bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1494: Intrinsic and extrinsic TME factors modulate breast cancer progression
Authors: George Andrea L. , Rajoria Shilpi , Suriano Robert , Mittelman Abraham , Tiwari Raj K. 
Published: August 2012

Abstract
The tumor microenvironment (TME) of breast cancer is a heterogeneous population of tumor cells, infiltrating endothelial cells, immunomodulatory cells, and underlying stroma. This cellular cross-talk is key to tumor progression; however the signaling pathways involved remain unclear. Rapid expansion of breast cancer cells requires sufficient supply of oxygenated blood supported by tumor induced neovasculature. Our previous studies demonstrated that estrogen mediates neovascularization via recruitment of bone marrow derived endothelial progenitor cells (BM-EPCs). However, hypoxia, a major cellular characteristic of cancer cell growth, mimics estrogen induced vascularization as evidenced by HIF-1α translocation and secretion of vascular endothelial growth factor (VEGF). These studies were carried out in the TG1-1 murine mammary cancer cell line and used as a model. Conditioned media from TG1-1 cells enhanced endothelial cell migration and tube formation in vitro. Treatment of tumor cells with the anti-estrogen Fulvestrant as well as the HIF-1 inhibitor YC-1 abrogated the effects of estrogen. Further, use of the PI3K inhibitor wortmannin as well as the protein inhibitor cyclohexamide, elucidated the necessity of a functional AKT signaling pathway in this estrogen induced neovasculogenesis. While the cell-cell interaction studies demonstrate a considerable modulation of the tumor microenvironment, the co-culture experiments using immunomodulatory cells and epithelial cells induced epithelial to mesenchymal transition (EMT) in TG1-1 cells. We demonstrated that the murine macrophage cell line RAW264.7 secretes factors that modulate tumor cell EMT via upregulation of TWIST and Slug and an increase in tumor cell migration and invasion. To elucidate the modulatory secreted factors, we performed western blot analysis of the TGF-β signaling pathway and observed differences in SMAD levels. However, neutralizing antibody studies indicate that TGF-β is not the sole modulator of RAW264.7 induced EMT in Tg1-1 cells. Taken together, cytokines as extrinisic factors and tumor hypoxic conditions generating intrinsic factors, act in concert to alter breast cancer progression. Our data demonstrate a need to target multiple TME interacting pathways as a future breast cancer treatment strategy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1494. doi:1538-7445.AM2012-1494
Abstract 1496: Changes in white adipose tissue progenitor populations with ovarian cancer
Authors: Shea Amanda A. , Cohen Courtney A. , Roberts Paul C. , Schmelz Eva M. 
Published: August 2012

Abstract
Ovarian cancer is the fourth leading cause of cancer death in women and has the highest mortality rate of all gynecological malignancies. Among the greatest risk factors are age, reproductive history, hormone therapy, and more recently suggested, obesity. Currently, the mechanism for how obesity contributes to ovarian cancer is unknown, but there is potential for adipose tissue-associated cells to be key players in this pathogenesis. The stromal vascular fraction (SVF) of white adipose tissue is a rich source of various stem and progenitor cell populations, which can be recruited by cancer cells to enhance cancer progression and metastatic potential. Studies have shown that there is an increase in progenitor populations within the adipose tissue with obesity and age, two risk factors for ovarian cancer. While it has been shown that SVF cells can contribute to cancer, it has not been determined what impact cancer progression has on adipose tissue. It is plausible that ovarian cancer has systemic effects, which may influence cell populations within adipose tissue to promote metastases. Our lab has developed a spontaneously transformed murine ovarian surface epithelial (MOSE) cell model that becomes increasingly more aggressive with repeated passaging. Late passage cells rapidly form tumors when injected into mice, while earlier passage cells do not. Using this model, we investigated the effects of ovarian cancer on systemic changes in progenitor populations. Firefly luciferase-expressing MOSE-L TICv cells, a highly aggressive, metastatic tumor-initiating cell variant were injected into the peritoneal cavity of C57BL/6 mice and stem/progenitor populations and various immune cell populations within the perigonadal white adipose tissue, blood, ascites, and omentum were immunophenotyped by flow cytometry. Changes in gene expression profiles were also analyzed using quantitative real-time PCR. Interestingly, peritoneal dissemination changed the profile and composition of progenitor populations in the various tissues, suggesting that ovarian cancer does have a more widespread impact, affecting the blood and perigonadal adipose tissue. Additionally, co-culture studies demonstrate that MOSE cells and SVF associated cells positively interact enhancing tumor spheroid growth and provide survival signals. This suggests a synergistic relationship between the MOSE and SVF cells. These discoveries may provide a mechanistic link for the detrimental impact of obesity on ovarian cancer progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1496. doi:1538-7445.AM2012-1496
Abstract 1525: Regulation of bone marrow angiogenesis by CXCL12 in the leukemia tumor microenvironment
Authors: Gibson Laura F. , Piktel Debra , Diamond Julie , Cavendish John , Gencheva Marieta , Wysolmerski Robert 
Published: August 2012

Abstract
While it is well established that angiogenesis is essential for the progression of solid tumors, its role in hematological tumors is more recently becoming fully appreciated. In the current study we have investigated the potential role of leukemic cells in regulating local angiogenesis as well as the modulation of tumor cell CXCL12 expression subsequent to interaction with bone marrow derived osteoblasts as one mechanism by which local vascular rich niches may be created. Human REH acute lymphoblastic leukemia (ALL; ATCC #CRL-8286) increased vessel density when placed on the chorioallantoic membrane (CAM) assay. Conditioned media from these same tumor cells increased human brain microvessel endothelial cell (HBMEC) motility and tube formation suggesting leukemia cell influence on surrounding vasculature. Strikingly, while REH cells express negligible CXCL12 at baseline, the chemokine is consistently induced to easily detectable levels upon co-culture with human osteoblasts indicating one mechanism by which tumor cells within the bone marrow microenvironment may be poised to enhance vascular cell recruitment even more robustly than leukemic cells alone. Preliminary evaluation of primary, patient-derived ALL leukophoresis samples demonstrated a comparable increase in tumor cell CXCL12 indicating this modulation is not limited to an established tumor cell line. Increased expression of CXCL12 by REH leukemic cells was consistent with enhanced chemotaxis of HUVECs toward the co-culture of tumor and osteoblasts when compared to either cell type alone. The inclusion of 5-Aza-deoxycytidine (Aza-C) to REH cells alone resulted in expression of CXCL12 in the absence of osteoblast co-culture, suggesting methylation may play a regulatory role in the suppression of this chemokine. As a site in which metastatic disease is often refractory to standard therapy, in addition to the anatomical niche in which hematopoietic malignancies initiate and most frequently relapse, regulation of local angiogenesis in the bone marrow microenvironment requires further investigation. Our preliminary observations suggest CXCL12 may play an important role in regulating leukemic cell niche angiogenesis, and targeting it could potentially represent a novel application of antagonists currently in clinical trials in an effort to treat refractory leukemia.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1525. doi:1538-7445.AM2012-1525
Abstract 1530: The obligate role of microglia in tumorigenesis in a mouse model of neurofibromatosis-1 optic glioma
Authors: Pong Winnie W. , Higer Samantha B. , Gianino Scott M. , Gutmann David H. 
Published: August 2012

Abstract
Brain tumors (gliomas) are composed of heterogeneous populations of neoplastic and non-neoplastic cells. While the neoplastic cells have classically been the target of therapeutic drug design, recent studies have demonstrated a critical role for non-neoplastic cells in brain tumor growth. The importance of non-neoplastic (stromal) cells is underscored by genetically-engineered mouse (GEM) models of Neurofibromatosis type 1 (NF1)-associated optic glioma. Whereas mice lacking Nf1 gene expression in GFAP+ glial cells do not develop brain tumors, nearly 100% of Nf1+/− mice with GFAP+ cell Nf1 inactivation form optic gliomas. These observations establish an obligate role for Nf1+/− non-neoplastic cells in gliomagenesis. One of the non-neoplastic cell types found in both mouse and human NF1-associated gliomas is microglia, a resident population of macrophage-like cells. To prove that microglia are essential drivers of glioma formation, we generated Nf1 optic glioma mice with reduced expression of the microglial chemokine receptor CX3CR1 (Nf1+/−GFAPCKO-cx3cr1+/GFP mice). Consistent with the critical role of CX3CR1 in microglial function, Nf1+/−GFAPCKO-cx3cr1+/GFP mice had reduced numbers of Iba1+ microglia in the optic nerve. Moreover, Nf1+/−GFAPCKO-cx3cr1+/GFP mice had optic glioma proliferative indices and optic nerve volumes comparable to those found in wild-type mice, demonstrating that microglia are necessary for optic nerve gliomagenesis. Collectively, these findings establish an obligate role for microglia in glioma formation and suggest that CX3CR1 is a potential target for future therapeutic drug design.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1530. doi:1538-7445.AM2012-1530
Abstract 1531: Reactive astrocytes promote the growth of cancer stem-like cells of metastatic breast tumor by activating Notch signaling in brain
Authors: Xing Fei , Kobayashi Aya , Okuda Hiroshi , Watabe Misako , Pandey Puspa R. , Pai Sudha K. , Fukuda Koji , Iiizumi Megumi , Watabe Kounosuke 
Published: August 2012

Abstract
Metastatic diseases are responsible for the majority of deaths in breast cancer patients, and brain is one of the most common metastatic sites. The metastatic tumor in the brain profoundly affects the cognitive and sensory functions as well as morbidity of patients, and the one year survival rate among these patients remains less than 20%. However, little is known about the pathogenesis of brain metastasis, and therefore, it is of paramount importance to elucidate the molecular mechanism of metastatic process in order to define a specific therapeutic target. Our analysis of existing microarray database indicate that interleukin-1α (IL-1α) is highly expressed in MDA-MB231BrM2a (231BrM) cell line which is capable of preferentially metastasizing to the brain. IL-1α is known to have an ability of “activating” astrocytes that are often found in the metastatic niche, and therefore, it is speculated that the reactive astrocytes can promote growth and invasion of metastasized cells in the brain. To explore this possibility, we examined the effect of IL-1α and the conditioned medium of 231BrM cells on rat primary astrocytes in vitro. Our results of qRT-PCR and Western blot analysis indicate that IL-1α and the conditioned medium significantly up-regulated the Notch ligand, JAG1, in astrocytes, and that this up-regulation was abrogated by the NF-κB inhibitor, PDTC. We also found that the interaction between CSCs and astrocytes significantly enhances the self-renewal ability of CSCs. To further examine the interaction of astrocytes and tumor cells in the brain, we intracardially injected 231BrM cells in nude mice, and tumor growth was monitored by Xenogen bioimager. After 4 weeks, metastatic tumor growth was observed at multiple sites of the brain, and the results of immunohistochemical analysis indicated that astrocytes adjacent to the metastatic lesions strongly expressed JAG1 and the reactive astrocyte marker, GFAP (Glial fibrillary acidic protein). Finally, we found that a BBB-permeable Notch inhibitor was able to significantly suppress metastatic growth of breast cancer in the brain in our animal model. These results represent a novel paradigm for the understanding of how metastatic breast CSCs re-establish their niche for their self-renewal in a totally different microenvironment, which opens a new avenue to identify a novel and specific target for the brain metastatic disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1531. doi:1538-7445.AM2012-1531
Abstract 1536: A novel immunocytokine generates a CD8+ T cell-mediated anti-tumor response in vivo
Authors: Fallon Jonathan K. , Tighe Robert , Strittmatter Wolfgang , Sabzevari Helen , Schlom Jeffrey , Greiner John W. 
Published: August 2012

Abstract
Interleukin-12 (IL-12) is a potent TH1 cytokine produced by dendritic cells and macrophages to activate NK cells and T cells. Data from preclinical studies in mice indicate that this cytokine may be useful for the treatment of cancer. However, cases of severe toxicity in human trials have impeded its successful clinical development. Targeting delivery of IL-12 to a tumor while reducing systemic IL-12 exposure could make this a safer, more effective cancer therapeutic agent. One strategy is to conjugate IL-12 to a tumor-binding antibody, as antibody conjugates have previously been used to deliver radioisotopes, other cytokines, and small molecule therapeutics to tumors in vivo. NHS-IL12 is a novel immunocytokine consisting of two molecules of the IL-12 heterodimer covalently fused to a fully humanized antibody (NHS76). This antibody targets necrotic portions of tumors because of its high affinity for single- and double-stranded DNA, which are often exposed as tumors outgrow their blood supply. NHS-IL12 may therefore be useful against a wide range of solid tumors, and mouse models can be used to study its mechanisms of action. Initial imaging studies clearly showed superior in vivo localization of IL-12 to mouse tumors following subcutaneous NHS-IL12 injection as compared to administration of recombinant IL-12 (rIL-12) or IL-12 fused to a control antibody (BC1). In the MC38/CEA+ colorectal carcinoma model in CEA.Tg mice, treatment with NHS-IL12 significantly delayed subcutaneous tumor growth more effectively than treatment with rIL-12. NHS-IL12 did not inhibit MC38/CEA+ tumor cell growth in vitro, suggesting that NHS-IL12 acts indirectly on tumors in vivo most probably via an immune-mediated mechanism. Subsequent findings revealed that tumor-bearing mice treated with NHS-IL12 developed a strong CD8+ T cell response directed against the endogenous p15E tumor antigen. In one study, a subset of mice bearing MC38/CEA+ tumors had complete tumor regression following NHS-IL12 treatment. Each of these mice still had a strong p15E-specific CTL response more than two months after tumor rejection, indicating that p15E may be the major tumor rejection antigen for this in vivo tumor model. Subsequent in vivo depletion studies are planned to investigate which immune cell subsets contribute to the anti-tumor efficacy of this agent. Taken together, these data show that targeted delivery of IL-12 to tumors can overcome the immunosuppressive tumor microenvironment and prime a robust CD8+ T cell response. These findings suggest that NHS-IL12 may be a promising cancer therapeutic as a single agent and/or as a potent vaccine adjuvant.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1536. doi:1538-7445.AM2012-1536
Abstract 1551: Targeting myeloid derived suppressor cells as novel strategy to enhance immunotherapy in murine prostate cancer models
Authors: Shen Li , Ciesielski Michael , Miles Kiersten M. , Ellis Leigh , Fenstermaker Robert , Pili Roberto 
Published: August 2012

Abstract
Purpose: Myeloid derived suppressor cells (MDSCs) are a major component of the immunosuppressive environment responsible for immune tolerance in cancer. These cells facilitate carcinogenesis and tumor progression by impairing T and NK cells activation and contributing to regulation of angiogenesis. In current study, we evaluated whether accumulation of MDSCs occur in two murine prostate cancer models: a castrate resistant, syngenic transplantable tumor (CR Myc-Cap) and the Hi-myc transgenic tumor models. Tasquinimod is an anti-angiogenic agent tested in prostate cancer and has been found to bind to an inflammatory protein S100A9 and therefore have the potential to affect accumulation and function of MDSCs. We investigated whether tasquinimod affects the induction and function of MDSCs and facilitate vaccine therapy in these castrate resistant prostate cancer models. Experimental design: Splenocytes and blood cells were isolated from naïve and CR Myc-Cap tumor bearing mice. Blood samples were taken from Hi-myc transgenic mice and age-matched littermates at different ages. All these splenocytes and blood samples were subjected to staining with MDSCs markers, Gr1 and CD11b, and to flow cytometry analysis. CR Myc-Cap tumor bearing mice were treated with either vehicle, tasquinimod (1mg/kg), modified survivin vaccine peptide SurVaxM, or combination. Tumor growth, MDSCs accumulation and function upon treatments were monitored. Results: The peripheral MDSCs (in blood and spleen) significantly increased in tumor bearing mice. The MDSCs number increase correlated with disease progression in the transgenic model. Low doses of tasquinimod (1-5mg/kg) did not change the CD11b+Gr1high MDSCs number, but CD11b+Gr1high, CD11b+Gr1int, CD11b+Gr1− cells were differently accumulated in vehicle or tasquinimod treated mice. Tasquinimod in vivo treatment reduced peripheral CD11b+Gr1int, CD11b+Gr1− cells number. Low doses of tasquinimod have minimal effect on CD11b+Gr1high MDSCs function and did not enhance the SurVaxM vaccine therapy in CR Myc-Cap model.Conclusions: In summary, our study demonstrates MDSCs accumulation in two prostate cancer models and suggests that MDSCs may contribute to immune tolerance in prostate cancer. The study also suggests low dose tasquinimod affect maturation of MDSCs into other immunosuppressive cell types (CD11b+Gr1int, CD11b+Gr1−). Higher doses of tasquinimod (≥10mg/kg) are being tested for their potential to affect MDSCs accumulation and function in prostate cancer models.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1551. doi:1538-7445.AM2012-1551
Abstract 1812: Development of Erlotinib derivatives as CIP2A inhibitors
Authors: Shiau Chung-Wai 
Published: August 2012

Abstract
PP2A is a protein phosphatase which involves in negatively regulating cell proliferation, survival and differentiation. Literature has shown that cancerous inhibitor of PP2A (CIP2A) is an inhibitor of PP2A in cancer cells. Overexpression of CIP2A contributes to tumor aggressiveness and renders resistance to chemotherapy. Inhibiton of CIP2A by small molecules shut off the downstream signal pathway of Akt through increasing PP2A phosphatase activity. For example, Bortezomib, a poteasome inhibitor, suppressed expression level of CIP2A and further reduced phospho-Akt in hepatocellular carcinoma cells. Hence, Agents that can repress CIP2A have potentials for the treatment in cancers. Erlotinib, an EGFR inhibitor, shows therapeutic effects in clinical. Our data show that CIP2A represents a major factor whereby erlotinib derivatives induce apoptosis in HCC cells. Here, a series of mono- and di-substituted erlotinb derivatives were synthesized and their bioactivities against hepatocellular carcinoma were evaluated. The di-substituted erlotinib derivatives were more potent inhibitors of cancer-cell proliferation than the mono-substituted derivatives. Further assays confirmed a correlation between cell death, and CIP2A and Akt inhibition by these derivatives. Among them, compound 19 provides a proof of concept for the design of a new class of agents that repress CIP2A activity in HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1812. doi:1538-7445.AM2012-1812