bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B101: NFAT regulates a gene expression program associated with invasiveness and poor prognosis in colorectal cancer
Authors: Tripathi Manish K. , Mima Shinji , Shi Zhiao , Prodduturi Naresh , Jing Zhu , Ciombor Kristen K. , Chen Xi , Deane Natasha , Beauchamp Robert D. , Zhang Bing 
Published: August 2014

Abstract
Colorectal cancer is the second leading cause of cancer-related death in the United States. In order to understand the regulatory mechanisms underlying poor prognosis in colorectal cancer, we analyzed fourteen human colorectal cancer microarray data sets and identified co-expressed modules using network analysis. We next filtered these modules using gene expression data from a mouse model of metastatic colon cancer, narrowing down to a candidate metastasis-related module, and identified NFAT as its potential transcriptional regulator. The NFAT family and their identified targets were found to be upregulated in human colorectal cancer patients. Analysis of NFAT family members expression in mouse and human microarray datasets, revealed NFATc1 to be differentially expressed between metastatic and non-metastatic, and between disease progression and no disease progression, respectively. We found that high NFATc1 expression correlated with significantly increased invasion (p&lt;0.0001) and migration (p&lt;0.005) in mouse colon cancer cells. We show that RNAi- based knockdown of NFATc1 and functional inhibition by the calcineurin inhibitor FK506 resulted in downregulation of predicted NFAT target genes from the metastatic module and decreased cancer cell invasiveness. Finally, we showed that the expression of NFAT target genes was significantly correlated with both disease-specific and disease-free survival in Stage II and III colorectal cancer patients. Our studies suggest a role for NFATs in colon cancer cell invasion and a potential application for the NFAT driven program as a biologically anchored prognostic gene expression signature.
Citation Format: Manish K. Tripathi, Shinji Mima, Zhiao Shi, Naresh Prodduturi, Zhu Jing, Kristen K. Ciombor, Xi Chen, Natasha Deane, Robert D. Beauchamp, Bing Zhang. NFAT regulates a gene expression program associated with invasiveness and poor prognosis in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B101.
Abstract B12: The role of stromal cells in supporting tumor-initiating cells in serous ovarian carcinoma
Authors: Hussain Ali , Stewart Jocelyn , Hyatt Elzbieta , Neel Benjamin , Ailles Laurie 
Published: August 2014

Abstract
High grade serous ovarian carcinoma has been shown to be a highly heterogeneous disease. In vivo studies demonstrate that the tumor initiating frequency (TIF) varies substantially from case to case. Nonetheless, the tumor initiating subset remains a rare population within the epithelial compartment and can be enriched using the cell surface marker CD133 (Stewart et al., PNAS, 2011). The tumor microenvironment may play a role in supporting and maintaining tumor initiating cells (TIC) through direct and/ or indirect cross talk. The contribution of the mesenchymal component of the microenvironment may prove to be essential in providing such support as has been previously shown in studies on breast and prostate cancers. We hypothesize that cancer associated fibroblasts (CAFs) serve as a niche that supports and maintains the tumorigenic potential of TICs in SOC.
We have derived and established CAF lines from bulk primary tumors and characterized their phenotype through immunostaining. Those lines stained positive for mesenchymal markers (Vimentin and Alpha-SMA), and stained negative for the epithelial marker Cytokertain. A profile of surface markers expressed on the surface of these CAF lines was then generated by running a flow cytometry-based high throughput screen (HTS) for 370 known cell surface proteins. Those markers are being validated for their specificity by immunostaining, FACS, qPCR, and in vivo work. Preliminary data obtained through immunoflourescnce and FACS support the specificity of our candidate stromal marker CD90. Furthermore, FACS data show that CD90 is expressed more brightly on fibroblasts than on epithelial cells (EpCAM+) in bulk SOC cases. Consequently, CD90 has been selected for sorting stromal cells for additional validation. Quantitative PCR analysis of CD90+EpCAM- sorted populations further validates their over-expression of mesenchymal genes when compared to CD90-EpCAM+ sorted populations. Moreover, functional validation of the influence of fibroblasts on the growth of tumor cells is currently being investigated through co-injection and co-culture assays. Preliminary data show that the presence of fibroblasts better supports the growth of epithelial colonies in culture than when compared to other conditions.
Interplay between the niche and a specific subset of epithelial cells may promote those cells to become more tumorigenic. Such an interaction may be dependent on direct physical contact and/or indirect cross talk. Ultimately, we aim on understanding the mechanisms that govern these interactions.
Citation Format: Ali Hussain, Jocelyn Stewart, Elzbieta Hyatt, Benjamin Neel, Laurie Ailles. The role of stromal cells in supporting tumor-initiating cells in serous ovarian carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B12.
Abstract B51: Potential role of CXCR3 in breast cancer bone metastasis
Authors: Feng Wendy , Unlap Tino 
Published: August 2014

Abstract
Breast cancer has a high tendency to metastasize to the bone. Breast cancer bone metastasis causes several serious clinical complications such as extreme bone pain, bone fracture, hypercalcemia, and spinal cord compression. Furthermore, once breast cancer metastasizes to the bone, it often becomes incurable. However, the molecular mechanism of breast cancer bone metastasis is not fully understood. CXCR3 and its ligands (CXCL9, CXCL10 and CXCL11) have been shown to play a role in the initiation and progression of cancer metastasis in various types of cancer including breast cancer. Specifically, it has been demonstrated that CXCR3 can promote breast cancer cell line metastasis to the lung in mouse models. A recent study has revealed that CXCR3 is highly expressed in breast cancer tissues and that its expression is positively associated with breast cancer progression. Since the bone is the most common site of breast cancer metastasis, it is possible that CXCR3 and one or more of its ligands are also involved in breast cancer bone metastasis by promoting extravasation of breast tumor cells to the bone. The objective of this study was to carry out several experiments to test this possibility. First, we assessed whether MDA-MB-231 breast cancer cell line expresses CXCR3 using RT-PCR and Western blot analysis. Our data indicate that both CXCR3 mRNA and protein are highly expressed in MDA-MB-231 cells. Next, the expression of CXCR3 ligands (CXCL9, CXCL10, and CXCL11) in bone cells (RAW264.7 and RAW264.7-derived osteoclasts) was examined using RT-PCR, and the data indicate that the bone cells express CXCL10 and CXCL11. In particular, CXCL11 mRNA expression levels increase during osteoclast differentiation. Finally, we performed chemotaxis assays to determine whether the bone cells are able to induce directed migration of MDA-MB-231 cells. We found that the bone cells can exert profound chemotactic effects on MDA-MB-231 cells. Taken together, these findings support the possibility that CXCR3 and its ligands may be involved in breast cancer bone metastasis by mediating breast cancer cell extravasation into the bone marrow. Future studies are needed to address whether CXCR3 is the predominant factor in mediating bone cell-dependent breast cancer migration. Moreover, animal model studies are also needed to investigate whether CXCR3 and its ligands are involved in breast cancer bone metastasis in vivo. If CXCR3 is in fact a predominant factor mediating breast cancer metastasis, CXCR3 may be a potential therapeutic target of breast cancer metastasis.
Citation Format: Wendy Feng, Tino Unlap. Potential role of CXCR3 in breast cancer bone metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B51.
Abstract B72: CX3CR1, a fractalkine receptor, can regulate peritoneal dissemination of epithelial ovarian cancer cells
Authors: Xie Jia , Gurler Hilal , Burdette Joanna , Barbolina Maria 
Published: August 2014

Abstract
Epithelial ovarian carcinoma (EOC) is a leading cause of death from gynecologic malignancies mainly due to metastasis. EOC metastases spread by shedding the malignant cells off from the ovarian surface and seeding to organs and tissues in the peritoneal cavity. The current standard of care, a combination of chemotherapy and surgery, fails to keep patients in remission. Thus, mechanistic understanding of the biology of EOC metastasis and identification of novel targetable molecules are crucial for the development of improved therapeutic approaches. Fractalkine receptor (CX3CR1) belongs to a chemokine family of G-protein coupled receptors. CX3CR1 is expressed by EOC cells and promotes cell migration and proliferation. CX3CR1-positive EOC cells have been shown to adhere to the CX3CL1-positive peritoneal mesothelial cells in vitro. Thus, we hypothesized that CX3CL1/CX3CR1 axis could be important for peritoneal dissemination of metastatic EOC.
In order to test this hypothesis, we performed short-term ex vivo and in vivo adhesion assays, as well as long-term metastasis formation assay. We found that EOC cells prefer omentum to other peritoneal tissues during the short-term in vivo and ex vivo adhesion. Importantly, reduction of CX3CR1 expression in EOC cells resulted in significantly reduced peritoneal adhesion. Furthermore, reduced adhesion correlated with the ability of EOC cells to form overt metastasis. Microenvironmental milieu has been histologically evaluated for stromal cells in the omentum expressing CX3CL1. Taken together, our data indicate that fractalkine signaling is one of the central regulators of EOC metastasis.
Citation Format: Jia Xie, Hilal Gurler, Joanna Burdette, Maria Barbolina. CX3CR1, a fractalkine receptor, can regulate peritoneal dissemination of epithelial ovarian cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B72.
Abstract B86: Ang-2-VEGF-A CrossMab, a novel bispecific human IgG1 antibody blocking VEGF-A and Ang-2 functions simultaneously, mediates potent antitumor, antiangiogenic, and antimetastatic efficiency
Authors: Lorenzon Erica , Kienast Yvonne , Raemsch Romi , Scheuer Werner , Herting Frank , Bernicke Dirk , Schaefer Wolfgang , Regula Joerg , Stubenrauch Kay , Yu Sidney , The Huynh Hung , Martarello Laurent , Klein Christian , Thomas Markus 
Published: August 2014

Abstract
Purpose: VEGF-A blockade has been validated clinically as a treatment for human cancers. Angiopoietin-2 (Ang-2) expression has been shown to function as a key regulator of tumor angiogenesis and metastasis.
Experimental Design: We have recently described a novel generic method for the production of bivalent bispecific human IgG1 antibodies. Subsequently, we have applied the CrossMab technology for the generation of a bispecific antibody recognizing VEGF-A with one arm based on Bevacizumab, and the other arm recognizing Ang-2 based on LC06, a highly Ang-2 selective human IgG1 antibody. Ang-2-VEGF CrossMab was evaluated in vitro and in vivo using molecular, biochemical, cellular and histological analyses to determine its pharmacologic properties, along with its mechanism of action.
Results: Ang-2-VEGF-A CrossMab showed potent tumor growth inhibition in a panel of orthotopic and subcutaneous syngeneic mouse tumors and patient and cell line-derived human tumor xenografts at both early and late stages of tumor development. Furthermore, a strong inhibition of angiogenesis and an enhanced vessel normalization phenotype were observed. In contrast to Ang-1 inhibition, anti-Ang-2-VEGF-A treatment did not aggravate the adverse effect of anti-VEGF treatment on physiological vessels. Moreover, treatment with Ang-2-VEGF-A CrossMab resulted in inhibition of hematogenous spread of tumor cells to other organs and reduced micrometastatic growth in the adjuvant setting.
Conclusion: Our data indicate that Ang-2-VEGF-A CrossMab mediates potent anti-tumor, anti-angiogenic, and anti-metastatic efficacy and represents a promising therapeutic agent for the therapy of cancer.
Citation Format: Erica Lorenzon, Yvonne Kienast, Romi Raemsch, Werner Scheuer, Frank Herting, Dirk Bernicke, Wolfgang Schaefer, Joerg Regula, Kay Stubenrauch, Sidney Yu, Huynh Hung The, Laurent Martarello, Christian Klein, Markus Thomas. Ang-2-VEGF-A CrossMab, a novel bispecific human IgG1 antibody blocking VEGF-A and Ang-2 functions simultaneously, mediates potent antitumor, antiangiogenic, and antimetastatic efficiency. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B86.
Abstract B90: Hypoxia-induced pathological angiogenesis mediates tumor cell dissemination, invasion, and metastasis in a zebrafish tumor model
Authors: Rouhi Pegah , Lee Samantha Lin , Jensen Lasse Dahl , Zhang Danfang , Ji Hong , Hauptmann Giselbert , Ingham Philip , Cao Yihai 
Published: August 2014

Abstract
Mechanisms underlying pathological angiogenesis in relation to hypoxia in tumor invasion and metastasis remain elusive. Here, we have developed a zebrafish tumor model that allows us to study the role of pathological angiogenesis under normoxia and hypoxia in arbitrating early events of the metastatic cascade at the single cell level. Under normoxia, implantation of a murine T241 fibrosarcoma into the perivitelline cavity of developing embryos of transgenic fli1:EGFP zebrafish did not result in significant dissemination, invasion, and metastasis. In marked contrast, under hypoxia substantial tumor cells disseminated from primary sites, invaded into neighboring tissues, and metastasized to distal parts of the fish body. Similarly, expression of the hypoxia-regulated angiogenic factor, vascular endothelial growth factor (VEGF) to a high level resulted in tumor cell dissemination and metastasis, which correlated with increased tumor neovascularization.
Inhibition of VEGF receptor signaling pathways by sunitinib or VEGFR2 morpholinos virtually completely ablated VEGFinduced tumor cell dissemination and metastasis. To the best of our knowledge, hypoxia- and VEGF-induced pathological angiogenesis in promoting tumor dissemination, invasion, and metastasis has not been described perviously at the single cell level. Our findings also shed light on molecular mechanisms of beneficial effects of clinically available anti-VEGF drugs for cancer therapy.
Citation Format: Pegah Rouhi, Samantha Lin Lee, Lasse Dahl Jensen, Danfang Zhang, Hong Ji, Giselbert Hauptmann, Philip Ingham, Yihai Cao. Hypoxia-induced pathological angiogenesis mediates tumor cell dissemination, invasion, and metastasis in a zebrafish tumor model. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B90.
Abstract B92: Identifying different functional mechanisms of invasion from mesenchymal and proneural subtypes of glioblastoma
Authors: Jung Sungwon , Kim Seungchan , Kiefer Jeff , Berens Michael E. 
Published: August 2014

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR12) of the Conference Proceedings.
Citation Format: Sungwon Jung, Seungchan Kim, Jeff Kiefer, Michael E. Berens. Identifying different functional mechanisms of invasion from mesenchymal and proneural subtypes of glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B92.
Abstract B98: Promoter methylation status of tumor suppressor genes and an inflammatory-related COX-2 gene in cervical intraepithelial neoplasia
Authors: Lin Sheng Hsiung , Yu Chun Chieh , Wu Ming Tsang , Li Ruei Nian 
Published: August 2014

Abstract
Cervical cancer is one of the most common cancer among women. Early detection and prompt treatment would be the best management options. DNA methylation is one of the epigenetic regulation mechanisms leading to gene silencing in neoplastic cells. Silencing of tumor suppressor gene resulted from aberrant methylation has been detected in a majority of human cancers. Here, we applied methylation-specific polymerase chain reaction (MSP) to examine the methylation state of three tumor suppressor genes (rar-beta, p16 and cdh1) and an inflammatory-related cox-2 gene in different stages of cervical intraepithelial neoplasia (CIN). Our analyses revealed that cox-2 gene is in unmethylated form from CIN I to carcinoma specimens. Besides, no significant increase in methylation levels of rar-beta and cdh1 genes was observed. However, the high frequency of aberrant hypermethylation of p16 gene (13.2% in normal specimens ; 18.2% in CIN I; 35.7% in CIN II; 31.6% in CIN III and 15.4% in carcinoma) suggesting that p16 is progressively increased during the development of malignant stages in cervical intraepithelial neoplasia, especially in the absence of HPV infection. The result of bisulfite sequencing indicated that the 10 CpG sites of p16 gene are all methylated in ten individuals. In conclusion, this study identifies promoter methylation analysis of p16 on cervical cell specimens may be an additional tool for current cervical cytomorphology based screening.
Citation Format: Sheng Hsiung Lin, Chun Chieh Yu, Ming Tsang Wu, Ruei Nian Li. Promoter methylation status of tumor suppressor genes and an inflammatory-related COX-2 gene in cervical intraepithelial neoplasia. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B98.
Abstract C14: Loss of haptotaxis facilitates invasion in LKB1-deficient melanoma
Authors: Chan Keefe T. , Asokan Sreeja B. , Bo Tao , Berginski Matthew E. , Liu Wenjin , Cochran Shelly D. , Sharpless Norman E. , Bear James E. 
Published: August 2014

Abstract
Germline mutations in the serine/threonine kinase STK11/LKB1 are associated with Peutz-Jehgers Syndrome, which is characterized by hyperpigmentation of the oral mucosa. Inactivating somatic mutations occur in approximately 10-20% of melanomas; however, how the loss of LKB1 facilitates melanoma invasion remains poorly understood. Using cell lines derived from simultaneous activation of KRas and inactivation of LKB1 in melanocytes, we have investigated melanoma migration upon reconstitution with LKB1. Reexpression of LKB1 diminishes migration during wound healing, spheroid outgrowth into 3D collagen, and overall single cell speed in random motility assays. Furthermore, the formation of invadopodia is independent of LKB1 status in both human and mouse melanomas. Interestingly, using microfluidic devices we have found that loss of LKB1 abrogates the ability of cells to respond to gradients of extracellular matrix (haptotaxis) but does not impair their ability to chemotax to EGF. We have also recently developed a model of orthotopic implantation of multicellular tumor spheroids into the dermis of the mouse ear skin and have validated this approach by recapitulating the finding that LKB1 limits tumorigenesis. We are using this model to image local invasion in vivo by multiphoton microscopy and are currently examining the intriguing hypothesis that loss of extracellular matrix sensing is one aspect that contributes to metastatic migration.
Citation Format: Keefe T. Chan, Sreeja B. Asokan, Tao Bo, Matthew E. Berginski, Wenjin Liu, Shelly D. Cochran, Norman E. Sharpless, James E. Bear. Loss of haptotaxis facilitates invasion in LKB1-deficient melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C14.
Abstract C15: CRMP1 functions to suppress epithelial-mesenchymal transition and invasion capacity of prostate cancer cells
Authors: Cai Ganhui , Yu Shan , Ji Yanping , Chan Franky Leung 
Published: August 2014

Abstract
Collapsin response mediator protein 1 (CRMP1) is originally identified and characterized as a cytoplasmic phosphoprotein involved in the Semaphorin 3A (Sema3A)-regulated growth cone collapse during neural development, via its regulation of cytoskeleton dynamics, and then also characterized as an invasion suppressor in lung cancer. Thus, we hypothesize that CRMP1 may be involved in the epithelial-mesenchymal transition (EMT) process and invasion or metastasis via its regulation on cytoskeleton organization in prostate cancer cells. Results of immunohistochemistry study showed that CRMP1 exhibited a reduced expression pattern in high Gleason-scored clinical prostate cancer tissues. In vitro functional studies showed that stable CRMP1-knockdown could induce EMT in prostate cancer cells (DU145), while its ectopic expression could induce the reverse process mesenchymal-epithelial transition (MET) in both DU145 and PC-3 prostate cancer cells, as evidenced by significant change of cellular morphology and altered expression levels of epithelial and mesenchymal markers. Confocal immunofluorescence showed that reorganization of F-actin was seen after shRNA-mediated CRMP1-knockdown in DU145 cells. It was also revealed that CRMP1 overexpression could confer the resistance to TGF-β1- and Snail-induced EMT in prostate cells. Results of CRMP1 promoter-driven luciferase reporter and ChIP assays indicated that Snail was a direct transrepressor of CRMP1 gene, which showed a downregulation pattern in both prostate cancer cells (DU145) and immortalized prostatic epithelial cells (BPH1) with overexpression of Snail. Furthermore, wound healing and Matrigel invasion assays showed that CRMP1 could inhibit cell migration and invasion capacity in DU145 and PC-3 cells. Taken together, our findings suggest that CRMP1 could play a role in prostate cancer invasion and metastasis, via its regulation on EMT and MET process. (This work was supported by a Direct Grant for Research and a RGC-GRF grant 2009/2010)
Citation Format: Ganhui Cai, Shan Yu, Yanping Ji, Franky Leung Chan. CRMP1 functions to suppress epithelial-mesenchymal transition and invasion capacity of prostate cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C15.