bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 718: Macrophage PI3Kgamma signaling promotes cancer immune suppression
Authors: Kaneda Megan M. , Varner Judith A. 
Published: July 2016

Abstract
Innate immune cells can switch from a pro-inflammatory state that defends against pathogens and to an anti-inflammatory state that repairs damaged tissue. Pro-inflammatory myeloid cells activate cytotoxic T cells to eliminate pathogens, but anti-inflammatory myeloid cells inhibit T cell mediated immunity, stimulate angiogenesis, and stimulate fibrosis, all of which promote tumor progression. The predominant isoform of PI(3)Kinase in myeloid cells, PI3Kgamma, controls the switch between immune stimulation and immune suppression during inflammation and cancer. Myeloid cell PI3Kgamma and its effectors Akt1, mTor, and S6Kinase stimulate C/EBPbeta-dependent expression of immunosuppressive factors, including Arginase and TGFbeta, but suppress NFkappaB-dependent expression of pro-inflammatory cytokines such as IL12 and IFNgamma, thereby inducing tumor immune suppression and consequent tumor growth and metastasis.
In contrast, inhibition of PI3Kgamma activity by genetic or pharmacological means suppresses C/EPBbeta-mediated transcription of anti-inflammatory factors and stimulates NFkappaB-mediated transcription of the pro-inflammatory cytokines IL12 and IFNgamma, thereby restoring CD8+ T cell-dependent cytotoxicity that inhibits tumor growth and metastasis. Therefore, inhibitory targeting of PI3Kgamma indirectly restores cytotoxic T cell immune responses that elicit tumor suppression without unwanted side effects. Our studies highlight the strong therapeutic potential of targeting this kinase to control inflammation and cancer.
This work was supported by grants to JAV from the NIH (5R01CA126820), the Landon Foundation-AACR (12-60-27-VARN), the Lustgarten Foundation for Pancreatic Research and the Whitworth Foundation for Cancer Research.
Citation Format: Megan M. Kaneda, Judith A. Varner. Macrophage PI3Kgamma signaling promotes cancer immune suppression. [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 718.
Abstract 722: MYB promotes pancreatic tumor associated-desmoplasia by up-regulating Sonic hedgehog and adrenomedullin
Authors: Bhardwaj Arun , Srivastava Sanjeev K. , Tyagi Nikhil , Arora Sumit , Singh Seema , Carter James E. , Singh Ajay P. 
Published: July 2016

Abstract
Pancreatic cancer (PC) stands as the fourth leading cause of cancer-related death in the United States. Unfortunately, even with the emergence of tumor-targeted therapies, the 5-year survival rate of PC continues to remain very dismal (∼ 7.0%). The presence of dense desmoplastic region at the tumor site is a prominent pathological characteristic of PC, and tumor-associated desmoplasia is suggested to limit the therapeutic efficacy by acting as a physical barrier for drug delivery. In addition, it plays pivotal roles in promoting the survival and aggressive phenotypes of tumor cells. Therefore, it is of utmost importance that we identify novel gene targets and associated molecular mechanisms accountable for the development of desmoplasia in pancreatic tumors. Our recent study provided first evidence for a role of MYB, an oncogenic transcription factor, in pancreatic tumor growth and metastasis. Upon histological examination of orthotopic tumor xenografts derived from MYB-overexpressing and -silenced pancreatic tumor cells, we noticed a positive association of MYB expression with the extent of desmoplastic reaction. This finding was further confirmed by staining the tumor xenograft sections with Collagen-I, fibronectin and á-SMA, the well-characterized markers of desmoplasia. In a co-culture experiment, we observed that MYB-overexpressing pancreatic tumor cells promoted greater proliferation of pancreatic stellate cells (PSCs) as compared to the MYB-silenced cells further supporting a role of MYB in desmoplasia. From the mechanistic standpoint, we identified MYB to be novel direct regulator of Sonic hedgehog (SHH) and Adrenomedullin (ADM) expression in PC cells as confirmed by chromatin immunoprecipitation (ChIP) analysis. Treatments of pancreatic tumor (high or low MYB) and stellate cells co-culture with specific inhibitors and/or recombinant SHH and ADM demonstrated that both SHH and ADM cooperatively mediated the effect of MYB on PC and stellate cells via autocrine and/or paracrine mechanisms. Together, our studies suggest that MYB promotes malignant phenotype of PC not only by directly impacting the tumor cells, but also by altering the tumor microenvironment.
Citation Format: Arun Bhardwaj, Sanjeev K. Srivastava, Nikhil Tyagi, Sumit Arora, Seema Singh, James E. Carter, Ajay P. Singh. MYB promotes pancreatic tumor associated-desmoplasia by up-regulating Sonic hedgehog and adrenomedullin. [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 722.
Abstract 730: The roles of FGF-2-NCAM/FGFR1 interplay in esophageal squamous cell carcinomas and its microenvironment including tumor-associated macrophages
Authors: TAKASE NOBUHISA , Koma Yuichiro , Arai Noriaki , Kodaira Himiko , Hosono Masayoshi , Ichihara Yumi , Nishio Mari , Shigeoka Manabu , Yokozaki Hiroshi 
Published: July 2016

Abstract
Tumor-associated macrophages (TAMs) have important roles in the angiogenesis, tumor immunosuppression and tumor infiltration of various cancers. Previously, we reported that a large number of infiltrated tumor promoting CD204+ TAMs within esophageal squamous cell carcinomas (ESCCs) contributed to the significant association of clinicopathological malignancy and poor disease free survival. However, the relevant malignant progression mechanisms have not been studied explicitly yet. To elucidate roles of TAMs in ESCCs, we established an in vitro macrophage model using human peripheral blood acquired by healthy volunteer donors. Peripheral blood monocytes were treated with 25 ng/mL recombinant human M-CSF for 6 days to induce macrophage-like differentiation (macrophage-like cells), then exposed to the conditioned media of TE series ESCC cell lines (TECM) for 2 days to induce TAM-like cells. From the cDNA microarray data between macrophages-like cells treated with and without TECM, we interested in upregulated genes. Among highly expressed genes in TAM-like cells, we focused on neural cell adhesion molecule (NCAM) which was a possibility to act on the regulation between tumor and its surrounding stroma. Gene knockdown of NCAM by siRNA in TAM-like cells revealed significant suppression of cell survival and migration via decrease of PI3K/Akt signaling and downregulation of fibroblast growth factor receptor 1 (FGFR1) expression. Interestingly, fibroblast growth factor-2 (FGF-2) derived from ESCCs promotes FGF2/FGFR1 autocrine loop, and activates FGFR1 signaling in TAM-like cells. Furthermore, we analyzed 70 ESCC tissue samples by immunohistochemistry whether the expression levels of FGF-2 were associated with clinicopathological background factors of ESCC patients. Relationships of the expression levels of FGF-2 in human ESCC stromal cells including macrophages had a correlation with the depth of invasion, blood vessel invasion, TNM classification UICC cancer staging and high number of infiltrating CD163 positive and CD204 positive macrophages as a marker for the M2 macrophage phenotype. These findings may indicate novel roles of FGF-2-NCAM/FGFR1 interplay in ESCCs and its microenvironment including TAMs.
Citation Format: NOBUHISA TAKASE, Yuichiro Koma, Noriaki Arai, Himiko Kodaira, Masayoshi Hosono, Yumi Ichihara, Mari Nishio, Manabu Shigeoka, Hiroshi Yokozaki. The roles of FGF-2-NCAM/FGFR1 interplay in esophageal squamous cell carcinomas and its microenvironment including tumor-associated macrophages. [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 730.
Abstract 734: Role of TGF-â in myeloid regulation of tumor-induced bone disease
Authors: Buenrostro Denise , Merkel Alyssa , Sterling Julie 
Published: July 2016

Abstract
Bone is one of the most common metastatic sites for breast cancer, where nearly 70% of patients that die from disease have reported skeletal metastases upon autopsy. Specifically in the bone microenvironment, TGF-â has a complex role in the regulation of tumor growth and is critical for the initiation and continuation of bone destruction, an important parameter of tumor-induced disease. Previous publications have demonstrated that TGF-â can affect myeloid cells by increasing their expansion in the tumor microenvironment and modulating host immune surveillance, thus supporting a tumor promoting environment. Therefore, we hypothesize that inhibition of TGF-â will decrease tumor-induced bone disease by reducing myeloid expansion and tumor growth in bone. To address this we injected mice with the TGF-â inhibitory antibody, 1D11, one week prior to tumor inoculation and continuously treated until sacrifice where myeloid expansion and parameters of tumor-induced bone disease were measured. Two mouse models were used to assess the importance of the immune system, an immunodeficient model inoculated with human breast cancer cells (MDA-MB-231) and a syngeneic model using murine breast cancer cells (4T1). Flow cytometry analysis revealed that TGF-â inhibition decreased a triple positive myeloid population (CD11b+F4/80+Gr-1+) in mice sacrificed at day 28 by five percent. This triple positive myeloid cell population has been associated with supporting tumor progression. Surprisingly our flow cytometry analysis demonstrated that myeloid-derived suppressor cells (MDSCs: CD11b+GR-1+) remained unchanged when TGF-â was inhibited. Micro-CT analysis demonstrated that 1D11 treated mice had a 2-fold increase in bone volume and connective density compared to control mice. X-ray analysis demonstrated that control mice had greater than 2-fold osteolytic bone destruction compared to mice treated with the TGF-â inhibitory antibody. Histomorphometric analyses suggests that TGF-â inhibition reduces tumor burden, increases osteoclast cell numbers and modulates macrophage cell populations. Together these results suggest that inhibiting TGF-â prior to tumor inoculation and subsequently after may prevent expansion of a tumor-promoting myeloid population and promote a bone-phenotype that does not support tumor growth in bone. Future studies will focus on investigating specific myeloid factors and assessing whether TGF-â inhibition decreases expression of these pro-tumorigenic factors.
Citation Format: Denise Buenrostro, Alyssa Merkel, Julie Sterling. Role of TGF-â in myeloid regulation of tumor-induced bone disease. [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 734.
Abstract 741: Insulin-like growth factor binding protein-3 (IGFBP-3) enhances obesity-related breast tumorigenesis
Authors: Scully Tiffany , Scott Carolyn D. , de Silva Hasanthi C. , Firth Sue M. , Twigg Stephen M. , Pintar John E. , Baxter Robert C. 
Published: July 2016

Abstract
Introduction and Aim: Epidemiological studies have shown an association between obesity and poor breast cancer prognosis. We have reported that IGFBP-3 influences both breast cancer growth and adipocyte maturation. This study investigated the role of endogenous IGFBP-3 on the development of obesity and subsequently on breast tumor growth. Methods: Wild-type (WT) C57BL/6 or IGFBP-3 knock-out (BP3KO) mice were fed either a high-fat diet (HFD) or control chow diet for 15 weeks, then injected with the syngeneic mouse breast cancer cell line E0771 in the 4th left mammary gland. When the largest tumor reached 1000 mm3, tissues including the mammary fat pad were excised, formalin-fixed and paraffin-embedded for immunohistochemical analysis. Results and Conclusion: Compared to WT mice, BP3KO mice showed both significantly reduced weight gain and mammary fat pad mass (contralateral to tumor) in response to HFD (p &lt; 0.0001, 1-way ANOVA), despite similar food intake between WT and BP3KO mice on HFD. E0771 tumor weight and volume were overall increased by HFD independent of IGFBP-3 status (p = 0.051), and decreased in BP3KO mice independently of diet (p &lt; 0.001, 2-way ANOVA). Despite differences in tumor volumes and weights, tumors from WT and BP3KO mice did not show differences in either the number of mitotically active (Ki67+) or apoptotic (cleaved caspase-3+) cells. Tumors from BP3KO mice however, showed greater infiltration of CD3+ T-cells compared to WT mice (p = 0.0299, 2-way ANOVA). WT and BP3KO mice showed similar intra-tumoral mean vessel densities (CD31+ area) but differed in terms of the relationship between vessel density and final tumor volume. Increased vessel density was associated with decreased tumor volume in BP3KO mice (r = -0.62, p = 0.03, Spearman's correlation test) in contrast to the increased vessel density associated with increased tumor volume in wild-type mice (r = 0.63, p = 0.02, Spearman's correlation test). These data suggest that endogenous (circulating and/or stromal) IGFBP-3 (i) has a potentially stimulatory role in the expansion of adipose tissue, (ii) can enhance mammary tumor growth in immune-competent mice, potentially by influencing T-cell infiltration into the tumor and (iii) may influence the relationship between tumor vascularity and growth.
Citation Format: Tiffany Scully, Carolyn D. Scott, Hasanthi C. de Silva, Sue M. Firth, Stephen M. Twigg, John E. Pintar, Robert C. Baxter. Insulin-like growth factor binding protein-3 (IGFBP-3) enhances obesity-related breast tumorigenesis. [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 741.
Abstract 742: A novel multidrug metronomic chemotherapy significantly delays tumor growth in mice
Authors: Tagliamonte Maria , Petrizzo Annacarmen , Tornesello Maria Lina , Luciano Antonio , Rea Domenica , Barbieri Antonio , Arra Claudio , Napolitano Maria , Ciliberto Gennaro , Buonaguro Franco M. , Buonaguro Luigi 
Published: July 2016

Abstract
The tumor immunosuppressive microenvironment represents a major obstacle to an effective tumor-specific cellular immune response.
We have previously shown that a novel multi-drug chemotherapy administered in a metronomic fashion was able to increase immune response to peptides. The chemotherapy consisted of a cocktail including taxanes (paclitaxel and docetaxel) and alkylating (cyclophosphamide) agents. The newly designed strategy was shown to be safe, well tolerated and significantly efficacious (Tagliamonte et al., CII 2015).
In the present study, the effect on the immunosuppressive tumor microenvironment by the same multi-drug cocktail was evaluated in a mouse model upon sub-cutaneous ectopic implantation of B16 melanoma cells.
Treated animals showed a remarkable delay in tumor growth and prolonged survival as compared to control group. Such an effect was directly correlated with CD4+ T cell reduction and CD8+ T cell increase. A significant reduction in the percentage of both CD25+FoxP3+ and CD25+CD127low regulatory T cell population was found in the spleens as well as in the tumor lesions. An intrinsic CD8+ T cell response specific to B16 naturally expressed Trp2 TAA was observed. The same metronomic chemotherapy combined to a vaccine based on mutated antigens, was subsequently shown to increase immune response to vaccine resulting in a significant delay of B16 tumor growth as well as animal survival.
The novel multi-drug daily metronomic chemotherapy evaluated in the present study was very effective in counterbalancing the immunosuppressive tumor microenvironment and enhancing vaccine efficacy. Consequently, the intrinsic as well as vaccine-induced anti-tumor T cell immunity could exert its function containing tumor growth.
Overall, the described metronomic chemotherapy may represent a promising adjuvant approach to enhance anti-tumor cellular immunity and amplify the biological effects of therapeutic cancer vaccines.
Citation Format: Maria Tagliamonte, Annacarmen Petrizzo, Maria Lina Tornesello, Antonio Luciano, Domenica Rea, Antonio Barbieri, Claudio Arra, Maria Napolitano, Gennaro Ciliberto, Franco M. Buonaguro, Luigi Buonaguro. A novel multidrug metronomic chemotherapy significantly delays tumor growth in mice. [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 742.
Abstract 75: CellMiner, a systems pharmacological web-application for the NCI-60 cancerous cell-lines: Updates, data integration, and translationally relevant results
Authors: Reinhold William C. , Sunshine Margot , Varma Sudir , Doroshow James , Pommier Yves 
Published: July 2016

Abstract
Understanding the influences of molecular alterations on pharmacological responses in the omic sense is at the fore of the effort to make oncology more effective and specific. At present, however, this remains a field in its infancy. The NCI-60 cancerous cell lines provide a premier set of databases for systems molecular pharmacological studies. This is due to the availability of both the robust, high-quality activity profiles generated by the Developmental Therapeutics Program (https://dtp.cancer.gov), and the panoply of molecular and phenotypic information available. The CellMiner web-application (http://discover.nci.nih.gov/cellminer) provides the user access to both of these. Activity data is available for 20,861 compounds, including 159 Food and Drug Administration (FDA)-approved, 85 clinical trial, and 443 known mechanism-of-action drugs. The molecular data includes transcript expression for 25,772 genes, genetic variants for 16,568 genes, transcript expression for 360 microRNAs, protein levels for 94 genes, DNA copy number (from aCGH) for 23,413 genes, and soon DNA methylation levels for 17,559 genes. “Cell line signatures” are provided for each of these data types, facilitating their comparison. It also provides “Pattern comparisons” for any input pattern of interest to 87,419 activity, molecular and phenotypic patterns (For CellMiner 1.7).
Here we present our CellMiner updates, examples of data integration, and translationally relevant results.
Citation Format: William C. Reinhold, Margot Sunshine, Sudir Varma, James Doroshow, Yves Pommier. CellMiner, a systems pharmacological web-application for the NCI-60 cancerous cell-lines: Updates, data integration, and translationally relevant results. [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 75.
Abstract 759: Sunitinib has opposite roles to regulate the myeloid-derived suppressor cells in tumors and peripheral blood
Authors: Chen Fang-Hsin , Fu Sheng-Yung , Wang Chun-Chieh , Chiang Chi-Shiun , Hong Ji-Hong 
Published: July 2016

Abstract
Recent studies indicate that sunitinib, a tyrosine kinase inhibitor, could decease accumulation of myeloid-derived suppressor cells (MDSC) in tumors and also in peripheral blood. This study aims to investigate the behavior and dynamic profile of myeloid-derived suppressor cells in tumor tissues and peripheral blood of sunitinib-treated mice bearing prostate adenocarcinoma TRAMP-C1 tumors. To this end, 3×106 TRAMP-C1 tumor cells were inoculated at shank muscle of C57BL6/J mouse and sunitinib was administered by intraperitoneal injection of a daily dose of 20mg/kg into mice bearing 4 mm diameter tumor. Comparing to tumors in untreated group, sunitinib administration slightly delayed tumor growth delay for 2 days, but significantly decreased micro-vascular density and induced chronic hypoxia in tumors, resulting in the specific accumulation of CD11b+Gr-1+ MDSCs at the tumor necrotic region within CA-IX positive chronic hypoxic area. Flow cytometry was used to analyze the change of CD11b+ myeloid cells within tumor tissues and peripheral blood. Results showed that sunitinib treatment decreased the percentage of CD11b+Ly6G-LyC- tumor-associated macrophages (TAMs), but increased the percentage of CD11b+Ly6G-Ly6C+ monocytic MDSCs (M-MDSCs) while had no effect on CD11b+Ly6G+Ly6C+ neutrophilic MDSCs (N-MDSCs) within tumor tissues. In contrast, both the percentage of N-MDSCs and M-MDSC were expanded in peripheral blood of sunitinib-treated mice. Multiplex immunoassay showed significant increase of CCL2, CCL3, CCL5, CXCL5, IL-17a, GM-CSF, G-CSF and VEGF-A in tumor tissues, but only CXCL5, IL-á, IL-6 and G-CSF in the peripheral blood of sunitinib-treated mice were affected. In conclusion, this study shows that sunitinib has anti-vascular effect and could disrupt the recruitment of CD11b+Ly6G-Ly6C- TAMs into tumors. We also propose that sunitinib might exert different effects on tumor microenvironment and peripheral blood.
Citation Format: Fang-Hsin Chen, Sheng-Yung Fu, Chun-Chieh Wang, Chi-Shiun Chiang, Ji-Hong Hong. Sunitinib has opposite roles to regulate the myeloid-derived suppressor cells in tumors and peripheral blood. [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 759.