bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3945: IKK-Epsilon, a novel factor identified by proteomics, contributes to prostate cancer cell-induced osteoclast activity in vitro.
Authors: Yang Xin , Xiao Zhen , Wang Jianhua , Lu Yi , Xu Yang , Huang Xin , Mizokami Atsushi , Keller Evan T. , Zhang Jian 
Published: August 2014

Abstract
Prostate cancer preferentially metastasizes to skeleton resulting in osteoblastic lesions with underlying osteoclast activity. Novel strategies to inhibit the tumor skeletal metastasis involve targeting not only tumor cells but also bone microenvironment which is composed of osteoclasts, osteoblasts and stromal cells that include fibroblasts, immune and inflammatory cells, adipocytes, glial cells, smooth muscle cells, and resident and recruited vascular cells. The microenvironment can exert both stimulatory and inhibitory influences on proliferation and malignant properties of tumor cells. In this study, we intended to identify factors that may play key roles in this bidirectional and dynamic interaction between tumor cells and bone microenvironment. First, we fractionated the prostate cancer PC3 cell conditioned media by the molecular weight of proteins in media using centricon column. Then we applied the fractions to culturing osteoclast precursor RAW 264.7 cells in vitro. We repeated and scaled up the above steps to collect enough conditioned media, and concentrated the fractions of interest. The fractions that showed activity of osteoclast induction were determined by mass spectrometry. We found that the conditioned media contained a large amount of IKK-Epsilon, a subunit of PMA-inducible IKK (I-KappaB Kinase) complex. We further observed that recombinant IKK-Epsilon could induce osteoclast activity in vitro, but unexpectedly it had no effect on the activation of NF-kappa-B by TNF or IL-1 in these cells. Together with the findings that several identified factors in the conditioned media such as MCP-1 and IL-8 that induced osteoclast activity, in vitro validation of the identified factor IKK-Epsilon was confirmed by using neutralizing antibody on the functional assays. We have not yet identified unknown factors in the current study, however it is clear that unknown factors in the conditioned media may also play key roles in the tumor-induced osteoclast activation since blocking MCP-1, IL-8, and IKK-Epsilon did not completely block the tumor-induced osteoclast activity. We conclude that IKK-Epsilon, a novel factor identified by proteomics, may contribute to prostate cancer cell-induced osteoclast activity in vitro. Supported by NSF key project 81130046; NSF projects 81171993 and 81272415; Guangxi projects 201201ZD004 and 2012GXNSFCB53004.
Citation Format: Xin Yang, Zhen Xiao, Jianhua Wang, Yi Lu, Yang Xu, Xin Huang, Atsushi Mizokami, Evan T. Keller, Jian Zhang. IKK-Epsilon, a novel factor identified by proteomics, contributes to prostate cancer cell-induced osteoclast activity in vitro. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3945. doi:10.1158/1538-7445.AM2013-3945
Abstract 3947: AMG 161, a fully human monoclonal antibody to human RANKL, inhibits tumor-induced osteoclastogenesis and reduces skeletal tumor burden in mice that express chimeric (murine / human) RANKL.
Authors: Canon Jude R. , Bryant Rebecca , Roudier Martine , Dougall William C. 
Published: August 2014

Abstract
Tumor cells can induce RANKL expression in the bone stroma, causing activation of osteoclasts which consequently mediate bone breakdown and subsequent tumor proliferation. RANKL is an essential mediator of osteoclast function and survival. RANKL inhibition by OPG-Fc can prevent tumor-induced osteolysis, decrease skeletal tumor burden, and increase survival in preclinical models. Denosumab is an anti-huRANKL antibody approved for the prevention of skeletal-related events due to bone metastases from solid tumors. Selective anti-huRANKL antibodies do not bind murine RANKL, therefore efficacy cannot be tested in typical mouse models. We developed a breast cancer bone metastasis model in mice in which exon 5 from murine RANKL was replaced with its human ortholog (“mu/huRANKL”). We tested the effect of AMG 161, an antibody which binds huRANKL and chimeric mu/huRANKL, on tumor burden and associated osteoclasts. After intra-cardiac injection of MCF-7Luc breast carcinoma cells, hind limb metastases formed and tumor burden was tracked by bioluminescence imaging (BLI). AMG 161 (0.3 or 3.0 mg/kg, 2x/week), OPG-Fc (3.0 mg/kg, 2x/week) or vehicle were administered beginning 10 days post tumor injection to treat established bone metastases until study termination at day 31. AMG 161 resulted in a dose-dependent decrease in skeletal tumor burden (3.0 mg/kg: 84% decrease vs. control p=0.0052) similar to that observed with OPG-Fc (85% decrease vs. control, p=0.0038). Histological analysis at the end of the study showed reductions in skeletal tumor burden consistent with the BLI. AMG 161 treatment resulted in a significant decrease in tumor-associated osteoclasts (TRAP staining) and inhibition of osteolytic lesions (X-ray). The inhibition of tumor burden by the anti-RANKL antibody was indirect via osteoclast inhibition since MCF-7Luc cells do not express RANK, and RANKL inhibition does not affect subcutaneous growth of MCF-7Luc cells. These data support the efficacy of anti-RANKL antibody treatment to inhibit tumor-induced osteoclastogenesis and to block the growth of bone metastases.
Citation Format: Jude R. Canon, Rebecca Bryant, Martine Roudier, William C. Dougall. AMG 161, a fully human monoclonal antibody to human RANKL, inhibits tumor-induced osteoclastogenesis and reduces skeletal tumor burden in mice that express chimeric (murine / human) RANKL. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3947. doi:10.1158/1538-7445.AM2013-3947
Abstract 395: Farnesyl diphosphate farnesyltransferase induces metastasis via upregulating secreted phosphoprotein 1 in non-small cell lung cancer.
Authors: Yang Yi-Fang , Jan Yi-Hua , Hsiao Michael 
Published: August 2014

Abstract
Identifying cancer progression associated genes that predicting patient outcome might provide opportunities for developing better therapeutic strategies for lung cancer patients. In the present study, we investigated whether farnesyl diphosphate farnesyltransferase (FDFT1), an enzyme of mevalonate pathway, is a potential biomarker of lung cancer metastasis. We further investigated its prognostic value and functional role in lung cancer invasion and metastasis. Our results by immunohistochemistry (IHC) analysis showed the expression of FDFT1 was significantly higher in tumors compared to normal lung tissues. Overexpression of FDFT1 was significantly associated with tumor size (P &lt; 0.001), advanced tumor stage (P &lt;0.001), lymph node metastasis (P = 0.02), distal metastasis (P = 0.043), and poor prognosis (P &lt;0.001). Loss of FDFT1 expression significantly suppressed invasion and migration potential of lung cancer cell lines, whereas FDFT1 overexpression promoted invasion and migration in vitro and in vivo. Microarray analysis further identified secreted phosphoprotein 1 (SPP1) as an important mediator for FDFT1-induced invasion and migration. Furthermore, patients with high FDFT1 and high SPP1 expression showed dismal outcomes as compared to patients with low FDFT1 and low SPP1 expression with good prognosis. In conclusion, we identified the FDFT1 in this study as a new lung cancer progression biomarker that is associated poor prognosis and its overexpression resulted in enhanced tumor invasion and metastasis through upregulation of SPP1. Our findings may implicate the possibility of targeting FDFT1 as a novel therapeutic strategy to inhibit lung cancer metastasis.
Citation Format: Yi-Fang Yang, Yi-Hua Jan, Michael Hsiao. Farnesyl diphosphate farnesyltransferase induces metastasis via upregulating secreted phosphoprotein 1 in non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 395. doi:10.1158/1538-7445.AM2013-395
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 3951: Imaging exosome transfer from colon cancer cells to stroma at liver metastatic sites in nude mouse.
Authors: Suetsugu Atsushi , Homma Kimi , Saji Shigetoyo , Moriwaki Hisataka , Ochiya Takahiro , Hoffman Robert M. 
Published: August 2014

Abstract
Exosomes play an important role in cell-to-cell communication to promote tumor metastasis. In order to image the fate of cancer-cell-derived exosomes in liver metastasis of colon cancer, we used green fluorescent protein (GFP)-tagged CD63, which is a general marker of exosomes. GFP-exosome producing RFP human colon cancer HCT cells (HCT-RFP/GFP- Exo cells) were injected in the spleen of nude mice. By day 28, HCT-RFP/GFP-Exo cells were visualized in the liver with the Olympus OV100 imaging system. HCT-RFP/GFP- Exo cells secrete GFP-exosomes in the liver metastasis site as observed with the Olympus FV1000 confocal microscope. Colon cancer cells secreted exosomes into the tumor microenvironment. Tumor-derived exosomes were incorporated into tumor-associated cells as well as circulating in the blood of mice with colon cancer metastases. These results suggest that tumor-derived exosomes may contribute to forming a niche to promote tumor growth and metastasis. Our results demonstrate the usefulness of GFP imaging to investigate the role of exosomes in colon cancer liver metastasis.
Citation Format: Atsushi Suetsugu, Kimi Homma, Shigetoyo Saji, Hisataka Moriwaki, Takahiro Ochiya, Robert M. Hoffman. Imaging exosome transfer from colon cancer cells to stroma at liver metastatic sites in nude mouse. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3951. doi:10.1158/1538-7445.AM2013-3951
Abstract 3955: The tumor suppressor C/EBPdelta promotes hypoxia-induced EMT and expression of stem cell markers through inhibition of FBXW7: Implications for mammary tumor metastasis.
Authors: Kuppusamy Balamurugan , Sterneck Esta 
Published: August 2014

Abstract
The transcription factor CCAAT/enhancer binding protein delta (C/EBPδ) exhibits tumor-suppressor like-qualities such as downregulation of cyclin D1, and promotion of growth arrest and apoptosis. However, using a mouse model of mammary tumorigenesis (MMTV-Neu), we had found that C/EBPδ has dual functions. C/EBPδ suppresses primary tumor incidence while also augmenting metastatic progression. The pro-metastatic function of C/EBPδ can be correlated with a role in hypoxia adaptation and expression of pro-inflammatory genes and macrophage activation. C/EBPδ exerts both of these functions through inhibition of FBXW7, a component of SCF E3 ubiquitin ligase complex, which targets substrates such as c-myc and Notch for degradation (Balamurugan et al, 2010; Balamurugan et al., under revision). Hypoxia is believed to promote tumor progression in part by inducing epithelial-mesenchymal transition (EMT), which contributes to the generation of stem-like cancer cells (CSCs). In the present study, we found that hypoxia-induced EMT and expression of CSCs markers were compromised in Cebpd null primary tumor cells and in human breast tumor cells when C/EBPδ expression was silenced. On the other hand, silencing of the C/EBPδ-repressed gene FBXW7 was sufficient to induce a mesenchymal-like phenotype. Loss of FBXW7 has been shown to promote acquisition of stemness. In line with this notion, we found that overexpression of FBXW7 in the breast tumor cell line MDA-MB-468 reduced expression of aldehyde dehydrogenase 1 (Aldh1), C/EBPδ and the active form of NOTCH (NICD). Together, these data suggest that C/EBPδ augments - whereas its target FBXW7 prevents - EMT and breast cancer stem cell development, which may be an additional mechanism by which C/EBPδ promotes metastatic progression. Our current investigations are aimed at understanding how the different functions of C/EBPδ are integrated depending on cellular environment and context that results in its tumor promoting function despite its tumor suppressor role.
Citation Format: Balamurugan Kuppusamy, Esta Sterneck. The tumor suppressor C/EBPdelta promotes hypoxia-induced EMT and expression of stem cell markers through inhibition of FBXW7: Implications for mammary tumor metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3955. doi:10.1158/1538-7445.AM2013-3955
Abstract 3959: MMP13 contributes to metastatic tumor growth in the steatotic liver microenvironment.
Authors: Mendonsa Alisha M. , VanSaun Michael , Gorden David L. 
Published: August 2014

Abstract
The expanding obesity epidemic has led to an escalation in the incidence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis, which are associated with an increase in incidence of primary and metastatic liver cancer. As NAFLD progresses, it is characterized by marked inflammation in the liver described as non-alcoholic steatohepatitis (NASH). The mechanisms by which NASH increases risk of liver cancer are not fully known but complete understanding of these mediators is necessary for effective therapeutic and preventive strategies. Importantly, metastasis represents the final stage in cancer progression and is the most significant cause of cancer related mortality. Using our mouse model of diet induced steatosis, coupled with a model of experimental liver metastasis, we have previously shown a significant increase in the number of metastatic foci in the steatotic liver compared to the normal livers. Microarray analysis revealed that MMP13, a member of the Matrix Metalloproteinase (MMP) family recognized to be involved in liver disease and cancer progression, is significantly upregulated in the steatotic liver compared to normal livers. Additionally, MMP13 is expressed in several cancer cell types. Emerging data suggests that MMP13 may play a key role in priming the microenvironment for the establishment of liver metastases, by modulation of cytokine profiles and recruitment of inflammatory cells. . We hypothesize that MMP13 is a key modulator of the steatotic microenvironment, and that increased MMP13 levels favor primary tumor growth as well as the establishment of metastases. To determine the role of stromal MMP13 on metastasis to the liver, we are using the experimental splenic injection model of liver metastasis with syngeneic MC38 colon cancer cells in mice genetically deficient in MMP13. Additionally, since the tumor cells themselves express MMP13, wildtype mice are injected with either shRNA control or MMP13 knockdown MC38 colon cancer cells to determine the role of tumor cell derived MMP13. Preliminary data shows localization of MMP13 expression to the hepatic stellate cells as well as CD11b positive myeloid cells from livers with NASH. Further, invitro analysis of migration and invasion ability of parental and MMP13 shRNA knockdown MC38 cells show that MMP13 promotes the invasive and migratory properties of the metastatic cancer cells themselves. MMP13 may thus be a potential mediator of inflammation in the tumor microenvironment as well as of the metastatic capacity of cancer cells to the liver.
Citation Format: Alisha M. Mendonsa, Michael VanSaun, David L. Gorden. MMP13 contributes to metastatic tumor growth in the steatotic liver microenvironment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3959. doi:10.1158/1538-7445.AM2013-3959
Abstract 396: Osteopontin-c splicing isoform contributes to ovarian cancer progression.
Authors: Tilli Tatiana M. , Mello Kivvi D. , Franco Vanessa , Robbs Bruno , Wanderley João Luiz , Silva Fabricio R A , Viola João P B , Weber Georg , Castronovo Vincent , Bellahcène Akeila , Gimba Etel R P 
Published: August 2014

Abstract
Introduction: Ovarian carcinoma (OC) is one of the most aggressive gynecological diseases and generally diagnosed at advanced stages. Osteopontin (OPN) is overexpressed in OC and is involved in tumorigenesis and metastasis. Alternative splicing of OPN generates 3 isoforms, OPNa, OPNb, and OPNc. Objective: This study aims to characterize the expression profile and functional role of OPN splicing isoforms (OPN-SI) in OC. Methodology: The expression patterns of OPN-SI and a series of genes involved in cancer pathways were analyzed by real-time PCR. In vitro and in vivo functional assays were performed using the ovarian cancer cell line OvCar-3, stably overexpressing the three OPN-SI. Results: OPNc, but not OPNa and OPNb, was specifically expressed on OC samples. We then demonstrated that OPNc isoform has stimulatory effects on OvCar-3 cell proliferation, migration, invasion and anchorage independent cells growth, besides activating tumor formation in nude mice. We also found that these features are mainly mediated by PI3K/Akt signaling pathway. Moreover, OvCar-3 OPNc-overexpressing cells are able to modulate the expression of 34 genes involved in key cancer pathways. Notably, tumors formed by OPNc-overexpressing cells present high expression levels of typical angiogenic markers, such as VEGF-A, VEGFR-2 and CD34. Based on this observation, we also investigated the molecular mechanisms by which OPNc stimulates angiogenic processes. Our data showed that OPNc overexpression activates VEGF-A expression and secretion, also through the PI3K/Akt pathway. This splicing isoform is also able to activate the expression of c-Fos, c-Jun and phospho-c-Jun. OPNc role on activating the phosphorylation of c-Jun is mediated by integrin receptor, in an RGD-dependent manner. In addition, OPNc-conditioned medium is able to induce HUVEC endothelial cell proliferation, migration and adhesion. Conclusion: Thus, the specific targeting of OPNc and its regulated signaling network could be a putative novel strategy to inhibit key steps involved in OC progression and may represent a putative strategy for developing new therapeutic approaches using OPNc as interesting target for OC treatment strategies.
Citation Format: Tatiana M. Tilli, Kivvi D. Mello, Vanessa Franco, Bruno Robbs, João Luiz Wanderley, Fabricio R A Silva, João P B Viola, Georg Weber, Vincent Castronovo, Akeila Bellahcène, Etel R P Gimba. Osteopontin-c splicing isoform contributes to ovarian cancer progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 396. doi:10.1158/1538-7445.AM2013-396
Abstract 4002: Differential regulation of the ERGF-MAPK pathway by deoxycholic acid (DCA) and Ursodeoxycholic acid (UDCA) in colon cancer.
Authors: Centuori Sara M. 
Published: August 2014

Abstract
Obesity and a western diet are risk factors for the development of colorectal cancer and correlate with high levels of bile acids. Specifically, the secondary bile acid deoxycholic acid (DCA) has been shown to act as a tumor promoter in animal studies. Interestingly, the tertiary bile acid Ursodeoxycholic acid (UDCA) was found to have chemopreventive activity in a clinical trial conducted in 1285 individuals with recently resected colorectal adenomas. The mechanism(s) of DCA's tumor promoting effects and UDCA's chemopreventive activities are unclear, however DCA and UDCA have been previously shown to regulate EGFR-MAPK signaling in a differential manner. Because this mitogenic pathway has been shown to play a role in colon cancer cell proliferation and survival, we hypothesize that DCA's tumor promoting effect may stem from its regulation of this mitogenic pathway. We therefore examined the role of DCA in the regulation of the EGFR MAPK pathway in human colon cancer cells as compared to UDCA. Our findings show that DCA can induce ERK1/2 phosphorylation in an EGFR-independent manner in HT-29 colon adenocarcinoma cells, and that this is at least partially dependent on PI3K activation. We also determined that UDCA pretreatment was able to suppress both EGF and DCA-induced EGFR-MAP signaling. By elucidating the mechanism by which DCA and UDCA differentially regulate colon cancer proliferation and survival, we may be able to skew the signaling in colon cancer cells to favor chemoprevention as opposed to tumorgenesis.
Citation Format: Sara M. Centuori. Differential regulation of the ERGF-MAPK pathway by deoxycholic acid (DCA) and Ursodeoxycholic acid (UDCA) in colon cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4002. doi:10.1158/1538-7445.AM2013-4002
Abstract 4008: Effects of a combination of Atorvastatin and Biochanin A on signal transduction and invasiveness of pancreatic cancer cell lines.
Authors: Tadinada Satya Murthy , Lai James C.K. , Bhushan Alok 
Published: August 2014

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer related deaths in the United States. Low survival rate associated with this cancer can be attributed to late detection, invasion and metastasis besides chemo-resistance and relapse following surgical resection. Our previous studies demonstrated combination treatment employing Biochanin A with Atorvastatin, an anti-hyperlipidemic drug, was more effective in inhibiting pancreatic cell growth compared to monotherapy. Biochanin A is a naturally occurring isoflavone exhibiting anti-cancer properties in different cancer models. Flow Cytometry studies have demonstrated early apoptosis in AsPC-1 pancreatic cancer cells following a 24-hour exposure to the combination treatment while PANC-1 pancreatic cancer cells did not show significant apoptosis after the treatment for 24 hours and 48 hours. Ongoing studies support the possibility that combination treatment induces cell cycle arrest in PANC-1 cells. We also studied the effects of the combination on invasiveness and on expression of proteins involved in signal transduction pathways in these cell lines. Gelatin zymography invasion assay showed a higher Matrix Metalloproteinase-2 (MMP-2) activity in cultures exposed to Atorvastatin while Biochanin A decreased the effects of atorvastatin induced MMP-2 activity in combination treatment. Combination treatment exerted differential effects on MAPK, PI3K/AKT, mTOR and JAK/STAT pathways in these cell lines. These results may have implications in design of new chemotherapeutic strategies for treating pancreatic cancer.
Acknowledgement
This study was supported by grants from INBRE Program, NIH Grant No. P20 RR016454, Mountain States Tumor and Medical Research Institute and University Research Committee, ISU grant.
Citation Format: Satya Murthy Tadinada, James C.K. Lai, Alok Bhushan. Effects of a combination of Atorvastatin and Biochanin A on signal transduction and invasiveness of pancreatic cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4008. doi:10.1158/1538-7445.AM2013-4008