochemically doubled-stained for a pericyte marker (α-SMA) and a differentiated vessel marker (CD34), followed by multispectral image capturing and computerized image analyses to quantify the microvessel density (MVD) and pericyte coverage of differentiated vessels. The correlations of PC or MVD with clinicopathological characteristics were analyzed. Univariate and multivariate survival analyses were performed. Results: Uneven distributions of differentiated MVD and PC were found, with higher MVD in the peripheral portion of the tumor and higher PC in the inner portion. There was an inverse correlation between differentiated MVD and PC. Higher PC correlated with more aggressive clinicopathological characteristics of CCRCC in both cohorts, including more advanced T-stage, higher pathological grades, and occurrence of tumor necrosis. The MVD:PC ratio was an independent favorable prognostic factor for overall survival in the Asian cohort and for recurrence-free survival in the U.S. cohort. PC and MVD were also independent prognostic factors, with higher PC or lower MVD predicting a poorer outcome. The combination of PC and MVD could better distinguish the outcome of CCRCC patients. PC combined with differentiated MVD, or MVD:PC ratio provided additional independent prognostic information to the Leibovich risk model, and using that information we generated improved risk models. Conclusions: The distributions of MVD and PC were uneven in CCRCC. Higher PC correlated with more aggressive clinicopathological characteristics. PC was an independent unfavorable prognostic factor. Targeting pericytes should be taken into consideration in anti-angiogenic therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4378. doi:1538-7445.AM2012-4378
Abstract 438: The importance of estrogen-ERβ axis in racial disparity of prostate cancer
Authors: Elmageed Zakaria Y. Abd , Moroz Krzysztof , Srivastav Sudesh K. , Crawford Byron E. , Moparty Krishnarao , Thomas Raju , Abdel-Mageed Asim B. 
Published: August 2012

Abstract
Purpose: The role of estrogens and estrogen receptors (ERs) in the disproportionate incidence and mortality of prostate cancer (PCa) has not been established. Although ERβ has been implicated in PCa progression, its ethnic-based expression and underlying mechanisms are not fully understood. The aim of this study is to establish correlation between estrogen-ERβ axis and clinical outcome in African American (AA) in comparison to Caucasian American (CA) men. Patients and Methods: 17β-Estradiol (E2) was determined in the blood procured from normal (n=30) and PCa patients (n=50) by ELISA. The expression of ERβ was assessed using an NCI-designed ethnicity-based tissue microarray (TMA) slide encompassing 150 each of AA and CA PCa tissue cores, 17 BPH, 13 normal biopsies, and 3 PCa cell lines (LNCaP, DU-145 and PC-3). Validation of ERβ in situ was validated by qRT-PCR in matched microdissected tumors and normal glands from both populations. Results: In comparison to normal subjects, circulating E2 levels were significantly (p=0.0160) elevated in AA-men than in CA-men with PCa. Additionally, a significant difference in E2 blood levels (p=0.0015) was observed between AA and AA PCa patients. Histoscore analysis demonstrate intense nuclear immunoreactivity (p=0.0018) against ERβ in tumors of AA than CA men. This notion was further validated by qRT-PCR on LCM-procured tumor cells (p=0.0315). In the adjusted multivariate analysis there was no correlation between ERβ expression and any clinical parameters in PCa tissues. In AA, there was a positive correlation between Gleason score (GS) and age but a negative correlation was found between GS, age and PSA-recurrence free. However, no correlation was found in CA. Conclusion: Together, high circulating levels of blood estrogens and mRNA levels coupled with a differential expression of ERβ in PCa tissues suggest a potential role for estrogen-ERβ axis in the development of castrate-resistant prostate cancer in AA men. Key words: E2, ER beta, mRNA, TMA, histoscore, African Americans, health disparities.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 438. doi:1538-7445.AM2012-438
Abstract 4385: PD-1 blockade enhances T-cell migration to tumor through induction of IFN-γ inducible chemokines
Authors: Peng Weiyi , Liu Chenwen , Xu Chunyu , Chen Jieqin , Lou Yanyan , Overwijk Willem , Lizée Gregory , Yagita Hideo , Hwu Patrick 
Published: August 2012

Abstract
Adoptive cell transfer (ACT) is a promising therapeutic modality for cancer. Although tumor regression can be dramatic in some ACT-treated patients, other patients do not experience any clinical response, underscoring the need for further improvements. One limiting factor in ACT is immune suppression within the tumor microenvironment. In this study, we used a murine ACT model by treating gp100-expressing tumor-bearing mice with transgenic Pmel T-cells, which recognize gp100 in the context of H-2Db. We demonstrated that the expression of programmed death 1(PD-1) on transferred Pmel T-cells was upregulated at the tumor site, compared with transferred T cells in the spleen (48.07% vs 4.87% respectively). Given that PD-1 has been shown to attenuate T-cell mediated antitumor immune responses, we tested whether blockade of the PD-1 pathway by anti-PD-1 antibody could enhance the antitumor activity of adoptively transferred T-cells. We found that tumor-bearing mice treated with a combination of anti-PD-1 and ACT showed enhanced tumor regression compared to mice treated with ACT alone (median tumor size 11.30± 1.89 vs 43.85±7.28 mm2 on day 24 after tumor inoculation, respectively, p &lt;0.001). We also observed increased accumulation of transferred Pmel T cells in the tumor sites of mice receiving combination therapy with ACT and anti-PD-1 using bioluminescence imaging compared to ACT alone (Median luciferase output of 6.5X106 vs 1.6X106 photons/s/cm2/sr, respectively on day 6 after T-cell transfer, p value =0.039). Although anti-PD-1 did not alter the number of immunosuppressive Treg cells and MDSCs, anti-PD-1 treatment did increase the expression of IFN-γ and the IFN-γ inducible chemokine, CXCL10, at the tumor site. Using flow cytometry to analyze the CXCL10 production in the tumor microenvironment, we found that most of the CXCL10-secreting cells were CD11b+ cells, indicating that myeloid cells are the major CXCL10-producing population. Furthermore, bone marrow chimera experiments with IFN-γR-/- mice implicated IFN-γ as a major nexus point for controlling PD-1 blockade-induced tumor infiltration by T cells. Taken together, our results imply that therapeutic blockade of the PD-1 pathway may trigger a positive feedback loop by increasing IFN-γ presence at the tumor site, which in turn induces chemokine-dependent trafficking of more immune cells to metastatic sites.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4385. doi:1538-7445.AM2012-4385
Abstract 4386: Effects of interferon-α-transduced tumor cell vaccines and blockade of programmed cell death 1 on the growth of established tumors
Authors: Omori Risa , Eguchi Junichi , Hiroishi Kazumasa , Ishii Shigeaki , Sasagawa Ayako , Sakaki Masashi , Doi Hiroyoshi , Kajiwara Atsushi , Imawari Michio 
Published: August 2012

Abstract
Progress in treatments for cancer has improved the prognosis of patients with colorectal cancer. However, there is a strong need for the development of a new intervention therapy that suppresses the occurrence or recurrence effectively with fewer side effects. Immunotherapy may be such a treatment and gene therapy using tumor cells that are genetically modified to produce cytokines has been studied in several therapeutic models. We have previously reported that the interferon (IFN)-α gene-transduced tumor-based vaccination therapy suppresses the outgrowth of established tumors. Although the suppressive effects on established tumors were observed, we did not see reductions in the size of all of the parental tumors. Therefore, further improvements in the treatment are needed before clinical application, we focused on programmed cell death 1 (PD-1), which has been identified as a marker of exhausted T cells. In this study, we evaluated the efficacy of the combination of IFN-γ-transduced tumor cell vaccines and PD-1 blockade, and investigated the mechanisms of the antitumor effects of the combined therapy. A poorly immunogenic murine colorectal cancer cell line, MC38, was transduced to overexpress IFN-γ (MC38-IFNα). In a therapeutic model, parental tumor-bearing mice were inoculated with MC38-IFNα cells and an anti-PD-1 antagonistic antibody. Significant suppression of outgrowth of the established tumors was observed in the IFN-γ and anti-PD-1 combination treatment group (IFN+ anti-PD-1, 174.17 ± 35.54 mm2 vs control, 328.67 ± 26.36 mm2 on day 28, P = 0.0114 vs controls). Immunohistochemical analyses showed marked infiltration of CD4+ cells as well as CD8+ cells in the established tumors of mice treated with both IFN-γ and anti-PD-1. To investigate induction of tumor-specific immune responses, we stimulated splenocytes of IFN-γ or/and anti-PD-1 treated mice twice weekly by DCs in vitro. Significant tumor-specific cytolysis was detected when splenocytes of mice treated with both IFN-γ and anti-PD-1 were used as effector cells (58.1% ± 6.7% for MC38 and 14.1% ± 1.7% for YAC-1, effector:target = 20, P &lt; 0.001). Our findings suggest that blockade of the PD-1 PD-ligand enhanced the Th1-type antitumor immune responses induced by IFN-γ. The combination of IFN-γ gene-transduced tumor cell vaccines and PD-1 blockade may be a possible candidate for a cancer vaccine for clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4386. doi:1538-7445.AM2012-4386
Abstract 4391: CD20 as a target for therapy in solid tumors
Authors: Affara Nesrine I. , Ruffell Brian , Johansson Magnus , Fujikawa Kerri , Bergsland Emily , DeNardo David G. , Chen Heather I. , Wadhwani Nikhil , Steinhoff Martin , Truitt Morgan , Olson Peter , Hanahan Douglas , Li Yijin , Gong Qian , Ma Yan , Wiesen Jane F. , Kim Grace , Tempero Margaret , Balkwill Frances , Irving Bryan , Coussens Lisa M. 
Published: August 2012

Abstract
Using the K14-HPV16 mouse model of squamous carcinogenesis (SCC), we previously reported that B cells foster neoplastic progression through deposition of immunoglobulin complexes in premalignant tissue via Fcα receptor-dependent activation of recruited myeloid cells. Here we evaluated therapeutic interventions targeting these pathways in preclinical trials through administration of depleting αCD20 antibody and small molecule inhibitor of Syk kinase. Both approaches harbored efficacy in preventing premalignant progression to the dysplastic/carcinoma in situ state. Screening a diverse spectrum of human solid tumors revealed SCCs of the vulva, head and neck, as well as pancreatic ductal adenocarcinomas (PDAC) as scoring positively for “signatures” of B cell or plasma cell infiltration, i.e. Ig or CD20 mRNA expression, thereby identifying carcinomas potentially amenable to anti-B cell therapies. Accordingly, B cell-deficient mice failed to support growth of either transplantable orthotopic SCC or PDAC. While administration of αCD20 mAB as a single agent was inefficient in impeding growth of preexisting SCCs, when delivered in combination with cytotoxic chemotherapy, e.g., paclitaxel, carboplatin or cisplatin, αCD20 mAb significantly improved chemotherapeutic response and improved survival by a mechanism dependent on CD8+ T cells. These data reveal that blocking protumorigenic programs regulating by humoral immunity, in combination with chemotherapy, effectively reprograms the tumor immune microenvironment and improves outcome. The authors acknowledge generous support from the NIH/NCI (R01CA130980, R01CA13256, R01CA140943, R01CA15531), the Department of Defense (W81XWH-09-1-0342, W81XWH-10-BCRP-EOHS-EXP) and the Susan G Komen Foundation (KG111084)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4391. doi:1538-7445.AM2012-4391