bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5124: Signaling networks potentially involved in breast cancer metastasis to the brain
Authors: Li Feng , Glinskii Olga V. , Wilson Landon , Barnes Stephen , Anthony Douglas C. , Glinsky Vladislav V. 
Published: June 2012

Abstract
Brain is a common site of breast cancer metastasis and is associated with significant neurologic morbidity, decreased quality of life, and greatly shortened survival. However, the molecular and cellular mechanisms underpinning brain colonization by breast carcinoma cells are poorly understood. In this study, we used 2D-DIGE (Difference in Gel Electrophoresis) proteomic analysis followed by LC-tandem mass spectrometry to identify the proteins differentially expressed in brain-targeting breast carcinoma cells (MB231-Br) compared with parental MDA-MB-231 cell line. Between the two cell lines, we identified 12 proteins consistently exhibiting greater than 2-fold (p&lt;0.05) difference in expression, which were associated by the Ingenuity Pathway Analysis (IPA) with two major signaling networks involving TNFα/TGFβ-, NFκB-, HSP-70-, TP53-, and IFNγ-associated pathways. Remarkably, highly related networks were revealed by the IPA analysis of a list of 19 brain-metastasis-associated proteins identified recently by the group of Dr. A. Sierra using MDA-MB-435-based experimental system (Martin et al., J Proteome Res 2008 7:908-20), or a 17-gene classifier associated with breast cancer brain relapse reported by the group of Dr. J. Massague based on a microarray analysis of clinically annotated breast tumors from 368 patients (Bos et al., Nature 2009 459: 1005-9). Even though only 2 out of 31 proteins were common between the MDA-MB-231-based set identified by our group in this study and MB-435-based set reported by Martin et al., and none of these proteins were present in a 17-gene brain relapse signature published by Bos et al., they all converged on the major signaling networks involving TNFα/TGFβ-, NFκB-, HSP70-, TP53-, and IFNα/γ-related pathways. Our results show that different experimental systems and approaches (2D-DIGE proteomics used on brain targeting cell lines or gene expression analysis of patient samples with documented brain relapse) yield highly related signaling networks. These findings suggest strongly that these signaling networks may be essential for colonization of the brain by metastatic breast carcinoma cells.
This work was supported in part by Award Number 1I01BX000609 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development to VVG and AHA National SDG 0830287N to OVG.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5124. doi:10.1158/1538-7445.AM2011-5124
Abstract 513: Stromal desmoplasia is induced by a hypoxia and HIF-1α mediated increase in sonic hedgehog formation in pancreatic cancer
Authors: Spivak-Kroizman Taly R. , Hostetter Galen , Posner Richard , Aziz Meraj , Hu Chengcheng , Demeure Michael , Hoff Daniel Von , Hingorani Sunil , Palculict Timothy B. , Abdelmelek Mena , Bartholomeusz Geoffrey , James Brian P. , Powis Garth 
Published: June 2012

Abstract
Pancreatic tumors are notoriously hypoxic and characterized by a dense fibro-inflammatory stromal reaction (desmoplasia). Hedgehog (Hh) signaling is a major contributor to tumor desmoplasia in pancreatic and other cancers, resulting in decreased tumor blood flow, decreased drug delivery and resistance to therapy. We hypothesized that the hypoxia inducible factor-1α (HIF-1α) transcription factor, a major component of the cell's response to hypoxia is an important mediator of the mechanism inducing desmoplasia in pancreatic cancer. We observed that a hypoxic environment (1% O2 for 24 hr) increased the expression of sonic Hh (SHH) mRNA and secreted SHH protein, in both MiaPaCa-2 and Panc-1 pancreatic cancer cells, and that this was blocked by siRNA targeting HIF-1α. NIH-3T3 fibroblasts transfected with a GLi1-firefly luciferase reporter exposed to conditioned media from hypoxic MiaPaCa-2 and Panc-1, or co-cultures of the Panc-1 and the fibroblasts showed an increase in GLi activity. siRNA to sHH transfected into Panc-1 tumor cells blocked the fibroblast GLi1 response. NIH-3T3 fibroblasts alone did not show an increase in Hh components or Hh signaling upon exposure to hypoxia. MiaPaCa-2 cells transfected with a GLi1-firefly luciferase reporter showed no increase in GLi1 activity upon exposure to hypoxia suggesting there is no autocrine stimulation of the cancer cells by the SHH they secrete. Fibroblasts co-cultured with the pancreatic cancer cells showed increased expression of two markers of desmoplasia, collagen-1 and fibronectin under hypoxic conditions that was blocked by siRNA to HIF-1α. Thus, increased pancreatic cancer cell SHH formation in response to hypoxia and mediated by HIF-1α, stimulates Hh signaling which increases fibroblast GLi1 transcriptional activity without activating Hh signaling in the cancer cell itself. We also compared levels of nuclear HIF-1α and SHH by immunohistochemistry in patient pancreatic cancer samples and found a significant correlation between tumor HIF-1α and stromal SHH (p&lt; 0.01). Furthermore, both tumor HIF-1α and stromal SHH correlated with decreased patient survival. The findings suggest that tumor hypoxia and increased HIF-1α in pancreatic cancer which is likely a consequence of the desmoplasia, is also a cause of the desmoplasia. Breaking the cycle of hypoxia, HIF-1α, and desmoplasia, could offer a new therapy for pancreatic cancer. Supported by CA109552-05
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 513. doi:10.1158/1538-7445.AM2011-513
Abstract 5132: Hypo-glycosylation of vascular endothelial growth factor receptor-1 may contribute to intracrine signaling in human colorectal cancer cells
Authors: Ye Xiangcang , Samuel Shaija , Zhou Yunfei , Fan Fan , Xia Ling , Lu Jia , Sceusi Eric , Tozzi Federico , Ellis Lee M. 
Published: June 2012

Abstract
Introduction: Vascular endothelial growth factor receptor-1 (VEGFR-1) is highly expressed in endothelial cells, macrophages and cancer cells in the tumor microenvironment. VEGFR-1 plays an important role in tumor angiogenesis, inflammation and metastasis. In colorectal cancer (CRC) cells with hyperactive Wnt signaling, its function has been linked to cell motility, anchorage-independent growth, and cell survival. To better understand the role of VEGFR-1 in CRC, we performed studies to define the subcellular location and post-translational modifications of VEGFR-1 in human CRC cells.
Methods/Results: Utilizing IHC analysis, GFP-tagged imaging and cell surface receptor assays, we observed that VEGFR-1 locates mostly in intracellular compartments in CRC cells, which is distinct from its membrane receptor status in endothelial cells. Moreover, spontaneous apoptosis was increased with endogenous VEGF knockout whereas treatment with the VEGF neutralizing antibody bevacizumab had no effect on apoptosis (Samuel et al. Oncogene, in press); these studies suggest that CRC cells require VEGF/VEGFR-1 intracrine signaling for suppression of apoptosis. In order to understand the means by which VEGFR-1 cellular localization is determined, we analyzed the glycosylation of VEGFR-1 in CRC cells, endothelial cells and clinical specimens of metastatic CRC from the liver. We found that VEGFR-1 is partially N-glycosylated by high mannose oligosaccharides in the CRC cells and human tumors, in contrast to complex, mature N-glycosylation of VEGFR-1 in the endothelial cells and normal liver tissue.
Conclusion: VEGFR-1 is differentially post-translationally modified and intracellularly localized in CRC cells and metastatic tumors. Because N-glycosylation is critical for the membrane receptor's intracellular trafficking and ligand interaction on the cell surface, hypo-glycosylation of VEGFR-1 in CRC cells likely contributes to its cytoplasmic localization and intracrine activation through a non-RTK pathway. The implications of intracrine function of VEGFR-1 in CRC warrant further investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5132. doi:10.1158/1538-7445.AM2011-5132
Abstract 5133: Transcriptional repression of VEGF by ZNF24: Mechanistic studies and vascular consequences in vivo
Authors: Jia Di , Hasso Sean , Chan Joanne , D'Amore Patricia , Zurakowski David , Rodig Scott , Moses Marsha 
Published: June 2012

Abstract
Vascular endothelial growth factor (VEGF) is a key regulator of both normal and pathological angiogenesis. It plays critical roles in physiological processes such as maintaining vascular stability and promoting skeletal muscle differentiation. Under pathological conditions such as cancer, VEGF serves as a principle proangiogenic factor to facilitate tumor angiogenesis. To date, although many trans-activating factors of VEGF have been well described, transcriptional repression of VEGF remains much less understood. We have previously reported the identification of a SCAN domain-containing C2H2 zinc finger protein, ZNF24, which functions to repress the transcription of VEGF via direct binding to the proximal VEGF promoter. In the current study, we have focused on mapping the ZNF24 binding site within the VEGF promoter and exploring its functions in vivo. Utilizing electrophoretic mobility shift assays, we have identified an 11bp fragment of the proximal VEGF promoter as the ZNF24 binding site and show that it is essential for ZNF24-mediated repression. In addition, this fragment can modulate VEGF transcription as a decoy for ZNF24 when introduced into human breast cancer cells. Using transgenic zebrafish as an in vivo model system, we have demonstrated that expression of human ZNF24 induces vascular defects similar to those induced by VEGF knockdown. Importantly, these defects can be rescued by overexpression of VEGF. Analysis of human breast cancer tissues has shown that ZNF24 protein levels are significantly decreased in malignant tissues compared to normal adjacent tissues. Our data support the conclusion that ZNF24 represses VEGF transcription through direct binding to an 11bp fragment of the VEGF proximal promoter and that it may function as a negative regulator of tumor growth by inhibiting tumor angiogenesis. (Supported by NIH P01 CA045548 and The Breast Cancer Research Foundation)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5133. doi:10.1158/1538-7445.AM2011-5133
Abstract 5138: Expression and circulating levels of VEGFC/VEGFD and their receptor VEGFR2, R3 in renal cell cancer: Relationship with clinicopathological parameters
Authors: de La Motte Rouge Thibault , Mouawad Roger , Comperat Eva , Thery Jean-Christophe , Vignot Stephane , Roupret Morgan , Spano Jean-Philippe , Khayat David 
Published: June 2012

Abstract
Background: Vascular endothelial growth factors C, VEGF-D and VEGFR-2, R-3, are overexpressed in different malignancies and associated with lymph node metastasis and poor prognosis. In renal cell cancer (RCC) lymphatic tumor spread exists but data focusing on lymphangiogenesis are rare. Since the VEGF-C/VEGF-D/VEGFR-2, R-3 axis appears to be the signaling pathway for tumor-induced lymphangiogenesis and an attractive target for therapeutic intervention; we analyzed the expression and the presence of the soluble forms in 30 non treated metastatic RCC patients and results were correlated with clinicopathological parameters. Methods: Tumor and sera from 30 metastatic renal cell cancer patients (20 clear cell (ccRCC)&10 papillary (pRCC) were included in this study. The expressions of VEGFR-2,R-3 &VEGF-C,-D expressions on tumor were evaluated by immunohistochemestry. Using ELISA assays, soluble vegfr-2–3 &sVEGF-C,-D were measured in sera of RCC patients in comparison to 20 healthy controls. Results: In overall patients, a high expression of VEGF-C,-D and their receptors were observed in more than 55% of the patients as compared to the negative control. Regarding circulating VEGF-C,-D, R2, R-3 they were variable in all samples from either patients or healthy donors. Only median sVEGF- R3 level was significantly higher (p=0.005) in RCC patients as compared to healthy donors. VEGF-C and VEGF-D expression was significantly correlated (r’=0.43, p=0.02) with each other but not with the expression of its receptors. An inverse correlation between Flt-4 expression & its soluble form was noted (r=−0.33 p=0.040). The expression of VEGF-C, VECF-D and sVEGFR-3 were significantly higher in pRCC than ccRCC (p=0.02, 0.01 and 0.035 respectively). The expression of VEGFR-2, VEGFR-3 were not different between the subgroups (p=0.11). Furthermore, no correlation with clinicopathological parameters was shown in either overall patients or in the two subgroups. Conclusions: we showed that in RCC the lymphangiogenic factors are expressed or present as soluble form, a different expression pattern in ccRCC and pRCC existe. Therefore, further studies are necessary to determine if lymphangiogenesis can play a role as a prognostic tool or a target for therapeutic intervention in renal cell carcinoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5138. doi:10.1158/1538-7445.AM2011-5138
Abstract 5139: Thymidine phosphorylase expression correlate with lymphangiogenesis and angiogenesis in metastatic gastric cancer
Authors: Shin You Keun , Jiang Xianglan , Lee Hye Ryung , Rha Sun Young , Rho Jae Kyung , Noh Sung Hoon , Chung Hyun Cheol , Jeung Hei-Cheul 
Published: June 2012

Abstract
Thymidine Phosphorylase (TP) (platelet-derived endothelial cell growth factor, PD-ECGF) is known as a proangiogenic factor. High TP expression in the primary tumor has been thought as a risk factor for hepatic and lymph node metastasis in patients with gastric adenocarcinoma. However, the molecular basis for induction of invasion and lymph node metastasis by TP and its therapeutic implication is largely unknown.
First, as a pilot study, the (lymph)angiogenic activity (D2-40, LYVE-1, VEGFC, VEGFR3) and TP expressions were evaluated in resected tumor samples. Sixty patients of gastric cancer with metastatic lymph nodes and in 46 patients without lymph node metastasis were included. With immunohistochemical study, we demonstrated that tumoral and stromal TP expressions were moderately correlated (Pearson correlation = 0.455). TP expression was also correlated with depth of invasion and nodal stage. TP-positive tumors had also increased lymphovascular invasion compared with TP-negative tumors (P = 0.044), and node positive tumor had higher density of lymphatic vessels, and it is correlated with TP expression (P = 0.023).
Then, we have shown that nude mice injected intraperitoneally with TP-overexpressing MKN-45 cells (MKN-45/TP) had decreased survival times compared with those injected with control cells (MKN-45/CV). MKN-45/TP tumors were more angiogenic (positive for CD31) and lymphangiogenic (positive for D2-40 and LYVE-1), and they were more invasive than MKN-45/CV tumors. A specific TP inhibitor, TPI, partially extended the survival period of TP tumor bearing mice, and its angiogenic activity was significantly reduced. All these findings imply that TP expression may be related to lymphangiogenesis in gastric cancer, and it could be further investigated as therapeutic targets for anti-metastatic therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5139. doi:10.1158/1538-7445.AM2011-5139
Abstract 5142: VEGFA gene amplification and protein expression in breast cancer
Authors: Andreozzi Mariacarla , Schneider Sandra , Zlobec Inti , Tapia Coya , Tornillo Luigi , Eppengerger Serenella , Terracciano Luigi , Ruiz Christian 
Published: June 2012

Abstract
Background: The vascular endothelial growth factor A (VEGFA) protein is a chemical signaling molecule that is known to be a major factor in the induction of angiogenesis during tumor initiation and progression, and is also a target of anti-angiogenic therapies. Recently, we discovered the genomic amplification of the VEGFA gene in a small subset of colorectal cancers. Aim of this study was to investigate the presence of VEGFA gene amplification in breast cancer and to determine its potential impact on VEGFA protein expression.
Methods: VEGFA gene amplification was evaluated by fluorescence in situ hybridization (FISH) on a multitumor tissue microarray (MTMA) comprising 3417 tissue samples from more than 100 different tumor types. Further, a small tissue microarray was constructed from breast carcinoma samples whose VEGFA protein concentration had been previously quantified by chemiluminescence immunoassay. In order to interrogate tissue heterogeneity, VEGFA gene amplification was also analyzed on large tissue sections from 70 primary breast cancers.
Results: We detected VEGFA gene amplification in 2% of the breast cancer samples from the MTMA and in 5% of the breast cancer samples with known VEGFA protein concentration. In addition, 8% of the samples (5 out of 70) were characterized by a high polysomy. Interestingly, elevated VEGFA gene copy number was strongly correlated with higher VEGFA protein levels (p&lt;0.0001).
Conclusions: VEGFA gene amplification defines a small subset of breast carcinomas with elevated VEGFA protein expression. Our data suggest that FISH analysis of VEGFA could represent an additional evaluation system for the identification of breast cancer patients who might benefit from anti-VEGFA therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5142. doi:10.1158/1538-7445.AM2011-5142
Abstract 5147: Tumor angiogenesis-promoting activity of a hypoxia-inducible cytokine, growth differentiation factor-15 (GDF-15)
Authors: Lee Jaeseob , Lee Hansoo , Choi Jeongsuk , Park Iha , Lee Jeong-Hyung , Kim Young-Myeong 
Published: June 2012

Abstract
Angiogenesis, growth of new blood vessels from pre-existing capillary blood vessels, is a marker of cancer and various ischemic and inflammatory diseases. Tumor growth depends on new blood vessel formation because tumor cells require oxygen and nutrients for their survival and proliferation. GDF-15, also known as MIC-1, NAG-1 and PTGF-beta, is a divergent member of the TGF-beta super family. GDF-15, like other TGF-beta family members, has shown janus-faced function in tumor development: pro-apoptotic and anti-tumorigenic vs. tumorigenic activity. Previously, we and others found that hypoxia-condition induced GDF-15 expression in various cancer cell types, leading to increased secretion from the cancer cells. Here, we present the tumor-promoting activity of GDF-15, along with pro-angiogenic activity. In in vivo mouse xenograft model using human melanoma cells, we found that tumors from GDF-15-expressing melanoma cells show higher degree of vessel formation with larger tumor volume than control tumors. Blood vessel inducing activity of GDF-15 was also observed when using human umbilical vein endothelial cells (HUVECs). GDF-15 treatment induced tube formation of HUVECs. Moreover, treatment of GDF-15 enhanced the growth and migration of HUVECs. Blood vessel inducing activity of GDF-15 was further confirmed by CAM and aortic ring sprouting assays, intravital microscopic analysis and matrigel plug assay. Furthermore, GDF-15 transgenic mice showed increased blood vessel development than wild type mice while lymphatic vessel development was no different. Interestingly, although angiogenic activity of GDF-15 was comparable to that of VEGF, its inflammatory activity was less significant than VEGF. Taken together, we show that GDF-15 functions as a potential angiogenic factor for tumor development with seemingly little inflammatory activity.
Key words: Cytokine, GDF-15, Tumor, Angiogenesis, Inflammation
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5147. doi:10.1158/1538-7445.AM2011-5147
Abstract 5158: Plastic tumor cells engaged in vasculogenic mimicry produce PDGF-B and attract structural support
Authors: Paulis Yvette WJ , van den Oord Joost J. , Tjan-Heijnen Vivianne CG , Griffioen Arjan W. 
Published: June 2012

Abstract
In developmental angiogenesis, pericytes are recruited by PDGF-B-expressing endothelial cells to remodel, stabilize and support the immature blood vessel. In a process called vasculogenic mimicry (VM) highly aggressive tumor cells gain the unique ability to dedifferentiate into multiple cellular phenotypes, and obtain endothelial-like characteristics. This process can lead to the formation of vasculogenic-like matrix-embedded networks, i.e. vascular-like structures, contributing to circulation. The presence of VM is associated with increased tumor malignancy. Interestingly, also the expression of PDGF in tumor cells has been demonstrated to be associated with an increased grade of malignancy. As plastic, highly aggressive tumor cells form vasculogenic-like structures resembling immature vessels, we hypothesize that plastic tumor cells engaged in VM also functionally resemble endothelial cells by seeking structural support.
We demonstrate that plastic, aggressive melanoma cells transcribe and secrete PDGF-B, while in poorly aggressive melanoma cells, PDGF-B is absent. Myofibroblasts, acquired from the human vena saphena, cultured in the presence of plastic tumor cell conditioned medium display an activated phenotype. Additionally, in vitro analysis of 3D-culture on Matrigel demonstrated the functional contribution of myofibroblasts to plastic tumor cells as they structurally support the VM-characteristic networks formed. Immunohistochemical analysis of a series of cutaneous melanoma tissues showed a gradient PDGF-B staining towards the outer surface of the nest structures, i.e. the tumor cells aligning the VM-characteristic matrix networks. Consistent with the above described data, we observed staining for alpha-smooth muscle actin (α-SMA), a pericyte-specific marker, within the VM-characteristic matrix networks, thereby revealing the presence of pericytes inside these networks.
Together our results demonstrate that highly aggressive, VM-positive tumor cells do not solely resemble endothelial cells phenotypically, but also actively behave like endothelial cells by producing PDGF-B and attracting structural support to their immature structures. The current findings suggest that targeting of pericytes may have an unexpected anti-tumor activity through affecting vasculogenic mimicry.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5158. doi:10.1158/1538-7445.AM2011-5158