bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of MiR-195 and MiR-497 Expression, Regulation and Role in Breast Cancer
Authors: Li Dan , Zhao Yulan , Liu Changxing , Chen Xiaona , Qi Yanting , Jiang Yue , Zou Chao , Zhang Xiaolong , Liu Shunying , Wang Xuejing , Zhao Dan , Sun Qiang , Zeng Zhenbing , Dress Andreas , Lin Marie C. , Kung Hsiang-Fu , Rui Hallgeir , Liu Ling-Zhi , Mao Feng , Jiang Bing-Hua , Lai Lihui 
Published: February 2011

Abstract
Purpose: To investigate expression, regulation, potential role and targets of miR-195 and miR-497 in breast cancer.
Experimental Design: The expression patterns of miR-195 and miR-497 were initially examined in breast cancer tissues and cell lines by Northern blotting and quantitative real-time PCR. Combined bisulfite restriction analysis and bisulfite sequencing were carried out to study the DNA methylation status of miR-195 and miR-497 genes. Breast cancer cells stably expressing miR-195 and miR-497 were established to study their role and targets. Finally, normal, fibroadenoma and breast cancer tissues were employed to analyze the correlation between miR-195/497 levels and malignant stages of breast tumor tissues.
Results: MiR-195 and miR-497 were significantly downregulated in breast cancer. The methylation state of CpG islands upstream of the miR-195/497 gene was found to be responsible for the downregulation of both miRNAs. Forced expression of miR-195 or miR-497 suppressed breast cancer cell proliferation and invasion. Raf-1 and Ccnd1 were identified as novel direct targets of miR-195 and miR-497. miR-195/497 expression levels in clinical specimens were found to be correlated inversely with malignancy of breast cancer.
Conclusions: Our data imply that both miR-195 and miR-497 play important inhibitory roles in breast cancer malignancy and may be the potential therapeutic and diagnostic targets. Clin Cancer Res; 17(7); 1722–30. ©2011 AACR.
Brain-Derived Neurotrophic Factor and Neurotrophin-4/5 Are Expressed in Breast Cancer and Can Be Targeted to Inhibit Tumor Cell Survival
Authors: Vanhecke Elsa , Adriaenssens Eric , Verbeke Stéphanie , Meignan Samuel , Germain Emmanuelle , Berteaux Nathalie , Nurcombe Victor , Le Bourhis Xuefen , Hondermarck Hubert 
Published: February 2011

AbstractPurpose: Given that nerve growth factor has previously been shown to be involved in breast cancer progression, we have tested here the hypothesis that the other neurotrophins (NT) are expressed and have an influence in breast tumor growth.Experimental Design: The expression of brain-derived neurotrophic factor (BDNF), NT-3 and NT-4/5, as well as the neurotrophin receptor p75NTR, TrkB, and TrkC, was studied by RT-PCR, Western blotting, and immunohistochemistry in cell lines and tumor biopsies. The biological impacts of neurotrophins, and associated mechanisms, were analyzed in cell cultures and xenografted mice.Results: BDNF and NT-4/5 were expressed and secreted by breast cancer cells, and the use of blocking antibodies suggested an autocrine loop mediating cell resistance to apoptosis. The corresponding tyrosine kinase receptor TrkB was only rarely observed at full length, whereas the expression of TrkB-T1, lacking the kinase domain, as well as p75NTR, were detected in all tested breast cancer cell lines and tumor biopsies. In contrast, NT-3 and TrkC were not detected. SiRNA against p75NTR and TrkB-T1 abolished the antiapoptotic effect of BDNF and NT-4/5, whereas the pharmacological inhibitors K252a and PD98059 had no effect, suggesting the involvement of p75NTR and TrkB-T1, but not kinase activities from Trks and MAPK. In xenografted mice, anti-BDNF, anti-NT-4/5, anti-p75NTR, or anti-TrkB-T1 treatments resulted in tumor growth inhibition, characterized by an increase in cell apoptosis, but with no change in proliferation.Conclusion: BDNF and NT-4/5 contribute to breast cancer cell survival and can serve as prospective targets in attempts to inhibit tumor growth. Clin Cancer Res; 17(7); 1741–52. ©2011 AACR.
Phase II, Open-Label Study of Brivanib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma
Authors: Park Joong-Won , Finn Richard S. , Kim Jun Suk , Karwal Mark , Li Ruby K. , Ismail Fuad , Thomas Melanie , Harris Rosemarie , Baudelet Christine , Walters Ian , Raoul Jean-Luc 
Published: February 2011

AbstractPurpose: Brivanib, a selective dual inhibitor of fibroblast growth factor and VEGF signaling, has demonstrated encouraging antitumor activity in preclinical and phase I studies. We performed a phase II open-label study of brivanib as first-line therapy in patients with unresectable, locally advanced, or metastatic hepatocellular carcinoma.Experimental Design: Brivanib was administered orally at a dose of 800 mg once daily. The primary objective was 6-month progression-free survival, progression-free survival rate; secondary objectives were tumor response rate, time to response, duration of response, median progression-free survival, median overall survival, disease control rate (complete response, partial response, or stable disease ≥ 42 days), and safety and tolerability.Results: Between March 2007 and May 2009, 55 patients were treated and were evaluable for response. Patients were assessed using modified World Health Organization (mWHO) criteria. According to mWHO criteria and as assessed by Independent Response Review Committee, the six-month progression-free survival rate (95% CI) was 18.2% (9.1%–30.9%). Median progression-free survival (95% CI) was 2.7 months (1.4–3.0). One patient achieved a complete response and three achieved a partial response. Twenty-two had stable disease. Median overall survival (95% CI) was 10 (6.8–15.2) months. Brivanib was generally well tolerated; the most common adverse events included fatigue, hypertension, and diarrhea.Conclusion: Brivanib as first-line therapy demonstrates promising antitumor activity and a manageable safety profile in patients with advanced, unresectable HCC. Clin Cancer Res; 17(7); 1973–83. ©2011 AACR.
CXCL12 (SDF1α)-CXCR4/CXCR7 Pathway Inhibition: An Emerging Sensitizer for Anticancer Therapies?
Authors: Duda Dan G. , Kozin Sergey V. , Kirkpatrick Nathaniel D. , Xu Lei , Fukumura Dai , Jain Rakesh K. 
Published: February 2011

AbstractAddition of multiple molecularly targeted agents to the existing armamentarium of chemotherapeutics and radiotherapies represents a significant advance in the management of several advanced cancers. In certain tumor types with no efficacious therapy options, these agents have become the first line of therapy, for example, sorafenib in advanced hepatocellular carcinoma or bevacizumab in recurrent glioblastoma. Unfortunately, in many cases, the survival benefits are modest, lasting only weeks to a few months. Moreover, they may not show benefit in patients with localized disease (i.e., in the adjuvant setting). Recent studies have provided increasing evidence that activation of the chemokine CXCL12 (SDF1α) pathway is a potential mechanism of tumor resistance to both conventional therapies and biological agents via multiple complementary actions: (i) by directly promoting cancer cell survival, invasion, and the cancer stem and/or tumor-initiating cell phenotype; (ii) by recruiting “distal stroma” (i.e., myeloid bone marrow–derived cells) to indirectly facilitate tumor recurrence and metastasis; and (iii) by promoting angiogenesis directly or in a paracrine manner. Here, we discuss recent preclinical and clinical data that support the potential use of anti-CXCL12 agents (e.g., AMD3100, NOX-A12, or CCX2066) as sensitizers to currently available therapies by targeting the CXCL12/CXCR4 and CXCL12/CXCR7 pathways. Clin Cancer Res; 17(8); 2074–80. ©2011 AACR.
The Association of MicroRNA Expression with Prognosis and Progression in Early-Stage, Non–Small Cell Lung Adenocarcinoma: A Retrospective Analysis of Three Cohorts
Authors: Saito Motonobu , Schetter Aaron J. , Mollerup Steen , Kohno Takashi , Skaug Vidar , Bowman Elise D. , Mathé Ewy A. , Takenoshita Seiichi , Yokota Jun , Haugen Aage , Harris Curtis C. 
Published: February 2011

Abstract
Purpose: There is increasing evidence that altered microRNA expression is associated with tumor progression and survival in cancer patients. We tested if the expression of specific microRNAs was associated with prognosis and disease progression in early-stage lung adenocarcinoma.
Experimental Design: The expression of miR-21, miR-17, and miR-155 was measured by quantitative RT-PCR in tissues from 317 non–small cell lung cancer (NSCLC) patients that originated from Maryland, Norway, and Japan. Kaplan-Meier and Cox regression analysis evaluated associations of microRNA expression with cancer-specific mortality and disease-free survival.
Results: Elevated miR-21 (HR 2.06, 1.13–3.75), miR-17 (HR 2.00, 1.10–3.61), and miR-155 (HR 2.37, 1.27–4.42) was associated with worse cancer-specific mortality in the Maryland cohort. These were evaluated in two additional cohorts and only miR-21 was associated with worse cancer-specific mortality in the Norwegian cohort (HR 2.78, 1.22–6.31) and worse relapse-free survival in the Japanese cohort (HR 2.82, 1.57–5.07). More advanced stage tumors expressed significantly higher levels of miR-21 compared with TNM stage I tumors. TNM stage I patients were evaluated separately and high levels of miR-21 was associated with worse cancer-specific mortality (HR 2.16, 1.11–4.21) and relapse-free survival (3.40, 1.57–7.36) independent of other clinical factors.
Conclusions: This is the first study to report that increased miR-21 expression is associated with disease progression and survival in stage I lung cancer. This suggests that expression of miR-21 may contribute to lung carcinogenesis and serve as a therapeutic target or early-stage prognostic biomarker for lung adenocarcinoma. Clin Cancer Res; 17(7); 1875–82. ©2011 AACR.
Abstract 10: Characterization of ovarian CSC using ALDH and CD133 identifies a cancer stem cell hierarchy
Authors: Silva Ines A. , Yang Kun , Mclean Karen , Minosyan Tamara , Spalinger Greg , Ginestier Christophe , Reynolds Kevin , Kueck Angie , Johnston Carolyn , Liu Rebecca , Wicha Max S. , Buckanovich Ronald J. 
Published: February 2011

Abstract
Recent studies in ovarian cancer suggest that the protein CD133 may be a marker of cancer stem cells (CSC). CSC studies in several solid tumors have identified Aldehyde dehyrogenase (ALDH) enzymatic activity as a CSC marker, however ALDH has not been studied in ovarian cancer. We sought to determine if ALDH alone or in combination with CD133 could better define CSC in ovarian cancer. We analyzed the expression of these markers in 13 consecutive primary human ovarian tumor specimens and 8 cell lines. 70% of primary ovarian tumors analyzed had CD133+ cells detectable in low number in, and many tumor cell lines lacked CD133 expression. In contrast, 100% of the primary human ovarian tumor specimens and ovarian cancer cell lines demonstrated ALDH activity. ALDH+ cells isolated from 6 ovarian cancer cell lines preferentially grew larger tumors at a faster rate compared to ALDH− cells. In some cases ALDH− cells were incapable of generating tumors, suggesting ALDH is a good marker of ovarian CSC in cell lines. Importantly, as few as 1000 ALDH+ cells directly isolated from human ovarian tumors were capable of generating tumors in immune deficient mice. ALDH− cells did not form tumors in mice. Interestingly, when ALDH was used in combination with CD133 to analyze ovarian cancer cell lines we observed greater growth in the ALDH+CD133+ cells compared to ALDH+CD133− cells suggesting a potential hierarchy of the stem cells. Consistent with this, as few as 11 ALDH+CD133+ cells freshly isolated from human tumors were capable of forming tumors in mice. Consistent with a stem cell hierarchy, tumors formed from ALDH+CD133+ cells demonstrated a poorly differentiated histology, whereas tumors formed from ALDH+ cells alone demonstrated a more differentiated histology. Finally analysis of tumors generated from ALDH+ and ALDH+CD133+ tumors demonstrated a significant increase in microvascular density compared to ALDH− tumors. qRT-PCR analysis demonstrated that ALDH+ cells compared to ALDH− cells preferentially express numerous angiogenic factors. Taken together our studies: (1) indicate ALDH as a marker of ovarian CSC, (2) suggest a hierarchy of ovarian cancer stem cell differentiation state, and (3) demonstrates that ovarian CSC are highly angiogenic to recruit vasculature to create a stem cell niche.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 10.
Abstract 1006: Tumor associated mesenchymal stem cells protect ovarian cancer cells from hyperthermia through stromal cell derived factor-1 (SDF-1) secretion
Authors: Lis Raphael , Mirshahi Pejman , Fares Fadoua , Touboul Cyril , Taha Rowaida , Mirshahi Massoud , Rafii Arash 
Published: February 2011

Abstract
Background: Hyperthermia therapy is a medical procedure where local body tissues are exposed to high temperatures ranging from 40oC to 43oC with the aim of killing microscopic tumor residue, being more susceptible to heat than normal cells. When combined with hyperthermia during cytoreductive surgeries, intraperitoneal chemotherapy was clinically proved to be more effective. While hyperthermia's cytotoxicity was tested on cancer cells, its effect on interactions between cancer cells and tumor stroma cells was minimally scrutinized. In this study, we investigate the effect of tumor associated mesenchymal stem cells, on inducing resistance of ovarian cancer cells (OCC) to hyperthermia.
Methods: OCC viability was challenges by heat shock at 42 degrees, in simple or co-culture systems. Cell viability was determined using Calcein Violet AM by Fluorescence Activated Cell Sorting, FACS. The same experiment was replicated using a transwell system. Using the trogocytosis assay we measured the interaction between the different cell types. Multiparameter flow cytometry was used to study the relation between intercellular interaction and thermoresistance. Finally using inhibitors and blocking antibodies we were able to analyse the role of SDF1 pathway in thermoresistance.
Results: At 42oC, an increase in viability of OCC, co-cultured with ‘MSC, was detected in comparison to cells cultured alone. The same result was attained using the transwell experiment. Antibody and siRNA for CXCR4 reversed the heat resistant effect of MSC cells on OCC. More interestingly we were able to demonstrate an increased expression of CXCR4 in cancer cells co-cultured with the MSC, and increased thermoresistance in the subset of cancer cells with more interaction (as measured by oncologic trogocytosis).
Conclusions: This study proved that contact and non contact-based cell to cell interactions between MSC cells and OCC help ovarian cancer cells resist hyperthermia. Within these interactions, MSC-secreted SDF-1 could be the major inducer of heat resistance. Combining monoclonal antibody against CXCR4 with hyperthermic intraperitoneal chemotherapy could eliminate the protective effect of tumor associated mesenchymal stem cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1006.
Abstract 1014: Semaphorin 4D involves in the regulation of cell motility through its receptor Plexin B1 in pancreatic cancer
Authors: Shingo Kato , Kubota Kensuke , Shimamura Takeshi , Kobayashi Noritoshi , Watanabe Seitaro , Nagashima Yoji , Nakajima Atsushi 
Published: February 2011

Abstract
Introduction: Semaphorins are a large family of either membrane-bound or secreted proteins that provide axonal guidance in neuronal tissues and regulate cell motility in many types of cells. Recent articles reported that Semaphorin 4D (Sema 4D) enhanced in vitro motility and invasiveness through its receptor Plexin B1 and Met, and increased in vivo metastasis potential in breast cancer. However, these expression and function in pancreatic cancer is not known.
Purpose: In the present study, we investigated the clinicopathological significance of Sema 4D and Plexin B1 expression in surgically resected pancreatic ductal adenocarcinoma sections and the regulation of cell motility through the Sema 4D - Plexin B1 signaling pathway.
Material & Methods: The mRNA expression level of Sema 4D and Plexin B1 were evaluated by Quantitative Real Time PCR from 12 surgical specimens and 10 normal pancreatic tissues. Expression of Sema 4D and Plexin B1 were also evaluated immunohistochemically from 90 patients. Using pancreatic cancer cell lines, the expression of endogenous Plexin B1 and Met protein was investigated by western blotting. And the phosphorylation of Met protein after stimulating by Sema4D was evaluated. As functional analysis, scratch assay and MTT assay were carried out.
Results: The mRNA expression level of Sema 4D and Plexin B1 were significantly high in cancer tissues compared to normal pancreas tissues. Immunostaining showed that Sema 4D strongly expressed in lymphocytes and macrophages, as previously reported. Ninety two percent (83 out of 90 cases) pancreatic cancer samples overexpressed Plexin B1 compared to normal pancreas tissues. Endogenous Plexin B1 and Met protein were detected in eight pancreatic cancer cell lines, with a variety of expression levels. Sema 4D stimulation activated Met protein, and significantly induced cell migration.
Discussion: Here we show that Sema 4D involves in the regulation of cell motility through its receptor Plexin B1. And the results of immunostaining suggest that Sema 4D could play a role in the interaction between tumor cells and tumor microenvironment in pancreatic cancer tissues. As many attempts are now ongoing to target the tumor stroma, these findings provide a new insight into molecular targeted therapies for pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1014.
Abstract 1021: Use of functional tumor cell line mitochondria to explore the mechanisms of BH3 peptides and ABT-737-induced mitochondrial membrane permeabilization
Authors: Buron Nelly , Porceddu Mathieu , Rustin Pierre , Jacotot Etienne , Borgne-Sanchez Annie 
Published: February 2011

Abstract
Current limitations of chemotherapy include toxicity on healthy tissues and multidrug resistance on malignant cells. A number of recent anti-cancer strategies are targeting the mitochondrial apoptotic machinery to induce tumor cell death. In this study, we set up protocols to isolate mitochondria from various origins with high purity, quality and functionality. We analyzed the effect of putative Bcl-2 inhibitors on both healthy and tumor isolated mitochondria. We measured mitochondrial membrane permeabilization (swelling), mitochondrial transmembrane potential (ΔΨm) and mitochondrial outer membrane permeabilization (MOMP) in both isolated healthy and tumoral cell mitochondria. Like t-Bid and some BH3 peptides, the molecule ABT-737 was found to present a tumor-specific mitochondrio-toxicity, while compounds like HA-14.1, YC-137, Chelerythrine, Gossypol, TW-37 or EM20-25 did not. We thus demonstrated that ABT-737 can induce a relatively large and targeted MOMP triggering the release of apoptotic proteins from tumoral cell mitochondria (Cytochrome c, Smac/Diablo and Omi/HtrA2 but not AIF) however without any mitochondrial swelling. Furthermore, ABT-737 addition to isolated tumoral cell mitochondria induced specific Bax/Bak channel formation by oligomerizing monomeric Bax and/or Bak already inserted in the mitochondrial membrane. We also provided evidence that tumoral cell mitochondria can be either resistant or sensitive to ABT-737-induced MOMP, depending on their origin and interactions between pro- and anti-apoptotic proteins. Finally, this method based on MOMP is an interesting screening tool, tailored for identifying Bcl-2 antagonists with selective toxicity profile against tumoral cell mitochondria but devoid of toxicity against healthy mitochondria.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1021.
Abstract 1025: Rac1 is a novel binding partner of the anti-apoptotic protein Bcl-2
Authors: Kang Jia , Velaithan Rathiga , Hirpara Jayshree L. , Loh Thomas , Brenner Catherine , Clement Marie-Veronique , Pervaiz Shazib 
Published: February 2011

Abstract
We have previously reported that Bcl-2 expression resulted in an increase in intracellular superoxide anion and that a dominant negative mutant of the small GTPase Rac1 sensitized Bcl-2 expressing cells to apoptosis. Here we report that silencing and functional inhibition of Rac1 blocks Bcl-2 mediated increases in intracellular and mitochondrial superoxide levels in tumor cells. We provide evidence that this effect is mediated via specific interaction between the two proteins using co-immunoprecipitation, confocal and electron microscopy, as well as GST-fusion proteins. Analysis of the sub-cellular localization of these proteins revealed increased association of Bcl-2 and mitochondrial Rac1 in Bcl-2 overexpressing cells. This interaction can be blocked in vitro and in vivo by BH3 mimetics such as HA14-I, BH3-I as well as synthetic Bcl-2 BH3 domain peptides. That this interaction is functionally relevant is supported by the ability of the Bcl-2 BH3 peptide to inhibit intracellular superoxide production as well as overcome drug resistance in Bcl-2 overexpressing cells. Lastly, using patient-derived primary tissues, we observed the interaction only in cancerous tissues with marked overexpression of Bcl-2 and not in peripheral blood leukocytes or samples from non-cancerous tissue. These data provide a novel facet in the biology of Bcl-2 with potential implications for targeted anti-cancer drug design.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1025.