bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3252: LGR5 suppresses colon cancer metastasis
Authors: Zhou Xiaolin , Wang Jing Jenny 
Published: August 2015

Abstract
Metastasis is the major cause of death for patients with solid tumors, mainly due to the lack of effective therapies once metastases begin to form. Further research into the mechanism of metastasis is therefore essential in order to have a better understanding of this process and eventually develop more efficient cancer therapies to prevent or treat metastasis. LGR5 is a leucin-rich G protein coupled receptor and a Wnt target gene. It marks the proliferating adult stem cells in the small intestine and has been shown to play an important role in the maintenance of intestine stem cell proliferation by enhancing the canonical Wnt signaling. It is overexpressed in human colorectal, ovary and liver tumors due to the inappropriate activation of Wnt signaling at the onset of those diseases. Recent studies are conflicting regarding the functional role of LGR5 in colon cancer initiation. However, its role in colon cancer progression and metastasis has not been studied. Analysis of copy number variation (CNV) of LGR5 from the Cancer Genome Atlas (TCGA) database revealed that CNV loss of LGR5 is enriched in late stage colon cancer (stage III and IV) with high lymph node spread and/or distant metastasis and in patients with recurrence whereas CNV gain is enriched in early stage disease with no regional or distant metastasis. These results suggest that LGR5 expression may increase during the onset of colon tumorigenesis and decrease thereafter during tumor progression. Functional studies showed that knockdown of LGR5 expression in colon cancer cells increased their clonogenecity, survival capacity and motility in vitro and metastatic dissemination to the liver and lungs in an orthotopic model in vivo. Our results demonstrate that LGR5 functions as a suppressor of colon cancer metastasis and that reduction of LGR5 expression contributes to colon cancer progression and metastasis.
Citation Format: Xiaolin Zhou, Jing Jenny Wang. LGR5 suppresses colon cancer metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3252. doi:10.1158/1538-7445.AM2015-3252
Abstract 3260: Identification of a novel signaling axis that leads to co-induction of two major actin-regulatory proteins with anti-migratory properties in breast cancer cells
Authors: Joy Marion , Roy Partha 
Published: August 2015

Abstract
Dysregulation of actin-regulatory proteins is a hallmark feature of tumor malignancy. Along this line, recent studies have established causal relationships between downregulation of expression of actin-binding proteins profilin-1 and -2 (Pfn1, Pfn2 - genes located on chromosomes 17 and 3, respectively) and increasing invasive ability of breast cancer cells. Conversely, genetically elevating expression of these Pfn isoforms suppresses aggressiveness of breast cancer cells. Therefore, identification of a common signaling pathway linking to regulation of these two Pfn isoforms may lead to a novel conceptual strategy to suppress metastatic potential of breast cancer cells in Pfn-dependent manner. We found that hyperactivating RhoA, a member of Rho-family GTPases, causes a marked depletion of cellular Pfn1 and Pfn2 expression, suggesting that a pathway downstream of activated RhoA is one of the major signaling axes for regulating Pfn1 and Pfn2 expression. Through overexpression and knockdown experiments, we further identified MKL1 (megakaryoblastic leukemia-1), a transcriptional co-factor that activates serum-response factor (SRF)-mediated gene transcription downstream of activated Rho, to be a major regulator of expression of Pfn isoforms. However, SRF does not appear to play a role in Rho-dependent Pfn regulation and furthermore, Rho-dependent Pfn regulation occurs post-transcriptionally suggesting that a non-canonical MKL1-linked pathway is involved in co-regulation of Pfn isoforms. Finally, MKL1-dependent induction of Pfn isoforms involves STAT1 and this pathway can be activated pharmacologically resulting in inhibition of breast cancer cell motility. In conclusion, we have identified a novel MKL1-STAT1 signaling axis for co-induction of the two major cellular isoforms of Pfn. This study could open up promising pharmacological points of attack in the context of metastatic breast cancer.
Citation Format: Marion Joy, Partha Roy. Identification of a novel signaling axis that leads to co-induction of two major actin-regulatory proteins with anti-migratory properties in breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3260. doi:10.1158/1538-7445.AM2015-3260
Abstract 3281: Oklahoma Nitrone-007: A novel compound for treating pediatric glioblastoma
Authors: Mallory Samantha , McNall-Knapp Rene , Coutinho deSouza Patricia , Fung Kar-Ming , Saunders Debra , Smith Nataliya , Smartwood Shanna , Towner Rheal 
Published: August 2015

Abstract
Brain tumors are the most common solid tumor in children, and despite current treatment options including surgical resection, chemotherapy, and radiation for pediatric high-grade gliomas, survival in these patients remains very poor. This research represents promising pre-clinical data of a novel compound, OKN-007 (OKlahoma Nitrone 007, a disulfonyl derivative of α-phenyl-tert-butyl nitrone (PBN)), as a new clinical therapy for pediatric high-grade gliomas (pHGGs). The objective is to establish if pHGGs, which are often hard to surgically resect, can be treated with OKN-007, either as a single agent or in combination with currently used chemotherapeutic agents. OKN-007 may be an ideal candidate that can have an anti-cancer effect on pHGG cells, due to its multiple anti-cancer effects, including induction of apoptosis, and inhibition of cell proliferation and angiogenesis, and may play an important role in the anti-cancer activity against pHGGs. Morphological magnetic resonance imaging (MRI) of xenograft nude athymic and SCID mice injected with pHGG cells TCCC3752 and KNS42 is used in this study to assess brain tumor volumes for response to therapy. Preliminary data regarding the regression of pHGGs in mice following treatment with OKN-007 is presented. Mean animal survival was found to be significantly increased with OKN-007 treatment in responsive animals compared to an untreated group, p&lt;0.05. Immunohistochemistry and microarray will be used to assess levels of angiogenic (VEGF (vascular endothelial growth factor), HIF-1α (hypoxia inducible factor-1α), MVD (microvessel density)), cell differentiation (CAIX (carbonic anhydrase IX)), cell proliferation (Glut-1 (glucose transporter 1), MIB-1), apoptosis (cleaved caspase 3) markers and assess inhibition of TGFB and PDGFR complexes and downstream pathways, which are overexpressed in tumors and thought to play a role in oncogenesis and progression. OKN-007 is currently an investigational drug undergoing clinical trial evaluation for recurrent gliomas in adult patients but will still require FDA approval for use in pediatric glioma patients. An outcome of the proposed research is to incorporate the pre-clinical data in an IND application to the FDA in order to translate this research to the clinic and benefit children with pHGGs.
Citation Format: Samantha Mallory, Rene McNall-Knapp, Patricia Coutinho deSouza, Kar-Ming Fung, Debra Saunders, Nataliya Smith, Shanna Smartwood, Rheal Towner. Oklahoma Nitrone-007: A novel compound for treating pediatric glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3281. doi:10.1158/1538-7445.AM2015-3281
Abstract 3300: Concerted epigenetic and signaling mechanisms regulate normal stem cell radiosensitivity
Authors: Jacobs Keith M. , Misri Sandeep , Meyer Barbara , Raj Suyash , Zobel Cheri L. , Sleckman Barry P. , Hallahan Dennis E. , Sharma Girdhar G. 
Published: August 2015

Abstract
Side effects resulting from ionizing radiation (IR) during cancer radiotherapy often involve normal tissue injury including depletion of tissue regenerative capacity. Utilizing multiple in vivo tissue niches and cell culture models, we demonstrate that normal stem cells are highly radiosensitive while differentiated progeny are radioresistant, and IR-induced apoptosis of stem cells is observed broadly throughout the cell cycle independent of proliferation status.
Our study demonstrates that normal stem cells fail to activate the DDR, do not display IR-induced foci in vivo as well as in culture, and exhibit severely attenuated DNA repair. Despite normal sensing of DNA breaks, recruitment/ retention of repair factors at DNA break sites is repressed in stem cells. Stem cells are unable to eliminate constitutive phosphorylation of H2AX-Y142 around break sites, abetting stem cells toward an apoptotic instead of repair pathway. The abrogated DDR in normal stem cells is associated with a constitutively enhanced histone-3 lysine-56 acetylation, which epigenetically contributes to muted retention of repair factors. Reinforced PP2A phosphatase expression was also identified as substantial regulators of stem cell radiosensitivity and transient inhibition of phosphatase activity restores stem cell survival.
We thus identify pluralistic interacting molecular and epigenetic mechanisms that collectively control and impart IR hypersensitive phenotype to the normal stem cells. These insights will be crucial in development of prevention and intervention therapeutic strategies to minimize IR-induced stem cell dropout and increase the efficacy of radiotherapy.
Citation Format: Keith M. Jacobs, Sandeep Misri, Barbara Meyer, Suyash Raj, Cheri L. Zobel, Barry P. Sleckman, Dennis E. Hallahan, Girdhar G. Sharma. Concerted epigenetic and signaling mechanisms regulate normal stem cell radiosensitivity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3300. doi:10.1158/1538-7445.AM2015-3300
Abstract 3304: Role of Vascular Endothelial Growth Factor C in promoting radioresistance of prostate cancer
Authors: Haberlau Steffi , Hönscheid Pia , Jimenez Rafael E. , Baretton Gustavo B. , Tindall Donald J. , Krause Mechthild , Datta Kaustubh , Muders Michael H. 
Published: August 2015

Abstract
Radiotherapy is an important treatment regimen for prostate cancer. We have shown that the lymphangiogenic growth factor, Vascular Endothelial Growth Factor C (VEGF-C), induces docetaxel resistance and autophagy in prostate cancer (Muders et al., Cancer Res 2009 and Stanton et al., Cancer Res 2013). In this study we have evaluated the role of VEGF-C and VEGF-C induced autophagy in radioresistance of prostate cancer using cell culture experiments and human tissue samples.
The human prostate carcinoma cell lines PC-3, LNCaP and DU145 were used in these cell culture experiments. Clonogenic survival of prostate cancer cells, after RNA interference (RNAi) of VEGF-C, autophagy related gene 5 (ATG5), and after addition of recombinant human VEGF-C following irradiation therapy, was evaluated. Autophagic flux was tested after ionizing irradiation using a Light-Chain-3 II immunoblot. To confirm our in vitro findings, human tissues of patients who underwent radical prostatectomy and adjuvant radiotherapy at Mayo Clinic were evaluated for VEGF-C expression. The quantity and intensity of VEGF-C staining was evaluated by two pathologists independently and correlated with biochemical relapse free survival (BRFS). The follow-up time is up to 23 years after radiotherapy. Multivariate Cox analysis was performed.
VEGF-C levels correlated with a significantly higher radioresistance in colony formation assays and human tissue samples by multivariate analysis. The risk of biochemical recurrence increased 2.8 fold (95% confidence interval: 1.109 to 7.237; p = 0.03) when VEGF-C was highly expressed in prostatectomy patients with adjuvant radiotherapy. In line with our studies on autophagy in VEGF-C mediated docetaxel resistance of prostate cancer, autophagic flux was reduced after VEGF-C depletion during radiation. Interestingly, RNAi for ATG5 showed no effect on radiosensitivity which suggests that the decrease in autophagic flux after VEGF-C depletion is not responsible for the increased radiosensitivity.
We conclude that VEGF-C is an important mediator of radiotherapy resistance in prostate cancer. In contrast to our published results on chemotherapy resistance, VEGF-C induced autophagy appears to be less important for resistance against ionizing radiation. Other VEGF-C dependent mechanisms for therapy resistance are under investigation.
Citation Format: Steffi Haberlau, Pia Hönscheid, Rafael E. Jimenez, Gustavo B. Baretton, Donald J. Tindall, Mechthild Krause, Kaustubh Datta, Michael H. Muders. Role of Vascular Endothelial Growth Factor C in promoting radioresistance of prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3304. doi:10.1158/1538-7445.AM2015-3304
Abstract 3310: Targeting MUC1-mediated metabolism sensitizes pancreatic cancer cells to radiation therapy
Authors: Gunda Venugopal , Abrego Jaime , Shukla Surendra K. , Chaika Nina V. , Yu Fang , Bessho Tadayoshi , Lin Chi , Singh Pankaj K. 
Published: August 2015

Abstract
Overexpression of MUC1 promotes growth promoting metabolic alterations in pancreatic cancer cells. We investigated the role played by MUC1-mediated metabolic alterations in radiation response of pancreatic cancer cells. Our findings indicate that cell survival and clonogenicity of pancreatic cancer cells upon radiation treatment correlate with MUC1 expression. MUC1 expression reduced radiation-induced reactive oxygen species (ROS) production and DNA damage, whereas, increased glucose uptake and lactate secretion upon irradiation. Metabolomic analysis through liquid chromatography-coupled tandem mass spectrometry approach revealed that pancreatic cancer cells exhibit spontaneous metabolic alterations upon irradiation. MUC1 expression further altered radiation-induced carbon flux especially in glycolysis and pentose phosphate pathway. We further investigated radiation-sensitization of MUC1-expressing cells by targeting glycolysis or pentose phosphate pathway using metabolic inhibitors, and observed that pre-treatment with 3-bromopyruvate (BrPA) effectively abrogates MUC1-mediated radiation-resistance by elevating ROS and DNA damage. BrPA treatment also reduced MUC1-induced carbon flux into glycolysis and pentose phosphate pathway, upon irradiation. Hence, our findings demonstrate that MUC1-mediated radiation-resistance in pancreatic cancer cells can be effectively targeted through inhibition of glycolysis.
Citation Format: Venugopal Gunda, Jaime Abrego, Surendra K. Shukla, Nina V. Chaika, Fang Yu, Tadayoshi Bessho, Chi Lin, Pankaj K. Singh. Targeting MUC1-mediated metabolism sensitizes pancreatic cancer cells to radiation therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3310. doi:10.1158/1538-7445.AM2015-3310
Abstract 3312: Growth inhibition of cancer cells by 5-aminolevulinic acid
Authors: Horiuchi Toshikatsu , Serizawa Yusuke , Tateishi Syoichiro , Iwaya Keiichi , Watanabe Junichi , Kobayashi Shinichi , Sato Ken , Kimura Fumihiko , Shinomiya Nariyoshi , Morimoto Yuji 
Published: August 2015

Abstract
Introduction: 5-aminolevulinic acid (ALA) is intracellularly metabolized to protoporphyrin IX (PpIX) in heme synthetic pathway. As PpIX is a fluorescent photosensitizer and has been shown to accumulate preferentially in cancer cells, exogenously administered ALA is used for photodynamic diagnosis (PDD) and photodynamic therapy (PDT). However, the influence of exogenously administered ALA on cellular proliferation is not elucidated. Overproduction of heme owing to exogenously administered ALA may induce an upregulation of heme oxygenase (HO-1), which is a potential inhibitor of cellular proliferation via a generation of carbon monoxide (CO) and an induction of P21. We therefore examined cytotoxicity when I was administered.
Methods and Materials: Human cancer cell lines (10 types) and human normal cell lines (2 types) were incubated with ALA (1.0 mM) for 24 hrs. A fluorometric measurement for PpIX (ex. 405 nm. em. 630 nm) and a proliferation assay using WST-8 were carried out. The expression of HO-1 was evaluated using Western blotting.
Results: In 8 out of 10 cancer cell lines, an amount of intracellularly synthesized PpIX after the administration of ALA was highly correlated with a decrease in number of cells (cell death) (R = 0.73), and two out of the eight cell lines (HepG2 and Caki-1) showed a significant reduction in number of cells (&gt; 15%) accompanied with a significant increase in PpIX generation (&gt; 90 a.u.). On the other hand, normal cell lines (HUVEC, SMC) showed less changes in cell count (within 1.5%) accompanied with less PpIX generation (within 35 a.u.). The HO-1 production rate, defined by HO-1 expression level in ALA-treated cells / HO-1 expression level in non-treated cells was highly correlated with the cell death (R = 0.67).
Conclusion: In some types of cancer cell lines, an exogenously administered ALA leads to cell death, probably due to the upregulation of HO-1 that is produced by the accumulation of PpIX. Meanwhile, in normal cell lines, the exogenously administered ALA is less likely to induce cell death.
Citation Format: Toshikatsu Horiuchi, Yusuke Serizawa, Syoichiro Tateishi, Keiichi Iwaya, Junichi Watanabe, Shinichi Kobayashi, Ken Sato, Fumihiko Kimura, Nariyoshi Shinomiya, Yuji Morimoto. Growth inhibition of cancer cells by 5-aminolevulinic acid. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3312. doi:10.1158/1538-7445.AM2015-3312
Abstract 3346: The ketone body β-hydroxybutyrate increases radiosensitivity in glioma cell lines in vitro
Authors: Rossi Alex P. , Woolf Eric C. , Brooks Kenneth S. , Fairres Marshall J. , Scheck Adrienne C. 
Published: August 2015

Abstract
Glioblastoma (GB) is the most common and aggressive primary malignant brain tumor. Despite aggressive treatment, including maximum surgical resection followed by both chemotherapy and radiotherapy, median survival for patients remains at approximately 1.5 years after diagnosis. Recent preclinical studies examining the potential of the ketogenic diet (KD) as an adjuvant therapy for the treatment of malignant gliomas demonstrated that animals fed a KD and treated with chemotherapy or radiation survived significantly longer than those treated with chemotherapy or radiation and fed a standard diet. One of the key results of the KD is an increase in the blood level of the ketone body β-hydroxybutyrate (BHB). To more fully examine the mechanism through which the KD potentiates radiation, we examined the potential of BHB to increase radiosensitivity in mouse glioma cells in vitro. Plating cells in 10mM BHB followed by treatment for 2 weeks following radiation prevented colony formation in both the control and the radiation groups. We therefore assessed the effect of pretreatment with 5mM or 10mM BHB alone prior to radiation with 4 Gy. A statistically significant change in survival was observed when cultures were pre-treated with 10mM BHB for 24 hours prior to irradiation but not with 5mM BHB. However, significant changes in clonogenic survival were observed with a dose of 5mM BHB when cells were treated for 7 days post irradiation, starting 24 hours after irradiation. The effect of BHB on cell growth was then assessed using live cell counts. Both 5mM and 10mM BHB were effective in significantly reducing the cell number by 192 hours post plating. Growth was similarly affected by 10mM BHB or 2 Gy of radiation alone; however, when 10mM BHB was added to 2 Gy of radiation there was a very strong potentiating effect. These data suggest that BHB is an effective radiosensitizer for mouse glioma cells when used alone. In addition, they provide evidence that the extended survival seen in our in vivo mouse model of glioma when radiation is used in addition to the ketogenic diet may be modulated, to a large extent, by blood ketone levels. Whether this is due to differences in radiation-induced DNA damage, DNA repair or changes in the growth rate of the tumor cells is currently under investigation.
Citation Format: Alex P. Rossi, Eric C. Woolf, Kenneth S. Brooks, Marshall J. Fairres, Adrienne C. Scheck. The ketone body β-hydroxybutyrate increases radiosensitivity in glioma cell lines in vitro. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3346. doi:10.1158/1538-7445.AM2015-3346
Abstract 3356: Diversity of CD8+ and rgulatory T cells is inversely correlated in follicular lymphoma: A potential predictive biomarker
Authors: Kline Justin Paul , Liu Xiao , Venkataraman Girish , Lin Jiaying , Kiyotani Kazuma , Smith Sonali M. , Montoya Magdeline , Nakamura Yusuke 
Published: August 2015

Abstract
Gene expression profiling experiments have demonstrated that the immune microenvironment in follicular lymphoma (FL) plays an important role in controlling the behavior of the disease. FL patients with tumors enriched for T cell-related transcripts have a more favorable prognosis. As T cells have been shown to mediate anti-tumor immunity in other cancers, they may also be critical in controlling the progression of FL. T cells are often identified in and around malignant follicles in FL by immunohistochemistry, but it is not known whether their presence relates to their specificity for antigens expressed by FL cells. Hypothesizing that at least a fraction of T cells in FL are truly lymphoma antigen-specific, we have begun to characterize the T cell receptor (TCR) repertoire of FL tissues using a next generation sequencing platform, and have deeply sequenced T cell receptor (TCR) cDNAs of T cell subset populations present in pretreatment FL biopsy specimens. Regulatory T cell (Treg) TCRs in FL tissues revealed a highly oligoclonal expansion, compared to those in control lymph nodes. Furthermore, an inverse correlation was observed between the diversity of Treg and CD8+ TCRs in FL specimens. Interestingly, a tumor from an FL patient, who has received no anticancer treatment for more than 10 years, was found to have missense mutations in the peptide-binding domain of both HLA class I and class II molecules, which might have presented tumor-specific antigens and enhanced host immune responses. Although further verification is required, our data suggest that the T cell repertoire is skewed and restricted in FL and support the evolving understanding of the microenvironment in this disease.
Citation Format: Justin Paul Kline, Xiao Liu, Girish Venkataraman, Jiaying Lin, Kazuma Kiyotani, Sonali M. Smith, Magdeline Montoya, Yusuke Nakamura. Diversity of CD8+ and rgulatory T cells is inversely correlated in follicular lymphoma: A potential predictive biomarker. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3356. doi:10.1158/1538-7445.AM2015-3356