bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4364: S1P generated by SphK1 is important not only for primary tumor growth but also for tumor-induced hemangiogenesis and lymphangiogenesis
Authors: Nagahashi Masayuki , Ramachandran Subramaniam , Kim Eugene Y. , Allegood Jeremy C. , Rashid Omar M. , Yamada Akimitsu , Zhao Renping , Milstien Sheldon , Zhou Huiping , Spiegel Sarah , Takabe Kazuaki 
Published: August 2012

Abstract
INTRODUCTION: Sphingosine-1-phosphate (S1P), a pleiotropic bioactive lipid mediator, regulates many cellular processes important for breast cancer progression. The aim of this study is to investigate a role for S1P produced by sphingosine kinase 1 (SphK1) in breast cancer progression and tumor-induced hemangiogenesis and lymphangiogenesis. METHODS: An isozyme-specific inhibitor of SphK1 (SK1-I) was used. Tumor burden were quantified using an in vivo imaging system (IVIS 2000). S1P and SK1-I levels were measured by LC-ESI-MS/MS. Hemangiogenesis and lymphangiogenesis are determined by morphological analysis of microvessel density as well as by flow cytometric analysis of endothelial cells. RESULTS: A significant dose dependent effect of SK1-I on inhibition of 4T1-luc2 murine breast cancer cell growth was observed. We confirmed that SK1-I decreased the enzymatic activity of SphK1 and that downregulation of SphK1 with specific siRNA also suppressed growth of these cells. We found that S1P levels increased in the tumor and in the circulation after orthotopic implantation of 4T1-luc2 cells. Similarly, serum S1P levels were significantly elevated in stage IIIA breast cancer patients who have lymph node metastases, compared to age/ethnicity-matched healthy volunteers. SK1-I blocked serum S1P increases in in vivo model and reduced lymph node and lung metastases and overall tumor burden in vivo as well. Importantly, SK1-I also decreased hem- and lymphangiogenesis not only in the primary tumor, but also in lymph nodes, the host tumor microenvironment. Whereas supernatants from 4T1-luc2 cells significantly stimulated tube formation of HUVECs and HLECs, shRNA knockdown of SphK1 markedly reduced them, indicating that S1P produced by SphK1 in 4T1-luc2 breast cancer cells is an important contributor to hem- and lymphangiogenesis. CONCLUSIONS: S1P generated by SphK1 is important for tumor progression, tumor-induced hemangiogenesis and lymphangiogenesis, and lymph node metastais. Therefore targeting SphK1 and its product S1P would be a multi-pronged attack against breast cancer. This work was supported by Sumitomo Life Social Welfare Services Foundation grant to MN, NIH (K12HD055881) and Susan G. Komen for the Cure (KG090510) to KT, and NCI (R01CA61774) to SS.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4364. doi:1538-7445.AM2012-4364
Abstract 4392: Vaccination targeting IGF-IR sensitizes tumors to tamoxifen therapy in an anti-estrogen resistant mouse model
Authors: Cecil Denise L. , Park Kyong Hwa , Gad Ekram , Rastetter Lauren , Disis Mary L. 
Published: August 2012

Abstract
Tamoxifen is a standard treatment for estrogen receptor (ER)-positive breast cancer patients. However, acquired or de novo resistance to therapy is a major clinical problem. In hormone-resistant tumors, there is increased activation of insulin-like growth factor-1 receptor (IGF-IR) and subsequent downstream signaling molecules, such as AKT. We have determined that IGF-IR is immunogenic in breast cancer and is a potential target for active immunization. It has been demonstrated that natural immunogenic human epitopes can be predicted by high binding affinity across multiple class II alleles, thus, we used a combined scoring system from five algorithms for predicting class II binding to determine Th epitopes of IGF-IR. Of the 20 potentially immunogenic peptides identified, five peptides (p1166-1181, p1212-1227, p1301-1316, 1307-1322 and p1311-1326) in the C-terminal domain were determined to elicit a predominantly inflammatory Th1 response compared to an immunosuppressive Th2 response in human PBMC. Overexpression of AKT induces tamoxifen resistance, while inhibition restores tamoxifen sensitivity. The tumor suppressor, PTEN, actively inhibits AKT. Data we have generated has demonstrated that vaccination restored PTEN activity in tumor cells. We questioned if modulation of PTEN could render tumors in the anti-estrogen-resistant MMTV-neu mouse model sensitive to tamoxifen therapy. Vaccination demonstrated a robust Th1 response (p&lt;0.001) and concomitant inhibition of tumor growth by 85% compared to adjuvant only control animals (p&lt;0.001). Treatment with tamoxifen in vaccinated tumor-bearing mice resulted in a further 38% reduction in growth (p=0.02). Thus, active immunization targeting IGF-IR may induce both immunologic and biologic effects resulting in the sensitization of the tumor to tamoxifen therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4392. doi:1538-7445.AM2012-4392
Abstract 4397: A TLR4-interacting peptide (SPA4) reduces the lipopolysaccharide-stimulated NF-kappaB signaling, cytokines and migration of colon cancer cells
Authors: Madhusoodhanan Rakhesh , Ramani Vijay , Moriasi Cate , Anant Shrikant , Awasthi Shanjana 
Published: August 2012

Abstract
Persistent inflammation in patients with colitis can lead to cancer. However, molecular mechanisms responsible for inflammation-induced cancer are not understood. Activation of TLR4-NF-kappaB signaling is associated with inflammation. Thus, we hypothesized that inhibition of TLR4-NF-kappaB signaling will help reduce inflammatory response and inflammation-induced cancer progression. In this work, we studied the effects of a TLR4-interacting surfactant protein-A-derived (SPA4) peptide on lipopolysaccharide (LPS)-induced TLR4-NF-kappaB signaling and cancer progression in colon adenocarcinoma SW480 cells. The SW480 cells were challenged with Escherichia coli-derived LPS. Cells were then treated with varying amounts of SPA4 peptide. Any changes in the expression of TLR4, intracellular-signaling molecules (IKBalpha, p65, phosphorylated IKBalpha, phosphorylated p65, RelB, Cox-2) and cytokines (IL-1beta, IL-6), and activity of NF-kappaB were studied by immunocytochemistry, immunoblotting and NF-kappaB reporter assay, respectively. Simultaneously, cell cycle progression, viability and migratory pattern of SW480 cells were followed. We found that the binding of SPA4 peptide to TLR4 inhibits the LPS-induced expression of TLR4, phosphorylated p65, Cox-2, IL-1beta and IL-6, activity of NF-kappaB and migration of SW480 cells. Although there was no significant change in cell cycle progression, the SPA4 peptide significantly inhibited the viability of SW480 cells. In conclusion, our preliminary results suggest that the inhibition of TLR4-NF-kappaB signaling by SPA4 peptide may be useful in prevention and treatment of inflammation and inflammation-induced cancer in patients with colitis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4397. doi:1538-7445.AM2012-4397
Abstract 44: Enhancement endometrial cancer cells malignant transformation by mutual interaction with mesenchymal stem cells through TGF-beta and SDF-1 signaling pathways
Authors: Ding Dah-Ching , Chu Tang-Yuan 
Published: August 2012

Abstract
Designated to cyclic shedding, endometrial glandular stroma is rich for mesenchymal stem cells and may play crucial roles in cancer invasion. This study aimed to explore the interaction between endometrial cancer cells and endometrial mesenchymal stem cells (HEMSC). HEMSC were derived from human endometrium and were co-cultured with RL95-2 endometrial cancer cells. Transformation phenotypes including proliferation, migration, anchorage independent growth, colony formation and invasion were characterized. Cancer associated transforming growth factor (TGF)-beta1 and mesenchymal cell associated stromal cell-derived factor (SDF) and their down-stream signaling pathways were investigated. HEMSC had a similar surface marker profile as bone marrow mesenchymal stem cells, i.e. CD44(+), CD90(+) and CD34(-) and CD45(-) and readily be inducible to osteogenic and adipogenic differentiations. Upon coculture with HEMSC, RL95-2 cell secreted TGF-beta 1 which subsequently induced SDF1 secretion from HEMSC. The mutual interaction of these factors is associated with enhancement of cancer cell migration through the CXCR4 receptor and downstream transducer and activator of Stat3, with resulting over-expression of alpha-SMA and cytoskeleton re-organization. The study observed unprecedented interactions between cancer cells and mesenchymal stem cells with resulting enhancement of malignant transformation through mutual activation of cytokines and downstream signals. Mesenchymal stem cells either in adjacent to the lesion or home to the lesion can therefore be important activators of carcinogenesis and good therapeutic targets.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 44. doi:1538-7445.AM2012-44
Abstract 4403: Combined antagonism of the IL-4R and IKKα inhibits melanoma tumor growth in immunocompetent mice
Authors: Hawkins Oriana E. , Horton Linda , Fordyce Krystle , Ayers Gregory , Richmond Ann 
Published: August 2012

Abstract
With over 8500 deaths each year in the USA, malignant melanoma is the deadliest of all skin cancers. Constitutive activation of the nuclear factor kappa B (NF-κB) is common in melanoma, promoting tumor growth, survival and metastasis. In light of its role in tumorigenesis, targeting of the NF-κB pathway has been considered a possible therapeutic option for the treatment of melanoma. However, NF- αB activation is critical for the development, survival, migration and function of immune cells. We hypothesized that systemic inhibition of the activation of NF-κB might have a deleterious effect on the tumor immune response. Melanoma bearing C57BL/6 mice received 50 mg/kg of BMS-345541, a selective inhibitor of the inhibitor of αB kinase (IKKα), twice daily. Tumors, spleens and bone marrow were harvested at different time points and analyzed by flow cytometry for leukocyte composition and cytokine production. Intracellular cytokine staining revealed an early induction of Interleukin-4 (IL-4) within the myeloid and B cell components of the tumor, as a result of BMS-345541 treatment. The production of IL-4 by these cells suggests an early switch to a tumor promoting T helper 2 (Th2) and M2 driven immune response, which may counteract the anti-tumor effect of IKKα inhibition by generating a pro-tumorigenic microenvironment. These results, in part, explain the modest delay in tumor growth demonstrated. IL-4 receptor (IL-4R) expression on human melanoma cells has been previously documented; however the effects of IL-4 on these cells have generated contradictory reports. IL-4R signaling has been shown to either inhibit growth of tumor cells in vitro or to promote survival of tumor cells. In C57Bl/6 mice bearing a murine melanoma, BMS345541 (75 mg/kg bid) was given in combination with 100 µg of IL-4R blocking antibody on day 4 and day 12 of treatment. This combination significantly inhibited tumor growth compared to BMS345541 treatment alone. These data suggest an important role for IL-4 in promoting melanoma growth in vivo. Dual targeting of IL-4R and NF-κB signaling pathways neutralizes the tumor promoting immune component. Currently, IL-4R antagonists are in clinical trials for the treatment of asthma, which makes the translational prospects of this study extraordinarily viable. We are grateful for support from the NCI (CA116021-07, 5T32CA119925-03) and the Department of Veterans Affairs for these studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4403. doi:1538-7445.AM2012-4403
Abstract 4408: Targeting cancer stem cells as potential new therapy for pancreatic cancer
Authors: Cleary John P. , Raman Divya , Punzalan Rubio R. , Sharma Michael Vr , Sharma Cristian Vr , Sharma Sherven P. , Jani Jitesh , Sharma Bhuvnesh , Narayan Satya , Sharma Jay P. 
Published: August 2012

Abstract
Pancreatic cancer is the fourth leading cause of cancer mortality in the US, despite significant improvements in diagnostic imaging and operative modalities. The 5-year survival rate remains less than 6% because of microscopic or gross metastatic disease at time of diagnosis. Although the treatment of pancreatic cancer remains a huge challenge, it is entering a new era with the development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with pancreatic cancer, the identification of robust prognostic and predictive markers and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. Over the past decade, increasing evidence suggested that stem cells play a crucial role not only in the generation of complex multicellular organisms, but also in the development and progression of malignant diseases. Most tumors have been shown to contain a subset of distinct cancer cells that is responsible for tumor initiation and propagation. These cells are termed cancer stem cells or tumor-initiating cells and they are highly resistant to chemotherapeutic agents. Here, we examined the efficacy of combined treatments of CEP1101 and gemcitabine in human pancreatic cancer cells, and pancreatic CSCs (CD133, CD44, CXCR4, SSEA3/4, Oct4, ALDH, Telomerase & Nestin) from the same donors. CEP1101 inhibited the growth of CSCs, while gemcitabine suppressed the viability of non-CSCs. In vivo studies showed that CEP1101 combined with gemcitabine eliminate the engraftment of human pancreatic cancer and CSCs, more effectively than the individual agents. These data demonstrate that administration of CEP1101, which targets CSCs, may constitute a potential therapeutic strategy for improving the efficacy of gemcitabine to eradicate pancreatic cancer. This study shows potential molecular therapeutic targets to eradicate the tumor - and metastasis-initiating cells and their progenies for the evaluation of new effective combination therapies against locally advanced and metastatic pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4408. doi:1538-7445.AM2012-4408
Abstract 4411: Farletuzumab (mAb003), a neutralizing monoclonal antibody to folate receptor alpha, enhances paclitaxel efficacy in an ovarian cancer model
Authors: Maddage Christopher , Rybinski Katherine , Zhou Yuhong , Grasso Luigi , Nicolaides Nicholas C. , Lin JianMin 
Published: August 2012

Abstract
Farletuzumab, MORAb-003 is a humanized monoclonal antibody (mAb) that recognizes the folate receptor alpha (FRα) which is over-expressed in various malignancies including ovarian and lung cancers. This presents a unique approach to an unmet medical need in ovarian cancer therapy by targeting this receptor. Farletuzumab is currently in clinical trials in combination with paclitaxel for metastatic ovarian and lung cancer. In this study we evaluated potential benefit that farletuzumab offers when added to a traditional chemotherapy in a pre-clinical murine model. In a human ovarian cancer model, female athymic nude mice were implanted intraperitoneally with IGROV cells which express FRα. One week post tumor establishment, these mice were treated with Paclitaxel, MORAb-003, or the combination of the two, respectively. A group of the tumor-bearing mice received PBS as control. Tumors found in peritoneal cavity were harvested and weighed, then recorded as tumor burden. In animals treated with MORAb-003 at 25mg/kg twice weekly for 4 weeks, tumor growth was reduced near 30%. With treatment of paclitaxel at 0.5 mg/kg weekly for 4 weeks, the tumor burden in these mice was reduced ∼65%. An enhancement of therapeutic effect on tumor burden was clearly observed when MORAb-003 was added to the chemo treatment and resulted in a growth inhibition of greater than 80%. Our results demonstrate the ability of MORAb003, as a mono-agent, in inhibiting the growth of ovarian cancer in a murine model. When added to the chemotherapeutic regimen, it enhances the therapeutic efficacy of traditional chemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4411. doi:1538-7445.AM2012-4411
Abstract 4413: Rosiglitazone prevents graft-versus-host disease (GVHD)
Authors: Song Eun-Kee , Yhim Ho-Young , Yim Jun-Mo , Yim Joo-Yun , Song Min-Young , Lee Na-Ri , Kwak Jae-Yong , Yim Chang-Yeol , Sohn Myung-Hee 
Published: August 2012

Abstract
GVHD is a host tissue injury mediated by donor-host immune reactions, and a major complication in allogeneic hematopoietic stem cell transplantation. Peroxisome proliferator-activated receptor-α (PPARδ) plays an important role in regulating immune responses. We investigated the role of rosiglitazone, a synthetic PPARδ agonist, in a murine parent-to-F1 GVHD model. During mixed lymphocyte reactions (MLR), rosiglitazone inhibited the proliferative response and cytotoxicity of responder cells, and induced more apoptosis in CD4+, CD8+, and B220+ cells than in NK1.1+, Mac-1+, CD4/CD25+ and CD3/NK1.1+ cells. The in vivo administration of rosiglitazone demonstrated histologic improvements of GVHD in the liver, skin, spleen and intestine. Rosiglitazone treatment inhibited GVHD-induced increases in serum levels of TNFα, IFNα, IL-6, and IL-12, and the decreases in TGFβ and IL-10. Splenic leukocyte immunophenotyping demonstrated that while the proportions of both donor and host CD4/CD25+ and CD3/NK1.1+ cells were increased by the treatment with rosiglitazone, both donor and host CD8+ cells were decreased. Rosiglitazone treatment inhibited GVHD-induced decreases in the expression of phosphate and tensin homologue deleted on chromosome ten (PTEN), and the increases in the expression of p-Akt and nuclear NF-κB in the spleen. These results indicate that rosiglitazone and activation of PPARδ may be useful to protect the host from GVHD.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4413. doi:1538-7445.AM2012-4413
Abstract 4476: Molecular typing of breast cancer cases among a Hispanic population and its association with body mass index
Authors: Diaz-Santana Mary V. , Ramos Gilberto , Nazario Cruz M. 
Published: August 2012

Abstract
Background: Breast cancer is a heterogeneous disease which can be divided into distinct molecular subtypes based on patterns of gene expressions and tumor marker staining. The prevalence of breast cancer molecular subtypes (BCMS), as well as specific risk factors by subtypes varies by ethnicity, highlighting the relevance of research focused in specific populations. Although the BCMS have been studied, there is scarce evidence of the association between breast cancer risk factors and molecular subtypes and the prevalence of each subtype among Hispanics populations. In Puerto Rico, breast cancer is the most frequently diagnosed malignancy and the leading cause of cancer death among females. However, little is known about the breast cancer subtypes distribution and its etiologic profile among Puerto Rican women. Objectives: We aimed to determine the prevalence of BCMS and assess whether obesity differs according to these subtypes among a female population of breast cancer cases in Puerto Rico. Methods: A case-case analysis was conducted using all cases of invasive breast carcinoma consulted to the UPR-School of Medicine Immunoperoxidase Laboratory, from 2008-2010, for which hormonal receptors and HER2 oncoprotein analysis were performed. To determine molecular subtypes we characterized 172 tumor specimens based on immunohistochemical (IHC) surrogates for ER, PR and HER-2+ status. The molecular subtypes were defined as: luminal (ER+ and/or PR+), non-luminal (ER-, PR-). Body Mass Index (BMI) was analyzed using the following categories: normal weight (BMI &lt;25.0 kg/m2), overweight (BMI 25.0-29.9 kg/m2), and obese (BMI α30.0 kg/m2). Logistic regression was used to estimate the associations between BMI and breast cancer molecular subtypes. Results: The luminal subtype was the most prevalent in our sample (75.0%) compared with the non-luminal (25.0%) subtype. Association with Body Mass Index, evaluated using unadjusted logistic regression model, differed by tumor subtypes. Using non-luminal subtype as the reference group we observed that overweight women were 1.87 (95% CI: 0.73, 4.77) times more likely to be diagnosed with the luminal disease compared to women with normal weight. However, obese women were 4% (OR: 0.96, 95% CI: 0.40, 2.30) less likely to be diagnosed with the luminal subtype compared to women with normal weight. Conclusion: Even though this is a small pilot study, it is very suggestive of an important association between body mass index and luminal breast cancer subtype. Future studies that further assess the association between BMI and BCMS will add to the biologic understanding of this disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4476. doi:1538-7445.AM2012-4476