bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1505: The role of cathepsin B in colorectal tumorigenesis
Authors: Bian Benjamin , Mongrain Sébastien , Boudreau Francois , Rivard Nathalie 
Published: June 2012

Abstract
Many cancers express elevated protease levels which contribute to certain aspects of tumor behavior such as growth and metastatic spread. Specifically, elevation of the cysteine protease cathepsin B has been shown to correlate with malignant progression of tumors. The majority of reports on cathepsin B expression in tumors have focused on measurements of activity or protein staining. However, multiple transcripts species have been detected resulting from alternative splicing in the 5’- or 3-untranslated regions, and possibly the use of alternative promoter regions. The specific role of these variants remains to be established. Methods: Expression of cathepsin B was analyzed in normal human intestinal epithelial cells (HIEC) and colorectal cancer cell lines (Caco-2/15, HCT116, DLD1, HT29, SW480, T84, Colo205) by qPCR and Western blot. The role of cathepsin B was examined in HT29 and DLD1 cell lines through recombinant lentiviruses encoding anti-cathepsin B short hairpin RNA (shRNA). Results: RT-PCR analyses demonstrated that the levels of the full transcript for cathepsin B containing exons 1-12 (CB) were similar between normal and cancerous cell lines. By contrast, the splice variant lacking exons 2 and 3 (CB-2,3) was expressed only in cancer cells and in biopsies from human colorectal tumors when compared to the adjacent healthy tissues. Immunofluorescence studies showed that this novel tumor form of cathepsin B (CB-2,3) was associated with nuclei and mitrochondria while the full-length cathepsin B protein (CB) was found in the lysosomes. Western blot analyses on culture media showed a strong secretion of various cathepsin B isoforms by cancer cell lines. The lentiviral infection of a shRNA which specifically knocked-down cathepsin B expression, while decreasing enzyme activity in cell lysates, did not influence colorectal cancer cell proliferation under anchorage-dependent conditions. By contrast, decrease of cathepsin B expression in HT29 and DLD1 colon cancer cell lines resulted in a marked reduction of their capacity to grow in soft agar. Levels of β-catenin protein and phosphorylated ERK1/2 were not affected following cathepsin B silencing in contrast to phosphorylated Akt which was significantly reduced. Further, migration and invasion through Matrigel was reduced by 60% in cells expressing the shRNA against cathepsin B compared to cells expressing a control shRNA. Conclusion: These results suggest that the alternative splicing of cathepsin B could contribute to the aberrant intracellular trafficking and function of cathepsin B in colorectal cancer.
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 1505. doi:10.1158/1538-7445.AM2011-1505
Abstract 1507: Ectopic expresion of cathepsin G in mammary tumor cells and its role in tumor growth and osteolytic bone metastasis
Authors: Varney Michelle L. , Gregory Clint , Singh Rakesh K. 
Published: June 2012

Abstract
Breast cancer has a high predilection to metastasize to the bone microenvironment. The resulting lesions are predominantly osteolytic and are associated with the resulting morbidity and mortality. We have demonstrated that tumor bone interaction plays an important role in osteolytic bone metastasis mediated by dysregulation of a unique set of genes. Among these genes several proteases have been found to be up-regulated at the tumor-bone interface, one of these is Cathepsin G, a serine protease. These proteases act as modulators between the tumor and stroma. Previously, we have shown that both malignant cells and osteoclasts at the TB-interface express higher levels of Cathepsin G, which is critical for osteolytic bone metastasis. The precise role of tumor and/or host-derived Cathepsin G in osteolytic bone metastasis is not known. In this report, we examined the contribution of tumor-derived Cathepsin G by testing the hypothesis that ectopic expression of Cathepsin G modulates malignant cell phenotype, osteoclast recruitment and activation, and osteolytic metastasis. We generated stable mammary tumor cell lines constitutively expressing Cathepsin G (Cl66-CTSG). Cathepsin G-expressing tumor cells showed diminished in vitro cell proliferative potential and in vivo mammary fat pad tumor growth as compared to vector control transfected Cl66-CMV cells. We demonstrated that Cathepsin G-overexpressing tumor cells induced osteoclast activation and differentiation in vitro and tumor-induced osteolysis in vivo. Our data suggest that tumor-derived Cathepsin G might have distinct tumor modulating activities in the bone microenvironment by regulating cell proliferation and osteoclast recruitment and activation.
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 1507. doi:10.1158/1538-7445.AM2011-1507
Abstract 1509: Analysis of interaction between tumor endothelial cells and tumor cells
Authors: Maishi Nako , Ohga Noritaka , Hida Yasuhiro , Ohba Yusuke , Kawamoto Taisuke , Akiyama Kosuke , Kitayama Kazuko , Kondoh Miyako , Osawa Takahiro , Yamamoto Kazuyuki , Inoue Nobuo , Shindoh Masanobu , Hida Kyoko 
Published: June 2012

Abstract
Interaction between tumor endothelial cells (TECs) and tumor cells plays a key role in the early stage of hematogenous metastasis. TECs provide the principal route by which tumor cells exit the primary tumor site and enter the circulation. We have reported TECs are different from normal endothelial cells (NECs) in various aspects, such as chromosomal abnormality and gene expression profiles. In this study, we isolated two types of TECs from different human tumor xenografts in nude mice to analyze interaction between TECs and tumor cells. One is HMTEC isolated from highly metastatic tumor and the other is LMTEC from low metastatic tumor. We also isolated NEC from dermis of normal nude mouse as normal control. HMTEC expressed higher levels of mRNA of angiogenesis-related genes than LMTEC or NEC. We hypothesized HMTECs may promote metastasis, in particular, intravasation at the primary site. We investigated the roles of TECs in tumor metastasis; 1) migration of tumor cells towards TECs, 2) adhesion to endothelial layer, 3) crossing the endothelium. Tumor cells migrated towards conditioned-media (CM) from HMTEC more than LMTEC-CM or NEC-CM in vitro. Tumor cells were more adhesive to HMTEC than to LMTEC or NEC. They migrated through the HMTEC-monolayer most among all ECs in transendothelial migration assay. These results suggested that HMTEC may help tumor cells to metastasize. Finally, we analyzed the effects of CM from highly metastatic tumor cells on NECs. Tumor CM induced mRNA expressions of several genes, such as CXCL12, VEGFA and extracellular matrix in NEC. Tumor cells more migrated towards tumor CM- treated NEC than non-treated NEC. Tumor cells adhered more to the tumor CM- treated NEC than to non-treated NEC. These results suggest that TECs “educated” in tumor microenvironment which have highly metastatic potential, may be collaborating with tumor cells for metastasis.
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 1509. doi:10.1158/1538-7445.AM2011-1509
Abstract 1510: Transcriptional profiling of a lethal breast cancer tumor microenvironment
Authors: Witkiewicz Agnieszka K. , Kline Jessica , Queenan Maria , Brody Jonathan , Sotgia Federica , Tsirigos Aristotelis , Lisanti Michael P. 
Published: June 2012

Abstract
Breast cancer growth and progression are governed by complex and reciprocal interactions between tumor cells and surrounding stromal elements. We have previously shown that a loss of stromal Cav-1 expression is associated with an increased risk of early tumor recurrence, metastasis and decreased overall survival. To identify and characterize the signaling pathways activated in Cav-1 negative tumor stroma, we performed gene expression profiling using laser micro-dissected breast cancer associated stroma.
Methods: Tumor stroma was laser capture micro-dissected using a Leica LCM system from 4 cases showing high stromal Cav-1 expression and 7 cases with loss of stromal Cav-1. Total RNA was amplified using the NuGEN™ WT-Ovation™ FFPE RNA Amplification System V2 and cDNA was hybridized to Affymetrix GeneChip® arrays. One-way ANOVA was setup to extract differentially expressed genes between Cav-1 positive and negative stromal samples.
Results: We identified 238 genes that were up-regulated and 232 genes that were down-regulated in the stroma of tumors showing a loss of Cav-1 expression (p-value &lt; = 0.01 and fold change &gt; = 1.5) Gene set enrichment analysis revealed “stemness”, inflammation, DNA damage, oxidative stress, hypoxia, autophagy, and mitochondrial dysfunction in the tumor stroma of patients lacking stromal Cav-1.
Conclusions: Our findings are consistent with the recently proposed “Autophagic Tumor Stroma Model of Cancer Metabolism”. In this model, cancer cells induce oxidative stress in adjacent stromal cells, which then forces these stromal cells to undergo autophagy. This, in turn, produces recycled nutrients to feed “hungry” cancer cells.
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 1510. doi:10.1158/1538-7445.AM2011-1510
Abstract 1516: Estrogen regulated TME factors are novel modulators of neovasculogenesis and EMT in breast cancer
Authors: George Andrea L. , Rajoria Shilpi , Shanmugam Arulkumaran , Prakash Pradeep Bangalore , Suriano Robert , Tiwari Raj K. 
Published: June 2012

Abstract
The tumor microenvironment plays host to multiple cell types that aid in tumor metastasis and recent work has begun to focus on the impact of non-malignant cells in breast cancer progression. Tumor metastasis relies on neovasculogenesis, aided by bone marrow-derived endothelial progenitor cells (BM-EPCs), which is critical for invasive tumor growth as well as an epithelial to mesenchymal transition (EMT) by malignant cells, allowing them to break from the primary tumor site and migrate to secondary foci. The modulators of tumor induced neovasculogenesis as well as EMT need elucidation. Previously we reported that estrogen significantly enhanced BM-EPC migration to mouse mammary tumor sites in vivo, resulting in an increase in neovasculogenesis and induction of proangiogenic and prometastatic proteins including vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Using in vitro assays, we observed that estrogen leads to stabilization of the transcription factor hypoxia inducible factor 1 α (HIF-1α), a key regulator of hypoxia signaling, in the mouse mammary tumor cell line TG1-1. We observed that estrogen signaling via HIF-1α leads to an increase in VEGF, and conditioned media from TG1-1 cells treated with estrogen leads to a significant increase in human umbilical vein endothelial cell (HUVEC) migration in vitro, an effect abrogated by the anti-estrogen Fulvestrant as well as 3-(5’-hydroxymethyl-2’-furyl)-1-benzylindazole (YC1) a specific HIF-1α inhibitor. While tumor growth induces neovasculogenesis via endothelial cell recruitment, the inflammatory environment created stimulates infiltration of tumor associated macrophages, or TAMs. We further observed that conditioned media from the mouse macrophage cell line RAW264.7 induced EMT in TG1-1 cells, leading to an increase in both the EMT transcription factor TWIST and TG1-1 cell migration. Thus, an inflammatory environment leads to macrophage dependent secretion of pro-metastatic factors, resulting in breast tumor cell EMT and migratory propensity. We conclude that estrogen modulated secreted factors in different cell types influence the tumor microenvironment and have functional consequences on tumor cell growth and metastasis and may provide targets for clinical therapeutic intervention.
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 1516. doi:10.1158/1538-7445.AM2011-1516
Abstract 1523: α4 integrin expression is a determinant for activity of the integrin antagonist HYD1 in multiple myeloma cell lines and patient specimens
Authors: Emmons Michael F. , Gebhard Anthony , Mclaughlin Mark , Cress Anne , Hazlehurst Lori 
Published: June 2012

Abstract
Our laboratory previously showed that the β1 integrin inhibitory peptide HYD1 causes caspase independent cell death in myeloma cell lines. To further characterize the mechanism of HYD1 induced cell death an isogenic drug resistant variant was developed. This variant, called H929-60, was developed by chronically exposing parental H929 cells to increasing doses of HYD1 over time until a drug resistant phenotype was observed. The resistant cell lines demonstrated reduced binding of FAM-conjugated HYD1 to the cell surface compared to the parental cell line. We previously reported that HYD1 blocks α4β1 mediated adhesion to fibronectin and thus we asked whether resistance towards HYD1 induced cell death correlated with reduced α4β1 integrin expression. The resistant variant showed deceased levels of α4 integrin protein expression despite no change in RNA levels, indicating a post-transcriptional regulation of α4 expression. These changes were consistent with decreased binding to fibronectin, VCAM-1 and HS-5 stromal cells. Moreover, we demonstrated that biotin conjugated HYD1 is able to pulldown a α4 containing complex and the amount of α4 bound to biotin-HYD1 was reduced in the drug resistant variant. Reducing the expression of α4 and β1 integrins on the cell surface in H929 cells was sufficient to confer partial resistance to HYD1 induced cell death. Because the H929 resistant variant showed reduced adhesion to stroma cells, we asked whether acquisition of resistance towards HYD1 resulted in reduced levels of drug resistance in the HS-5 co-culture model of drug resistance. Using the HS-5 co-culture model, we show that the drug resistant variant H929-60 cells treated with either melphalan or velcade were drug sensitive in the HS-5 stromal co-culture model of drug resistance. Thus the drug resistant variant failed to demonstrate a cell adhesion mediate drug resistance (CAM-DR), indicating that as cells acquire resistance to HYD1 they lose resistance initiated by the tumor microenvironment. Finally, we show that HYD1 was significantly more potent in relapsed/refractory patient specimens compared to newly diagnosed patient specimens. Additionally, we show that α4 integrin expression positively correlates with HYD1 sensitivity. Together our data indicate that HYD1 is an attractive novel agent for the treatment of relapsed/refractory multiple myeloma with high levels of α4 integrin expression.
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 1523. doi:10.1158/1538-7445.AM2011-1523
Abstract 1524: Overcoming temozolomide resistance in MGMT positive glioblastoma by targeting ALDH1
Authors: Schäfer Andrea , Teufel Julian , Höpner Ingrid , Ringel Florian , Bettstetter Markus , Schlegel Jürgen 
Published: June 2012

Abstract
Despite aggressive therapy, including radical surgical resection, radiation, and chemotherapy, the prognosis for patients with glioblastoma (GBM) remains poor and relapse occurs regularly. Implementation of the chemotherapy drug temozolomide (TMZ), as a standard in adjuvant GBM therapy, significantly increased the overall survival of patients with an epigenetic silenced MGMT promoter (MGMT-). To date, no comparable therapeutic approach for GBM patients with MGMT expression (MGMT+) is applied.
Tumor re-growth in MGMT+ and MGMT- GBM corroborates the tumor stem cell (TSC) paradigm, postulating that a therapy-resistant subpopulation of cells harbors the ability to keep the tumor alive and growing. Recently, we presented aldehyde dehydrogenase 1 (ALDH1) as a marker for glioblastoma cells with stem cell capacity.
In this study, we demonstrate that ALDH1 overexpression in established and primary MGMT+ GBM cell lines correlates with resistance to TMZ, while concomitant inhibition of ALDH1 by 4-diethylaminobenzaldehyde (DEAB) or tetraethylthiuramdisulfide (DSF) re-sensibilized the cells significantly. Application of TMZ in combination with DEAB strikingly attenuated the stem cell capacity of both MGMT + and MGMT – cells. For further verification of the specific impact of ALDH1 on therapy resistance, shRNA constructs were applied. Moreover, immunohistochemical analysis of ALDH1 expression in specimens of glioblastoma patients revealed a significant correlation between expression of this enzyme and a poor clinical prognosis.
All these findings demonstrate that ALDH1 is a marker for brain tumor stem cells, a strong predictor of clinical outcome and a potential target for an improved therapy of MGMT positive GBM.
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 1524. doi:10.1158/1538-7445.AM2011-1524
Abstract 1535: Increasing integrin function from within the cell sensitizes melanomas to chemotherapy
Authors: Nelson Elke S. , Folkmann Andrew , DeMali Kris 
Published: June 2012

Abstract
Metastatic melanoma is an aggressive skin disease for which there are no effective therapies. Emerging evidence indicates that melanomas can be sensitized to chemotherapy by increasing integrin function. Current therapies work by targeting integrins from outside the cell, resulting in complete gains or losses of integrin function that lead to mechanism-based toxicities. An attractive alternative approach would be to target proteins, such as vinculin, that associate with the integrin cytoplasmic domains and regulate its ligand binding properties. Here we report that a novel reagent, denoted vinculin activating peptide or VAP, increases integrin activity from within the cell, as measured by elevated: (1) active integrins on the cell surface, (2) adhesion of cells to extracellular matrix ligands, (3) numbers of cell-matrix adhesions, and (4) downstream signaling. These effects are dependent on both integrins and a key regulatory residue A50 in the vinculin head. We further show that VAP enhances integrin function independent of both its mode of delivery and the melanoma cell type tested. Furthermore, VAP dramatically increases the sensitivity of melanomas to chemotherapy in clonal growth assays and in vivo mouse models of melanoma. Finally, we demonstrate that the increase in chemosensitivity results from increases in p53-dependent DNA damage-induced apoptosis. Collectively these findings demonstrate for the first time that integrin function can be manipulated from within the cell and validate integrins as a new strategy for the treatment of chemoresistant melanomas.
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 1535. doi:10.1158/1538-7445.AM2011-1535
Abstract 1537: Role of S100PBP in pancreatic adenocarcinoma
Authors: Lines Kate E. , Audi Namaa , Chelala Claude , Wijesuriya Nilu , Kocher Hemant , Hurst Helen , Crnogorac-Jurcevic Tatjana 
Published: June 2012

Abstract
We have recently discovered a 37kDa novel S100P-binding protein, S100PBP which exhibits no homology to any currently known protein. We have therefore explored its expression in a wide range of normal and cancer tissues, and performed several in vitro functional assays to define its putative roles.
In order to determine S100PBP localization in human samples immunohistochemistry was performed on a multi-organ tissue array (Pantomics) and on an in-house made pancreatic tissue array including normal pancreas, primary cancer and metastatic lesions. To determine S100PBP functions cells with both silenced and stably over-expressing S100PBP were established. Affymetrix gene expression arrays and a battery of functional assays including adhesion, migration and invasion were performed using these cells.
We show that S100PBP is ubiquitously expressed in different normal and tumor specimens in a cell and tissue type dependent manor. In normal pancreas S100PBP is widely expressed in both exocrine and endocrine compartments while in pancreatic adenocarcinoma it is present in early precursor lesions, PanINs, and retained in some cancer cells, but with significantly lower intensity.
We further show that in pancreatic cancer cells S100PBP binds, in addition to S100P, several other S100 proteins, namely S100A2, S100A4 and S100A6 in a calcium-dependant fashion. Over-expression of S100PBP also causes changes in the expression levels of S100P and S100A9, which were both down-regulated, while the levels of the S100A4 transcript increased. Furthermore, manipulation of S100PBP expression leads to phenotypic changes affecting the adhesive, migratory and invasive capacity of pancreatic cancer cells, which varied depending on the cellular context and constellation of presence of different S100 proteins. Both over-expression and silencing of S100PBP also induced an increase/decrease in Cathepsin Z levels, respectively. This protease appears to be critically important for inducing the observed changes in cellular adhesion.
In summary, S100PBP is ubiquitously expressed and modulates the function of several S100 proteins, as well as Cathepsin Z, and appears to play an important role in the adhesive, migratory and invasive capabilities of pancreatic cancer cells.
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 1537. doi:10.1158/1538-7445.AM2011-1537