bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3278: Dopamine inhibits growth of multiple myeloma
Authors: Sarkar Chandrani , Chakroborty Debanjan , Basu Sujit 
Published: July 2016

Abstract
Introduction: Multiple myeloma (MM), progressive plasma cell tumor leading to overproduction of monoclonal immunoglobulins, osteolytic bone lesions, renal disease and immunodeficiency, is the second most prevalent hematologic malignancy in the United States. Vascular endothelial growth factor-A (VEGF-A) is a critical cytokine responsible for the induction of angiogenesis in several solid and hematological malignancies like MM. It is likely that VEGF-A induced bone marrow (BM) angiogenesis promotes the survival, growth and proliferation of MM .Therefore targeting BM angiogenesis in MM may be effective for the treatment of MM patients
Objective/Hypothesis: Bone marrow stromal cells (BMSC) are believed to play a central role in progression of MM pathogenesis. Along with other factors, these cells overproduce IL-6 that in turn stimulates growth, survival and progression of MM cells. Since it has been shown that VEGF-A can stimulate IL-6 secretion by these cells and because we have demonstrated that neurotransmitter dopamine (DA) can inhibit VEGF-A functions by acting through its D2 receptors (D2R) and BMSC express DAD2R, we therefore hypothesize that DA or D2R agonists have a role in inhibiting VEGF-A mediated IL-6 secretion by BMSC and thereby, MM progression.
Results: Our results indicate that VEGF-A can significantly increase the secretion of IL6 by isolated BMSC cells in vitro. Addition of DA or D2R agonist, quinpirole, to VEGF-A treated BM cells results in suppression of IL-6 production. However treatment with D2R antagonist, eticlopride, prior to treatment with DA results in abrogation of the effect of DA. Similar effects of DA on VEGF-A induced IL-6 secretion was also observed in HS-5 human BM stromal cells. Our results further indicate that VEGF-A induced VEGFR1 phosphorylation is suppressed in HS-5 cells on treatment with D2R agonist. Furthermore, DA also inhibits the proliferation of MM1.S human MM cells in vitro.
Conclusion: DA may be a new and an effective approach to retard the progression of MM. Since anti-angiogenic monotherapy cannot eradicate the disease completely, strategies using DA with more traditional modalities to eradicate the disease at the time of initial treatment might be beneficial. Finally, DA or its D2R agonists are being used in the clinics for several years for the treatment of other disorders, therefore these inexpensive drugs (in comparison to presently available drugs for the treatment of MM) with known and manageable side effects can be used in the clinics in near future for the treatment of both early and late stage MM.
Citation Format: Chandrani Sarkar, Debanjan Chakroborty, Sujit Basu. Dopamine inhibits growth of multiple myeloma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3278.
Abstract 3286: Targeting mir101/ EZH2/NFkb axis by FGFR1 inhibitor in mantle cell lymphoma
Authors: Sehgal Lalit , Jain Neeraj , Khashab Tamer , wang xin , Neelapu Sattva , Samaniego Felipe 
Published: July 2016

Abstract
Mantle cell lymphoma is classified as distinct non-Hodgkin's lymphoma subtype characterized by the t(11;14)(q13;q32) translocation, which results in overexpression of Cyclin D1. The clinical presentation often includes extra-nodal involvement, of the bone marrow and gut. The prognosis of patients with mantle cell lymphoma (median overall survival, 3-5 years) is poorest among B-cell lymphoma patients. However, MCL pathogenesis has been delayed until the recent development of a tissue culture system, using stromal cells and adipocytes, suitable for propagating primary MCL cells. We hypothesized that tumor microenvironment might activate survival-signaling pathways essential for survival and maintenance of MCL, and targeting the identified signaling pathways might be an ideal for designing of curative treatment strategies. We developed an in-vitro culture system, mimicking bone marrow microenvironment that can be exploited to understand the biology of MCL resistance to death pathways. Primary MCL cells grown in co-culture with bone marrow stromal cells grew faster than cells cultured alone. We identified the soluble factors responsible for survival of MCL cancer stem cells (MCL-IC) that can be targeted to prevent relapse. We found the IL6 secretion triggered FGF-2 autocrine loop in MCL cells contributing to cell survival and growth by regulating mir101/EZH2/NFkb axis. The death signaling pathways inactive in MCL are restored upon therapeutic intervention by specific pathways inhibitors. In conclusion, we delineated three different signaling arm regulated in MCL cells to promote cell survival and resistance. We defined the factors supporting MCL and MCL-ICs survival essential for forming new targeting treatment strategies. To overcome MCL resistance to death pathways we have outlined the hMSCs-mediated support of MCL and identified drug targets to sensitize MCL to apoptosis.
Citation Format: Lalit Sehgal, Neeraj Jain, Tamer Khashab, xin wang, Sattva Neelapu, Felipe Samaniego. Targeting mir101/ EZH2/NFkb axis by FGFR1 inhibitor in mantle cell lymphoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3286.
Abstract 3300: Gal-GalNAc overexpressed in colorectal carcinoma mediates attachment and colonization of Fusobacterium nucleatum utilizing the Fap2 lectin
Authors: Abed Jawad H. , Emgård Johanna , Chaushu Stella , Garrett Wendy , Bachrach Gilad 
Published: July 2016

Abstract
Recent reports revealed overabundance of oral Fusobacterium nucleatum (Fn) in colorectal carcinoma (CRC) compared to adjacent healthy tissue. This study aims to investigate the molecular mechanisms that mediate CRC colonization by Fn.
Using the orthotopic Colon-26 colorectal cancer model, we found that intravascular injected Fn colonizes CRC more than adjacent healthy tissue. Fusobacterial localization in the colon is tumor-dependent, as injected fusobacteria were undetected in the colons of tumor-free mice. CRC colonization is species specific as the gram-negative, anaerobe and periodontitis-related pathogen Prophyromonas gingivalis, which was shown to be abundant in oral tumors failed to colonize CRC.
Higher levels of D-galactose-β(1-3)-N-acetyl-D-galactosamine (Gal-GalNAc) are known to be detected in CRC. We recently identified the fusobacterial Fap2 outer-surface protein as a galactose binding lectin, suggesting that it might promote binding of fusobacteria to CRC. A fluorescent-labeled Peanut Agglutinin lectin (PNA) detected more Gal-GalNAc in human and mouse CRC compared to adjacent healthy tissues. Binding of FITC-labeled Fn corresponded with the levels of Gal-GalNAc and colocalized with Gal-GalNAc in the tumor. Flow cytometry revealed that Fap2-deficient Fn mutants are impaired in binding to CRC cell lines compared with their WT parent. Soluble GalNAc inhibited the binding of PNA and WT Fn to CRC cells in a dose-dependent manner, but did not affect the residual CRC binding of fap2 mutated Fn. Furthermore, in the colorectal cancer murine model, tumor colonization by Fap2-deficient Fn mutants was significantly lower than that of the Fap2 sufficient parental strain.
Our results demonstrate that the fusobacterial Fap2 lectin binds to Gal-GalNAc on CRC and mediates the tumor-specific attachment of Fn. Understanding the interaction of Fn with CRC, may enable future development of novel diagnostic and therapeutic agents for this disease.
Citation Format: Jawad H. Abed, Johanna Emgård, Stella Chaushu, Wendy Garrett, Gilad Bachrach. Gal-GalNAc overexpressed in colorectal carcinoma mediates attachment and colonization of Fusobacterium nucleatum utilizing the Fap2 lectin. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3300.
Abstract 3301: Breast cancer subtypes have distinct microbial and immune cytolytic transcriptomic signatures
Authors: Pedamallu Chandra Sekhar , Meyerson Matthew , Ojesina Akinyemi 
Published: July 2016

Abstract
Background: The role of genetic mutations in breast cancer is well documented and has formed the basis for novel therapies. However, the impact of viral and bacterial infection in the pathogenesis of breast cancer is not well understood.
Methods: We analyzed RNA sequencing (RNASeq) data generated by the Cancer Genome Atlas (TCGA) from over 900 pairs of breast tumor and adjacent normal tissues, using our pathogen discovery tool, PathSeq. We developed a novel metric for quantifying and normalizing microbial sequence abundance from RNASeq data by correcting for both the sequencing coverage and relative genome sizes of bacteria in the dataset. We also performed linear discriminant analyses (LDA) to test the hypothesis that the differences between the canonical breast cancer subtypes can be modeled on microbial abundance data. In addition, we interrogated the human gene expression data derived from the RNASeq dataset to determine the relationships between the breast cancer subtypes and immune cytolytic activity (CYT index; defined as the geometric mean of the expression levels of perforin and granzyme).
Results: Viral sequences were rare but we identified bacterial sequences to varying degrees of abundance. Intriguingly, we demonstrated that microbial abundance data can be used to recapitulate the well-established PAM50 gene expression-based subsets. Comparison of tumors and adjacent normal tissues also revealed subtype-associated microbial profiles. In addition, we observed that the basal and Her2 subtypes of breast cancer had a higher frequency of tumors with high CYT index compared with luminal A and B subtypes.
Conclusion: This study has revealed that the various breast cancer subtypes have unique microbial transcriptomic signatures as well as differential immune cytolytic activity profiles. These data suggest the potential for differential responses of breast cancer subsets to immunotherapy.
Citation Format: Chandra Sekhar Pedamallu, Matthew Meyerson, Akinyemi Ojesina. Breast cancer subtypes have distinct microbial and immune cytolytic transcriptomic signatures. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3301.
Abstract 331: Beta-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG
Authors: Lee Kevin J. , Lindsey Ashley S. , da Silva Luciana Madeira , Trinh Alisa , Gary Bernard , Andrews Joel , Ramirez-Alcantara Veronica , Keeton Adam B. , Chang Wen-Chi , Clapper Margie , Piazza Gary A. 
Published: July 2016

Abstract
Phosphodiesterase 10A (PDE10A) is a cGMP and cAMP degrading PDE isozyme that is highly expressed in the brain striatum where it appears to play an important role in cognition and psychomotor activity. PDE10 inhibitors are being developed for the treatment of schizophrenia and Huntington's disease and are generally well tolerated, possibly because of low expression levels in most peripheral tissues. We recently reported high levels of PDE10 in colon tumors and that genetic silencing of PDE10 by siRNA or inhibition with small molecule inhibitors can suppress colon tumor cell growth with a high degree of selectivity over normal colonocytes (Li et al., Oncogene 2015). These observations suggest PDE10 may have an unrecognized role in tumorigenesis. Here we report that the concentration range by which the highly specific PDE10 inhibitor, Pf-2545920 (MP-10), inhibited colon tumor cell growth parallels the concentration range required to increase cGMP and cAMP levels, and activate PKG and PKA, respectively. Moreover, PDE10 knockdown by shRNA reduced the sensitivity of colon tumor cells to the growth inhibitory activity of Pf-2545920. Pf-2545920 also inhibited the translocation of β-catenin to the nucleus, thereby reducing β-catenin mediated transcription of survivin, which resulted in caspase activation and apoptosis. This was determined to be through a PKG mediated pathway through the use of small molecule inhibitors of PKG and PKA. PDE10 mRNA was also found to be elevated in colon tumors compared with normal tissues in a cDNA array. We also report the increase in PDE10 mRNA in 50% of a small collection of human clinical specimens collected at the Mitchell Cancer Institute (n = 13). In addition, novel PDE10 inhibitor, MCI-030, reduced tumor size and activated PDE10 signaling mechanisms in vivo. These findings suggest that PDE10 can be targeted for cancer therapy or prevention whereby inhibition results in cGMP elevation and PKG activation to reduce β-catenin-mediated transcription of survival proteins leading to the selective apoptosis of cancer cells.
Citation Format: Kevin J. Lee, Ashley S. Lindsey, Luciana Madeira da Silva, Alisa Trinh, Bernard Gary, Joel Andrews, Veronica Ramirez-Alcantara, Adam B. Keeton, Wen-Chi Chang, Margie Clapper, Gary A. Piazza. Beta-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 331.
Abstract 3310: Riboflavin targets autofluorescent-positive breast cancer stem cells upon light exposure
Authors: Fouladdel Shamileh , Luther Tahra , Harvey Kaitlin , Martin-Trevino Rachel , Granger Jill , Azizi Ebrahim , Wicha Max S. 
Published: July 2016

Abstract
Most tumors are hierarchically organized and driven by a population of cells that display stem cell properties. These cancer stem cells (CSCs) have been characterized by in vitro assays such as sphere formation and in vivo by tumor initiation. In addition cell surface markers have been utilized to enrich for CSC populations. More recently a subtype of CSCs have been reported to display autofluorescence (AF), a property mediated by cellular uptake and concentration of riboflavin. In order to characterize the molecular heterogeneity of CSCs, we studied AF positive sorted single cells in different subtypes of breast cancer cell lines and also patient derived xenograft (PDX) breast tumor cells. Exposure of cell lines and PDXs to riboflavin significantly increased the percentage of AF+ cells 3-5 fold. These sorted AF+ cells were enriched for tumorsphere forming capacity in vitro. Flow cytometry analysis revealed partial overlap of AF+ cells with the previously characterized EMT-CSC phenotype CD44+/CD24- cells. We also utilized the microfluidic C1 and BioMark HD instruments to determine the expression patterns of 96 target genes using TaqMan assays in a multiplex RT-qPCR setting at single cell resolution. Single cell gene expression data showed a distinct signature in AF+ cells with high expression levels of MKI67, PCNA, ABCG2, BRCA1, Jag2, EZH2, and MMP9 genes. Since AF is mediated by specific cellular uptake and concentration of riboflavin, and the report that riboflavin is capable of generating cytotoxic free radicals upon light exposure, we determined whether this property could be exploited to selectively target CSCs. The AF+ cells were cultured in the presence and absence of riboflavin, exposed to visible light and analyzed by MTT cytotoxicity assay. Data revealed significant cytotoxicity of riboflavin on AF+ cells that were exposed to visible light. In conclusion, AF+ cells show distinct cancer stem cell features and are sensitive to light-activated riboflavin. These findings will help better understanding of tumor biology to identify new target therapies for treatment of cancer patients.
Citation Format: Shamileh Fouladdel, Tahra Luther, Kaitlin Harvey, Rachel Martin-Trevino, Jill Granger, Ebrahim Azizi, Max S. Wicha. Riboflavin targets autofluorescent-positive breast cancer stem cells upon light exposure. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3310.
Abstract 3314: Targeting Hsp90 affects stem cell signaling in triple negative breast cancer
Authors: Ramamoorthy Prabhu , Rangarajan Parthasarathy , Jensen Roy , Anant Shrikant 
Published: July 2016

Abstract
Background: Triple Negative Breast Cancer (TNBC) exhibit dismal survival rates due to their propensity to develop distant metastases. Heat shock protein 90 (Hsp90) is a molecular chaperone that aids in the folding and maturation of various proteins involved in breast cancer progression and resistance to therapy. Many studies have also suggested that breast cancer's ability to proliferate, progress, and spread is due to the presence of a rare subpopulation of cancer stem cells. The aim of this study is to investigate the efficacy of HSP90 inhibitors celastrol and triptolide (from the Chinese herb “Thunder God of Vine” (Tripterygium wilfordii) on stem cells as a novel therapy for TNBC.
Methods: We performed in vitro studies using the TNBC cell lines BT20 and MDA-MB-231. We performed mammosphere assays to determine self-renewal capacity. For in vivo, we injected BT20 cells into flanks of athymic nude mice and treated with celastrol and triptolide at 3 mg/Kg bw and 0.25 mg/Kg bw, respectively.
Results: Both celastrol and triptolide significantly suppressed mammosphere size and number. Furthermore, expression of breast cancer stem cell markers DCLK1, ALDH1 and CD133 were significantly reduced in the two cell lines following treatment. Flow cytometry also suggested a significant reduction in DCLK1+, ALDH+ and CD133+ cells. Recently, Notch signaling has been shown to be critical for self-renewal of cancer stem cells. In cells treated with either celastrol or triptolide, there was a significant reduction in activated Notch intracellullar domain (NICD), and its downstream target Hes-1. However, in cells where we ectopically overexpressed NICD, neither compound was as potent as control, vector transfected cells in reducing 2D cell proliferation or 3D mammosphere formation, suggesting the direct role for inhibiting Notch activation as a mechanism of action for the two compounds. Furthermore, inhibition of Notch signaling pathway by using Υ-secretase inhibitor DAPT shows further reduction in mammosphere formation and Notch and its downstream target gene. We confirmed these finding in vivo using BT20 tumor xenografts grown in athymic nude mice. There was a reduction in the size and weight of tumors in mice treated with celastrol or triptolide. Western blot data showed that there is a decrease in activated Notch-1 protein and stem cell marker, DCLK1+ and ALDH+ in celastrol and triptolide treated xenograft tissue.
Conclusion: Taken together these data suggest that both celastrol and triptolide affect cancer stem cells in TNBC, in part through inhibition of Notch signaling.
Citation Format: Prabhu Ramamoorthy, Parthasarathy Rangarajan, Roy Jensen, Shrikant Anant. Targeting Hsp90 affects stem cell signaling in triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3314.
Abstract 3315: Breast cancer stem cell induction by COX-2 via EP4/PI3K-AKT/NOTCH-WNT axis: EP4 as therapeutic target
Authors: Majumder Mousumi , Xin Xiping , Liu Ling , Tutunea-Fatan Elena , Rodriguez-Torres Mauricio , Vincent Krista , Deweyert Andrew , Postovit Lynne-Marie , Hess David , Lala Peeyush K. 
Published: July 2016

Abstract
Cancer stem-like cells (SLC) resist conventional therapies, necessitating searches for SLC-specific targets. We established that cyclo-oxygenase(COX)-2 expression promotes human breast cancer progression by activation of the prostaglandin(PG)E-2 receptor EP4. Present study revealed that COX-2 induces SLCs by EP4-mediated NOTCH and WNT up-regulation. EP4 antagonist (EP4A) treatment ablated SLCs both in vitro and in vivo. Ectopic COX-2 over-expression in MCF-7 and SKBR-3 human breast cancer cell lines (named MCF-7-COX-2 and SKBR-3-COX-2) resulted in aggressive phenotypes: increased migration/invasion/proliferation, EMT, elevated SLCs, evidenced by spheroid formation for successive generations, increased ALDH activity and co-expression of COX-2/SLC markers. These changes were reversed with COX-2 inhibitor or EP4A, indicating dependence on COX-2/EP4 activities. COX-2 overexpression or EP4 agonist treatment of COX-2 low cells caused up-regulation of NOTCH/WNT pathway genes, blocked with PI3K/AKT inhibitors. Supporting above findings, micro-array analysis
showed up-regulation of numerous SLC-regulatory and EMT-associated genes in MCF-7-COX-2 cells. MCF-7-COX-2 cells showed increased orthotopic tumorigenicity and spontaneous multi-organ metastases in NOD/SCID/IL-2Rγ-deficient mice for successive generations with limiting cell inocula. Orthotopic tumors showed significant up-regulation of VEGF-A/C/D, Vimentin and phospho-AKT, down-regulation of E-Cadherin and enrichment of SLC marker positive and spheroid forming cells. MCF-7-COX-2 cells also showed increased lung colonization in NOD/SCID/GUSB-null mice, an effect reversed with EP4 knockdown or EP4A treatment. COX-2, EP4 and ALDH1A expression in situ in human breast cancer tissues were highly correlated with one other, more marked in progressive stage of disease. High COX-2/EP4 expression was linked with poor survival. Thus EP4 represents a novel SLC-ablative target in human breast cancer. (Supported by a grant of the OICR to PKL and a TBCRU fellowship to MM)
Citation Format: Mousumi Majumder, Xiping Xin, Ling Liu, Elena Tutunea-Fatan, Mauricio Rodriguez-Torres, Krista Vincent, Andrew Deweyert, Lynne-Marie Postovit, David Hess, Peeyush K. Lala. Breast cancer stem cell induction by COX-2 via EP4/PI3K-AKT/NOTCH-WNT axis: EP4 as therapeutic target. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3315.