bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 380: Sunitinib treatment induces up-regulation of CXCR4
Authors: Kubacka Urszula , Nagengast Wouter B. , Kruizinga Roeliene C. , Lub-deHooge Marjolijn N. , Gietema Jourik A. , Oosting Sjoukje F. , Timmer-Boscha Hetty , Hospers Geke A. , den Dunnen Wilfred F. , de Vries Elisabeth G. , Huls Gerwin , Walenkamp Annemiek M. 
Published: February 2011

Abstract
Background: Chemokine receptors expressed on solid tumor cells and their corresponding ligands are an example of a network which is used by these cells to interact with their microenvironment to sustain survival, proliferation, invasive growth, angiogenesis, and to promote organ-specific localization of distant metastases. Indeed, CXCR4/CXCL12 signaling can induce angiogenesis and progression of tumors, for example by increasing the expression of vascular endothelial growth factor (VEGF). Inversely, it is hypothesized that anti-angiogenic treatment increases the expression of CXCR4/CXCL12 which could explain the in preclinical models observed invasive growth characteristics of tumors.
Methods: A human A2780 ovarian xenograft mouse model was used. When the tumor was established, mice were treated with vehicle or sunitinib (60 mg/kg i.p.) daily for 2 weeks. CXCR4 expression was assessed by immunohistochemistry at baseline and after 1 and 2 weeks of treatment and compared with markers like HIF1α, VEGF, Ki67, VEGFR2, mean vessel density (MVD) and blood vessel diameter. In addition human plasma VEGF levels were analyzed.
Results: Moderate cell membrane CXCR4 expression was seen in untreated tumors. One week of sunitinib treatment resulted in decrease angiogenice markers and tumor proliferation (Ki67) in both the tumor center and rim. Two weeks of sunitinib treatment resulted in up regulation of CXCR4 with a 2.2 fold increase (P = 0.046) particularly in the tumor rim. This coincided with normalization of blood vessel diameters, intense VEGF staining and increased tumor proliferation (Ki67) to baseline levels in the tumor rim. In contrast, an increase of HIF1α (P = 0.017) and decrease of angiogenic markers like VEGFR2 (P = 0.019) and MVD (P = 0.016) was still observed in the tumor center.
Conclusion: This study shows that anti-angiogenic treatment with sunitinib up regulates CXCR4 expression, mainly in the rim of the tumor. CXCR4 is a potential target to block anti-angiogenic induced invasive growth/metastasis.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 380.
Abstract 3802: PPAR gamma mediated induction of transglutaminase in aerodigestive preneoplasia in vitro
Authors: Weidman Elizabeth K. , Wuertz Beverly R. , Gaffney Patrick M. , Ondrey Frank G. 
Published: February 2011

Abstract
Currently there are no validated biomarkers or therapies for human aerodigestive preneoplasia. There is increasing interest in the utilization of PPAR gamma mediated therapy for oral leukoplakia reversal based on preliminary clinical trial results. Transglutaminases (TGMs) are associated with squamous differentiation, and therefore might be hypothesized to be upregulated with PPAR gamma differentiation therapies. In the present study we sought to examine the feasibility of utilizing transglutaminases as a downstream readout for PPAR gamma activator treatment of oral leukoplakia. First we examined our Affymetrix database of human head and neck tumors for the presence or absence of transglutaminases 1-3 in 41 tumors compared to 13 normal oral mucosa samples. We discovered that TGM 1 and 3 were significantly upregulated in normal tissues compared to tumors (p&lt;0.0001). Next, we examined whether PPAR gamma activators could activate TGM1 reporter genes in cell lines. We found that TGM1 luciferase reporters were significantly activated by ciglitazone (0-5uM) and pioglitazone (0-10 uM) in MSK leuk and HOK oral preneoplastic cell lines, as well as CA-9-22 oral cancer cells in several experiments. Next we examined pioglitazone activation of transglutaminases in these cell lines by real time PCR. We found that pioglitazone significantly activated TGM 1 and 2 in MSK leuk and CA-9-22 oral cancer cells on qRT-PCR. We conclude that the clinically relevant PPAR gamma activator, pioglitazone, can activate transglutaminases in aerodigetsive cancer cell lines and may be useful in upregulating differentiation in oral preneoplasia in clinical trials. We also conclude that transglutaminases may provide a family of proteins for PPAR gamma effects and should be included as exploratory biomarkers in leukoplakia clinical trials with PPAR gamma activators.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3802.
Abstract 3805: Furanodienone downregulates EGFR and Her-2 signaling in BT-474 breast cancer cells
Authors: Li Yingwei , Zhu Guoyuan , Dong Suisui , Shen Xiaoling , Yu Zhiling , Fong Wang-fun David 
Published: February 2011

Abstract
Epidermal growth factor receptor (EGFR) and Her-2 are members of the ErbB receptor family of type 1 tyrosine kinases. Also, ligand-induced EGFR /Her-2 heterodimerization triggers potent proliferative and survival signals. EGFR and Her2 frequently overexpress in breast cancer and their overexpression is correlated with a poor prognosis. Therefore dual EGFR/ Her-2 inhibition is an attractive therapeutic strategy for breast cancer treatment. Furanodienone is a compound isolated from Rhizoma Curcumae, which is commonly used in cancer treatment in China. In this study, we used the breast cancer cell BT-474 as the model to investigate the mechanism of furanodienone in breast cancer treatment. We found that furanodienone induced G1 arrest and effectively blocked EGF-stimulated cell cycle progression in BT-474 cells. Moreover, furanodienone decreased protein levels of EGFR, phosphorylation of EGFR and Her-2, so that it prevented the activation of downstream molecules like Akt, Gsk3β and c-Raf, which resulted in inhibiting cell cycle progression. These findings suggested that furanodienone induced growth inhibition in BT-474 human breast cancer cells through inhibiting EGFR /Her-2 signaling pathway. Furthermore, furanodienone and its related compounds provided insights into novel approaches for the prevention and treatment of human breast cancers, especially for those with EGFR /Her-2 overexpression.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3805.
Abstract 3814: Association of Toll-like receptor-4 (TLR4) expression with stage and grade in endometrial cancer
Authors: Papez Michael , Ko Emily , Kaufman David , Gehrig Paola , Young Steven , Bae-Jump Victoria L. 
Published: February 2011

Abstract
Objectives: Toll-like receptors (TLRs) are known to initiate immune responses upon binding bacterial glycolipids and have been implicated in the pathogenesis of a variety of human diseases including cancer. It is thought that cancers may sabotage TLR signaling pathways leading to enhanced tumor cell invasion and immune surveillance evasion. Upon glycolipid binding, TLR4 induces the production of proinflammatory cytokines through the adaptor protein, MyD88. Although TLR4 expression has been evaluated in normal endometrium, it has not been well-characterized in endometrial cancer. Thus, we sought to assess TLR4 and MyD88 expression in endometrial cancer specimens.
Methods: TLR4 and MyD88 expression was evaluated by immunohistochemistry in 82 formalin-fixed, paraffin-embedded endometrial cancer specimens and 14 specimens of benign endometrium. Tissue microarrays were constructed, and two cores were analyzed for each patient. Immunohistochemical staining was scored according to the intensity (1+ to 3+) and qualitative percent cells staining per core. A “histoscore” was calculated, based on multiplying these two determinants ranging from 0 to 300 (i.e. intensity x % labeled). Results were analyzed using the Student t-test and ANOVA.
Results: TLR4 and MyD88 staining was localized in the cytoplasm of both the benign and malignant endometrium. TLR4 and MyD88 expression was highest in the atrophic endometrium (mean 276 & 251, respectively) and lowest in the secretory endometrium (mean 182 & 136, respectively) (p=0.0182 for TLR4; p=0.0043 for MyD88). Expression was intermediary in the proliferative endometrium (mean 214 for TLR4; p=0.0278) (mean 210 for MyD88; p=0.0520). Of the endometrial cancer specimens, 87% were of endometrioid histology, and 13% were of serous histology. 77% of these tumors were from women with early stage cancers (stage 1/2), and 24% were from patients with advanced stage disease (stage 3/4). 89% of the endometrial cancers expressed TLR4, and 91% expressed MyD88. Decreased TLR4 expression correlated with higher stage (mean 205 for stage 1/2 and 169 for stage 3/4; p=0.0163) and grade (mean 214 for G1 and 176 for G3; p=0.0165). TLR4 and MyD88 expression did not significantly differ between endometrioid and serous histologies.
Conclusions: TLR4 and MyD88 are expressed in endometrial cancers, and decreased TLR4 expression was associated with advanced stage and higher grade. Thus, the TLR4 pathway may represent a novel therapeutic target in endometrial cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3814.
Abstract 3819: Activation of toll-like receptor 5 on breast cancer cells by flagellin suppresses tumor development and growth
Authors: Zhenyu Cai , Shi Zhongcheng , Amir Sanchez , Zhang Dekai , McKeehan Wallace L 
Published: February 2011

Abstract
Toll-like receptors (TLRs) play key roles in both the innate and adaptive immune systems, particularly in inflammatory responses against pathogen infection. Recent evidence showed that functional TLRs are also expressed on a wide variety of tumor cells; however, their activation exhibits either antitumor or pro-tumor effects. In order to investigate the function of TLR signaling pathways in breast cancers, we analyzed the expression of TLRs and their functional status in breast cancer cells by RT-PCR and NF-κB reporter gene assays in response to synthetic ligands for these receptors. We found that only TLR5 signaling is highly responsive in breast cancer cells. The phosphorylation levels of IκB, ERK, and JNK after flagellin (an agonist of TLR5) stimulation were increased in tumor cells. Activation of TLR5 signaling in tumor cells by flagellin induces the secretion of various cytokines and chemokines including interleukin-6, interleukin-8, and TNF-α. Moreover, flagellin/TLR5 signaling in MCF-7 cells inhibits an anchorage-independent growth, a hallmark of tumorigenic transformation. In addition, the secretion of soluble factors induced by flagellin contributed to the growth-inhibitive activity in an autocrine fashion. The inhibitive activity was further confirmed in mouse xenografts of human breast cancer model. Administration of flagellin inhibits tumor growth and therefore prolongs the survival of tumor-bearing mice. These findings indicate that TLR5 activation by flagellin mediates innate immunity to elicit potent antitumor activity in breast cancers, which may serve as a novel therapeutic target for human breast cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3819.
Abstract 3820: Inhibition of M1 macrophages may aid the conversion process to M2, which may aid tumor survival and growth
Authors: Enz Ryley A. , Knechtel Charles , Enz Amanda Dee , Swanson Bryan , Robison Richard , O'Neill Kim 
Published: February 2011

Abstract
Macrophages perform a variety of functions, from phagocytosis to the repair and remodeling of damaged tissues. Two phenotypes have been proposed: M1 and M2. The M1 macrophage performs phagocytosis of tumor cells and releases pro-inflammatory cytokines. The M2 macrophage acts as a support cell by promoting the healing of damaged cells by angiogenesis and tissue remodeling. The transition from M1 to M2 may be facilitated by tumor environments. To further study the relationship between cancer and macrophages we developed a live-cell migration assay, which measures cancer's ability to recruit macrophages. We hypothesize that cancer cell lines have varied abilities to recruit macrophages and convert them into M2, and that this ability corresponds to the aggressiveness of the cell line. Macrophages were derived from the human mononuclear phagocyte cell line U937, after addition of phorbol 12-myristate 13-acetate (PMA). These U937 cells were incubated with three adenocarcinomas of varying aggressivity. The adenocarcinomas were MDA-MB-435, MDA-MB-231, and MCF7. The U937 cells were separated from the three cell lines by 3.0 µm trans-permeable polycarbonate membranes (Corning Inc.) which allowed the U937 cells to migrate to the cell lines. After 1 hour non-migratory U937 cells were isolated and counted by means of a hemocytometer. The control without cancer caused 73.86% of U937 cells to remain, MDA-MB-435 69.28% (N=24, P=0.29), MCF7 61.09% (N=24, P&lt;0.01), and MDA-MB-231 55.83% (N=24, P&lt;0.01). This data was then compared with expression levels of macrophage Migration Inhibition Factor (MIF) analyzed from Real Time PCR data. These samples consisted of monocytes, from human blood, which were co-incubated with the cell lines for 48 hours. The cells were separated by 0.4 µm trans-permeable polycarbonate membranes (Corning Inc.) to prevent cells from coming into contact and allowing signal exchange. The RT-PCR data correlated with the migration data. The amount of MIF increased 7.56 fold, (N=9) in MDA-MB-435 when compared to controls, 3.13 fold for MCF7 (N=9), and 1.33 fold for MDA- MB-231 (N=9). This data suggests that the more aggressive the cancer the more MIF emitted and the greater the potential to inhibit macrophages. Previous studies have shown Interleukin-10, (IL-10), IL-6, IL-4, and prostaglandin F2 (PGF2) to be released from tumors and inhibit the cytotoxic activity of macrophages. This exposure to IL-10 has been suggested to convert M1 macrophages to a M2 phenotype. The migration inhibition observed from this study might be the initial step in the conversion process from M1 to M2.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3820.
Abstract 3824: Induction of potent antitumor immunity by intratumoral injection of mT-bet transduced dendritic cells
Authors: Qu Yanyan , Lipscomb Michael W. , Taylor Jennifer L. , Storkus Walter J. 
Published: February 2011

Abstract
T-bet is a T-box transcription factor (Tbx21) previously identified as a master regulator of Type-1 polarization in T cells. We have previously demonstrated that ectopic expression of hT-bet converts dendritic cells (DC) into Type 1-biasing APCs. In the current study, we investigated whether mouse DC overexpressing mT-bet promote superior Type 1 anti-tumor T cell responses when applied as an intratumoral therapy. CD11c+ DCs were then purified and transduced with recombinant adenovirus to express high levels of mT-bet. DC. mT-bet stimulated stronger Tc1 and Th1 T cell responses when compared with control DC and retained the capacity to kill and then uptake tumor cells/debris, allowing for the cross-priming of specific T cell responses in vitro. Surprisingly, in contrast to human DC. T-bet, CD40L-activated DC. mT-bet produced elevated levels (vs. control DC) of IL-12p70/TNF-α. DC. mT-bet exerted potent anti-tumor activity in the (day 7 established) s.c. CMS4 sarcoma after intratumoral administration. These anti-tumor effects were mediated primarily by Tc1 cells, however, both CD4+ T cells and NK cells appeared to also be involved in therapeutic response. In situ imaging suggested that DC. mT-bet treatment inhibited the accumulation of CD11b+Gr1+ myeloid-derived suppressor cells and tumor-associated vascular structures. Collectively, these findings suggest that DC. mT-bet-based therapy has the potential to promote superior Type-1 anti-tumor immunity in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3824.
Abstract 3828: Uncarinic acid C plus IFN-γ generates monocyte-derived dendritic cells and induces a potent Th1 polarization with capacity to migrate
Authors: Lee Ji Hee , Chung Ik-Joo , Umeyama Akemi , Lee Je-Jung , Takei Masao , Jung Young Do , Bae Woo Kyun 
Published: February 2011

Abstract
Uncarinic acid C (URC) is triterpene isolated from Uncaria rhynchophylla and modulates human DC function in a fashion that favors Th1 cell polarization depending on TLR4 signaling. The induction of dendritic cells (DC) is critical for the induction of Ag-specific T lymphocyte responses and may be essential for the development of human vaccines relying on T cell immunity. Monocyte-derived DCs are used as adjuvant cells in cancer immunotherapy and have shown promising results. We studied the effect of interferons (IFN-α and IFN-γ) and TNF-α on phenotypic and functional maturation, and cytokine production of URC-primed DC in vitro. Human monocytes were exposed to URC alone, or in combination with TNF-α, IFN-α and IFN-γ. All three cytokines induced phenotypically mature DC. The expression levels of CD38 and CCR7 on URC-primed DC were enhanced by IFN-γ and IFN-γ augmented the T cell stimulatory capacity in allo MLR to URC-primed DC. DC matured with URC plus IFN-γ produce high levels of IL-12p70 upon CD40 triggering. IFN-γ secretion from naïve T cells co-cultured with URC-primed DC also augmented by IFN-γ. In addition, DC maturated with URC plus IFN-γ has an intermediate migratory capacity towards CCL19 and CCL21. In contrast, surface molecule up-regulation and function of URC-primed DC were slightly enhanced by TNF-α and IFN-α. These data support that DC differentiated with URC in combination with IFN-γ might be used on DC-based vaccine for cancer immunotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3828.
Abstract 3830: Inhibition of IL-4 function decreases fibrosis and lymphatic dysfunction in a mouse model of lymphedema
Authors: Avraham Tomer , Daluvoy Sanjay V. , Kueberuwa Essie , Zampell Jamie C. , Yan Alan , Mehrara Babak J. 
Published: February 2011

Abstract
Background: Lymphedema, commonly encountered in cancer survivors, is characterized by chronic swelling and fibrosis. Previous studies have shown that fibrotic disorders involving other organ systems are dependent on T-helper 2 (Th-2) chronic inflammatory changes. The purpose of these experiments was therefore to evaluate the role of Th-2 cells in the pathological changes associated with lymphedema.
Methods: We developed a surgical mouse model that results in tail lymphedema for prolonged periods (&gt;9 weeks) and is histologically is similar to clinical lymphedema. Using this model in wild-type and athymic nude mice we evaluated the role of T-cells in general on the development of lymphedema and fibrosis. Furthermore, using a specific monoclonal neutralizing antibody against IL-4, a molecule necessary for Th-2 differentiation, we evaluated the role of Th2 cells in the initiation and maintenance of chronic lymphedema.
Results: Lymphedema in wild-type mice resulted in a chronic inflammation consisting predominantly of CD-4+cells with a mixed Th1-Th2+ differentiation. Interestingly, application of this model to athymic nude mice resulted in markedly decreased tail edema and fibrosis, demonstrating that these outcomes are T-cell dependent. While inhibition of Th2 differentiation immediately after surgery did not prevent initiation of lymphedema, it did result in early resolution, with a marked reduction in fibrosis and improved lymphatic function 6 weeks post-operatively. Consistent with this, inhibition of Th2 cell function in mice with established lymphedema resulted in resolution of lymphedema and fibrosis with just 3 weekly treatments. In contrast, lymphedema was sustained in animals treated with isotype control.
Conclusions: We have shown that Th2 differentiation is necessary for maintenance of the pathologic changes associated with lymphedema. Inhibition of Th2 differentiation completely reversed the fibrosis and lymphatic dysfunction in animals with established lymphedema, with resultant resolution of swelling. These results indicate that similar approaches may be clinically useful in patients with chronic lymphedema.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3830.