bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 346: Functional role for axonal guidance molecule Sema7A in breast cancer metastasis: Epithelial to mesenchymal transition and tumor metastasis
Authors: Garcia-Areas Ramon , Libreros Stephania , Onwuha-Ekpete Lillian , Schilling Kathy , Iragavarapu-Charyulu Vijaya 
Published: August 2012

Abstract
Reactivation of embryogenesis related processes such as neurogenesis is a powerful mechanism used by tumor cells to enhance their survival and propagation. Recent studies have shown that many types of solid tumors express neurogenic molecules independent of the tumor's geography. Semaphorins are a compelling example of these pleiotropic neuronal molecules. Semaphorins were originally characterized for their role in axonal guidance and several of them have been found to play a role in cancer and other inflammatory diseases. Of the Semaphorins, Semaphorin7A (Sema7A) has not yet been studied in the context of cancer. It has however been associated with fibrosis, inflammation and immune modulation. Most semaphorins are repellent cues and inhibit cellular migration, but Sema7A is the only vertebrate semaphorin that serves as an axon chemoattractant. Sema7A also promotes dendricity, adhesion and motility during neuronal development, monocyte differentiation and osteoclast development. All these cellular properties have been attributed to Sema7A's ability to activate p38 mitogen-activated protein kinase pathway (MAP-kinase) through α1β1 integrins. We have recently discovered that Sema7A is over-expressed in the tumor tissue of breast cancer patients compared to the adjacent normal tissue. Within the tumor tissue, the mesenchymal cancer stem cells had the highest expression of Sema7A. We have also found that breast cancer cell lines of a mesenchymal phenotype express high levels of Sema7A and that transforming growth factor beta-1 can induce Sema7A expression in breast epithelial cells. Further, we show that mice bearing Sema7A gene silenced mammary tumors had decreased tumor growth and metastasis with enhanced survival compared to the control tumors. Our studies aim to unravel the functional role of Sema7A in breast cancer progression. We hypothesize that Sema7A expression in tumor cells may lead to increased tumor cell dendricity, migration, and adhesion through the activation of the MAP-kinase pathway and mediating epithelial to mesenchymal transition (EMT). Similar to its role in neurogenesis, in the tumor microenvironment Sema7A could contribute to tumor cell migration and tissue remodeling. Therefore, Sema7A could prove to be a novel therapeutic target to limit tumor growth and metastasis not only for breast cancer but for other solid tumors as well.
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 346. doi:1538-7445.AM2012-346
Abstract 3460: Inhibition of c-met radio-sensitizes in breast cancer brain metastatic cancer
Authors: Yang Heekyoung , Jin Juyoun , Kim Misuk , Kim Kang Ho , Kim Donggeon , Kang Wonyoung , Lee Hyewon , Joo Kyeung Min , Nam Do-Hyun 
Published: August 2012

Abstract
Ionizing radiation (IR) is a critical component in the treatments of breast cancer patients with all stages of the disease and a gold standard modality in patients with multiple brain metastasis, demonstrating improved overall survival (OS) in recent meta-analysis. However, the problem of recurrent or persistent disease exists due to tumor radio-resistance, and the development of distant metastasis after IR has presented a major obstacle to treatment. We investigated which molecule could be targeted for radio-sensitization. We found that c-Met over-expression and activation of downstream-signaling were induced in response to IR in a panel of human breast cancer cells by q-PCR, FACS, and Western blot analysis. The radio-sensitizing effect of c-Met silencing in vitro showed that increased c-Met activity is required for radio-resistance. In addition, c-Met inhibition combined with IR showed synergistic antitumor response including improved tumor regression and lengthened overall survival in breast cancer orthotopic and experimental brain metastasis xenograft models. Our preclinical findings establish a basis for a novel strategy to target the HGF/c-Met pathway with radiation when treating primary and brain metastatic breast cancer and possibly other c-Met pathway dependent cancers.
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 3460. doi:1538-7445.AM2012-3460
Abstract 3464: Aminolevulinic acid-mediated photodynamic therapy induces cell death in human osteosarcoma cells
Authors: Newton Mariko , White Bradley , Rossi Vincent , Baugher Paige J. 
Published: August 2012

Abstract
Photodynamic therapy (PDT) is a localized cancer treatment that requires a photosensitizer (PS), molecular oxygen, and light to induce cell death. Aminolevulinic acid (ALA)-mediated PDT utilizes ALA as an inert precursor to the required PS. Subsequent to cellular uptake ALA is converted to a PS, protoporphyrin IX (PpIX), in the mitochondria via the heme pathway. The excitation of PpIX by light can then result in the generation of reactive oxygen species, leading to direct tumor cell death, damage to the microvasculature, and induction of local inflammatory response. Interestingly, PDT can evoke apoptotic and/or necrotic cell death pathways within the same cell population. The balance between apoptosis and necrosis depends on several parameters, including the total PDT dose, the intracellular localization of the PS, the fluence rate, and the cell type. Recent studies show that the cell death mechanism induced has a direct influence on the systemic immune response. Therefore, a better understanding of the interplay between different cell death mechanisms in response to PDT could lead to improved tumor response and could inform better therapeutic strategies. We first determined the cytotoxicity of ALA to the human osteosarcoma cell line MG-63. PDT is a relatively unexplored method of treatment for human osteosarcoma, and could represent a superior method to existing therapies. Data from our lab show that ALA is not significantly cytotoxic to MG-63 cells, and that it is efficiently converted to PpIX within 24 hours of treatment. We also demonstrate that ALA-mediated PDT significantly induces cell death in MG-63 cells, and that cell death increases with increased ALA concentration and light fluence. Our findings indicate that this cell death results from a combination of both apoptosis and necrosis, with necrosis representing the major pathway. Finally, we show that increased light fluence decreases the amount of observed apoptosis subsequent to ALA-mediated PDT. These results taken together suggest that ALA-mediated PDT can induce cell death in human osteosarcoma cells, and that most cells are dying by necrosis. Furthermore, our data suggests that by adjusting specific therapeutic parameters, we can shift the balance between separate death pathways.
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 3464. doi:1538-7445.AM2012-3464
Abstract 3466: Mitochondrial targeting photosensitizer-lipophilic cation conjugates for photodynamic therapy
Authors: Rajaputra Pallavi , Nkepang Gregory , You Youngjae 
Published: August 2012

Abstract
Mitochondrion of a living cell plays a pivotal role in apoptosis. Targeting the mitochondria of cancer cell for the induction of apoptosis in photodynamic therapy (PDT) has gained importance. Cancer cells have higher plasma and mitochondrial membrane potential compared to normal cells, consequently delocalized lipophilic cations (DLCs) tend to accumulate more in them than in normal cells. In PDT photosensitizers can be specifically delivered to the mitochondria of cancerous cell by conjugating them with DLCs. Three conjugates: CMP-TPP (a porphyrin-triphenyl phosphene monocation conjugate) and CMP-(TPP)2 (a porphyrin- triphenyl phosphene dication conjugate), CMP-Rh (a porphyrin -rhodamine monocation conjugate) were synthesized as mitochondria targeting photosensitizers. The conjugates were synthesized by conjugating a core modified porphyrin (CMP-TPP) to either 1 or 2 triphenyl phosphene (TPP) molecules or rhodamine B (Rh B) respectively via a saturated hydrocarbon linker. To evaluate the efficiency of the conjugates, the photophysical properties like fluorescence resonance energy transfer (FRET in CMP-Rh) and singlet oxygen generation was compared to that of the unconjugated CMP. Potent in vitro photodynamic activity was observed in Colon 26 cells upon treatment with CMP conjugates and exposure to 690 nm diode laser light source (5.6 mW/cm2 for 30 min, 10.8 J/cm2). No significant darktotoxicity was observed in cells treated up to 5 μM of the conjugates. The conjugates showed approximately 12-14 times higher uptake in Colon 26 cells compared to unconjugated porphyrin. Further, sub-cellular localization, comparison of preferential uptake by cancerous cells versus normal cells, in vivo bio-distribution, PDT in BALB/c mice will be discussed.
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 3466. doi:1538-7445.AM2012-3466
Abstract 3468: Endoscopic diagnosis and treatment of esophageal tumor using a novel DDS-type photoactivatable agent
Authors: Miyazaki Kozo , Morimoto Yuji , Hiruma Hitomi , Inoue Aki , Nomoto Takahiro , Fukushima Shigeto , Iwaya Keiichi , Shinomiya Nariyoshi , Nishiyama Nobuhiro , Kataoka Kazunori 
Published: August 2012

Abstract
Introduction: Photodynamic diagnosis (PDD) and therapy (PDT) have been clinically used for the early phase cancer of hollow organs. We are advancing the photomedicine to the next stage, in which treatment is carried out immediately after the detection of lesions. For achieving the simultaneous diagnosis and treatment, we established a novel DDS-type photoactivatable agent, micelle-based photosensitizer loading dendrimer porphyrin (DP/M). A micelle-based shell structure is expected to be selectively accumulated in tumors. An intensely emitted fluorescence from porphyrin can be used for lesion detection and a highly quantum yield of porphyrin promises an effective PDT. Apart from the agent, we recently developed a fluorometric system equipped with an ultrathin endoscope that has a spatial resolution of 15,000 pixels even with a diameter of 0.8 mm. The aim of this study was to verify practical effectiveness of the novel photosensitizer combined with the endoscopic fluorometric system for simultaneous diagnosis and treatment. In this study, we targeted esophageal cancer because satisfactory results are not always obtained with conventional therapies and an endoscopic approach is applicable. Materials and Methods: A rat orthotopic esophageal tumor model was established in female Fischer F344 rats by orally administered with NMBuA (N-Nitroso Methylbutylamine) solved in drinking water. After intravenous administration of DP/M, PDD was carried out using the endoscopic fluorometric system (ex. 405 nm, em. &gt; 630 nm). After the detection of lesions, tumors were irradiated using a diffuser tip fiber connected to a 635nm LD laser. Results: About 6 weeks after the administration of NMBuA, polypoid tumors were observed in the esophagus. Pathological analysis revealed that proliferated polymorphonuclear cells were seen: a part of which reached the muscular layer of mucosa. A selective accumulation of DP/M in the tumors was confirmed with the endoscopic fluorometric system. This modality enabled repeated observations of tumors without sacrifice. The following PDT provided a promising result. Conclusions: DP/M combined with the endoscopic fluorometric system brought the simultaneous diagnosis and treatment for the orthotopic rat esophagus tumor models. Acknowledgment: This research is granted by the Japan Society for the Promotion of Science (JSPS) through the “Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program),” initiated by the Council for Science and Technology Policy (CSTP).
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 3468. doi:1538-7445.AM2012-3468
Abstract 3476: Hyaluronan-mediated motility receptor as a novel target for inhibiting glioblastoma stem cells
Authors: Ying Mingyao , Tilghman Jessica , Laterra John 
Published: August 2012

Abstract
Introduction: Glioblastoma stem cells (GSCs) are a subpopulation of tumor cells that promote tumor invasion and angiogenesis, therapeutic resistance and tumor recurrence. Here, we study the function of hyaluronan-mediated motility receptor (HMMR) in human GSCs. HMMR is hyper-expressed in human glioblastoma samples relative to lower-grade glioma and non-neoplastic specimens. Hyper-expression of HMMR also correlates with poor survival in glioma patients. HMMR is a multifunctional oncogenic protein that plays essential roles in tumorgenesis. Extracellular HMMR forms a complex with CD44 that upon binding to hyaluronan activates intracellular signaling pathways that regulate tumor cell survival, proliferation and invasion. Intracellular HMMR associates with microtubules, interacts with the mitotic spindle and contributes to tumor progression by promoting genomic instability. HMMR and CD44 are two ubiquitous receptors for hyaluronan, which is a prominent component of the microenvironment in most malignant tumors. CD44 has been identified as a cancer stem cell marker and CD44 directly regulates cancer stem cells in a variety of cancers including glioblastoma. Critical evidence regarding the function of HMMR in actual glioblastoma tumors and in the context of tumor-initiating GSCs is still lacking. Results: We found that HMMR is ubiquitously expressed in a panel of human glioblastoma-derived neurosphere cultures that are enriched for GSCs. Targeting HMMR by lentivirus-mediated shRNA delivery potently disrupted in vitro self-renewal of GSCs and inhibited the expression of key GSC markers, such as CD133, SOX2 and Olig2. HMMR knockdown also blocked the in vivo tumorigenic potential of GSCs in mouse orthotopic xenograft model. Notably, disruption of HMMR in GSCs attenuated the activity of Notch signaling, which supports the cancer stem cell hierarchy in glioblastoma and various other cancer types. Significance: This research identifies HMMR as a novel therapeutic target in the treatment of glioblastoma by depleting the tumor-initiating GSCs. It also introduces a novel hypothesis regarding the mechanistic crosstalk between HMMR-mediated signaling and Notch signaling pathway. Understanding this crosstalk between HMMR and Notch signaling will have a significant impact on current efforts to target Notch driven mechanisms for GBM therapy. Overall, these studies will lay an essential foundation for the development of HMMR-targeting strategies, such as HMMR inhibitors or monoclonal antibodies, as new therapeutic approaches targeting glioblastoma.
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 3476. doi:1538-7445.AM2012-3476
Abstract 3479: Targeting FoxM1 selectively depletes hepatic cancer stem cells
Authors: Kopanja Dragana , Raychaudhuri Pradip 
Published: August 2012

Abstract
Over-expression of the Forkhead box M1 (FoxM1) transcription factor coincides with highly aggressive, poorly differentiated hepatocellular carcinoma (HCC). Over-expression of FoxM1 in HCC also correlates with poorer overall survival after hepatectomy. Since HCC progression involves hepatic cancer stem cells (HCSCs), we considered the roles of FoxM1 in HCSCs. We found that FoxM1 expression correlates with the expression of the stemness genes in human HCC cell lines. Interestingly, depletion of FoxM1 in human HCC lines causes a selective reduction in the population of the CD90+ HCSCs due to selective apoptosis. Moreover, FoxM1 silencing decreases sphere formation potential of the same cell lines, suggesting that FoxM1 is critical for survival of the HCSCs. Consistent with the loss of HCSCs, depletion of FoxM1 causes decrease in tumorigenic potential of the HCC cells in vitro as well as inhibition of tumor formation in mouse xenografts. Furthermore, we found that FoxM1 directly regulates expression of CD44, previously shown to be important for the tumorigenic potential of CD90+ HCC cells. These studies have exciting implications in further considerations of FoxM1 as a target of HCC 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 3479. doi:1538-7445.AM2012-3479
Abstract 3481: Dietary acetate supplementation as a means of inducing glioma stem cell growth arrest
Authors: Long Patrick M. , Tsen Andrew , Moffett John R. , Namboodiri Aryan M. A. , Viapiano Mariano S. , Jaworski Diane M. 
Published: August 2012

Abstract
Glioma, the most common primary brain tumor of the adult central nervous system, is associated with a poor prognosis due, in part, to the presence of chemoradiotherapy-resistant glioma stem-like cells responsible for inevitable post-surgical recurrence. N-acetyl-L-aspartate (NAA), one of the most concentrated metabolic sources of acetate in the brain, and aspartoacylase (ASPA), the enzyme responsible for NAA degradation, are significantly reduced in glioma tumors. NAA-derived acetate is converted to acetyl coenzyme A via acetyl-CoA synthetase (AceCS) for use in lipogenesis, protein/histone acetylation, and the TCA cycle. We propose that glyceryltriacetate (GTA), a FDA approved food additive with “generally regarded as safe” status, may be an effective means of reducing glioma growth via restoration of acetate levels. The effect of GTA on the growth of both established (Hs683, HOG) and stem-like (grade II OG33, grade III OG35) oligodendroglioma cell lines was assessed. In vitro, GTA induced growth arrest in all cells examined (i.e., increased proportion of cells in G0/G1 and reduced S phase cells by flow cytometry of propidium iodide labeled cells 24 hours after treatment and unbiased trypan blue exclusion based cytometry up to 5 days post-treatment). Growth arrest was not associated with apoptosis (lack of cleaved poly ADP-ribose polymerase immunolabeling), but differentiation (increased CNPase expression). ASPA expression was greater in stem-like cells when grown in stem cell media than differentiation media and was decreased in GTA-treated OG35 cells. Interestingly, GTA did not decrease ASPA expression in OG33 cells, but induced a novel 26 kDa ASPA isoform. ASPA and AceCS1 were co-localized within the nucleus. Nuclear, but not cytosolic, ASPA expression was decreased upon GTA addition in stem cell media, but not differentiation media. Finally, the effect of GTA on orthotopically grafted luciferase expressing OG33 and OG35 cells was assessed. Bioluminescence and tumor volume were reduced in GTA treated mice. These data suggest that the nuclear ASPA/AceCS1 co-localization provides acetate for histone acetylation to maintain cells in a progenitor/stem-like state and that decreased ASPA promotes gliomagenesis. Inasmuch as infants with Canavan Disease, a leukodystrophy due to ASPA mutation, treated with high dose GTA showed no significant side effects, GTA may prove an effective therapy to prevent recurrence by inducing growth arrest/differentiation of glioma stem-like cells.
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 3481. doi:1538-7445.AM2012-3481
Abstract 3483: Inhibition of Monocarboxylate Transporter 4 (MCT4) targets stem-like cells in glioblastoma
Authors: Lim Kah Suan , Lim Kah Jing , Orr Brent A. , Price Antoinette C. , Eberhart Charles G. , Bar Eli E. 
Published: August 2012

Abstract
Glioblastomas (GBM) are the most common adult malignant brain tumors and contain a hypoxic/necrotic core surrounded by proliferative cells. To unmask genes important in hypoxia, we exposed 2 GBM neurosphere lines, HSR-GBM1 and JHH-GBM10, to 1% and 21% oxygen levels for 24 hours and compared gene expression using Agilent oligonucleotide microarrays. We identified SLC16A3 (Monocarboxylate transporter-4, MCT4) as one of the most upregulated genes in response to hypoxia. To investigate the clinical importance of MCT4 in GBM, we examined the Kaplan-Meier survival curves of glioma patients using public databases. We found that patients with upregulation of MCT4 (≥2.0X) have a significantly shorter survival (p&lt;0.0001) than patients with intermediate expression. Consistent with this, MCT4 upregulation correlated with the aggressive mesenchymal subset of GBM (p&lt;0.0001). We next examined MCT4 protein levels using immunohistochemical analysis of tissue microarrays, confirming that MCT4 protein levels were increased in high-grade as compared to lower grade astrocytomas (p&lt;0.0001). These data clearly demonstrated that MCT4 is a clinically relevant target. We next tested the requirement of MCT4 in vitro. We found that when neurospheres were transduced with viruses encoding short hairpin RNA (shRNA) against MCT4, cell growth was inhibited by 30-69% in hypoxia. Interestingly, similar results were observed in normoxia, suggesting that MCT4 may be critical to tumor growth and survival independent of oxygen levels. We next explored the role that MCT4 may play in the maintenance of the stem-like population in our neurosphere lines. We found that MCT4 is overexpressed in sorted CD133-positive cells compared to CD133-negative cells in both HSR-GBM1 and JHH-GBM10. Furthermore, flow cytometric analysis of shMCT4-expressing neurospheres showed a decrease in the percentage of CD133-positive cells as compared to controls. This suggested to us that MCT4 silencing might inhibit stem-like cell proliferation/survival, offering a potential explanation for growth inhibition following MCT4 knockdown in normoxia. To test this hypothesis, we examined the effect of MCT4 inhibition functionally using a clonogenic assay. Cells were exposed to normoxia or hypoxia for 48 hours followed by recovery in normoxia. We found that MCT4 silencing resulted in significant reduction in sphere number and size in both normoxic and hypoxic cells, consistent with a loss of clonogenicity. In agreement with what we found in vitro, MCT4 silencing also slowed GBM intracranial xenograft growth in vivo (p=0.009).
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 3483. doi:1538-7445.AM2012-3483