bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lung Metastasis Fails in MMTV-PyMT Oncomice Lacking S100A4 Due to a T-Cell Deficiency in Primary Tumors
Authors: Grum-Schwensen Birgitte , Klingelhöfer Jörg , Grigorian Mariam , Almholt Kasper , Nielsen Boye Schnack , Lukanidin Eugene , Ambartsumian Noona 
Published: January 2010

Abstract
Interactions between tumor and stroma cells are essential for the progression of cancer from its initial growth at a primary site to its metastasis to distant organs. The metastasis-stimulating protein S100A4 exerts its function as a stroma cell–derived factor. Genetic depletion of S100A4 significantly reduced the metastatic burden in lungs of PyMT-induced mammary tumors. In S100A4+/+ PyMT mice, massive leukocyte infiltration at the site of the growing tumor at the stage of malignant transition was associated with increased concentration of extracellular S100A4 in the tumor microenvironment. In contrast, in S100A4−/− PyMT tumors, a significant suppression of T-cell infiltration was documented at the transition period. In vitro, the S100A4 protein mediated the attraction of T cells. Moreover, S100A4+/+, but not S100A4−/−, fibroblasts stimulated the invasion of T lymphocytes into fibroblast monolayers. In vivo, the presence of S100A4+/+, but not S100A4−/−, fibroblasts significantly stimulated the attraction of T lymphocytes to the site of the growing tumor. Increased levels of T cells were also observed in the premetastatic lungs of tumor-bearing mice primed to metastasize by S100A4+/+ fibroblasts. Treatment of T cells with the S100A4 protein stimulated production of cytokines, particularly granulocyte colony-stimulating factor and eotaxin-2. The same cytokines were detected in the fluid of S100A4+/+ PyMT tumors at the transition period. We suggest that release of S100A4 in the primary tumor stimulates infiltration of T cells and activates secretion of cytokines, thus triggering sequential events that fuel tumor cells to metastasize. Similar processes could occur in the premetastatic lungs, facilitating generation of inflammatory milieu favorable for metastasis formation. Cancer Res; 70(3); 936–47
Heterotrimerization of the Growth Factor Receptors erbB2, erbB3, and Insulin-like Growth Factor-I Receptor in Breast Cancer Cells Resistant to Herceptin
Authors: Huang Xiaoping , Gao Lizhi , Wang Shuiliang , McManaman James L. , Thor Ann D. , Yang XiaoHe , Esteva Francisco J. , Liu Bolin 
Published: January 2010

Abstract
Primary and acquired resistance to the breast cancer drug trastuzumab (Herceptin) is a significant clinical problem. Here, we report enhanced activation of downstream signaling pathways emanating from the growth factor receptors erbB2, erbB3, and insulin-like growth factor-I receptor (IGF-IR) in trastuzumab-resistant breast cancer cells. Interactions between IGF-IR and erbB2 or erbB3 occur exclusively in trastuzumab-resistant cells, where enhanced erbB2-erbB3 interactions are also observed. Moreover, these three receptors form a heterotrimeric complex in resistant cells. erbB3 or IGF-IR knockdown by short hairpin RNA–mediated strategies upregulates p27kip1, inactivates downstream receptor signaling, and resensitizes resistant cells to trastuzumab. Our findings reveal a heterotrimer complex with a key role in trastuzumab resistance. On the basis of our results, we propose that trastuzumab resistance in breast cancer might be overcome by therapeutic strategies that jointly target erbB3, erbB2, and IGF-IR. Cancer Res; 70(3); 1204–14
Vascular Endothelial Growth Factor—A Positive and Negative Regulator of Tumor Growth
Authors: Vecchiarelli-Federico Laura M. , Cervi David , Haeri Mehran , Li Yanmei , Nagy Andras , Ben-David Yaacov 
Published: January 2010

Abstract
Over the past decade, the well-documented role of vascular endothelial growth factor (VEGF) in tumor angiogenesis has led it to become one of the leading therapeutic targets for the treatment of cancer. Emerging evidence from genetically modified animal models, however, suggests that elevated levels of VEGF, or a proangiogenic phenotype, may impede, rather than promote, early tumor development and progression. For example, hypermorph VEGF transgenic mice display delayed progression of a retroviral-induced murine leukemia, and knockdown of VEGF expression within the myeloid compartment accelerates tumor progression. Several mechanisms have been proposed to explain this paradox, whereby VEGF induces changes within the hematopoietic compartment and tumor microenvironment through recruitment of tumor inhibitory monocytic cells and the negative regulation of tumor angiogenesis. Thus, it is apparent that the levels of VEGF expression in both tumor and nontumor tissues, as well as the context and timing of its modulation relative to cancer induction, play an important role in determining the effects of VEGF expression on tumorigenicity. In light of these recent findings, the various mechanisms underlying the negative role of VEGF during early tumor development, progression, and metastasis will be discussed. Cancer Res; 70(3); 863–7
Sunitinib Acts Primarily on Tumor Endothelium rather than Tumor Cells to Inhibit the Growth of Renal Cell Carcinoma
Authors: Huang Dan , Ding Yan , Li Yan , Luo Wang-Mei , Zhang Zhong-Fa , Snider John , VandenBeldt Kristin , Qian Chao-Nan , Teh Bin Tean 
Published: January 2010

Abstract
Sunitinib is a broad-spectrum small-molecule inhibitor of receptor tyrosine kinases (RTK) that serves as the present standard of care for first-line therapy of advanced clear cell renal cell carcinoma (ccRCC). A full understanding of the targets and mechanism of action of sunitinib in ccRCC treatment remains incomplete. In this study, we evaluated several tumor cell and endothelial targets of sunitinib and investigated which RTK(s) may specifically contribute to its therapeutic effects. Microarray expression profiling and Western blot analysis revealed that among known sunitinib targets, only platelet-derived growth factor receptor-β and vascular endothelial growth factor receptor-2 (VEGFR-2) were overexpressed in ccRCCs relative to normal tissues. Sunitinib was unable to inhibit survival or proliferation of ccRCC cells at pharmacologically relevant concentrations (∼0.1 μmol/L) that inhibit RTK targets. In contrast, sunitinib inhibited endothelial cell proliferation and motility at the same concentrations by suppressing VEGFR-2 signaling. Moreover, whereas sunitinib inhibited the growth of ccRCC xenograft tumors and decreased tumor microvessel density as soon as 12 hours after treatment, sunitinib showed no significant effects on tumor cell proliferation or apoptosis up to 72 hours after treatment. Our findings indicate that sunitinib inhibits ccRCC growth primarily through an antiangiogenic mechanism and not through direct targeting of ccRCC tumor cells. Cancer Res; 70(3); 1053–62
Interleukin-8 Mediates Resistance to Antiangiogenic Agent Sunitinib in Renal Cell Carcinoma
Authors: Huang Dan , Ding Yan , Zhou Ming , Rini Brian I. , Petillo David , Qian Chao-Nan , Kahnoski Richard , Futreal P. Andrew , Furge Kyle A. , Teh Bin Tean 
Published: January 2010

Abstract
The broad spectrum kinase inhibitor sunitinib is a first-line therapy for advanced clear cell renal cell carcinoma (ccRCC), a deadly form of kidney cancer. Unfortunately, most patients develop sunitinib resistance and progressive disease after about 1 year of treatment. In this study, we evaluated the mechanisms of resistance to sunitinib to identify the potential tactics to overcome it. Xenograft models were generated that mimicked clinical resistance to sunitinib. Higher microvessel density was found in sunitinib-resistant tumors, indicating that an escape from antiangiogenesis occurred. Notably, escape coincided with increased secretion of interleukin-8 (IL-8) from tumors into the plasma, and coadministration of an IL-8 neutralizing antibody resensitized tumors to sunitinib treatment. In patients who were refractory to sunitinib treatment, IL-8 expression was elevated in ccRCC tumors, supporting the concept that IL-8 levels might predict clinical response to sunitinib. Our results reveal IL-8 as an important contributor to sunitinib resistance in ccRCC and a candidate therapeutic target to reverse acquired or intrinsic resistance to sunitinib in this malignancy. Cancer Res; 70(3); 1063–71
Nuclear Factor-κB and Tumor-Associated Macrophages
Authors: Mancino Alessandra , Lawrence Toby 
Published: January 2010

Abstract
Tumor-associated macrophages (TAM) have been linked with the progression of cancer by favoring tumor angiogenesis, growth, and metastasis. The precise mechanisms that maintain the protumor phenotype of TAM are poorly understood, but recent research has highlighted a number of signaling pathways that are important in TAM phenotype and function. Nuclear factor-κB (NF-κB) is considered the master regulator of inflammatory and immune responses. Recently several genetic studies have indicated NF-κB is an important pathway in TAM for the integration of signals from the tumor microenvironment that promote carcinogenesis. This review will focus on the role of NF-κB in TAM and the potential of targeting this pathway as a novel therapeutic strategy against cancer. Clin Cancer Res; 16(3); 784–9
Delta-Like Ligand 4 Plays a Critical Role in Pericyte/Vascular Smooth Muscle Cell Formation during Vasculogenesis and Tumor Vessel Expansion in Ewing's Sarcoma
Authors: Schadler Keri L. , Zweidler-McKay Patrick A. , Guan Hui , Kleinerman Eugenie S. 
Published: January 2010

Abstract
Purpose: Bone marrow (BM) cells contribute to tumor vessel formation that supports the growth of Ewing's sarcoma. These BM cells migrate into the tumor and differentiate into endothelial cells and pericytes. We investigated whether delta-like ligand 4 (DLL4) played a role in the formation of BM-derived pericytes/vascular smooth muscle cells (vSMC) during tumor vessel formation.
Experimental Design: Using immunohistochemistry, we examined the expression pattern of DLL4 in 14 patient samples and two xenograft mouse models of Ewing's sarcoma. We then used intratumor injections of short hairpin RNA to inhibit DLL4 expression in Ewing's sarcoma tumors in mice, and evaluated the effect on BM-derived pericytes/vSMCs.
Results: DLL4 was expressed by perivascular cells in 12 of 14 human samples and in BM-derived pericytes/vSMCs in both A4573 and TC71 xenograft tumors. Inhibition of DLL4 expression by short hairpin RNA correlated with the decreased numbers of BM-derived cells in tumor vessels and the decreased numbers of α-SMA+, desmin+, and NG2+ pericytes/vSMCs, as well as increased tumor hypoxia.
Conclusions: DLL4 is important for the formation of BM-derived pericytes/vSMCs during vasculogenesis in Ewing's sarcoma. DLL4 may be a therapeutic target for treatment of Ewing's sarcoma by inhibition of blood vessel formation. Clin Cancer Res; 16(3); 848–56
Antitumor Activity of Targeting Src Kinases in Endothelial and Myeloid Cell Compartments of the Tumor Microenvironment
Authors: Liang Wei , Kujawski Maciej , Wu Jun , Lu Jianming , Herrmann Andreas , Loera Sofia , Yen Yun , Lee Frank , Yu Hua , Wen Wei , Jove Richard 
Published: January 2010

Abstract
Purpose: Several Src family kinase (SFK) inhibitors have entered clinical trials based on their direct effects against tumor cells. Here, we characterize the effects of targeting Src kinases on the tumor microenvironment and how these effects influence tumor growth.
Experimental Design: Human cancer cells grown in cell culture or in mice were treated with dasatinib, a small-molecule inhibitor of SFKs. Tumor cell, endothelial cell, and myeloid cell compartments within the tumor microenvironment were analyzed. Primary human endothelial cells and freshly isolated CD11b+/CD11c− myeloid cells from mice were treated with dasatinib in cell culture. Cellular functions and signaling pathways affected by dasatinib were evaluated.
Results: Dasatinib was not cytotoxic in cell culture against the human cancer cell lines investigated here. However, dasatinib administration in human tumor–bearing mice suppressed tumor growth associated with increased tumor cell apoptosis, decreased microvessel density, and reduced intratumoral CD11b+ myeloid cells. Dasatinib directly inhibited motility and other functions of endothelial and myeloid cells, accompanied by the inhibition of phosphorylation of SFKs and downstream signaling. Tumor-infiltrating myeloid cells were identified as the major source of matrix metalloproteinase (MMP)-9 in the tumor microenvironment. Dasatinib treatment reduced MMP-9 levels in the tumor microenvironment through the simultaneous inhibition of recruitment of MMP9+ myeloid cells and MMP-9 gene expression in tumor-infiltrating myeloid cells.
Conclusions: These findings suggest that Src kinase inhibitors such as dasatinib possess a previously unrecognized anticancer mechanism of action by targeting both host-derived endothelial and myeloid cell compartments within the tumor microenvironment. Clin Cancer Res; 16(3); 924–35
Validation of SAG/RBX2/ROC2 E3 Ubiquitin Ligase as an Anticancer and Radiosensitizing Target
Authors: Jia Lijun , Yang Jie , Hao Xinbao , Zheng Min , He Hongbin , Xiong Xiufang , Xu Liang , Sun Yi 
Published: January 2010

Abstract
Purpose: Sensitive to apoptosis gene (SAG; also known as RBX2 or ROC2) was originally cloned as a redox-inducible antioxidant protein and was later characterized as a RING component of SCF E3 ubiquitin ligases. SAG overexpression inhibits apoptosis induced by many stimuli both in vitro and in vivo. SAG mRNA was overexpressed in human lung tumor tissues with a correlation to poor patient survival. To investigate whether SAG serves as an anticancer target, we determined the effect of SAG silencing on cell proliferation, survival, and radiosensitivity.
Experimental Design: SAG protein expression in human tumors was evaluated by immunohistochemical staining using tumor tissue arrays. SAG expression in cancer cells was knocked down by siRNA silencing. The anticancer effects of SAG silencing were evaluated by in vitro assays for cell growth and survival and by an in vivo orthotopic xenograft tumor model. Radiosensitization by SAG silencing of human cancer cells was determined by clonogenic survival assay. Apoptosis induction was evaluated by fluorescence-activated cell sorting analysis, caspase-3 activation assay, and Western blotting of apoptosis-associated proteins.
Results: SAG was overexpressed in multiple human tumor tissues compared with their normal counterparts. SAG silencing selectively inhibited cancer cell proliferation, suppressed in vivo tumor growth, and sensitized radiation-resistant cancer cells to radiation. Mechanistically, SAG silencing induced apoptosis with accumulation of NOXA, whereas SAG overexpression reduced NOXA levels and shortened NOXA protein half-life.
Conclusions: The findings showed that SAG E3 ubiquitin ligase plays an essential role in cancer cell proliferation and tumor growth and may serve as a promising anticancer and radiosensitizing target. Clin Cancer Res; 16(3); 814–24
MiR-222 Overexpression Confers Cell Migratory Advantages in Hepatocellular Carcinoma through Enhancing AKT Signaling
Authors: Wong Queenie W-L. , Ching Arthur K-K. , Chan Anthony W-H. , Choy Kwong-Wai , To Ka-Fai , Lai Paul B-S. , Wong Nathalie 
Published: January 2010

Abstract
Purpose: This study aims to profile the expressions of 156 microRNAs (miRNA) in hepatocellular carcinoma (HCC) and to characterize the functions of miR-222, the most significantly upregulated candidate identified.
Experimental Design: miRNA expression profile in HCC tumors, matching adjacent cirrhotic livers, and cell lines was conducted using quantitative PCR. Common miR-222 upregulations were further validated in a larger cohort of tumors. The functional effects of miR-222 inhibition on HCC cell lines were examined. The downstream modulated pathways and target of miR-222 were investigated by coupling gene expression profiling and pathway analysis, and by in silico prediction, respectively. Luciferase reporter assay was done to confirm target interaction.
Results: We identified a 40-miRNA signature that could discriminate tumors from adjacent cirrhotic liver tissue, and further corroborated common miR-222 overexpression in tumors relative to its premalignant counterpart (55.3%; P &lt; 0.0001). Increased miR-222 expression correlated significantly with advanced stage HCC and with the shorter disease-free survival of patients (P ≤ 0.01). Inhibition of miR-222 in Hep3B and HKCI-9 significantly retarded cell motility (P &lt; 0.05). Further investigations suggested that AKT signaling was the major pathway influenced by miR-222. A consistent reduction of AKT phosphorylation in Hep3B and HKCI-9 was shown following miR-222 suppression. The protein phosphatase 2A subunit B (PPP2R2A) was predicted as a putative miR-222 target in silico. We found that miR-222 inhibition could augment the tumor protein level and restore luciferase activity in reporter construct containing the PPP2R2A 3′ untranslated region (P = 0.0066).
Conclusions: Our study showed that miR-222 overexpression is common in HCC and could confer metastatic potentials in HCC cells, possibly through activating AKT signaling. Clin Cancer Res; 16(3); 867–75
Clinical Pharmacokinetics of Amifostine and WR1065 in Pediatric Patients with Medulloblastoma
Authors: McKibbin Trevor , Panetta John C. , Fouladi Maryam , Gajjar Amar , Bai Feng , Okcu M. Fatih , Stewart Clinton F. 
Published: January 2010

AbstractPurpose: We evaluated the pharmacokinetics of amifostine and WR1065 in pediatric patients with newly diagnosed medulloblastoma to assess the influence of patient covariates, including demographics, clinical characteristics, and genetic polymorphisms, on amifostine and WR1065 pharmacokinetic parameters.Experimental Design: We assessed the pharmacokinetics of amifostine and WR1065 in 33 children who received amifostine (1-minute infusion, 600 mg/m2) just before the start of and 3 hours into a 6-hour cisplatin infusion. Serial blood samples were collected after doses 1 (0 hour) and 2 (3 hours) of course 1. Amifostine and WR1065 were quantitated by high performance liquid chromatography with electrochemical detection. A pharmacokinetic model was simultaneously fit to amifostine and WR1065 plasma or whole blood concentration-versus-time data. The influence of demographic, biochemical, and pharmacogenetic covariates on amifostine and WR1065 disposition was evaluated.Results: Body surface area was the primary size-based covariate for amifostine pharmacokinetics explaining 53% and 56% of interindividual variability in plasma and whole-blood amifostine clearance, respectively. The population-predicted values for amifostine clearance, volume, and apparent WR1065 clearance from the plasma data were 107 L/h/m2, 5.53 L/m2, and 30.6 L/h/m2. The population-predicted values for amifostine clearance, volume, and apparent WR1065 clearance from whole blood data were 136 L/h/m2, 7.23 L/m2, and 12.5 L/h/m2.Conclusions: These results support using body surface area for calculating doses of amifostine in children. Similar to data in adults, amifostine and WR1065 are rapidly cleared from plasma and whole blood in children. Clin Cancer Res; 16(3); 1049–57
TKTL1 Is Activated by Promoter Hypomethylation and Contributes to Head and Neck Squamous Cell Carcinoma Carcinogenesis through Increased Aerobic Glycolysis and HIF1α Stabilization
Authors: Sun Wenyue , Liu Yan , Glazer Chad A. , Shao Chunbo , Bhan Sheetal , Demokan Semra , Zhao Ming , Rudek Michelle A. , Ha Patrick K. , Califano Joseph A. 
Published: January 2010

Abstract
Purpose: This study aims to investigate the role of the aberrant expression of Transkelolase-like 1 (TKTL1) in head and neck squamous cell carcinoma (HNSCC) tumorigenesis and to characterize TKTL1 contribution to HNSCC tumorigenesis through aerobic glycolysis and HIF1α stabilization.
Experimental Design: TKTL1 promoter hypomethylation and mRNA/protein aberrant expression were studied in human HNSCC tumor samples and normal mucosas. Oncogenic functions of TKTL1 were examined in HNSCC cell line panels and tumor xenograft models with TKTL1 expression construct. The metabolite levels of fructose-6-phosphate, glyceraldehydes-3-phosphate, pyruvate, lactate, and the levels of HIF1α protein and its downsteam glycolytic targets were compared between the TKTL1-expressing and vehicle-expressing HNSCC cells. Meanwhile, the effects of HIF1α/glycolytic inhibitors were evaluated on the TKTL1 transfectants.
Results: TKTL1 exhibits high frequency of promoter hypomethylation in HNSCC tumors compared with the normal mucosas, correlating with its overexpression in HNSCC. Overexpression of TKTL1 in HNSCC cells promoted cellular proliferation and enhanced tumor growth in vitro and in vivo. Overexpression of TKTL1 increased the production of fructose-6-phosphate and glyceraldehyde-3-phosphate, in turn elevating the production of pyruvate and lactate, resulting in the normoxic stabilization of the malignancy-promoting transcription factor HIF1α and the upregulation of downstream glycolytic enzymes. Notably, the reduction of TKTL1 expression decreased HIF1α accumulation and inhibition with HIF1α and/or the glycolysis inhibitor could abrogate the growth effects mediated by TKTL1 overexpression.
Conclusion: TKTL1 is a novel candidate oncogene that is epigenetically activated by aberrant hypomethlation and contributes to a malignant phenotype through altered glycolytic metabolism and HIF1α accumulation. Clin Cancer Res; 16(3); 857–66
Plasma EBV DNA Clearance Rate as a Novel Prognostic Marker for Metastatic/Recurrent Nasopharyngeal Carcinoma
Authors: Wang Wen-Yi , Twu Chih-Wen , Chen Hsin-Hong , Jan Jian-Sheng , Jiang Rong-San , Chao Jeffrey Y.C. , Liang Kai-Li , Chen Kuan-Wen , Wu Ching-Te , Lin Jin-Ching 
Published: January 2010

Abstract
Purpose: To investigate the prognostic effect of the concentrations and clearance rates of plasma EBV DNA in metastatic/recurrent nasopharyngeal carcinoma (NPC).
Experimental Design: Thirty relapsed and four previously nontreated metastatic NPC patients were treated according to the consensus guidelines of the head and neck cancer team in our hospital (i.v. chemotherapy first, followed by local irradiation boost and oral maintenance chemotherapy where applicable). Multiple plasma samples were collected during the first month of chemotherapy. Circulating EBV DNA concentrations were measured by a real-time quantitative PCR. The half-life values (t1/2) of plasma EBV DNA clearance were calculated. The associations between clinical outcome and plasma EBV DNA assays were analyzed.
Results: Tumor response evaluated after 12 weeks of treatment showed 14 complete responses (41.2%), 12 partial responses (35.3%), 7 stable diseases (20.6%), and 1 progression disease (2.9%). The plasma EBV DNA concentrations have no significant effects on outcome prediction. The t1/2 of plasma EBV DNA clearance ranged from 1.85 to 28.29 days (median, 3.99). Patients with a short t1/2 of plasma EBV DNA clearance have significantly higher complete response rate and overall survival than those with long t1/2. Multivariate analysis revealed a significant effect of the t1/2 of plasma EBV DNA clearance on survival.
Conclusions: The clearance rates of plasma EBV DNA during the first month of chemotherapy can predict tumor response and patient survival. Early change of chemotherapy regimen may be considered for patients with slow plasma EBV DNA clearance rate. Clin Cancer Res; 16(3); 1016–24
Targeting the Tumor Microenvironment With Src Kinase Inhibition
Authors: Chung Alicia S. , Ferrara Napoleone 
Published: January 2010

Abstract
Although most cancer therapies are directed against tumor cells, an emerging area of cancer therapeutics focuses on targeting cells of the tumor microenvironment. Inhibiting the Src family kinase with dasatinib decreases tumor growth through inhibiting growth of tumor-associated endothelial and myeloid cells. Clin Cancer Res; 16(3); 775–7