bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1405: Deficiency of Fes tyrosine kinase expression correlates with delayed mammary tumor onset in a HER2/Neu over-expressing transgenic mouse model.
Authors: Zhang Connie S. , Greer Peter A. 
Published: August 2014

Abstract
Fes (a.k.a. Fps) is a cytoplasmic protein tyrosine kinase that is highly expressed in breast epithelial cells during lactation, as well as in vascular endothelial and myeloid cells. Retrovially encoded oncogenic alleles of Fes are associated with tumors in chickens and cats and cause tumors in transgenic mice; however, a role for Fes in human cancer has not been established.
Using an orthotopic mouse mammary engraftment model, we previously found that Fes deficiency correlated with reduction in engrafted tumor growth rates, lung metastasis, and circulating tumor cells. Reduced vascularity and fewer infiltrating macrophages suggested the tumor microenvironment of Fes-deficient mice was less supportive of tumor growth and metastasis. In co-culture with tumor cells, Fes-deficiency in macrophages correlated with a reduced ability to promote tumor cell invasive behavior. These results suggested a tumor promoting role of Fes kinase in breast cancer through roles in cells of the tumor microenvironment.
In a transgenic mouse model of breast cancer driven by an activated HER2/Neu allele expressed in the mammary epithelium, we observed delayed tumor onset in Fes-deficient mice compared to wild-type mice. However, there was no difference in tumor growth rates.
Taken together, these observations argue that Fes inhibition might provide therapeutic benefits in breast cancer, by attenuating tumor-associated angiogenesis and the metastasis-promoting functions of tumor-associated macrophages, or by delaying breast tumor onset in women with HER2 overexpression.
Citation Format: Connie S. Zhang, Peter A. Greer. Deficiency of Fes tyrosine kinase expression correlates with delayed mammary tumor onset in a HER2/Neu over-expressing transgenic mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1405. doi:10.1158/1538-7445.AM2013-1405
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1410: Forced expression of EWS/ATF1 induces sarcomas in mice.
Authors: Yamada Kazunari , Ohno Takatoshi , Hara Akira , Yamada Yasuhiro , Shimizu Katsuji 
Published: August 2014

Abstract
Clear cell sarcoma (CCS) is an aggressive soft tissue malignant tumor characterized by a unique t(12; 22) translocation, leading to the expression of a chimeric EWS/ATF1 fusion gene. However, little is known about the mechanisms underlying how EWS/ATF1 is involved in the development of CCSs. In addition, the cells of origin for CCSs remain to be determined. We generated EWS/ATF1-inducible mice, and examined the effects of EWS/ATF1 expression in adult somatic cells. We show that the forced expression of EWS/ATF1 results in the development of EWS/ATF1-dependent sarcomas in mice. The histology of EWS/ATF1-induced sarcomas resembles that of CCSs and EWS/ATF1-induced tumor cells express CCS-markers, such as S100, Sox10, and Mitf. Lineage tracing experiments using Wnt1-Cre and P0-Cre alleles indicated that neural crest-lineage cells are permissive to EWS-ATF1-driven transformation.
Citation Format: Kazunari Yamada, Takatoshi Ohno, Akira Hara, Yasuhiro Yamada, Katsuji Shimizu. Forced expression of EWS/ATF1 induces sarcomas in mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1410. doi:10.1158/1538-7445.AM2013-1410
Abstract 1415: Role of IL-8 in uveal melanoma induced angiogenesis.
Authors: Lattanzio Laura , Torta Ilaria , Tonissi Federica , Monteverde Martino , Merlano Marco , Milano Gerard , Lo Nigro Cristiana 
Published: August 2014

Abstract
Background: The pro-angiogenic IL-8 pathway has already been associated with resistance to VEGF-targeted therapies in various tumour types, particularly in melanoma. IL-8 expression is higher in tumour as compared to normal tissues and both tumour and endothelial cells express this chemokine and its receptors, CXCR1 and CXCR2. Uveal melanoma (UM) is a highly vascularised tumour that is generally treated with radiations (RT). In a previous pre-clinical study (Sudaka A. et al., Invest. New Drugs, 2012, Jun 20), we reported that RT-associated anti-angiogenic therapy has more than additive effects by modulating VEGF levels and allowing to deliver lower radiation doses for identical cytotoxic effects. Aim: In order to better understand the microenvironment contribution to treatment efficacy in UM we investigated the release of IL-8 in response to the anti-angiogenic drug Bevacizumab, and the cross-talk between IL-8 and VEGF signalling. Materials and methods: OCM-1 uveal melanoma cell line and Huvec cells were grown in transwell plates. Bevacizumab was used at a final concentration of 2.5 mg/ml and cells were irradiated with a 6Gy dose. Il-8 concentrations were determined by ELISA assay. Results: Bevacizumab alone or combined with RT induced a 6 fold decrease in IL-8 concentration in culture medium from OCM-1 cells grown alone (Bev vs control/CT p&lt;0,001%; Bev vs CT p&lt;0,01%), but this effect was completely abolished when OCM-1 cells were cultured in Huvec-conditioned medium. When cells were co-cultured on transwell plates and treated with Bevacizumab IL-8 level increased by 30% in OCM-1 culture supernatant (Bev vs CT p=0,12) whereas it was 35% lower in Huvec culture medium (Bev vs CT p&lt;0,05). Conclusions: These data indicate that the UM microenvironment, beside VEGF, can activate IL-8 signalling as an alternative pro-angiogenic pathway. The latter seems to be upregulated in UM cells by anti-VEGF therapy only when they are co-cultured with endothelial cells, thus suggesting that this effect may be dependent on a crosstalk between the two cell types. The decrease in IL-8 concentration, observed in the Huvec chamber of the transwell plates after incubation with Bevacizumab, may be due to a more efficient Il-8 binding by CXCR1 and/or CXCR2 (hypothesis currently tested). Therefore, although preliminary, our results suggest a possible synergic effect for a therapeutic approach combining IL-8 inhibitors with anti-VEGF compounds in UM.
Citation Format: Laura Lattanzio, Ilaria Torta, Federica Tonissi, Martino Monteverde, Marco Merlano, Gerard Milano, Cristiana Lo Nigro. Role of IL-8 in uveal melanoma induced angiogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1415. doi:10.1158/1538-7445.AM2013-1415
Abstract 1420: Mechanisms of stroma-derived CCL7 in promoting lung cancer.
Authors: Choi Hyejin , Durrans Anna , Gao Dingcheng , Ryu Seongho , Altorki Nasser , Mittal Vivek 
Published: August 2014

Abstract
Lung cancer is a leading cause of cancer related deaths worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent form. Considerable attention has been directed to cancer cell intrinsic abnormalities (K-ras, p53, EGFR, AML-ALK4 fusions etc.), but little is known about the contribution of stromal cells to NSCLC progression.
We have undertaken a comprehensive analysis to determine the contribution and biological function of the stromal cells in NSCLC. We show increased recruitment of BM hematopoietic cells in the tumor beds compared to matched adjacent non-neoplastic lung tissue in NSCLC patients. Genome-wide transcriptome analysis on specific cell populations from fresh samples of NSCLC patients identified differentially regulated genes and mRNA isoforms in NSCLC stromal cells. Genes that were successfully validated by independent RT-PCR on sorted stromal cells and tumor cells were used for further analysis. Many genes encoded secreted proteins, suggesting the activation of aberrant autocrine and paracrine regulatory loops likely to support stroma-mediated tumor progression.
Among these genes, CCL7 was upregulated in myeloid progenitor cells and was selected for further investigation. Immunostaining of lung tumor and adjacent non-neoplastic tissue of patients shows highest expression of CCL7 in BM-derived cells (CD45+ cells) in the tumor.
Cross species analysis showed that, consistent with the observation in human tissue, CCL7 was differentially regulated in BM derived cells in a mouse model of NSCLC generated in KrasG12D and p53-/- transgenic mice. We have genetically ablated CCL7 in the BM cells using lentiviral shRNA and BMT approaches and will discuss consequences of this ablation in CCL7-mediated crosstalk between tumor cells and stromal cells that regulate NSCLC progression.
Citation Format: Hyejin Choi, Anna Durrans, Dingcheng Gao, Seongho Ryu, Nasser Altorki, Vivek Mittal. Mechanisms of stroma-derived CCL7 in promoting lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1420. doi:10.1158/1538-7445.AM2013-1420
Abstract 1422: Interleukin-17A activates tumor progression locus 2 to induce neoplastic cell transformation and breast carcinogenesis.
Authors: Kim Garam , Choi Hong Seok 
Published: August 2014

Abstract
Interleukin-17 (IL-17) is a pro-inflammatory cytokine secreted by activated CD4+ memory T cells. Although the role of T cells in cancer promotion has been examined, little is known about the underlying molecular mechanisms of interleukin-17 A (IL-17A) in carcinogenesis. In the present study, we first found that IL-17A induces neoplastic transformation of JB6 Cl41 cells through activation of tumor progression locus 2 (TPL2). IL-17A activates MEKs-ERKs, JNKs-c-Jun, and STAT3 signaling pathways, which are inhibited by a TPL2 kinase inhibitor (TKI). Furthermore, IL-17A activates c-fos and c-jun promoter activity, resulting in increased activator protein-1 (AP-1) activity. When small interfering RNA (siRNA) of IL-17A receptor (IL-17R), IL-17A, and TPL2 were introduced into JB6 Cl41 cells, respectively, IL-17A-induced AP-1 activity was significantly decreased compared to control cells. Similarly, TPL2 inhibition suppressed AP-1 activity induced by IL-17A. The knockdown of IL-17R and TKI treatment in JB6 Cl41 cells resulted in decreased IL-17A-induced cell transformation. The in vivo chorioallantoic membrane (CAM) assay also showed that IL-17A increased tumor formation of JB6 Cl41 cells, whereas TKI inhibited the tumorigenesis promoted by IL-17A. Consistent with these observations, knockdown of IL-17A and/or inhibition of TPL2 attenuated tumorigenecity of human breast cancer MCF7 cells. Moreover, immunohistochemical staining showed that both expressions of IL-17A and TPL2 were highly upregulated in human breast cancers. Together, our findings point to a critical role for the IL-17A-induced TPL2 signaling pathway in supporting cancer-associated inflammation in the tumor microenvironment. Therapeutic approaches that target this pathway may therefore effectively inhibit carcinogenesis.
Citation Format: Garam Kim, Hong Seok Choi. Interleukin-17A activates tumor progression locus 2 to induce neoplastic cell transformation and breast carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1422. doi:10.1158/1538-7445.AM2013-1422
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1423: Proinflammatory activity of type II interleukin 1 receptor, a decoy receptor.
Authors: Mar Ai-Chung , Lee Hui-Ju , Lee Te-Chang 
Published: August 2014

Abstract
We have previously demonstrated that type II interleukin 1 receptor (IL1R2), an IL-1 decoy receptor, plays a dual role on regulation of inflammatory signaling, i.e., IL1R2 inhibits the exogenous interleukin 1 (IL-1) signaling on the one hand but activates intracellular IL-1α and its downstream proinflammatory cytokines. To have a better understanding of the proinflammatory activity of IL1R2, we modulated the intracellular IL1R2 levels by ectopic expression or siRNA silencing techniques. In the present study, our results showed that ectopic expression of IL1R2 in HaCaT cells, an immortalized cell line of human keratinocyte, significantly enhanced the expression of IL-6, MMP-1, and VEGF-A. Since T4R2 cells, a tumorigenic cell line derived from HaCaT cells by long-term exposure to inorganic arsenic, expressed a significant amount of IL1R2, we therefore silenced the expression of IL1R2 in T4R2 cells by RNAi technique. Our results consistently showed that silencing of IL1R2 in T4R2 cells decreased expression of IL-6, MMP-1, and VEGF-A. Meanwhile, our results demonstrated that the intracellular levels of IL1R2 are closely associated with migration ability of HaCaT cells. Moreover, IL1R2 silencing reduced the growth rate of T4R2 cells in nude mice. The conditioned medium harvested from T4R2 cells was able to stimulate migration, proliferation, and tube formation of cultured endothelial cells, whereas the angiogenesis activity of conditioned medium harvested from IL1R2 silenced T4R2 cells was significantly suppressed. Furthermore, the enhanced migration ability of endothelial cells culturing in T4R2 conditioned medium was suppressed by antibodies against VEGF-A and IL-6. We also demonstrated that tumors derived from T4R2 cells contained higher levels of CD31 positive cells as compared to those derived from IL1R2 silenced T4R2 cells, indicating more blood vessels formed in T4R2 tumor tissues. Mechanistically, our present studies showed that IL1R2 may work together with cFos and bind to Ap-1 site of promoters of IL-6 and VEGF-A. Taken together, we revealed that intracellular IL1R2 acts as a proinflammatory factor and hence enhances the expression of several inflammatory cytokines involving in angiogenesis and tumor malignancy.
Citation Format: Ai-Chung Mar, Hui-Ju Lee, Te-Chang Lee. Proinflammatory activity of type II interleukin 1 receptor, a decoy receptor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1423. doi:10.1158/1538-7445.AM2013-1423
Abstract 1424: Inhibition of M-CSF or MCP-1 expression in tumor cells reduces tumor growth and lung metastasis in a murine mammary cancer model.
Authors: Cho Han Jin , Park Jung Han Yoon 
Published: August 2014

Abstract
Tumor-associated macrophages, which are derived from the infiltration of circulating bone marrow-derived monocytes, consist primarily of a polarized M2 macrophage population and are associated with poor prognosis in various cancers. We previously observed that solid tumor growth and lung metastasis were enhanced when 4T1 mammary carcinoma cells were injected with M2 macrophages into the mammary fat pad of BALB/c mice. Cancer cell proliferation and macrophage infiltration were markedly increased when M2 macrophages were co-injected with 4T1 cells. In the present study, we explored the mechanisms underlying the crosstalk between 4T1 cells and M2 macrophages in tumor microenvironment. The results of in vitro experiments revealed that the migration of monocytes and the secretion of many cytokines including macrophage-colony stimulating factor (M-CSF) and monocyte chemotactic protein-1 (MCP-1) were increased when 4T1 cells were co-cultured with M2 macrophages, as compared to when the 4T1 cells were cultured alone. The mRNA expression of M-CSF and MCP-1 increased in 4T1 cells when 4T1 cells were co-cultured with M2 macrophages. To investigate the potential roles of M-CSF and MCP-1 in tumor growth and metastasis, 4T1 cells were infected with M-CSF, MCP-1, or control shRNA lentivirus particles and selected with puromycin. 4T1 cells infected with M-CSF shRNA did not grow or metastasize to the lung when injected into the mammary fat pads of BALB/c mice. Inhibition of MCP-1 expression in tumor cells also suppressed 4T1 tumor growth and metastasis, however, the degree of inhibition was much smaller than that of M-CSF inhibition. M-CSF knockdown decreased M2 macrophage (mouse mannose receptor+) population, whereas MCP-1 knockdown decreased the number of both M1 and M2 macrophages in tumor tissues. Taken together, these results indicate that M-CSF and MCP-1 are produced by the crosstalk between 4T1 cells and M2 macrophages, and these cytokines play important roles in mammary tumor progression.
Citation Format: Han Jin Cho, Jung Han Yoon Park. Inhibition of M-CSF or MCP-1 expression in tumor cells reduces tumor growth and lung metastasis in a murine mammary cancer model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1424. doi:10.1158/1538-7445.AM2013-1424
Abstract 1426: Functional analysis of membrane bound versus soluble RANKL: implications for cancer-induced osteolysis.
Authors: McGuire Jeremy J. , Futakuchi Mitsuru , Lynch Conor 
Published: August 2014

Abstract
The primary site of prostate cancer metastasis is the skeleton with the resultant metastases containing areas of extensive osteogenesis and osteolysis. The latter is a process controlled by multinucleated osteoclasts and receptor activator of nuclear kappa B ligand (RANKL) is critical for osteoclastogenesis. RANKL is a type II transmembrane molecule that forms a trimer on the cell surface and mediates its effects via RANK. We have shown that matrix metalloproteinases-3 and -7 (MMP-3, MMP-7) can process RANKL to a soluble form, sRANKL. The objective of this study is to determine the functionality of membrane bound RANKL versus sRANKL in promoting osteoclastogenesis.
Full-length murine RANKL cDNA was isolated and inserted into the pcDNA 3.1(+) expression construct. In vitro translation experiments demonstrated that RANKL was being generated and could be processed by MMP-3 and MMP-7. N-terminal amino acid sequencing revealed that the site of cleavage occurs in the juxtamembrane region of RANKL between amino acids 145 and 146. We hypothesized that cleavage in the juxtamembrane region could generate an active soluble form of sRANKL. Osteoclastogenesis and resorption assays with myeloid precursors demonstrated the functionality of sRANKL. To determine whether RANKL or sRANKL is the major mediator of osteoclastogenesis in vivo we have generated RANKL mutants that are resistant to cleavage by MMPs and other proteases. Using a site directed mutagenesis kit we have designed a number of mutants and found that Δ158, (deletion of amino acids 71-157) and, Δ148, deletion of amino acids 72-147), were resistant to proteolytic cleavage. We anticipate that the while Δ158 and Δ148 are resistant to cleavage, they will be functional. We will therefore test the functionality of these two deletion mutants in-vitro by co-culturing myeloid precursor cells with Cos-7/Cos-1 cells expressing wild type and mutant RANKL proteins.
In conclusion, we have demonstrated that RANKL is proteolytically cleaved to generate a soluble active form. We have generated non-cleavable mutant forms of RANKL that will allow us to assess the role of membrane bound versus soluble RANKL in-vitro and in-vivo. The results of these experiments will further elucidate the roles of RANKL and sRANKL in prostate to bone metastases in addition to being informative for the engineering of future RANKL based therapies.
Citation Format: Jeremy J. McGuire, Mitsuru Futakuchi, Conor Lynch. Functional analysis of membrane bound versus soluble RANKL: implications for cancer-induced osteolysis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1426. doi:10.1158/1538-7445.AM2013-1426
Abstract 1427: CCL9 mediates TGF-β regulation of tumor cell survival and lung metastasis.
Authors: Yan Hangyi , Yang Li 
Published: August 2014

Abstract
Cancer metastasis is an ominous feature of tumor progression and accounts for over 90% of cancer-associated deaths. Tumor cell survival in the distant organ is the rate-limiting step in the metastatic process. Primary tumors modulate the pre-metastatic organs and build up a tumor favorable “soil” for the “seeds” (tumor cells). However, the precise cellular and molecular mechanisms remain to be elucidated.
We found that Gr-1+CD11b+ cells or myeloid derived suppressor cells (MDSCs) infiltrate and landscape the pre-metastatic lung into an inflammatory, proliferative, and immune suppressive environment. Tumor cells co-cultured or co-injected with MDSCs showed increased survival and metastasis. Using a cytokine protein array screening, we found that CCL9 (MIP1-γ, macrophage inflammatory protein-1 gamma) is highly secreted in the supernatant of co-culture as well as the metastatic lung. We identified that MDSCs, particularly Ly6C+CD11b+ and F4/80+CD11b+ subsets, are the main source for CCL9 expression. Interestingly, deletion of transforming growth factor -β receptor II (TβRII) in myeloid cells, results in significantly decreased lung metastasis and CCL9 expression. The mechanisms underlying CCL9 regulation of metastasis is currently under investigation.
Citation Format: Hangyi Yan, Li Yang. CCL9 mediates TGF-β regulation of tumor cell survival and lung metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1427. doi:10.1158/1538-7445.AM2013-1427
Abstract 1435: Myeloid TGF-β signaling regulates Platelet factor 4 expression that is important in host immune suppression and tumor metastasis.
Authors: Pang Yanli , Zhu Guiquan , Yang Li 
Published: August 2014

Abstract
Myeloid cells are the most abundant hematopoietic cells in the human body and play a crucial role in tumor angiogenesis, invasion, and metastasis. Here we found that deletion of the gene encoding TGFβ receptor 2 (Tgfbr2) specifically in myeloid cells reduced the level of platelet factor-4 (PF4) in the myeloid cells of 4T1 tumor bearing mice. This is accompanied by decreased lung metastasis of 4T1 mammary carcinoma. Interestingly, deletion of Cxcr3, encoding the receptor for PF4, significantly decreased the lung metastasis of 4T1 mammary carcinoma. The decreased metastasis may attribute to augmented anti-immunity. First, myeloid cells with Cxcr3 deletion showed decreased expression of IL-10, IL-4, iNOs, and arginase. In addition, there was an increased number of both CD4+ and CD8+ T cell in Cxcr3-/- mice compared to the wilt type controls. Our results suggest that TGFβ regulation of PF4 may modulate cancer metastasis through suppressing host anti-tumor immunity.
Citation Format: Yanli Pang, Guiquan Zhu, Li Yang. Myeloid TGF-β signaling regulates Platelet factor 4 expression that is important in host immune suppression and tumor metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1435. doi:10.1158/1538-7445.AM2013-1435