bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of p130 Accelerates Tumor Development in a Mouse Model for Human Small-Cell Lung Carcinoma
Authors: Schaffer Bethany E. , Park Kwon-Sik , Yiu Gloria , Conklin Jamie F. , Lin Chenwei , Burkhart Deborah L. , Karnezis Anthony N. , Sweet-Cordero E. Alejandro , Sage Julien 
Published: April 2010

Abstract
Small-cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer. Although SCLC patients often initially respond to therapy, tumors nearly always recur, resulting in a 5-year survival rate of less than 10%. A mouse model has been developed based on the fact that the RB and p53 tumor suppressor genes are mutated in more than 90% of human SCLCs. Emerging evidence in patients and mouse models suggests that p130, a gene related to RB, may act as a tumor suppressor in SCLC cells. To test this idea, we used conditional mutant mice to delete p130 in combination with Rb and p53 in adult lung epithelial cells. We found that loss of p130 resulted in increased proliferation and significant acceleration of SCLC development in this triple-knockout mouse model. The histopathologic features of the triple-mutant mouse tumors closely resembled that of human SCLC. Genome-wide expression profiling experiments further showed that Rb/p53/p130-mutant mouse tumors were similar to human SCLC. These findings indicate that p130 plays a key tumor suppressor role in SCLC. Rb/p53/p130-mutant mice provide a novel preclinical mouse model to identify novel therapeutic targets against SCLC. Cancer Res; 70(10); 3877–83. ©2010 AACR.
Requirement of the NF-κB Subunit p65/RelA for K-Ras–Induced Lung Tumorigenesis
Authors: Bassères Daniela S. , Ebbs Aaron , Levantini Elena , Baldwin Albert S. 
Published: April 2010

Abstract
K-Ras–induced lung cancer is a very common disease, for which there are currently no effective therapies. Because therapy directly targeting the activity of oncogenic Ras has been unsuccessful, a different approach for novel therapy design is to identify critical Ras downstream oncogenic targets. Given that oncogenic Ras proteins activate the transcription factor NF-κB, and the importance of NF-κB in oncogenesis, we hypothesized that NF-κB would be an important K-Ras target in lung cancer. To address this hypothesis, we generated a NF-κB-EGFP reporter mouse model of K-Ras–induced lung cancer and determined that K-Ras activates NF-κB in lung tumors in situ. Furthermore, a mouse model was generated where activation of oncogenic K-Ras in lung cells was coupled with inactivation of the NF-κB subunit p65/RelA. In this model, deletion of p65/RelA reduces the number of K-Ras–induced lung tumors both in the presence and in the absence of the tumor suppressor p53. Lung tumors with loss of p65/RelA have higher numbers of apoptotic cells, reduced spread, and lower grade. Using lung cell lines expressing oncogenic K-Ras, we show that NF-κB is activated in these cells in a K-Ras–dependent manner and that NF-κB activation by K-Ras requires inhibitor of κB kinase β (IKKβ) kinase activity. Taken together, these results show the importance of the NF-κB subunit p65/RelA in K-Ras–induced lung transformation and identify IKKβ as a potential therapeutic target for K-Ras–induced lung cancer. Cancer Res; 70(9); 3537–46. ©2010 AACR.
4-1BB Ligand as an Effective Multifunctional Immunomodulator and Antigen Delivery Vehicle for the Development of Therapeutic Cancer Vaccines
Authors: Sharma Rajesh K. , Schabowsky Rich-Henry , Srivastava Abhishek K. , Elpek Kutlu G. , Madireddi Shravan , Zhao Hong , Zhong Zhenping , Miller Robert W. , MacLeod Kathryn J. , Yolcu Esma S. , Shirwan Haval 
Published: April 2010

Abstract
Therapeutic subunit vaccines based on tumor-associated antigens (TAA) represent an attractive approach for the treatment of cancer. However, poor immunogenicity of TAAs requires potent adjuvants for therapeutic efficacy. We recently proposed the tumor necrosis factor family costimulatory ligands as potential adjuvants for therapeutic vaccines and, hence, generated a soluble form of 4-1BBL chimeric with streptavidin (SA-4-1BBL) that has pleiotropic effects on cells of innate, adaptive, and regulatory immunity. We herein tested whether these effects can translate into effective cancer immunotherapy when SA-4-1BBL was also used as a vehicle to deliver TAAs in vivo to dendritic cells (DCs) constitutively expressing the 4-1BB receptor. SA-4-1BBL was internalized by DCs upon receptor binding and immunization with biotinylated antigens conjugated to SA-4-1BBL resulted in increased antigen uptake and cross-presentation by DCs, leading to the generation of effective T-cell immune responses. Conjugate vaccines containing human papillomavirus 16 E7 oncoprotein or survivin as a self-TAA had potent therapeutic efficacy against TC-1 cervical and 3LL lung carcinoma tumors, respectively. Therapeutic efficacy of the vaccines was associated with increased CD4+ T and CD8+ T-cell effector and memory responses and higher intratumoral CD8+ T effector/CD4+CD25+Foxp3+ T regulatory cell ratio. Thus, potent pleiotropic immune functions of SA-4-1BBL combined with its ability to serve as a vehicle to increase the delivery of antigens to DCs in vivo endow this molecule with the potential to serve as an effective immunomodulatory component of therapeutic vaccines against cancer and chronic infections. Cancer Res; 70(10); 3945–54. ©2010 AACR.
Direct Activation of Emmprin and Associated Pathogenesis by an Oncogenic Herpesvirus
Authors: Qin Zhiqiang , Dai Lu , Slomiany Mark G. , Toole Bryan P. , Parsons Chris 
Published: April 2010

Abstract
Emmprin (extracellular matrix metalloproteinase inducer) is a multifunctional glycoprotein expressed by cancer cells and stromal cells in the tumor microenvironment. Through both direct effects within tumor cells and promotion of tumor-stroma interactions, emmprin induces tumor cell invasiveness and regional angiogenesis. The Kaposi's sarcoma–associated herpesvirus (KSHV) is a common etiology for cancers arising in the setting of immune suppression, including Kaposi's sarcoma and primary effusion lymphoma. However, whether emmprin expression and function are regulated by KSHV or other oncogenic viruses in the tumor microenvironment to promote viral cancer pathogenesis remains unknown. Fibroblasts and endothelial cells support latent KSHV infection and represent cellular components of Kaposi's sarcoma lesions. Therefore, we used primary human fibroblasts and endothelial cells to determine whether KSHV itself regulates emmprin expression, and whether KSHV-emmprin interactions mediate cell invasiveness. We found that KSHV promotes fibroblast and endothelial cell invasiveness following de novo infection through the upregulation of emmprin, and that this effect is mediated by the KSHV-encoded latency-associated nuclear antigen. We also found that emmprin promotes invasiveness, as well as colony formation, by primary effusion lymphoma cells derived from human tumors. Collectively, these data implicate KSHV activation of emmprin as an important mechanism for cancer progression and support the potential utility of targeting emmprin as a novel therapeutic approach for KSHV-associated tumors. Cancer Res; 70(10); 3884–9. ©2010 AACR.
Receptor Tyrosine Kinase Coactivation Networks in Cancer
Authors: Xu Alexander M. , Huang Paul H. 
Published: April 2010

Abstract
Cancer cells employ multiple mechanisms to evade tightly regulated cellular processes such as proliferation, apoptosis, and senescence. Systems-wide analyses of tumors have recently identified receptor tyrosine kinase (RTK) coactivation as an important mechanism by which cancer cells achieve chemoresistance. This mini-review discusses our current understanding of the complex and dynamic process of RTK coactivation. We highlight how systems biology and computational modeling have been employed to predict integrated signaling outcomes and cancer phenotypes downstream of RTK coactivation. We conclude by providing an outlook on the feasibility of targeting RTK networks to overcome chemoresistance in cancer. Cancer Res; 70(10); 3857–60. ©2010 AACR.
Functional Imaging Using Diffuse Optical Spectroscopy of Neoadjuvant Chemotherapy Response in Women with Locally Advanced Breast Cancer
Authors: Soliman Hany , Gunasekara Anoma , Rycroft Mary , Zubovits Judit , Dent Rebecca , Spayne Jacqueline , Yaffe Martin J. , Czarnota Gregory J. 
Published: April 2010

Abstract
Purpose: Functional imaging with tomographic near-infrared diffuse optical spectroscopy (DOS) can measure tissue concentration of deoxyhemoglobin (Hb), oxyhemoglobin (HbO2), percent water (%water), and scattering power (SP). In this study, we evaluated tumor DOS parameters and described their relationship to clinical and pathologic outcome in patients undergoing neoadjuvant therapy for locally advanced breast cancer.
Experimental Design: Ten patients were enrolled and intended to undergo five scans each. Scans were taken up to 3 days before treatment and at 1, 4, and 8 weeks after neoadjuvant treatment before surgery. Changes in volume of interest weighted tissue Hb, HbO2, %water, and SP corresponding to the tumor were compared with clinical and pathologic response.
Results: All patients' tumor volumes of interest were significantly different compared with background tissue for all parameters. Five patients had a good pathologic response. Four patients were considered nonresponders. One patient initially did not respond to chemotherapy but, after a change in chemotherapy, had a good response. In the five patients with a good response, the mean drop in Hb, HbO2, %water, and SP from baseline to the 4-week scan was 67.6% (SD = 20.8), 58.9% (SD = 20.3), 51.2% (SD = 28.3), and 52.6% (SD = 26.4), respectively. In contrast, the four nonresponders had a mean drop of 17.7% (SD = 9.8), 18.0% (SD = 20.8), 15.4% (SD = 11.7), and 12.6% (SD = 10.2) for Hb, HbO2, %water, and SP, respectively.
Conclusions: Responders and nonresponders were significantly different for all functional parameters at the 4-week scan, except for %water, which approached significance. Thus, DOS could be used as an early detector of tumor response. Clin Cancer Res; 16(9); 2605–14. ©2010 AACR.
Detection and HER2 Expression of Circulating Tumor Cells: Prospective Monitoring in Breast Cancer Patients Treated in the Neoadjuvant GeparQuattro Trial
Authors: Riethdorf Sabine , Müller Volkmar , Zhang Liling , Rau Thomas , Loibl Sibylle , Komor Martina , Roller Marc , Huober Jens , Fehm Tanja , Schrader Iris , Hilfrich Jörn , Holms Frank , Tesch Hans , Eidtmann Holger , Untch Michael , von Minckwitz Gunter , Pantel Klaus 
Published: April 2010

Abstract
Purpose: This study was aimed at detecting and characterizing circulating tumor cells (CTC) before and after neoadjuvant therapy (NT) in the peripheral blood of patients with breast cancer.
Experimental Design: The clinical trial GeparQuattro incorporated NT approaches (epirubicin/cyclophosphamide prior to randomization to docetaxel alone, docetaxel in combination with capecitabine, or docetaxel followed by capecitabine) and additional trastuzumab treatment for patients with HER2-positive tumors. We used the Food and Drug Administration–approved CellSearch system for CTC detection and evaluation of HER2 expression and developed HER2 immunoscoring for CTC.
Results: We detected ≥1 CTC/7.5 mL in 46 of 213 patients (21.6%) before NT and in 22 of 207 patients (10.6%) after NT (P = 0.002). Twenty (15.0%) initially CTC-positive cases were CTC-negative after NT, whereas 11 (8.3%) cases were CTC-positive after NT, although no CTC could be found before NT. CTC detection did not correlate with primary tumor characteristics. Furthermore, there was no association between tumor response to NT and CTC detection. HER2-overexpressing CTC were observed in 14 of 58 CTC-positive patients (24.1%), including 8 patients with HER2-negative primary tumors and 3 patients after trastuzumab treatment. CTC scored HER2-negative or weakly HER2-positive before or after NT were present in 11 of 21 patients with HER2-positive primary tumors. HER2 overexpression on CTC was restricted to ductal carcinomas and associated with high tumor stage (P = 0.002).
Conclusion: CTC number was low in patients with primary breast cancer. The decrease in CTC incidence during treatment was not correlated with standard clinical characteristics and primary tumor response. Information on the HER2 status of CTC might be helpful for stratification and monitoring of HER2-directed therapies. Clin Cancer Res; 16(9); 2634–45. ©2010 AACR.
TRAIL and Doxorubicin Combination Induces Proapoptotic and Antiangiogenic Effects in Soft Tissue Sarcoma In vivo
Authors: Wang Suizhao , Ren Wenhong , Liu Jeffery , Lahat Guy , Torres Keila , Lopez Gonzalo , Lazar Alexander J. , Hayes-Jordan Andrea , Liu Kebin , Bankson Jim , Hazle John D. , Lev Dina 
Published: April 2010

Abstract
Purpose: Novel therapeutic approaches for complex karyotype soft tissue sarcoma (STS) are crucially needed. Consequently, we assessed the efficacy of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), in combination with chemotherapy, on local and metastatic growth of human STS xenografts in vivo.
Experimental Design: TRAIL was evaluated alone and combined with low-dose doxorubicin in two human STS severe combined immunodeficient mouse xenograft models using fibrosarcoma (HT1080; wild-type p53) and leiomyosarcoma (SKLMS1; mutated p53), testing for effects on local growth, metastasis, and overall survival. Magnetic resonance imaging was used to evaluate local growth and bioluminescence was used to longitudinally assess lung metastases. Tissues were evaluated through immunohistocemistry and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling staining for treatment effects on tumor cell proliferation, apoptosis, angiogenesis, angiogenic factors, and TRAIL receptor expression. Quantitative real-time polymerase chain reaction (QRTPCR) angiogenesis array was used to assess therapy-induced gene expression changes.
Results: TRAIL/doxorubicin combination induced marked STS local and metastatic growth inhibition in a p53-independent manner. Significantly increased (P &lt; 0.001) host survival was also demonstrable. Combined therapy induced significant apoptosis, decreased tumor cell proliferation, and increased TRAIL receptor (DR4 and DR5) expression in all treated tumors. Moreover, decreased microvessel density was observed, possibly secondary to increased expression of the antiangiogenic factor CXCL10 and decreased proangiogenic interleukin-8 cytokine in response to TRAIL/doxorubicin combination, as was also observed in vitro.
Conclusions: Given the urgent need for better systemic approaches to STS, clinical trials evaluating TRAIL in combination with low-dose chemotherapy are potentially warranted. Clin Cancer Res; 16(9); 2591–604. ©2010 AACR.
Chromosomal and MicroRNA Expression Patterns Reveal Biologically Distinct Subgroups of 11q− Neuroblastoma
Authors: Buckley Patrick G. , Alcock Leah , Bryan Kenneth , Bray Isabella , Schulte Johannes H. , Schramm Alexander , Eggert Angelika , Mestdagh Pieter , De Preter Katleen , Vandesompele Jo , Speleman Frank , Stallings Raymond L. 
Published: April 2010

Abstract
Purpose: The purpose of this study was to further define the biology of the 11q− neuroblastoma tumor subgroup by the integration of array-based comparative genomic hybridization with microRNA (miRNA) expression profiling data to determine if improved patient stratification is possible.
Experimental Design: A set of primary neuroblastoma (n = 160), which was broadly representative of all genetic subtypes, was analyzed by array-based comparative genomic hybridization and for the expression of 430 miRNAs. A 15-miRNA expression signature previously shown to be predictive of clinical outcome was used to analyze an independent cohort of 11q− tumors (n = 37).
Results: Loss of 4p and gain of 7q occurred at a significantly higher frequency in the 11q− tumors, further defining the genetic characteristics of this subtype. The 11q− tumors could be split into two subgroups using a miRNA expression survival signature that differed significantly in clinical outcome and the overall frequency of large-scale genomic imbalances, with the poor survival subgroup having significantly more imbalances. miRNAs from the expression signature, which were upregulated in unfavorable tumors, were predicted to target downregulated genes from a published mRNA expression classifier of clinical outcome at a higher-than-expected frequency, indicating the miRNAs might contribute to the regulation of genes within the signature.
Conclusion: We show that two distinct biological subtypes of neuroblastoma with loss of 11q occur, which differ in their miRNA expression profiles, frequency of segmental imbalances, and clinical outcome. A miRNA expression signature, combined with an analysis of segmental imbalances, provides greater prediction of event-free survival and overall survival outcomes than 11q status by itself, improving patient stratification. Clin Cancer Res; 16(11); 2971–8. ©2010 AACR.
The Histone Deacetylase Inhibitor MGCD0103 Induces Apoptosis in B-Cell Chronic Lymphocytic Leukemia Cells through a Mitochondria-Mediated Caspase Activation Cascade
Authors: El-Khoury Victoria , Moussay Etienne , Janji Bassam , Palissot Valérie , Aouali Nasséra , Brons Nicolaas H.C. , Van Moer Kris , Pierson Sandrine , Van Dyck Eric , Berchem Guy 
Published: April 2010

Abstract
Clinical trials have shown activity of the isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 in different hematologic malignancies. There are data to support the use of HDAC inhibitors in association with other cancer therapies. To propose a rational combination therapy, it is necessary to depict the molecular basis behind the cytotoxic effect of MGCD0103. In this study, we found that MGCD0103 was substantially more toxic in neoplastic B cells relative to normal cells, and we described the death pathways activated by MGCD0103 in B-cell chronic lymphocytic leukemia (CLL) cells from 32 patients. MGCD0103 decreased the expression of Mcl-1 and induced translocation of Bax to the mitochondria, mitochondrial depolarization, and release of cytochrome c in the cytosol. Caspase processing in the presence of the caspase inhibitor Q-VD-OPh and time course experiments showed that caspase-9 was the apical caspase. Thus, MGCD0103 induced the intrinsic pathway of apoptosis in CLL cells. Moreover, MGCD0103 treatment resulted in the activation of a caspase cascade downstream of caspase-9, caspase-dependent amplification of mitochondrial depolarization, activation of calpain, and Bax cleavage. We propose a model whereby the intrinsic pathway of apoptosis triggered by MGCD0103 in CLL is associated with a mitochondrial death amplification loop. Mol Cancer Ther; 9(5); 1349–60. ©2010 AACR.
Dasatinib Is Preclinically Active against Src-Overexpressing Human Transitional Cell Carcinoma of the Urothelium with Activated Src Signaling
Authors: Levitt Jonathan M. , Yamashita Hideyuki , Jian Weiguo , Lerner Seth P. , Sonpavde Guru 
Published: April 2010

AbstractDasatinib is an orally administered multitargeted kinase inhibitor that targets Src family tyrosine kinases, Abl, c-Kit, and PDGFR. A preclinical study was conducted to evaluate dasatinib alone or combined with cisplatin for human transitional cell carcinoma (TCC). Expression of Src in a human TCC tissue microarray was evaluated by immunohistochemistry. The activity of dasatinib and/or cisplatin was evaluated in six human TCC cell lines. Western blot was done to assess Src and phosphorylated-Src (p-Src) expression. The activity of dasatinib alone and in combination with cisplatin was determined in murine subcutaneous xenografts. Sixty-two percent to 75% of human TCC expressed Src. Dasatinib displayed significant antiproliferative activity at nanomolar concentrations against two human TCC cell lines (RT4 and Hu456) that exhibited high Src and p-Src expression and were cisplatin-resistant. RT4 cells were the most sensitive and displayed the highest level of Src pathway activation (p-Src/Src ratio). Dasatinib downregulated p-Src in either sensitive or resistant cells. TCC cells that were sensitive to cisplatin (5637 and TCC-SUP) were highly resistant to dasatinib and exhibited low Src expression. Dasatinib showed antitumor activity in RT4 murine xenografts, and the combination of dasatinib and cisplatin was significantly more active than placebo. Combination dasatinib plus cisplatin significantly inhibited proliferation and promoted apoptosis in vivo. In conclusion, dasatinib displayed significant preclinical antitumor activity against Src-overexpressing human TCC with active Src signaling and was highly active in combination with cisplatin in vivo. Further clinical development might be warranted in selected human subjects. Mol Cancer Ther; 9(5); 1128–35. ©2010 AACR.
X-Linked Inhibitor of Apoptosis Protein Inhibits Apoptosis in Inflammatory Breast Cancer Cells with Acquired Resistance to an ErbB1/2 Tyrosine Kinase Inhibitor
Authors: Aird Katherine M. , Ghanayem Rami B. , Peplinski Sharon , Lyerly Herbert K. , Devi Gayathri R. 
Published: April 2010

AbstractInflammatory breast cancer (IBC) is a highly aggressive subtype of breast cancer that is often characterized by ErbB2 overexpression. ErbB2 targeting is clinically relevant using trastuzumab (anti-ErbB2 antibody) and lapatinib (small-molecule ErbB1/2 inhibitor). However, acquired resistance is a common outcome even in IBC patients who show an initial clinical response, which limits the efficacy of these agents. In the present study, using a clonal population of GW583340 (lapatinib analogue, ErbB1/2 inhibitor)–resistant IBC cells, we identified the overexpression of an antiapoptotic protein, X-linked inhibitor of apoptosis protein (XIAP), in acquired resistance to GW583340 in both ErbB2-overexpressing SUM190 and ErbB1-activated SUM149 cell lines derived from primary IBC tumors. A marked decrease in p-ErbB2, p-ErbB1, and downstream signaling was evident in the GW583340-resistant cells (rSUM190 and rSUM149) similar to parental counterparts treated with the drug, suggesting that the primary mechanism of action of GW583340 was not compromised in resistant cells. However, rSUM190 and rSUM149 cells growing in GW583340 had significant XIAP overexpression and resistance to GW583340-mediated apoptosis. Additionally, stable XIAP overexpression using a lentiviral system reversed sensitivity to GW583340 in parental cells. The observed overexpression was identified to be caused by IRES-mediated XIAP translation. XIAP downregulation in rSUM190 and rSUM149 cells using a small-molecule inhibitor (embelin), which abrogates the XIAP/procaspase-9 interaction, resulted in decreased viability, showing that XIAP is required for survival of cells with acquired resistance to GW583340. These studies establish the feasibility of development of an XIAP inhibitor that potentiates apoptosis for use in IBC patients with resistance to ErbB2-targeting agents. Mol Cancer Ther; 9(5); 1432–42. ©2010 AACR.