bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5159: Investigation of local vitamin D metabolism in breast cancer using an ex vivo tissue explant system
Authors: Suetani Rachel J. , Ho Kristen , Jindal Shalini , Neilsen Paul M. , Gill Grantley , Morris Howard A. , Callen David F. 
Published: August 2012

Abstract
Vitamin D is an essential molecule obtained either by UV irradiation of the skin, or ingested through diet or supplementation. Sequential hydroxylations of vitamin D are required to generate the inactive precursor 25-hydroxyvitamin D (25D), and the active metabolite 1,25-dihydroxyvitamin D (1,25D) which activates the vitamin D receptor to alter transcription of target genes. In addition to its role in calcium homeostasis, vitamin D has been shown to have anti-proliferative, apoptotic and immunomodulating effects. Furthermore, many epidemiological studies have shown a link between a low vitamin D status and an increased risk of breast cancer. However, the mechanistic basis of this link remains unknown. We have utilized a breast explant system whereby fresh tumour and matched non-malignant breast tissues are obtained from women undergoing mastectomies. These tissues are placed on gelatin sponges in tissue culture media supplemented with either 25D or 1,25D. Tissues are then collected and analysed for alterations in gene expression and biological response. This system allows for the analysis of dynamic changes in viable tissue in response to exogenously applied compounds, and can easily be used to examine other compounds of interest. Explanted non-malignant and tumour tissue both displayed an increase in expression of the vitamin D metabolizing enzyme CYP24A1 when directly treated with 1,25D. In response to the precursor molecule 25D, non-malignant breast tissue showed a similar pattern of enzyme induction, indicating an intact and competent vitamin D metabolic pathway in these tissues. Metabolism in breast tumour tissue however was somewhat disrupted, with some cases showing little potential in converting 25D to the active metabolite 1,25D. Proliferation markers have also been examined in the non-malignant and tumour breast samples. Interestingly, some tumour specimens did not show any change in proliferation despite favourable changes in gene expression, indicating further dysregulation of vitamin D metabolism in these samples. These data will have implications for any future clinical studies of vitamin D supplementation to complement current chemopreventative therapies.
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 5159. doi:1538-7445.AM2012-5159
Abstract 5164: Using metabolomic flux to uncover new targets for the modulation of breast cancer metastasis
Authors: Van Wassenhove Lauren D. , Wynn Michelle L. , Ashrafzadeh Sepideh , Merajver Sofia D. 
Published: August 2012

Abstract
Inflammatory breast cancer (IBC) is the most deadly breast cancer because of its ability to rapidly metastasize, often before the primary lesion is detected. To better understand what drives this highly aggressive form of cancer, we studied central carbon metabolism in IBC. The Warburg effect, which is characterized by high rates of glucose uptake and glycolysis even under aerobic conditions, occurs in most cancer cells and plays an important role in the tumorigenic capacity of breast cancer. Specifically, we examined metabolic changes that occur when breast cancer cells switch from a proliferating phenotype to a highly motile phenotype. In primary tumor formation rapid proliferation is crucial, while in metastasis motility to new sites is critical. We hypothesize that alterations in the regulation of metabolic pathways leads to the direction of energy from proliferation to motility, and that this change is important in the progression of breast cancer towards metastases. Understanding if a coincident metabolic shift occurs when malignant cells switch from a proliferative to a more aggressive motile form may help identify new therapeutics for highly aggressive breast cancers. For our studies, we are using “normal-like” MCF-10A breast cells, which proliferate quickly and move slower than cancer cells, and two highly metastatic breast cancer cell lines (MDA-MB-231 and the IBC-derived line SUM 149), which have the ability to move quickly and proliferate relatively slowly. Using these cell lines as a model, we have examined metabolic changes as cancer progresses. We are conducting targeted metabolomic studies to determine relative concentrations of metabolites in the glycolysis, tricarboxylic acid (TCA) cycle, and mevalonate pathway. In addition, we are using 13C-labeled pyruvate and glucose to measure the transient and steady state flux through these metabolic pathways. Our preliminary results indicate interesting and unexpected changes in both the transient and steady state metabolic fluxes across the different cell lines. In addition, the metabolic flux through the TCA cycle is very active in the metastatic cancer cells despite an increase in glycolysis. In agreement with flux studies of other cancer cell lines, our results suggest that the cancer cells are likely using intermediates from the TCA cycle to generate nucleotides and fatty acids needed for replication. The results from this work, once validated, can be used to identify new therapeutic metabolic targets to modulate breast cancer metastasis.
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 5164. doi:1538-7445.AM2012-5164
Abstract 5166: Tumor adiponectin signaling underlies the association between obesity and lethal outcome in prostate cancer
Authors: Martin Neil E. , Gerke Travis , Loda Massimo , Stampfer Meir , Finn Stephen , Rider Jennifer , Mucci Lorelei A. 
Published: August 2012

Abstract
Background: Obesity is associated with poor outcomes in men with prostate cancer. The biologic drivers of this relationship are poorly understood. Adiponectin is produced by adipose tissue and has been shown to regulate multiple pathways including inflammation, angiogenisis and insulin sensitivity. Low circulating levels are associated both with obesity and with lethal prostate cancer. Here we investigate whether adiponectin signaling has a differential effect on cancer outcomes in the tumors of obese compared to healthy weight men. Methods: The study cohort consisted of men diagnosed with prostate cancer from the Physicians’ Health Study (1982-2004) and the Health Professionals Follow Up Study (1986-2004) for whom archival tumor specimens were available. Follow-up data for development of metastases and cancer-specific mortality (defined as lethal prostate cancer) was available through 2010. Gene set analyses was undertaken for 116 men using gene expression profiling data from cDNA-mediated annealing, selection, extension, and ligation (DASL) assay of 6000 genes. Genes differentially expressed between lethal (n=30 lethal events) and indolent disease among the obese and healthy weight men were explored. Immunohistochemistry for adiponectin receptor 2 (ADIPOR2) protein expression in tumors and adjacent normal was performed on tissue microarrays representing tumor tissue from 1017 patients (n=98 lethal events). Anthropometric measures were obtained from validated questionnaires. Results: Gene set analysis identified distinct gene sets that were enriched in the comparison of lethal to indolent among the obese and healthy weight men. In the obese men, five gene sets were enriched in the lethal cases with a false discovery rate &lt;0.1. The second most enriched set associated with lethality was the KEGG adiponectin signaling pathway. We found that protein expression of ADIPOR2 in prostate tumors, but not normal prostate, was higher among obese compared to healthy weight men. Moreover, high expression of ADIPOR2 protein expression was associated with a 3-fold greater risk of lethal outcomes. Conclusion: Tumor adiponectin signaling appears to be key pathway underlying lethal outcomes in obese men with prostate cancer. This work supports the hypothesis that there are unique drivers of poor outcome among obese men with prostate 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 5166. doi:1538-7445.AM2012-5166
Abstract 5171: Restoration of fibronectin matrix assembly impedes invasion and reduces tumor-stromal cell affinity in prostate cancer
Authors: Jia Dongxuan , Entersz Ildiko , Butler Christine , Vaca Connan , Foty Ramsey A. 
Published: August 2012

Abstract
Cell-cell and cell-ECM interactions are important regulators of cohesion, a property previously demonstrated to mediate malignant invasion. Intermixing of the epithelial and stromal compartments is often associated with increased invasive capacity and poor prognosis. The studies reported here propose a novel role for α5β1 integrin, the principle mediator of fibronectin matrix assembly (FNMA), as an invasion suppressor in prostate cancer cells. Employing a combination of biophysical and cell biological techniques we explore the relationship between cohesion, invasion, FNMA and tumor-stromal interactions, using a well-characterized prostate cancer model. We show that cohesion is inversely proportional to invasive capacity. We also show that the most invasive cells are deficient in FNMA and express reduced levels of α5β1 integrin. We generated cells over-expressing either wild-type α5 integrin or a non-functional α5 in which the cytoplasmic domain was replaced with that of α2. We show that only wild-type α5 was able to increase cohesion and reduce the invasiveness of aggressive cells. In order to further explore the influence of FNMA on tumor-stromal cell interaction we employed a liquid miscibility model in which interactions between tumor and stroma are rooted in the same thermodynamic principles that govern the mixing of simple fluids. In this model, whether tumor and stromal cells segregate or intermix depends on the ratio of the strength of self-cohesion to cross-adhesion; a high ratio corresponds with segregation, whereas a lower ratio denotes intermixing. We hypothesized that segregation between tumor and stroma can be promoted by increasing the strength of tumor cell cohesion. To test this hypothesis, we first showed that aggressive prostate cancer cells intermix with prostate fibroblasts. We then treated the cancer cells with MEK inhibitors (MEKi) and showed that treatment restored FNMA, leading to increased cell-cell cohesion. When mixed with prostate stromal cells, MEKi-treated cells segregated, suggesting that increasing cohesion between tumor cells is sufficient to reduce their affinity for stromal cells. These data suggest that by increasing tumor cell cohesion through a fibronectin matrix mediated adhesion mechanism, it may be possible to effectively reduce affinity of tumor cells for stroma, thus inhibiting invasion.
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 5171. doi:1538-7445.AM2012-5171
Abstract 5172: The role of vimentin in FAK-mediated cell adhesion and metastasis
Authors: Havel Lauren S. , Marcus Adam 
Published: August 2012

Abstract
Lung cancer is the leading cause of cancer death in the United States. Specifcally, non-small cell lung cancer (NSCLC) is responsible for about 80% of lung cancer deaths and has a 5-year survival rate of only 15-25%. This poor survival statistic results from diagnosis at advanced stages of the disease when metastasis of the primary tumor has already occurred; therefore, identifying the molecular mechanisms guiding metastasis is crucial for advances in treatment. The intermediate filament vimentin is overexpressed in metastatic cancers and its expression correlates with increased invasive capacity and reduced patient survival. A population of vimentin filaments localizes to focal adhesions, which attach to the extracellular matrix and are required for cell motility. Focal adhesions are composed of a complex of proteins, including focal adhesion kinase (FAK), which is overexpressed in NSCLC. Since evidence suggests that both FAK and vimentin co-localize at focal adhesions, we hypothesize that vimentin acts through FAK to regulate cell adhesion and thereby cell migration. Our results show that vimentin depletion leads to decreased cell adhesion and migration, with decreased FAK activation and expression. We show that vimentin filaments directly enter total FAK and pFAK- Y397 sites at the cellular leading edge of motile lung cancer cells. Using immunoprecipitation, we show vimentin interacts with several members of the focal adhesion complex, suggesting that vimentin can regulate focal adhesion activity. To address the mechanism by which this may occur, we hypothesize that the phosphorylation state of vimentin, which is important for cell migration, is crucial for proper functioning at focal adhesions. This is the focus of our future work with the goal of identifying potential new therapeutic targets to block metastasis and improve lung cancer patients’ prognosis.
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 5172. doi:1538-7445.AM2012-5172
Abstract 5175: Discovering a novel role of claudin-7 as a basolateral protein maintaining cell-matrix interactions in human lung cancer cells and in mouse intestines
Authors: Lu Zhe , Ding Lei , Lu Qun , Chen Yan-Hua 
Published: August 2012

Abstract
The ability to invade host tissues and metastasize is the major cause of cancer-related death. During tumor invasion, metastasizing cells disrupt normal cell-matrix adhesion and acquire an invasive phenotype. Claudins are adhesion proteins localized at tight junctions (TJs). Claudin-7 is a unique TJ membrane protein in that it has a stronger basolateral membrane distribution than that of apical TJs in epithelial cells. To study the basolateral function of claudin-7, claudin-7 gene silencing experiments were carried out in a lung cancer cell line using the lentivirus shRNA approach. We found that claudin-7 knockdown (KD) cells showed disrupted cell-matrix interactions. Consequently, when claudin-7 KD cells were plated on the uncoated glass surface, they were unable to attach to the glass and died the day after plating. In contrast, control cells adhered well and grew normally. Using immunofluorescent microscopy and biochemistry methods, we found that claudin-7 co-localized and co-immunoprecipitated with integrin β1 at the basolateral compartment. Knockdown of claudin-7 by lentivirus claudin-7 shRNA downregulated integrin β1 at both mRNA and protein levels. This cell-matrix defect can be rescued by transfecting claudin-7 or integrin β1 back to the claudin-7 KD cells. Suppression of claudin-7 also upregulated matrix metalloproteinase-3 (MMP-3) at both mRNA and protein levels and downregulated several collagens, such as type V α1, type XV α1, and type XVI α1, at the mRNA level. We also generated claudin-7-deficient (Cldn7−/−) mice using targeted-gene deletion method. Cldn7−/− mice displayed severe intestinal defects including attenuated villi, mucosal ulcerations and epithelial cell sloughing. Using immunofluorescent microscopy and biochemistry methods, we found that claudin-7 co-localized and co-immunoprecipitated with integrin α2 in Cldn7+/+ mouse intestines where claudin-7 was highly expressed. Deletion of claudin-7 reduced integrin α2 expression and altered its localization. Electron microscopy revealed significant intercellular gaps below TJs and the cell-matrix loosening in Cldn7−/− intestines. Thus, our current study highlights a novel non-TJ function of claudin-7 in maintaining epithelial cell-matrix interactions by interacting with integrins.
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 5175. doi:1538-7445.AM2012-5175
Abstract 5176: Imaging αv integrin-GFP during tumor blood vessel interaction in the chick CAM
Authors: Tome Yasunori , Sugimoto Naotoshi , Yano Shuya , Momiyama Masashi , Maehara Hiroki , Tsuchiya Hiroyuki , Tomita Katsuro , Kanaya Fuminori , Hoffman Robert M. 
Published: August 2012

Abstract
In this study, we describe imaging of αv integrin-GFP in cancer cells interacting with blood vessels. Osteosarcoma cells (143B) (5×106) expressing αv integrin-GFP were injected in the 10-day old chick chorioallontoic membrane (CAM). In vivo imaging with the Olympus OV-100, visualized tumor-induced angiogenesis one week after transplantation. Osteosarcoma cells expressing αv integrin-GFP were aligned along the tumor-induced blood vessels. High resolution ex vivo imaging with the Olympus FV1000 confocal microscope showed narrow capillary vessels surrounded by osteosarcoma cells which strongly expressing αv integrin-GFP compared to those cells far from vessels. This result imply that expressed of osteosarcoma αv integrin is related to the interaction of the osteosarcoma cells and blood vessels. The ability to image αv integrin during interaction of cancer cells and blood vessels will enable the further understanding of its role in this process.
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 5176. doi:1538-7445.AM2012-5176
Abstract 5177: Molecular targeting of αvβ3 integrin by echistatin inhibits tumor progression and metastasis in osteosarcoma
Authors: Tome Yasunori , Kimura Hiroaki , Maehara Hiroki , Sugimoto Naotoshi , Tomita Katsuro , Tsuchiya Hiroyuki , Kanaya Fuminori , Bouvet Michael , Hoffman Robert M. 
Published: August 2012

Abstract
Expression of αvβ3 integrin is associated with tumor progression and metastasis in several types of cancer, including metastatic osteosarcoma. We tested echistatin, an antagonist of αvβ3 integrin, as a molecular targeting drug, in an imageable orthotopic mouse model of human metastatic osteosarcoma. αvβ3 integrin expression was measured in a series of human osteosarcoma cell lines (143B parental and LM1-LM4) with increasing metastatic potential, using RT-PCR and immunoprecipitation. The cell lines expressed GFP in the nucleus and RFP in the cytoplasm and therefore could be imaged down to the subcellular level in vitro and in vivo. αvβ3 integrin expression correlated with the metastatic potential of the cells, with the LM4 cells showing the highest expression and highest metastatic capability, 6-fold and 18-fold, respectively, compared to parental 143B cells. In vitro cell proliferation of LM4 was inhibited by echistatin (p&lt;0.01). In vitro migration, invasion, and adhesion of LM4 were also inhibited by echistatin (p&lt;0.01). Tumor-induced angiogenesis by LM4 in the chick CAM model was also inhibited by echistatin (p&lt;0.05). Mice treated with an echistatin-doxorubicin conjugate had significantly smaller primary tumors and longer survival compared to control untreated tumor-bearing mice (p&lt;0.05 and p&lt;0.01, respectively). Treatment with echistatin resulted in decreased experimental pulmonary metastases, imaged at the cellular level, in a nude mouse model compared to the untreated control (p&lt;0.01). The results of this study indicate that αvβ3 integrin plays an essential role in osteosarcoma metastasis and that echistatin has potential to target αvβ3 integrin and inhibit tumor progression and metastasis.
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 5177. doi:1538-7445.AM2012-5177
Abstract 5178: Evaluation of lumican expression profiles in prostate cancer
Authors: Yoshimura Kazuhiro , De Velasco Marco A. , Hatanaka Yuji , Yamamoto Yutaka , Kodama Mitsumasa , Tanaka Motoyoshi , Shimizu Nobutaka , Nozawa Masahiro , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: August 2012

Abstract
The transcription factor, Stat3, has been implicated in the growth and progression of several cancer types including lung skin, liver, ovarian, kidney, colon cancer and prostate. Stat3 has also been shown to induce the metastatic behavior of prostate cancer cells in vitro and in vivo. Activation of Stat3 occurs by the binding of various cytokines to its receptors leading to the activation of the JAK/Stat3 signaling pathway. Of these cytokines, interleukin-6 (IL-6) has been implicated in regulating growth of various malignant tumors and activated IL-6 has been shown to be elevated in the sera from patients with metastatic prostate cancer. In the present study we examined the IL6-induced Stat3 transcriptional activation in the development and progression of prostate cancer and its possible role as a target for the treatment of prostate cancer using the prostate-specific conditional targeting PTEN knockout mouse model. Homozygous PTEN-mutants develop prostate cancer in a stage-specific manner and have the ability to grow and develop castration-resistant prostate cancer after total androgen ablation by castration. ELISA assays revealed increased expression of soluble IL-6 receptor (IL-6R) in tissue lysates from prostate tumors in non-castrated and castrated mice (77.0 ± 6.17 vs. 23.75 ± 5.17 ng/g of tissue, p&lt;0.001, respectively) at 32 weeks of age. Immunohistochemical analysis revealed correlated expression of with Stat3 transcriptional activation, proliferation and androgen receptor in tumors from castrated mice. To determine the role of IL-6R induced transcriptional activation of Stat3, non-castrated and castrated tumor bearing mice were treated with an anti-mouse IL-6R antibody (MR-16). Mice treated with MR-16 showed downregulation of phosphorylated Stat3, however, treatment failed to inhibit tumor development and cellular proliferation. However, it was discovered that therapeutic doses of MR16 treatment resulted in increased phosphorylation of Erk1/2. Our data suggests that inhibition of IL-6R-induced Stat3 activation alone is insufficient to suppress tumor growth; however, further studies need to be conducted to evaluate the efficacy of horizontal combination strategies targeting Stat3 and MAP kinase signaling cascades
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 5178. doi:1538-7445.AM2012-5178