bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1632: Paracrine Hedgehog as a mediator of stromal cell steroidogenesis that contributes to progression of prostate cancer to castration resistant disease.
Authors: Lubik Amy A. , Adomat Hans , Guns Emma S. , Buttyan Ralph 
Published: August 2014

Abstract
Androgen deprivation therapy (ADT) is frontline treatment for metastatic prostate cancer (PCa). ADT initially blocks disease progression but eventually allows the outgrowth of castration resistant disease (CRPC) that is refractory to the diminished systemic androgen levels in ADT-treated patients. CRPC is associated with acquired intratumoral steroidogenesis (IS), a process that increases the androgen levels in the local microenvironment of prostate tumors and enables further tumor growth and progression. IS has mainly been attributed to a steroidogenic process linked to CRPC cells and here we present evidence that benign tumor-associated prostate stromal cells (PrSCs) can also contribute to IS through a paracrine Hedgehog (HH) tumor microenvironment associated with increased production and release ofHedgehog ligands (Hhs) from prostate cancer cells in response to ADT (Chen, et al., Mol Cancer, 9: 89, 2010). Primary human PrSCs upregulate expression of a large repertoire of steroidogenic genes upon treatment with HH chemical agonists, SAG (100 nM) or Hg 1.5 (1 nM). These effects are Gli2-dependent (Levina, et al., Prostate, 72: 817, 2012) and they can be inhibited by the HH antagonist, KAAD-cyclopamine. Previously we showed that this upregulation significantly increased output of testosterone (T) in PrSCs fed DHEA precursor. More comprehensive analysis (via LC/MS/MS) of androgen outputs from PrSCs fed 22 OH-cholesterol showed that Hg1.5 significantly increased the outputs of Progesterone, DHEA, androsterone, T and dihydrotestosterone (DHT) showing that HH signaling activity effects outputs throughout the androgen biosynthetic pathway. Upregulation of the RDH5 gene by Hg1.5 suggests that the effects on production of DHT from PrSCs might be generated by increased synthesis through both classical and back-door pathways. On a weight-to-weight basis, Hg1.5-stimulated PrSCs produce higher T and DHT outputs than LNCaP cells or an androgen growth-independent variant, LNCaP-AI. Finally, we found that treatment of Sonic Hh-producing LNCaP cells with simvastatin reduced the ability of conditioned medium from these cells to induce steroidogenic gene expression from PrSCs. In summary, this work provides evidence for a stromal cell contribution to IS in CRPC mediated by a paracrine-active HH signaling tumor microenvironment induced by ADT-treatment and identifies potential treatment strategies to interfere with this process.
Citation Format: Amy A. Lubik, Hans Adomat, Emma S. Guns, Ralph Buttyan. Paracrine Hedgehog as a mediator of stromal cell steroidogenesis that contributes to progression of prostate cancer to castration resistant disease. [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 1632. doi:10.1158/1538-7445.AM2013-1632
Abstract 1636: Altering the function of cancer-associated fibroblasts via activation of Notch signaling to inhibit tumor growth.
Authors: Shao Hongwei , Moller Mecker G. , Velazquez Omaida C. , Liu Zhao-Jun 
Published: August 2014

Abstract
Objectives. Cancer-associated fibroblasts (CAF) play critical roles in determining tumor growth, invasion, metastasis, drug response and tumor angiogenesis. We have previously demonstrated that activation of the Notch1 pathway confers normal human dermal fibroblasts a suppressive phenotype to melanoma growth. Here, we further investigated whether manipulation of Notch signaling in melanoma-associated fibroblasts (MAF) alter their regulatory phenotype by which affects melanoma growth.
Methods. MAF were isolated from human metastatic melanoma and characterized. Notch pathway activity in MAF versus normal human dermal fibroblasts was examined using Notch pathway RT2-PCRArray and immunoblotting. Enforced activation of Notch pathway was achieved by transducing MAF with lentiviral vector encoding active form of Notch1 (NIC). The effect of active Notch1-engineered MAF on melanoma growth was tested by in vitro co-culture and in vivo co-xenografting animal model.
Results. Isolated MAF are α-smooth muscle actin (α-SMA) and fibroblast activation protein (FAP) positive. MAF exhibited a relatively lower Notch activity compared to normal human dermal fibroblasts. Enforced activation of Notch1 pathway suppressed cellular activities of MAF. Active Notch1-engineered MAF significantly inhibited melanoma cell growth in vitro and retarded xenografted human melanoma cell growth on mouse skin.
Conclusions. Notch pathway activity is lower in MAF. Constitutive activation of Notch pathway confers MAF to a suppressive phenotype in regulating melanoma growth. Our study demonstrated that Notch signaling functions as a critical molecular switch in determining the regulatory role of tumor stromal fibroblasts and provided a novel approach to target tumor microenvironment through modulating stromal fibroblasts by manipulation of Notch signaling.
Citation Format: Hongwei Shao, Mecker G. Moller, Omaida C. Velazquez, Zhao-Jun Liu. Altering the function of cancer-associated fibroblasts via activation of Notch signaling to inhibit tumor growth. [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 1636. doi:10.1158/1538-7445.AM2013-1636
Abstract 1641: Color-coded imaging of interaction between RFP-expressing blood vessels and αv integrin-GFP expressing osteosarcoma cells.
Authors: Uehara Fuminori , Tome Yasunori , Maehara Hiroki , Kanaya Fuminori , Hoffman Robert M. 
Published: August 2014

Abstract
We report here imaging the interaction between αv integrin tagged to GFP in human osteosarcoma cells and blood vessels growing on Gelfoam@ implanted subcutaneously in mice. 143B osteosarcoma cells expressing αv integrin-GFP were generated by transfection of an αv integrin-GFP vector. Gelfoam@ (5×5 mm) was treated with basic fibroblast growth factor (bFGF) and transplanted subcutaneously in RFP transgenic nude mice. Skin-flap imaging windows were made at days 7, 14, 21, 28 after transplantation of Gelfoam@. Angiogenesis was observed in the Gelfoam@ using fluorescence imaging via the skin flap windows. Frozen sections were made at day 28 after Gelfoam@ transplantation. RFP-expressing blood vessels were imaged growing into the Gelfoam@. Immunohistochemical (IHC) staining showed that CD31 and RFP fluorescence co-localized in the newly formed RFP-expressing blood vessels in the Gelfoam@. To observe the interaction of tumor cells and RFP blood vessels, 143B cells (5×105),expressing αv integrin-GFP, were injected into the Gelfoam@ 7 days after transplantation. Seven days after cancer-cell injection, the cancer cells were observed in the Gelfoam@ by confocal microscopy via skin-flap windows. 143B cells expressing αv integrin-GFP proliferated into the Gelfoam@ as observed by skin-flap-window imaging. Strong expression of αv integrin-GFP cells was observed near RFP vessels in the Gelfoam@ in the RFP mice 28 days after cancer cell injection. The results show that Gelfoam@ is a useful tool to observe angiogensis in vivo and the interactions of αv integrin-GFP with blood vessels which will allow further understanding of its role in angiogenesis and tumor progression.
Citation Format: Fuminori Uehara, Yasunori Tome, Hiroki Maehara, Fuminori Kanaya, Robert M. Hoffman. Color-coded imaging of interaction between RFP-expressing blood vessels and αv integrin-GFP expressing osteosarcoma cells. [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 1641. doi:10.1158/1538-7445.AM2013-1641
Abstract 1655: Synthetic lethal interaction of CDK inhibition and autophagy inhibition in human solid cancer cell lines.
Authors: Okada Yoshinari , Kato Shunsuke , Sakamoto Yasuhiro , Oishi Takayuki , Ishioka Chikashi 
Published: August 2014

Abstract
Autophagy is a stress-induced cellular reaction in cancer cells. Recent studies showed that cyclin dependent kinase inhibitor proteins, such as p27 or p16, also induced cytoprotective autophagy in cancer cells. However, it is not clear whether small molecule CDK inhibitors also induce autophagy in solid cancer cells. In this study, we revealed that CDK4 inhibitor and a broad-range CDK inhibitor (flavopiridol) induced autophagy in some solid cancer cell lines, but not all. The autophagy induced by CDK4 inhibitors was observed in BT474, MDA-MB435S, SKBr3 (derived from breast cancer), A431 (derived from lung cancer) and SW480 (derived from colorectal cancer), While it was not observed in MCF7, MDA-MB231 (derived from breast cancer), NCI-N87 (derived from gastric cancer) and KMST-6 (derived from fibroblast). In the cell lines which were induced autophagy by CDK inhibitors, the combination of a CDK4 inhibitor and an autophagy inhibition, by either chloroquine or knockdown of ATG5 or BECN1, induced apoptosis. However it did not induce apoptosis in the cell lines which were not induced autophagy by CDK4 inhibitor. From these results, the autophagy induced by CDK4 inhibitor mimic the stress-induced autophagy in some solid cancer cell lines. The combination of a small-molecule CDK inhibitor and an autophagy inhibitor is a synthetic lethal interaction and could become a new antitumor strategy in solid tumors which are induced cytoprotective autophagy by CDK inhibitors.
Citation Format: Yoshinari Okada, Shunsuke Kato, Yasuhiro Sakamoto, Takayuki Oishi, Chikashi Ishioka. Synthetic lethal interaction of CDK inhibition and autophagy inhibition in human solid 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 1655. doi:10.1158/1538-7445.AM2013-1655
Abstract 166: Elevated levels of serum fatty acid synthase (FAS) in patients with gastric carcinoma.
Authors: Ito Tomoaki , Sato Koichi , Maekawa Hiroshi , Tada Takashi , Sakurada Mutsumi , Orita Hajime , Shimada Kazunori , Wada Ryo , Abe Masaaki , Hino Okio , Kajiyama Yoshiaki 
Published: August 2014

Abstract
Aim: Gastric cancer is the second leading cause of cancer mortality in the world. In East Asia especially, in countries such as China, Japan, and Korea, more than one million new cases are diagnosed each year. The need remains for biomarkers to detect early stage gastric cancer. Fatty acid synthase (FAS) is highly expressed in many human cancers, but the potential utility of measuring FAS for detection of gastric cancer has not been previously investigated. The aim of this study was to provide a preliminary assessment of serum FAS as a marker of gastric carcinoma.
Materials and methods: Our study included 47 patients with gastric cancer (37 men and 10 women, aged 33-89 years) and 150 healthy subjects (113 men and 37 women, aged 33-83 years). Serum
FAS levels were measured by ELISA and compared across the two groups of patients. Blood samples were collected from each cancer patient before treatment, and additionally, post-therapeutic samples were obtained from eleven of the patients with gastric cancer. Measurement data were analyzed using the
Mann-Whitney test. P&lt;0.05 was considered statistically significant. The receiver operator characteristic (ROC) curve was used to determine sensitivity and specificity values.
Results: We found significantly higher levels of serum FAS in gastric cancer patients (95% confidence interval,
95% CI=30.37-52.46) than in healthy controls (95% CI=1.331-2.131), with elevated levels even in patients with early stage tumors. Using 5.5 ng/ml as the cut-off value, the sum of sensitivity (95.74%) and specificity (91.33%) was the highest, and the positive predictive values and negative predictive values were 77.59% and 98.56%, respectively (Area Under the Curve=0.9845,
Standard Error=0.0084, 95% CI=0.9681-1.001). The pre-therapeutic FAS levels were greater than 5.5 ng/ml, and in 8 of 11 patients, the post- therapeutic serum FAS levels decreased to less than 5.5 ng/ml.
Conclusion: Our results suggest that measuring serum FAS levels has strong potential to provide a biomarker for detection of gastric cancer with high sensitivity and high specificity.
Citation Format: Tomoaki Ito, Koichi Sato, Hiroshi Maekawa, Takashi Tada, Mutsumi Sakurada, Hajime Orita, Kazunori Shimada, Ryo Wada, Masaaki Abe, Okio Hino, Yoshiaki Kajiyama. Elevated levels of serum fatty acid synthase (FAS) in patients with gastric carcinoma. [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 166. doi:10.1158/1538-7445.AM2013-166
Abstract 1660: Therapeutic targeting cross talk between ROS/autophagy and apoptosis for pancreatic cancer by a herbal extract.
Authors: Jingjing Gong , Kumar Addanki P. 
Published: August 2014

Abstract
5-year survival for pancreatic cancer (PanCA) continuous to be lower than any other solid tumor due to late stage diagnosis combined with lack of effective therapeutic options. Therefore developing novel strategies possibly based on molecular targets is critical for successful management of PanCA. Recent studies from our laboratory show potential anti-pancreatic cancer activity for NexrutineR (Nx), a bark extract isolated from traditional Chinese medicine Phellodendron amurense. These studies also show that Nx reduces pancreatic fibrosis in preclinical animal model through targeting two critical oncogenic transcription factors including NF-κB and Stat3. Nonetheless, the precise molecular mechanism associated with the observed biological activity is unclear. We investigated whether Nx inhibits pancreatic cell proliferation and pancreatic fibrosis via reactive oxygen species (ROS)-mediated activation of autophagy. Our data show that Nx can induce autophagy at earlier time points (4h) but inhibit autophagy at later time points (24h) in human pancreatic cancer cell lines Capan-2 and BxPC-3 as evidenced by autophagosome formation, alteration in the expression and levels of various autophagy related genes. Interestingly Nx also induced apoptosis at 24h time point but not at 4h suggesting that autophagy precedes apoptosis. Further under these experimental conditions, treatment of pancreatic cancer cells with Nx enhanced intracellular production of ROS implicating a cross talk between Nx-induced ROS, autophagy and apoptosis. Overall, our findings divulge an important role for ROS/autophagy/apoptosis in Nx-mediated anti-pancreatic cancer effects. Supported by NCCAM (APK).
Citation Format: Gong Jingjing, Addanki P. Kumar. Therapeutic targeting cross talk between ROS/autophagy and apoptosis for pancreatic cancer by a herbal extract. [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 1660. doi:10.1158/1538-7445.AM2013-1660
Abstract 1678: Metastatic breast cancer cell phenotype is regulated by autophagy.
Authors: Li Yi , Lewis Monica J. , Liu Jianzhong , Cody James J. , Hurst Douglas R. 
Published: August 2014

Abstract
Autophagy is a catabolic process that is tightly regulated during normal cell growth, development, and homeostasis. Although it may be death inducing, it is also an important survival mechanism for cells in stressful environments, including hypoxia, nutrient deprivation, chemical or physical pressure, or detachment from colonies. Considering the stress associated with the process of metastasis, we hypothesized that autophagy may play a role in the ability of breast cancer cells to survive and metastasize. To test this, we first compared cell proliferation after autophagic induction between metastatic breast cancer cell lines (MDA-MB-231 and -435), a non-metastatic breast cancer cell line (MDA-MB-436), and a ‘normal’ breast epithelial cell line (MCF10A). Both metastatic cell lines continued to proliferate following induction of autophagy; however, the non-metastatic and normal cell lines were growth-inhibited. Autophagy was also more rapidly induced by rapamycin in the metastatic cell lines as demonstrated by an increase in LC3II expression. To test the different survival capabilities between metastatic and normal cells, we selected cells through five rounds of starvation with Earle's balanced salt solution (EBSS) and compared their ability to induce autophagy. Although both the normal and metastatic cells maintained their ability to proliferate under normal conditions, the MDA-MB-231 cells that survived starvation (231-EB5) proliferated more rapidly than the parental population following induction of autophagy. In contrast, both MCF10A and MCF10A-EB5 cells were growth-inhibited. The 231-EB5 cells induced autophagy more rapidly than the parental population as demonstrated by increased expression of LC3II (analyzed by immunoblot) and increased LC3 puncta (analyzed by immunofluorescence). Migration of parental 231 cells was inhibited by rapamycin; however, there was no change in the ability of 231-EB5 cells to migrate after treatment with rapamycin. Growth in three dimensions also was significantly altered. MCF10A-EB5 cells were more extended compared to the spherical growth of the parental MCF10A cells. Protrusions emitted from the 231-EB5 cells were more rounded compared to the extended spikes of the parental 231 cells. Altogether, these results demonstrate that select populations derived from metastatic breast cancer cells have different abilities to survive, proliferate, and migrate following induction of autophagy, suggesting that autophagy may be a key mechanism for tumor progression and metastasis.
Citation Format: Yi Li, Monica J. Lewis, Jianzhong Liu, James J. Cody, Douglas R. Hurst. Metastatic breast cancer cell phenotype is regulated by autophagy. [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 1678. doi:10.1158/1538-7445.AM2013-1678
Abstract 1693: Intracellular hypoxia is dominantly determined by mitochondrial respiratory activity.
Authors: Prior Sara , Kim Ara , Tobita Seiji , Takeuchi Toshiyuki , Higuchi Masahiro 
Published: August 2014

Abstract
Intracellular oxygen concentration ([O2]i.c.) regulates key biological functions such as HIF-1α activation, glucose transport, potassium pumps, intracellular calcium concentration, P450 family enzymes and HMGR expression. However, the mechanisms regulating [O2]i.c remain to be defined. Here, we provide direct evidence of the mitochondrion's role in [O2]i.c. regulation. We used bis(2-(2′-benzothienyl)-pyridianto-N,C3’irridium(acetylacetonate) (BTP) to measure [O2]i.c. in living cells via microscopy.5 Well-differentiated cancers, LNCaP and MCF-7 showed intracellular hypoxia without exogenous hypoxia. In contrast, poorly-differentiated cancers exhibited intracellular normoxia, and exogenous hypoxia could induce hypoxia. The specific complex I inhibitor, rotenone, and the reduction of mitochondrial DNA (mtDNA) content increased in [O2]i.c,, indicating that [O2]i.c. is regulated by mitochondrial respiratory activity. [O2]i.c. is additionally regulated by glucose, but the dose-dependent relationship is parabolic. The no glucose condition induced normoxia, and the low concentration glucose condition (0.045mg/ml) induced strong hypoxia. [O2]i.c. was found to be additionally determined by the presence of FCS in the growth medium, and this effect was mimicked by an androgen analog, R1881, suggesting that androgen, glucose concentration and respiratory function are important regulators of [O2]i.c..
Citation Format: Sara Prior, Ara Kim, Seiji Tobita, Toshiyuki Takeuchi, Masahiro Higuchi. Intracellular hypoxia is dominantly determined by mitochondrial respiratory activity. [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 1693. doi:10.1158/1538-7445.AM2013-1693
Abstract 1694: Warburg effect increases intracellular oxygen concentration and determines membrane localization of Ras and other prenylated proteins.
Authors: Kim Ara , Higuchi Masahiro 
Published: August 2014

Abstract
The Warburg effect is a famous cancer-related phenomenon which describes a metabolic shift from oxidative phosphorylation to glycolysis and fermentation in a cancer cell. Many studies suggest that the Warburg effect is in response to changes (mutation, deletion, and depletion) within the mitochondrial genome. We previously showed that poorly differentiated prostate cancer cells have reduced mitochondrial genome content and are more influenced by the Warburg effect than well differentiated prostate cancer cells. The reduction of mitochondrial genome content induced overexpression and activation of proto-oncogenic Ras, which is responsible for the activation of AKT and ERK, leading to advanced phenotypes of prostate cancer. Farnesylation (membrane localization) of Ras was required for Ras activation and was induced by the overexpression of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), the rate-limiting enzyme of the mevalonate pathway, through inhibition of hypoxia-dependent degradation of HMGR. We hypothesize that increased intracellular oxygen concentration due to the Warburg effect responding to the reduction of mitochondrial genome content determines membrane localization of Ras via induction of farnesylation mediated by overexpression of HMGR. In the poorly differentiated prostate cancer cells such as LNCaP (intracellularly normoxic cells), Ras localized in both the plasma membrane and Golgi, whereas in well differentiated prostate cancer cells such as PC-3 (intracellularly hypoxic cells), Ras is prominent in the cytosol. Exogenous hypoxic conditions eliminated Ras localization in the membrane in PC-3, possibly through inhibition of the farnesylation of Ras. In contrast, exogenous hyperoxic condition increased membrane localization of Ras in LNCaP. Next, we demonstrated the localization of other prenylated proteins, such as Rab5a and prelamin A. In the PC-3, Rab5a and prelamin A were localized in the early endosomes and the nuclear membrane, respectively. In LNCaP, they were present throughout the cytosol and inside of the nucleus. Similar to Ras, the localization of Rab5a and prelamin A was reversible with changes in exogenous oxygen concentration. Our results revealed a coherent mechanism that directly links changes in intracellular oxygen concentration, determined by the mitochondrial genome, with the progression of prostate cancer.
Citation Format: Ara Kim, Masahiro Higuchi. Warburg effect increases intracellular oxygen concentration and determines membrane localization of Ras and other prenylated proteins. [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 1694. doi:10.1158/1538-7445.AM2013-1694