bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3789: Elevated inorganic phosphate stimulates immediate early gene expression and requires FGF receptor signaling
Authors: Beck George R. , Camalier Corinne E. , Hood Brian , Conrads Thomas P. 
Published: February 2011

Abstract
Dietary inorganic phosphate represents a novel chemoprevention target. Recent results from two different mouse models of tumorigenesis; the two-stage skin carcinogenesis and KrasLA1 lung tumor models suggest that a high phosphate diet increases tumor/papilloma number by approximately 50% relative to a low phosphate diet. Additionally, a low phosphate diet resulted in delayed incidence and growth of papillomas. These results suggest that increased consumption of dietary inorganic phosphate may have long-term consequences on overall health and particularly to tumorigenesis and consequently reducing dietary phosphate intake may be a novel chemoprevention strategy. Our in vitro studies have revealed an active role of inorganic phosphate in altering cell function in various cell types and suggest that the amount of available inorganic phosphate may have significant cell autonomous consequences on cell behavior including activation of ras and ERK1/2 signaling, and increased expression of transformation and metastasis associated genes such as osteopontin (spp1). However, the mechanism by which cells sense and respond to changes in extracellular phosphate resulting in increased proliferation and transformation is not fully understood. We have performed an analysis of the temporal changes in gene expression in response to elevated phosphate. Results identified the strong stimulation of immediate early genes within 15 minutes of exposure to elevated phosphate. Reporter and DNA binding assays revealed the requirement of serum response and AP-1 transcriptional elements and taken together characterize phosphate as a novel mitogen. Furthermore, we have identified the requirement of FGF receptor signaling as one of the earliest events in the phosphate signaling cascade. This finding provides a novel link between growth factor signaling, nutrient sensing and cell growth and tumorigenesis.
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 3789.
Abstract 38: Saturated free fatty acids activate a c-Src-JNK1 axis within lipid rafts: Implications for the development of insulin resistance, obesity, and obesity-associated cancer
Authors: Holzer Ryan , Tran Helen , Salinas Giovanni , Karin Michael 
Published: February 2011

Abstract
Obesity is a risk factor for the development of insulin resistance/type 2 diabetes and several types of cancer, including cancers of the colon, breast, liver, endometrium and esophagus. Obese individuals have increased levels of free fatty acids (FFAs) in their serum, and so we are investigating signaling pathways that are activated by FFAs in vitro to gain insight into pathways that may trigger insulin resistance and the activation of oncogenes in obese individuals in vivo. Obesity is associated with chronic activation of c-Jun NH2-terminal kinase (JNK)1 in liver, fat and muscle tissue, and studies using JNK1-deficient mice demonstrate that JNK activation is important for adiposity, peripheral insulin resistance and the production of the proinflammatory cytokines, but the mechanism of JNK1 activation in obesity is unclear. Our data demonstrate that JNK1 is activated by FFAs in vitro in a c-Src-dependent manner, and that activation of c-Src occurs within lipid rafts. Src-deficient murine embryonic fibroblasts (MEFs) and SYF MEFs, which are deficient in c-Src family kinases c-Src, c-Yes and c-Fyn, do not activate JNK1 after exposure to FFAs in vitro, while NIH 3T3 MEFs and SYF MEFs reconstituted with c-Src activate JNK1 normally. In contrast, SYF MEFs reconstituted with c-Yes and c-Fyn do not activate JNK1. Knockdown of c-Src with shRNA in HEK 293T cells also inhibits FFA-induced activation of JNK1, and inhibition of c-Src with pharmacologic inhibitors has the same effect in J774 mouse macrophages. Pharmacologic inhibition of c-Src also prevents the FFA-induced upregulation of tumor necrosis factor (TNF)-α mRNA in macrophages. Importantly, c-Src is activated within lipid rafts after FFA treatment, as seen by both detergent-dependent and detergent-independent methods of raft isolation. Interestingly, omega-3 polyunsaturated fatty acids (PUFAs), which can protect against the onset of obesity, will also block JNK activation following treatment with saturated FFAs, and we suspect that this effect may be due to the ability of PUFAs to exclude c-Src from lipid rafts. Finally, preliminary data suggests that c-Src may be aberrantly activated in liver tissue from obese mice that were fed a high-fat diet. Experiments are currently underway to verify the role of c-src in the activation of JNK1 in vivo by acutely infusing mice with a free fatty acid emulsion in the presence of a pharmacologic inhibitor of c-src.
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 38.
Abstract 3801: p53 acetylation by green tea polyphenols leads to upregulation of GSTP1 activity
Authors: Thakur Vijay S. , Gupta Karishma , Gupta Sanjay 
Published: February 2011

Abstract
Epigenetic modifications including DNA methylation and post-translational changes in histone proteins cause alteration in gene regulation. Expression of glutathione-S-transferase Pi (GSTP1), an enzyme of phase II cellular metabolism involved in detoxification of carcinogens and other cellular functions found to be silenced in 80-90% prostate cancers due to hypermethylation of its promoter. We have recently demonstrated that green tea polyphenols (GTPs) cause re-expression of GSTP1 in human prostate cancer LNCaP cells [Int J Cancer. 2009; PMID: 19856314]. However, the mechanism of GSTP1 re-expression is not fully elucidated. Similar to GSTP1 gene, p53 tumor suppressor is also involved in a number of important cellular events including cell cycle, DNA repair, and apoptosis which is reported to be mutated or has defective signaling in most human cancers including prostate cancer. Human GSTP1 gene has a p53-binding motif located in intron 4 and is highly homologous to consensus p53-binding motifs in other p53-responsive genes having the ability to transcriptionally activate GSTP1. Whether p53 participates in GTP-mediated re-expression of GSTP1 is unknown. In the present study we attempted to elucidate the role of tumor suppressor p53 in GSTP1 re-expression after treatment with GTPs. Human prostate cancer LNCaP cells which possess epigenetic signatures of GSTP1 silencing and functional p53 were treated with physiologically achievable doses of GTPs (5μg/mL) or its major constituent epigallocatechin-3-gallate (20μM) up to 7 days. Exposure of LNCaP cells to green tea polyphenols caused acetylation of p53 at its C-terminal amino acid positions K373 and K382, other than K305, which correlated with increased GSTP1 expression. Discontinuation of treatment with GTPs resulted in the loss of p53 acetylation with progressive decrease in GSTP1 expression in these cells. Furthermore, GSTP1 levels were significantly reduced after GTP treatment in cells with the knockdown of p53 expression achieved using shRNA in lentiviral vector. Taken together, our results demonstrate that expression of GSTP1, in part, could be enhanced through p53 acetylation after treatment with green tea polyphenols and thus protect the cells from undergoing epigenetic alterations which may contribute to prostate tumorigenesis.
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 3801.
Abstract 3811: Robust anti-tumor activity through targeting integrin α5β1 and eliciting ADCC with a dual functional monoclonal antibody PF-04605412
Authors: Hu-Lowe Dana D. , Li Gary , Chen Enhong , Wang Jianying , Zhang Lianglin , Chen Jeffrey H. , Amundson Karin , James Zobel , Kraynov Eugenia , Sharp Leslie , Wickman Grant , Jiang Xin , Bender Steve , Casperson Gerald 
Published: February 2011

Abstract
Integrin α5β1 and its ligand fibronectin are significantly and coordinately over-expressed in tumor associated blood vessels and cancer cells. These molecules have been reported to mediate angiogenesis, tumor survival and metastasis. α5β1 has also been implicated as a poor prognostic marker in a number of human tumor types including NSCLC and ovarian carcinoma. Thus, α5β1 is a potential target for cancer therapy. Accumulating evidence suggests an important role of innate immune effector cells in tumor killing via antibody dependent cellular cytotoxicity (ADCC). Taking advantage of both of these mechanisms, we generated an α5 integrin-specific neutralizing monoclonal antibody (mAb, PF-04605412) with high affinity for Fcγ receptors. In vitro, PF-04605412 potently inhibited α5β1-mediated intracellular signaling, cell adhesion, migration, endothelial cell tubulogenesis, and induced apoptosis of endothelial and tumor cells. Compared to a wild type IgG1 of identical antigen specificity (wt IgG1), PF-04605412 induced a significantly greater tumor and endothelial cell cytotoxicity. ADCC activity correlated with the abundance of NK cells within PBMCs of human donors, but was independent of donor FcγRIIIa polymorphism. In in vivo studies using human xenograft, immuno-xenograft and syngeneic tumor models, PF-04605412 (and an anti-murine α5 surrogate mAb) displayed robust and dose-dependent anti-angiogenesis and anti-tumor efficacy including tumor growth delay, regression and metastasis inhibition, all of which were superior to effects observed with an IgG2 or wt IgG1 of identical antigen specificity. Western blotting and immunohistochemistry analysis of tumor samples showed that anti-tumor efficacy was associated with reduction of total and phosphorylated focal adhesion kinase and positively correlated with α5 expression, infiltrating macrophages, markers of effector cell activity, and apoptosis. Furthermore, depletion of host macrophages abrogated anti-tumor efficacy, indicating a critical contribution of ADCC/phagocytosis to the anti-tumor activity of PF-04605412. The PK-PD relationship, efficacy of PF-04605412 in combination with anti-angiogenic and tumor targeting agents will also be reported. The distinct dual mechanism of action and robust anti-tumor efficacy of PF-04605412 supports the clinical development of this agent for the treatment of human cancers.
Short Title: Dual functional mAb PF-04605412
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 3811.
Abstract 3815: Murine tumors demonstrate variable responses to ischemia-reperfusion injury
Authors: Sheu Eric G. , Wakatsuki Kohei , Oakes Sean M. , Ahmadi-Yazdi Cyrus , Moore Francis D. 
Published: February 2011

Abstract
Introduction: Acute ischemia/reperfusion (I/R) of normal tissues causes an inflammatory reaction initiated by binding of auto-reactive IgM antibody to an ischemia-induced self-antigen. Whether this inflammatory cascade also affects cancers - for example, after acute I/R during surgical resection or in conditions of chronic ischemia - is unclear. We examined the effect of I/R injury in three murine tumor models: B16F10 melanoma, Lewis lung carcinoma (LLC), and small intestinal adenomas of the APCmin/+ mouse.
Methods: LLC and B16F10 cell lines were implanted into the hindlimbs of C57BL/6 mice. Ischemia was induced by external tourniquet ligation of the femoral vessels. Small intestinal tumors in APC min/+ mice were subjected to ischemia by vascular clip occlusion of the superior mesenteric artery. Control animals underwent hindlimb ischemia to the non-tumor bearing hindlimb or laparotomy alone. Following graded times of ischemia and reperfusion, tumors and surrounding normal tissue were harvested for histological examination. Immunohistochemistry was performed for IgM and activated caspase-3. For hindlimb injury, mice were recovered and followed for LLC and B16F10 tumor growth.
Results: Ischemia-reperfusion causes injury of LLC and B16F10 tumors. In contrast, intestinal adenomas of APCmin/+ mice showed no signs of injury following ischemia, despite induction of necrosis and apoptosis of adjacent normal intestinal epithelium. Tumor susceptibility to ischemic injury correlated with immuno-histochemical deposition of IgM antibody. Ischemic injury of B16F10 significantly reduced tumor growth (36% volume reduction compared to control injury, p &lt;0.05). In contrast, LLC tumor growth was significantly increased after ischemia (35% increased compared to control injury, p &lt; 0.01)
Conclusions: The three murine tumor models examined are each affected differently by an acute I/R injury, in contrast to the conserved inflammatory cascade induced in normal tissues following ischemia. APCmin/+ adenomas evade ischemia-induced IgM binding and injury. While both LLC and B16F10 are acutely injured, the long term effects on growth are divergent. Targeted manipulation of the host inflammatory response to ischemia-reperfusion may be a method to influence tumor progression and growth.
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 3815.
Abstract 3817: Initial characterization of the prolactin-inducible protein (PIP) null mouse suggests an immunomodulatory role for mPIP
Authors: Yeganeh Behzad , Blanchard Anne , Nistor Andreea , Myal Yvonne 
Published: February 2011

Abstract
Mouse prolactin-inducible protein (mPIP) is the homologue of the human PIP which is a known marker of both malignant and benign human breast cancer. PIP is shown to be highly expressed and secreted by submandibular, lacrimal and salivary glands. Secreted PIP in saliva has been shown to bind to bacteria suggesting that PIP may play a role in innate host defence. Furthermore, human PIP was shown to be a ligand of the CD4 molecule of T lymphocytes, acting as a potential inhibitor of T cell apoptosis suggesting a role in immune host defence.
To address the role of mPIP in innate and adaptive host defence, we generated a PIP knockout mouse (PIP−/−) by targeted gene disruption. Histological as well as physiological and behavioural analyses were used to study the phenotype of these mice. Microarray was also conducted to assess the global effect of mPIP abrogation on gene expression in submandibular glands.
PIP−/− mice develop normally with no obvious phenotypic differences that distinguish them from wild-type siblings. However, some adult mutant mice exhibit increased proliferative activity in lymphoid tissues, evident with enlarged submandibular lymph nodes. Light microscopy of these submandibular lymph nodes revealed activated germinal centres with an increased number of immune cells displaying high mitotic and apoptotic rates. Additional analyses showed enlarged medullary regions in the thymus of some PIP−/− mice populated with mature lymphocytes and lymphocytic aggregations within the prostate lobes. As well, analysis of blood cell profiles revealed significant increased in the number of monocytes (p&lt;0.005, n=6) in PIP−/− mice compared to their corresponding littermates. Microarray analysis of gene expression of the submandibular gland of PIP−/− mice also showed differential expression of multiple genes such as Xiap, Dmtf1, Runx1t1, Ccnb2, Notch4, Zeb2 genes which have been shown to be associated with immune disease, cancer and cell survival.
In summary our data suggests a role for mPIP in modulation of adaptive and innate immune response in mice. Furthermore, our microarray analysis has revealed novel potential genes and pathways involved in mPIP signalling.
(Supported by: Natural Sciences and Engineering Research Council of Canada)
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 3817.
Abstract 3823: Platinum anti-cancer drugs attenuate T cell-mediated immune suppression through STAT6/PD-L2
Authors: Lesterhuis W. Joost , Punt Cornelis J.A. , Eleveld-Trancikova Dagmar , Jansen Bas J.H. , Schreibelt Gerty , Boer Annemiek De , Adema Gosse J. , Figdor Carl G. , De Vries I. Jolanda M. 
Published: February 2011

Abstract
It has become evident that many immune inhibitory mechanisms in the tumor micro-environment prevent the development of effective T cell responses against the tumor cells in cancer patients. Therapeutic interventions aimed at blocking these pathways have been shown to result in enhanced anti-tumor immunity, but they lack direct cytotoxic effects. Cancer chemotherapeutic drugs have these direct cytotoxic anti-tumor effects and although for some anti-cancer drugs indirect activation of the immune system via induction of an immunogenic type of tumor cell death has been described, their effect on inhibitory pathways in anti-tumor immunity is unknown.
We investigated the effect of a wide array of chemotherapeutics on dendritic cell (DC) function and on tumor cell immunogenicity.
Using allogeneic and antigen-specific in vitro models, we found that when DCs were matured/activated in the presence of platinum-based chemotherapy, they showed strongly enhanced T cell stimulatory capacity. Programmed death receptor-ligand 2 (PD-L2) expression by DC was markedly reduced upon platinum exposure. The enhanced T cell stimulatory capacity by DC upon platinum exposure was abrogated in the presence of PD-L2 blocking antibodies. This was also observed when the regulator of PD-L2 expression, signal transducer and activator of transcription 6 (Stat6), was knocked down using siRNA.
In addition, we found that STAT6 was dephosphorylated in tumor cells by platinum compounds, leading to marked downregulation of PD-L2, resulting in enhanced recognition by tumor-specific T cells.
In line with these in vitro findings, we found enhanced Th1 cytokine secretion and T cell proliferative responses in cancer patients upon treatment with platinum-based chemotherapy, confirming the in vivo occurrence of platinum-induced immune deviation.
Our findings show that treatment with platinum compounds not only results in enhanced T cell stimulation by DC, but at the same time enhances the sensitivity of the tumor for lysis by cytotoxic T cells. This novel double action of platinum compounds may initiate combinations with other immune stimulatory compounds to increase clinical efficacy.
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 3823.
Abstract 3826: Neutralization of TGFβ enhances the efficacy of chemotherapeutics in a preclinical model of triple negative breast cancer
Authors: Harper Jay W. , Green Tessa , Munroe Kenneth , Manning Charlene , Tao Jingzang , Simon Kailene , Wakefield Lalage , Hsu Frank , McPherson John , Kaplan Johanne , Gregory Rick , Lonning Scott 
Published: February 2011

Abstract
TGFβ plays a key role in metastasis by promoting epithelial to mesenchymal transition, up-regulating proteases that degrade extracellular matrix, enhancing tumor cell motility and suppressing antitumor immunity. Previously we have demonstrated that neutralizing TGFβ with the antibody 1D11 significantly inhibited metastasis in preclinical models of breast cancer and melanoma, with minimal effects on primary tumor growth. Neutralizing the protumorigenic effects that TGFβ has on the immune system and tumor microenvironment could, hypothetically, enhance the direct anti-tumor effects of chemotherapeutic agents. To test this hypothesis, several studies were conducted testing combinatorial therapies with 1D11 and chemotherapeutics against subcutaneous (SQ) 4T1, a murine model of triple negative breast cancer (TNBC), with subsequent metastasis to the lung. Paclitaxel is currently the front-line therapy for TNBC in the clinic. Combining 1D11 with paclitaxel had little effect on enhancing the efficacy of paclitaxel alone against primary tumor growth. However, the combinatorial therapy of 1D11 and paclitaxel inhibited spontaneous metastasis from the primary SQ tumor to the lung to a greater extent than either agent alone. In the clinic TNBC typically becomes resistant to taxane therapy and another treatment that has shown some promise in taxane-refractory TNBC is the combinatorial therapy of capecitabine and ixabepilone. In the 4T1 preclinical model, both capecitabine and ixabepilone inhibited the growth of SQ 4T1 tumors as single agents, and the combination of the two therapeutics resulted in slightly greater efficacy. However, the addition of 1D11 to capecitabine and ixabepilone resulted in even greater efficacy than with the combination alone. Currently, the effects of neutralizing TGFβ with 1D11 during the course of capecitabine/ixabepilone therapy on metastasis in the 4T1 model are being investigated. Additionally, mechanism of action studies are being conducted to determine the mechanisms by which 1D11 is enhancing the efficacy of paclitaxel and the combinatorial therapy. The data from these chemo-combo studies with 1D11 suggests that therapies that target TGFβ may enhance the efficacy of paclitaxel against TNBC metastasis and may potentiate the efficacy of the combinatorial therapy of capecitabine/ixabepilone in taxane-refractory TNBC.
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 3826.