bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3247: Granulocytic MDSCs (CD11b+CD15+CD14-HLADR-) in peripheral blood of mesothelioma patients are elevated and suppress T cell proliferation and function via reactive oxygen species
Authors: Khanna Swati , Mussai Francis , Thomas Anish , Middleton Gary , Yuan Constance , Morrow Betsy , Zhang Jingli , Pastan Ira , Stetler-Stevenson Maryalice , Hassan Raffit 
Published: July 2016

Abstract
The role of myeloid derived suppressor cells (MDSCs) in mediating tumor immunosuppression in patients with malignant mesothelioma has not been well characterized. The goal of our study was to analyze for the presence of both monocytic (Mo) and granulocytic (Gr) MDSCs in blood of mesothelioma patients, and characterize their mechanism of suppression of T cells responses. We evaluated the peripheral blood of patients (n = 23) for the presence of Gr-MDSC (CD11b+CD15+CD14-HLADR-) and Mo-MDSC (CD11b+CD14+HLADR-). Gr-MDSC (62.3±13.9% vs. 47.8±17.8%; p = 0.005) as well as monocytic MDSC (0.2±0.4% vs. 0.1±0.3%; p = 0.01) were significantly elevated in peripheral blood of mesothelioma patients as compared to healthy donors (n = 21). The frequency of Gr-MDSC was higher than Mo-MDSC. Thus, Gr-MDSCs appeared to be the main immunosuppressive population and were investigated further.Gr-MDSC from mesothelioma patients were found to inhibit the proliferation of both autologous CD4 and CD8 T cells (mean inhibition of proliferation of 61.9% for CD4 and 75.5% for CD8 at 1:2 T: Gr-MDSC ratio) and was accompanied by a decrease in IFN-γ released by T cells in the co-culture supernatants (92.4 pg/mL at 1:2 ratio). To determine the mechanism by which Gr-MDSC inhibit T cells, we tested the levels of reactive oxygen species (ROS), and nitrite oxide species and arginase activity in Gr-MDSC sorted from peripheral blood. Both arginase (0.3±0.3 vs. 0.2±0.3 μM) and nitrite levels (1.8±2.5 vs. 0 μM) in Gr-MDSC were below detection limit in both patients and donors and were marginally affected by the addition of their respective inhibitors (nor-NOHA and L-NMMA). However, the levels of ROS in Gr-MDSCs derived from mesothelioma patients were on average 3 folds higher than the Gr-myeloid cells from healthy donors (average MFI ∼15000 vs. ∼5000). In summary our results show that the major immunosuppressive cell population in mesothelioma patients are Gr-MDSCs and they suppress T cell proliferation and activation through release of reactive oxygen species.
Citation Format: Swati Khanna, Francis Mussai, Anish Thomas, Gary Middleton, Constance Yuan, Betsy Morrow, Jingli Zhang, Ira Pastan, Maryalice Stetler-Stevenson, Raffit Hassan. Granulocytic MDSCs (CD11b+CD15+CD14-HLADR-) in peripheral blood of mesothelioma patients are elevated and suppress T cell proliferation and function via reactive oxygen species. [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 3247.
Abstract 3249: Regulation of interferon regulatory factor-8 (IRF8) during myelopoiesis is a critical checkpoint for the formation of defective myeloid cells in cancer
Authors: Netherby Colleen S. , Messmer Michelle N. , Abrams Scott I. 
Published: July 2016

Abstract
Aberrant myelopoiesis is commonly observed in patients with solid cancers. This results in the production of myeloid-derived suppressive cells (MDSCs) which promote tumor growth and metastasis. However, the molecular mechanisms underlying MDSC development have remained poorly understood. The transcription factor IRF8 is integral for overseeing myelopoietic fate; high IRF8 expression during normal myelopoiesis favors monocytic differentiation and directly inhibits granulocytic differentiation. We recently showed that tumor-derived STAT3/5-activating cytokines downregulate the expression of IRF8 in myeloid cells leading to the accumulation of MDSCs in the periphery, which are primarily granulocytic. However it is unclear if MDSC production is a consequence of IRF8 downregulation in the periphery or upstream in the bone marrow during myelopoiesis. To that end, we utilized a novel mouse model expressing an IRF8-EGFP fusion protein which allowed us to investigate changes in IRF8 expression during both orthotopic and spontaneous mammary tumor growth and progression. Our results showed that: 1) the total granulocyte-monocyte progenitor (GMP) fraction, as with the peripheral MDSC population, was responsive to tumor burden and greatly expanded with increasing tumor size, and 2) IRF8 expression within the total GMPs significantly decreased during tumor growth, reflecting the expansion of a newly defined primarily IRF8lo granulocyte progenitor (GP) population, and 3) tumor-induced GPs were hyper-responsive not only to G-CSF, but also M-CSF to generate a ‘biased’ granulocytic MDSC-like phenotype. Expression of IRF8 in other progenitor populations was not affected, suggesting that IRF8lo GMPs/GPs are a key source of the peripheral MDSC response. Lastly, genetically enforced IRF8 expression in myeloid progenitors of the bone marrow constrained aberrant myelopoiesis during tumor growth, resulting in delayed autochthonous tumor growth and reduced spontaneous lung metastasis. Altogether, these data reinforce the notion that modulation of IRF8 in myeloid progenitors is an early consequence of the neoplastic process and a potential target for therapeutic intervention.
NIH R01CA140622
NIH T32CA085183
Citation Format: Colleen S. Netherby, Michelle N. Messmer, Scott I. Abrams. Regulation of interferon regulatory factor-8 (IRF8) during myelopoiesis is a critical checkpoint for the formation of defective myeloid cells in 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 3249.
Abstract 3260: Differential effects of antiangiogenesis treatments on betel-nuts-related head and neck squamous cell carcinoma in Taiwan
Authors: Chen Jo-Pai , Chang Jui-Ying , Kuo Sung-Hsin , Hong Ruey-Long 
Published: July 2016

Abstract
Background:
The treatment of head and neck squamous cell carcinoma(HNSCC) in Taiwan is very challenging and might be related to betel-nuts use. Betel-nuts chewing might contribute to (1)strong inflammation, invasion, and angiogenesis; (2)easy recurrence or metastasis; (3) poor response to chemotherapy, radiation, and epidermal growth factor receptor(EGFR) inhibitors.
Purpose:
We try to prove different kinds of anti-angiogenesis treatments will lead to different response on betel-nuts related HNSCC in Taiwan.
Methods:
Different anti-angiogenesis treatments, such as axitinib(VEGFR2 inhibitor), nintedanib(VEGFR2/FGFR inhibitor), and regorafenib(VEGFR2/FGFR/ more other signals inhibitor) were first used to treat (1)HUVEC; (2)HNSCC cell lines(SCC4, SCC9, SCC15, SCC25, FaDu, SAS, KB, Cal27, and TW2.6, betel-nuts related) to evaluate (a) invasion capacity by wound healing; (b) drug sensitivity by MTT assay; (c)synergistic effect with chemotherapy, EGFR inhibitor, and polo-like kinase inhibitor. Western blotting was also used to test signal change by treatments. TW2.6 had already been proved to possess defective p53, p16 loss, and increased Bcl2.
Results:
In our previous study, TW2.6 was resistant to chemotherapy, radiation, EGFR inhibitors, and ani-angiogenesis treamtents, such as axitinib and sunitinib. Axitinib, pure VEGFR2 inhibitor, was found to suppress HUVEC more prominently than nintedanib or regorafenib did. Invasion capacity of all HNSCC cell lines were all blocked by the three drugs but regorafenib did mostly well. However, axitinib had no effect on TW2.6; but nintedanb and regorafenib had moderate response on TW2.6. Besides, nintedanib and regorafenib both would resensitize TW2.6 to respond to chemotherapy, EGFR inhibitor, and polo-like kinase inhibitor again. Western blotting showed mesenchaml differentiation markers(slug, Twist, snail, Axl, c-MET, Vimentin) decreased after nintedanib and regorafenib use, too.
Conclusion:
TW2.6 might reflect treatment refractoriness of betel-nuts related HNSCC in Taiwan. In addition to PI3K/mTOR dual inhibition and polo-like kinase inhibitor with radiation(our studies shown in AACR and ESMO2015), VEGFR2/FGFR dual blockage might be effective on TW2,6 and resensitize TW2.6 to EGFR inhibitor, polo-like kinase inhibitor, & chemotherapy, maybe through the inhibition of mesenchymal transformation. VEGFR2/FGFR dual blockage will be one future combination backbone of betel-nuts related HNSCC.
Citation Format: Jo-Pai Chen, Jui-Ying Chang, Sung-Hsin Kuo, Ruey-Long Hong. Differential effects of antiangiogenesis treatments on betel-nuts-related head and neck squamous cell carcinoma in Taiwan. [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 3260.
Abstract 3263: Dietary supplement 3, 3’-diindolylmethane (DIM) as an antiangiogenic agent in breast cancer
Authors: Ben Rahoma Ghada M. , Tuli Neha Y. , Bednarczyk Robert B. , Maniyar Rachana R. , Mittelman Abraham , Geliebter Jan , Tiwari Raj 
Published: July 2016

Abstract
Tumor angiogenesis refers to the sprouting and cooption of proliferating endothelial cells (EC’s) from adjacent pre-existing host vasculature, and is a key target of cancer therapy. Tumor cells exploit their microenvironment by releasing cytokines and growth factors to promote and support angiogenesis. Within this complex tumor microenvironment, we and others have shown that tumors can recruit bone marrow derived endothelial progenitor cells that differentiate into mature bone marrow-derived endothelial cells and incorporate into sprouting tumor neovessels. Under pathological circumstances, such as breast cancer, a clear association between estrogen receptor expression by EC’s, angiogenic activity, and/or tumor invasiveness has been made. Approximately, 80% of breast cancers are hormone-receptor-positive cancers, thus enabling tamoxifen as the mainstay of breast cancer therapy. The roles of the anti-estrogens fulvestrant (ICI) and the dietary supplement 3, 3’-diindolylmethane (DIM) on cell-cell interaction and angiogenesis have not been fully elucidated. This study is designed to evaluate and compare the effect of these antiestrogens on angiogenesis at the cellular and molecular levels using tube formation of human umbilical vein endothelial cells (HUVEC) as an in vitro angiogenesis model. HUVEC cells were treated with serial dilutions of either DIM or ICI in presence and absence of (3nM) estrogen, and subjected to in vitro tube formation, proliferation, migration, and angiogenesis antibody array assays. We report that HUVEC cells are more sensitive to DIM than ICI. At 25 μM concentration, DIM significantly inhibited the crucial steps of angiogenesis including HUVEC cells proliferation, migration, cytokine release, and tube formation in an estrogen independent manner. On the other hand, at 1 μM concentration, ICI significantly exerted an antiangiogenic effects inhibiting HUVEC cells proliferation, migration, and tube formation, but this effect was totally dependent on the presence of estrogen. These results are validated by our observation that HUVEC cells express estrogen receptor beta (ER-β) and not estrogen receptor alpha (ER-α). A correlative effect between the antiangiogenic activity of DIM and ER-β upregulation was noted. We believe that the anti-estrogenic activity of DIM is mediated through the genomic and non-genomic activity of ER-β in endothelial cells predicting a new target for DIM to manifest its antiangiogenic effect.
Citation Format: Ghada M. Ben Rahoma, Neha Y. Tuli, Robert B. Bednarczyk, Rachana R. Maniyar, Abraham Mittelman, Jan Geliebter, Raj Tiwari. Dietary supplement 3, 3’-diindolylmethane (DIM) as an antiangiogenic agent in 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 3263.
Abstract 3267: Eltd1 as an anti-angiogenic therapy against glioma tumors
Authors: Ziegler Jadith , Smith Nataliya , Saunders Debra , Evans Blake , Battiste James D. , Sughrue Michael , Tompkins Paul , Sutton Jake , Lerner Megan , Coutinho de Souza Patricia , Fung Kar-Ming , Wren Jonathan , Towner Rheal 
Published: July 2016

Abstract
Gliomas consist of up to 80% of malignant brain tumors that are invasive and typically resistant to radiotherapy and chemotherapy. Finding biomarkers to high-grade gliomas can enable better diagnosis and therapeutic intervention for this disease. We have identified ELTD1 as a biomarker for high-grade human gliomas. Here, we report our findings in vivo using anti-ELTD1 (at two different concentrations), Bevacizumab, and IgG antibodies on human G55 xenograft glioma models. Using MRI, we investigate tumor growth, perfusion, tumor blood flow, and microvessel density changes in mice. In addition, survival rates were measured.
Mice were implanted with human G55 xenograft glioma cells and were left untreated, administered anti-ELTD1, (1 mg/kg or 2 mg/kg every 2-3 days) Bevacizumab (2 mg/kg every 2-3 days) or IgG (1 mg/kg every 2-3 days). MRI experiments were performed to assess tumor growth and calculate tumor volumes. In order to assess angiogenesis, representative histology slides were obtained and stained for blood vessels using CD34 antibody and microvessel density (MVD) was then calculated. Finally, cerebral blood flow rates from MR perfusion imaging was obtained as well as MR angiography to determine tumor blood volume from mice in each group.
Our results show a significant decrease in tumor volumes and increase in percent survival for mice treated with 1 mg/kg and 2 mg/kg of ELTD1 antibody compared to untreated mice and IgG treated mice. Mice also had an increase in perfusion, decrease in tumor blood volume and decrease in MVD. Anti-ELTD1 antibody therapy reduced tumor volumes, prolonged life, and overall decreased angiogenesis in our mouse model. Anti-ELTD1 therapy may be an ideal anti-angiogenic treatment for high-grade gliomas.
Citation Format: Jadith Ziegler, Nataliya Smith, Debra Saunders, Blake Evans, James D. Battiste, Michael Sughrue, Paul Tompkins, Jake Sutton, Megan Lerner, Patricia Coutinho de Souza, Kar-Ming Fung, Jonathan Wren, Rheal Towner. Eltd1 as an anti-angiogenic therapy against glioma tumors. [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 3267.
Abstract 3269: Recapitulating the BETH adjuvant breast cancer trial (NCT00625898) using clinically accurate orthotopic surgical resection models
Authors: Shiels Liam S. , Miller Ian S. , Morgan Clare , Cremona Mattia , Kerbel Robert , Hennessey Bryan , O’Donovan Norma , Crown John , Byrne Annette T. 
Published: July 2016

Abstract
Background: An overwhelming majority of phase III clinical trials in the oncology setting fail as promising results observed in the ‘pre-clinic’ are not successfully translated to patients. As such, improved models which more accurately predict outcomes are now required. Herein, we have established orthotopic surgical resection models of Her2+ breast cancer, which replicate the phenotype of clinical post-resection metastasis [1,2]. Using these models we have recapitulated the BETH adjuvant breast cancer trial (NCT00625898) where the addition of bevacizumab (BVZ) to chemotherapy plus trastuzumab (TRAST) failed to provide additional benefit in the adjuvant setting. Methods: SCID mice were orthotopically implanted with bioluminescent Her2+ MDA-MB-231or HCC1954 cells and palpable tumors resected approximately 5 weeks later. 3 weeks after resection, mice were treated with 10 mg/kg TRAST + 5mg/kg paclitaxel IP once weekly for 6 cycles with or without weekly BVZ (5mg/kg IP). Metastasis was monitored by weekly bioluminescence imaging. Results: Tumor growth and imaging data confirmed that the addition of BVZ to adjuvant TRAST + chemotherapy provided no additional benefit compared with TRAST + chemotherapy alone. Previous pre-clinical studies using inappropriate non-resection models failed to predict this response. Furthermore, Reverse Phase Protein Array analysis of treated tumors implicated HER2, VEGF, mTOR and the intrinsic mitochondrial cell death apoptotic pathways in treatment resistance. Conclusion: In summary, our data provides evidence for pre-clinical models which better predict clinical outcome in the breast cancer adjuvant setting, and which represent an important resource for interrogating resistance pathways and identifying novel biomarker signatures. [1]. Breast. 2013 Aug;22 Suppl 2:S57-65; [2]. Cancer Res. 2013 May 1;73(9):2743-8.This work was performed under Irish HPRA Authorization AE18982 and was supported by the Clinical Cancer Research Trust. ATB receives funding from the Irish Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT Grant (CCRC13GAL).
Citation Format: Liam S. Shiels, Ian S. Miller, Clare Morgan, Mattia Cremona, Robert Kerbel, Bryan Hennessey, Norma O’Donovan, John Crown, Annette T. Byrne. Recapitulating the BETH adjuvant breast cancer trial (NCT00625898) using clinically accurate orthotopic surgical resection models. [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 3269.
Abstract 3270: Myriocin, an inhibitor of serine palmitoyltransferase activity, has the anti-angiogenic effect by attenuating VEGF-induced angiogenesis signaling pathway
Authors: Lee Sun Hee , Jung Yuk Dong , Lee Hye-Eun , Lee You Mie 
Published: July 2016

Abstract
Myriocin is a powerful serine palmitoyl transferase inhibitor, by inhibiting of sphingosine biosynthesis. Myriocin is also known to have immunosuppressive activity. Here, we demonstrate the anti-angiogenic effect of myriocin. Myriocin decreased vascular endothelial cell growth factor (VEGF)-induced angiogenic process, that include proliferation, migration, invasion, tube formation and cell adhesion in human umbilical vein endothelial cells (HUVECs). Myriocin down-regulated VEGF-induced VEGFR2, focal adhesion kinase, AKT kinase, rho-associated coiled-coil-containing protein kinase 1 (ROCK1) and matrix metalloproteinase-2 (MMP2) expression. Myriocin greatly reduced new vessel formation in chick chorioallantoic membrane and vessel sprouting in mouse aortic ring assay. Furthermore, VEGF-induced phalloidin expression was inhibited by miyriocin in HUVECs. Our result indicated that myriocin inhibited VEGF-induced proliferation, migration, invasion, tube formation and cell adhesion in vitro by inhibiting VEGFR2-mediated activation of FAK, AKT, ROCK1 and MMP2. Taken together, we suggest that myriocin may act as significant angiogenic inhibitor by inhibiting VEGF-induced signaling pathway.
Citation Format: Sun Hee Lee, Yuk Dong Jung, Hye-Eun Lee, You Mie Lee. Myriocin, an inhibitor of serine palmitoyltransferase activity, has the anti-angiogenic effect by attenuating VEGF-induced angiogenesis signaling pathway. [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 3270.
Abstract 3277: Prion-like protein “Doppel” is a selective therapeutic target for tumoral angiogenesis
Authors: Al-Hilal Taslim , Yang Yoosoo , Kim In-San , Byun Youngro , Ahsan Fakhrul 
Published: July 2016

Abstract
Regulating growth factor signaling in a controlled and site-specific manner is the main hurdle that current antiangiogenic treatment modalities face. Here we show that the prion-like protein, doppel, is uniquely found in tumoral endothelial cells (TEC) but not in the normal ECs. Tissue sections containing primary human tumor (lung and colon) and normal tissues were used to study doppel protein expression. Strong expression and clear co-localization of doppel protein with CD34, a classical endothelial marker, was observed in both lung and colon cancer tissues compared to normal tissues. To evaluate doppel expression at the molecular level, we isolated TECs from different tumors derived from mouse xenografts. Extensive analysis showed that doppel was highly and ubiquitously expressed in the vasculature of squamous, breast, lung, and colon cancers. To elucidate the role of doppel in TEC during tumor angiogenesis, we generated a gain-of-function EC model to express doppel in ECs. Inducible overexpression of doppel in ECs correlates with high vessel formation in a spheroid-based EC transplantation technique. To integrate doppel expression with the canonical angiogenic circuits, we studied the mechanism by which doppel regulates angiogenesis. We evidently observed that doppel co-localized and formed complexes with vascular endothelial growth factor receptor 2 (VEGFR2). Also, doppel prolonged the surface residency of VEGFR2 and amplified the responsiveness of VEGF to VEGFR2. Genetic deletion of doppel in TEC not only depleted membrane residency but also induced internalization and degradation of VEGFR2. This indicates that doppel blocking can lead to effective control of VEGF-signaling in TECs and selective inhibition of tumor angiogenesis. Based on the functional role of doppel in angiogenesis and tumor growth inhibition, we generated doppel knockout mice on immunogenic C57BL6 mice. Tumor growth was inhibited in both hetero (Dpl+/-) and homo (Dpl-/-)-type mice compared to their wild-type littermate controls when syngeneic cancer cell lines including melanoma (B16f10) and lymphoma (EL4) or allogeneic colon cancer CT26 cell line were inoculated. Moreover, we developed doppel targeting monoclonal antibodies. Anti-doppel antibodies, 5C7 and 4D6, were effective against both murine CT26 and human HCT116 colon cancer cell lines. Our studies thus demonstrate the success of doppel targeting in inhibiting pathological tumor growth and establish doppel-VEGFR2 interactions as a specific molecular and therapeutic target in tumoral angiogenesis.
Citation Format: Taslim Al-Hilal, Yoosoo Yang, In-San Kim, Youngro Byun, Fakhrul Ahsan. Prion-like protein “Doppel” is a selective therapeutic target for tumoral angiogenesis. [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 3277.