bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4360: CD87 is essential for mediating growth-factor induced angiogenesis via distribution of integrin beta-1
Authors: Unseld Matthias , Poettler Marina , Novotny Rene , Zielinski Christoph , Prager Gerald W.
Published: August 2012

CD87 (urokinase-type plasminogen activator receptor, uPAR) expression has been correlated with tumor progression most likely via its functional ole as a central receptor for extracellular proteolysis, but also via its role in initiating intracellular signal transduction. The role of CD87 in angiogenesis has recently been elucidated. Thus, we observed that in VEGF-stimulated ndothelial cells CD87 is essential for endothelial cell survival as well as for n efficient growth factor- induced endothelial cell migration. Thereby, the PI-anchored protein CD87 formed a complex with its ligand urokinase uPA) as well as the inhibitor plasminogen activator inhibitor-1 (PAI-1), which became redistributed to the leading edge via low density lipoprotein receptor- (LDLR-) like proteins. In this study, we analyzed the functional role of CD87 in integrin redistribution during growth factor-induced endothelial cell migration. CD87, thereby, directly interacted with integrin adhesion receptors (a5b1) as well as with LDLR- proteins. Either by interfering with CD87/integrin nteraction or by interfering with CD87/LDLR-protein interaction by using specific interfering peptides, we observed disruption of integrin redistribution to the leading edge in migrating cells. As a consequence diminished focal adhesion formations were observed and endothelial cell migration was diminished. In CD87-deficient HEK 293 cells as well as in endothelial cells derived from CD87 -/- mice, expression of CD87 mutants (mutL3/uPAR), which lacked the binding motif for LDLR, led to an impaired cell spreading as well as a diminished migratory response towards VEGF, while full length CD87 (wt/CD87) reconstituted this phenotype. That CD87 plays a central role in growth factor induced endothelial cell invasion and capillary-like tube formation in vivo was demonstrated by a directed in vivo angiogenesis assay (DIVAA), which was performed either in CD87 deficient or wild type animals in the presence or absence of interfering peptides. Our data give novel insights into the central role of CD87 in pro- angiogenic endothelial cell behavior as well as in its role in angiogenesis. Thus, CD87 might lead to a novel therapeutic strategies in tumor- angiogenesis.

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 4360. doi:1538-7445.AM2012-4360
Abstract 4363: Tumor regulation of myeloid-derived suppressor cell proliferation, circulation and apoptosis.
Authors: Talmadge James E. , Dafferner Alicia J. , Britton Holly C. , Younos Ibrahim H.
Published: August 2012

In response to stress, myeloid progenitor cells (MPCs) mobilize and establish sites of extramedullary hematopoiesis (EMH) within lymphoid and parenchymal organs. We report that the spleens of 4T1 mammary tumor-bearing (TB) mice are the primary site of MPC proliferation resulting in extensive EMH in association with decreased apoptosis, increased myeloid cell survival, and increased hematopoietic growth factor (GF) transcription by the tumor cells. MPC trafficking and survival differs between TB and naïve mice with leukocyte arrest in the lungs of naïve mice and accumulation in the splenic red pulp of TB mice with little marrow or tumor arrest or proliferation. Indeed, despite the high levels of GF transcription by tumor cells MDSC apoptosis in tumors is very high perhaps due to the high levels of NOS2 in the tumor microenvironment. Further myeloid proliferation directly correlates with the decrease in T-cell frequency, which is associated with extrathymic, but not thymic T-cell proliferation. In summary, tumor cytokines regulate a dynamic relationship between MPCs and T-cells regulating their proliferation, trafficking, accumulation, apoptosis, and survival.

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 4363. doi:1538-7445.AM2012-4363
Abstract 4365: A cellular model for investigation of circulating tumor cells and identification of therapeutic target and regimen
Authors: Chang Yao-Wen , Chong Kowit-Yu , Lin Pei-Yun , Hsieh Pei-Wen , Liao Chang-Hui , Tseng Ching-Ping
Published: August 2012

Tumor cells disseminating into circulatory system is crucial for cancer metastasis during cancer progression and surgical operation in removing tumor mass. Due to technical hurdles, it is not yet available to culture and propagate circulating tumor cells derived from cancer patients. Not yet any model system has been established to investigate the cellular and molecular changes associate with the entry of primary tumor cells into bloodstream. In this study, genetically modified C6 glioma cells (C6-LG) that elicit high procoagulant activity and express luciferase/GFP reporter gene were used for xenograft injection into nude mice to establish a metastatic model. Two C6-derived sublines, C6-lung and C6-blood, were isolated and established from the cells that colonized at lung tissue and from blood circulation, respectively. Cellular analyses revealed that C6-lung and C6-blood had differential cell cycle distribution, cell growth rate, migration and metastatic potential. Microarray analyses also revealed differential gene expression signatures between these two sublines. Nevertheless, podoplanin was up-regulated in both cell lines when compared to the parental C6-LG. Consistent with these observations, C6-lung and C6-blood activated platelet and induced platelet aggregation that is closely associated with their in vivo metastatic potential as revealed by gene knockdown analysis. Using these C6-sublines as the cellular screening platform, we have identified a novel compound designated as CGU-07 that elicited inhibitory activity in cancer cell-induced platelet aggregation. In conclusion, circulating and primary tumor cells have both common and distinguished cellular and molecular profiles. Targeting on the common molecular signature such as podoplanin raises the hope to further application of its therapeutic use in the prevention and treatment of tumor metastasis.

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 4365. doi:1538-7445.AM2012-4365
Abstract 4428: Diethylnitrosamine-induced hepatocarcinogenesis is suppressed in mice lacking hepatic retinoid storage
Authors: Shirakami Yohei , Blaner William S. , Shimizu Masahito , Moriwaki Hisataka
Published: August 2012

Retinoids are known to possess anti-cancer effects and a clinical trial of a synthetic retinoid for hepatocellular carcinoma (HCC) is ongoing recently in Japan. Loss of retinoid-containing lipid droplets upon hepatic stellate cell (HSC) activation is one of the first events in the development of liver disease leading to hepatocellular carcinoma (HCC). Although retinoid stores are progressively lost from HSCs during the development of hepatic disease, how this affects hepatocarcinogenesis is unclear. To investigate this, we used diethylnitrosamine (DEN) to induce hepatic tumorigenesis in matched wild-type (WT) and lecithin:retinol acyltransferase (LRAT) knockout (KO) mice, which lack stored retinoid and HSC lipid droplets. Male 15 day-old WT or Lrat KO mice were given intraperitoneal injections of DEN (25 mg/kg body weight). Eight months later Lrat KO mice showed significantly less liver tumor development compared to WT mice, characterized by less liver tumor incidence and smaller tumor size. Two days after DEN injection, lower serum levels of alanine aminotransferase and decreased hepatic levels of cyclin D1 were observed in Lrat KO mice. Lrat KO mice also exhibited increased levels of retinoic acid-responsive genes, including p21, lower levels of cytochrome P450 enzymes required for DEN-bioactivation, and higher levels of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), both before and after DEN treatment. Our results indicate that Lrat KO mice are less susceptible to DEN-induced hepatocarcinogenesis due to increased retinoid signaling and higher expression of p21, which is accompanied by altered hepatic levels of DEN-activating enzymes and MGMT in Lrat KO mice also contribute to decreased cancer initiation and suppressed liver tumor development.

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 4428. doi:1538-7445.AM2012-4428
Abstract 443: Expression of the RECK tumor and metastasis suppressor gene in human breast cancer: a poor prognosis marker
Authors: Gomes Luciana R. , Fujita Andre , Soares Fernando A. , Labriola Leticia , Sogayar Mari C.
Published: August 2012

Metastasis is the main cause of mortality in breast cancer human patients. The organized breakdown of the extracellular matrix (ECM) compounds by matrix metalloproteinases (MMPs) is the key event in this metastatic process. Consistent with their role in tumor progression, high levels of several MMP family members have been shown to be correlated with poor prognosis. The MMP activities are tightly regulated by their inhibitors, namely: the metalloproteinases tissue inhibitors (TIMPs) and the membrane-associated inhibitor (RECK - Reversion-inducing Cysteine-rich protein with Kazal motifs). Due to RECK's ability to down modulate MMPs (MMP-2, 9 and 14), it is described as an important inhibitor of invasion and metastasis in several types of cancer. In order to investigate possible correlations between the RECK expression profile and clinical-pathological data in a breast cancer model, we evaluated the RECK protein in 1,040 tissue samples from invasive breast tumors using Tissue Microarray Assays (TMA). Associations between RECK expression and different clinical-pathological parameters and other biomarkers were evaluated using the Chi-square test. RECK immunoreactivity was significantly associated with higher SBR grade (p<0.05) and TNM stage (p=0.002). Moreover, higher RECK expression levels were correlated with p53 (p<0.001), her-2 (p=0.011), CK5,6 (p<0.001) and egfr (p<0.001) positivity. We also analyzed the relationship between RECK expression and the patient outcome, using Kaplan-Meier curves, demonstrating that patients with RECK positive tumors display significantly shorter disease free survival time (p=0.031) than those with RECK negative tumors. Furthermore, RECK expression was positively correlated with short disease free survival in five-years in patients diagnosed with tumors: low SBR grade (p=0.03), her-2 negative (p<0.05) and luminal markers (CK8/CK18) positive (p=0.02 and p=0.003, respectively). In addition, RECK was a predictor of poor prognosis for post-menopause (p=0.011) and patients older than 50 years (p=0.05). All together, our results indicate that higher RECK expression is associated with poor prognosis variables, being a predictor of shorter disease-free survival in five years. Moreover, we verified that RECK is a biomarker of poor prognosis mainly for patients diagnosed with less aggressive breast tumor. Therefore, in contrast to other tumor types, our results indicate that RECK is related to a more aggressive phenotype. Support: FAPESP, CNPq, FINEP, CAPES, BNDES

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 443. doi:1538-7445.AM2012-443
Abstract 4432: Pancreatic normal duct epithelial and cancer cells express an autocrine catecholamine loop that is activated by the α3, 5 and 7 nicotinic acetylcholine receptors
Authors: Al-Wadei Mohammed H. , Al-Wadei Hussein A. , Schuller Hildegard M.
Published: August 2012

Pancreatic cancer is the fourth leading cause of cancer deaths in developed countries. Smoking is an established risk factor for this malignancy but the underlying mechanisms are poorly understood. Previous reports have provided evidence that nicotinic acetylcholine receptors (nAChRs) and beta-adrenergic receptors (α-ARs) stimulate the growth and migration of pancreatic cancer cells. But a potential cooperation of these two receptor families in the regulation of pancreatic cancer has not been studied to date. Using two pancreatic cancer cell lines and immortalized pancreatic duct epithelia in vitro, our current data show, that all three cell lines synthesized and released the catecholamine neurotransmitters noradrenaline and adrenaline upon exposure to nicotine and that this activity was regulated by the α3, 5 & 7-nAChRs. In accord with the established function of these catecholamines as α-AR agonists, nicotine-induced cell proliferation was blocked by the α-AR antagonist propranolol. Nicotine-induced proliferation was also abolished by the α7-nAChR antagonist α-bungarotoxin and catecholamine production in response to nicotine was blocked by α3, 5 or 7-nAChR gene knockdown. Moreover, our results show that the nicotinic agonists acetylcholine, nicotine, and its nitrosated carcinogenic derivative NNK induced the phosphorylation of CREB, ERK, Src and AKT and that those responses were inhibited by the beta-blocker, propranolol. Our findings identify this hitherto unknown autocrine catecholamine loop as an important regulatory cascade in pancreatic cancer that may prove a promising new target for cancer intervention. Supported by R01CA042829 and R01CA130888 with the National Cancer Institute.

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 4432. doi:1538-7445.AM2012-4432
Abstract 4433: RB mediates TGF-β effects on growth inhibition and invasion in pancreatic cancer cells
Authors: Gore Jesse , Korc Murray
Published: August 2012

Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that arises from precursor lesions, termed pancreatic intraepithelial neoplasia (PanIN). PDAC's aggressiveness derives from its advanced stage when patients present clinically, the high frequency of driver mutations (KRAS, INK4A, TP53 and SMAD4) and the heterogeneous distribution of low frequency driver mutations. To study the potential role of RB in PDAC pathobiology, we generated a novel mouse model with pancreatic RB deletion and oncogenic Kras expression (Rb/K mice). These mice rapidly developed highly proliferative PanIN that progress to PDAC with high frequency, underscoring RB's tumor suppressive role in the pancreas. RB deletion alone, however, did not alter pancreatic histology. Previously, we have demonstrated that Smad7-induced loss of TGF-β-mediated growth inhibition is due to functional inactivation of RB. To further examine RB's role in TGF-β action, we established pancreatic cancer cell lines from the Rb/K model. These cells were resistant to TGF-β1-mediated growth inhibition, whereas growth of murine cell lines that retained RB was markedly inhibited. RB loss also abolished TGF-β-induced cell invasion, but did not alter Smad-dependent TGF-β1 signaling since TGF-β1 induced Smad2 phosphorylation, Smad3/4 nuclear translocation, and transactivation of TGF-β1-dependent reporters. By contrast, RB loss did not affect TGF-β1-induced epithelial-to-mesenchymal transition. Array analysis revealed marked alterations in the gene expression profile of Rb/K cells. These data suggest that RB loss contributes to the dysregulation of TGF-β actions in PDAC and suggest that delineation of these perturbations may yield novel therapeutic approaches in this malignancy.

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 4433. doi:1538-7445.AM2012-4433
Abstract 4435: Overexpression of Rhotekin confers gastric cancer cells resistance to interferon-α-mediated growth inhibition
Authors: Yin Tsun-Ying , Hsiao Ya-Wen , Peng Wen-Hsin , Wang Mei-June , Chen Jeou-Yuan
Published: August 2012

Tumor infiltrating lymphocytes (TILs) are frequently detected in a variety of malignancies, including gastric cancer (GC). TILs are known to produce high level of interferon-gamma (IFN-γ) in GC, but fail to suppress tumor growth. We have previously shown that Rhotekin (RTKN), the gene encoding the Rho effector RTKN, is overexpressed in human GC, and its expression is correlated with disease progression. In this study, we show that RTKN expression efficiently blocks IFN-γ-mediated anti-growth and immunologic responses, suggesting a role of RTKN in attenuating tumor immunosurveillance during GC pathogenesis. We show that RTKN attenuates STAT1 phosphorylation in response to IFN-γ, and confers increased resistance to IFN-γ-mediated growth suppression in GC cells through inhibiting the expression of STAT1-dependent downstream target genes, including cyclin-dependent kinase inhibitor p21 and antiapoptotic genes BCL-2 and BCL-xL. Conversely, elimination of RTKN expression by knockdown approach facilitates IFN-γ-mediated STAT1 phosphorylation and promotes IFN-γ-mediated growth arrest and apoptosis. We further show that RTKN-mediated inhibition of STAT1 phosphorylation can be reversed by the treatment of sodium orthovanadate, a tyrosine phosphatase inhibitor, suggesting the involvement of tyrosine phosphatases in RTKN-mediated process. In support, our data show that RTKN suppresses IFN-γ-mediated STAT1 phosphorylation partly through facilitating the interactions of SHP2 and STAT1. In summary, our data suggest that RTKN overexpression confers growth advantages to GC by evading immunosurveillance through suppression of IFN-γ-mediated anti-tumor activity.

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 4435. doi:1538-7445.AM2012-4435
Abstract 4436: Chronic inflammation and gastric carcinogenesis: the role of CD44 variant expression
Authors: Wada Takeyuki , Nagano Osamu , Ishimoto Takatsugu , Yae Toshifumi , Kitagawa Yuko , Saya Hideyuki
Published: August 2012

CD44 is a marker of tumor-initiating cells in gastric cancer. Recently, we have reported that a CD44 variant (CD44v) interacts with xCT, a glutamate-cystine transporter, and manifests enhanced protection against reactive oxygen species (ROS), contributing to tumor growth and resistance to chemo- or radiotherapy. Although an inflammation related metaplasia and/or dysplasia of gastric epithelium is considered as key events in gastric carcinogenesis, the cause or process of these phenomena is not known. We investigated the relationship between CD44v expression and gastric carcinogenesis, using three lineages of gastric cancer mouse models, K19-Wnt1, K19-C2mE, and K19-Wnt1/C2mE mice. We also used CD44-/- K19-Wnt1/C2mE mice and Helicobacter. felis-infected C57BL/6 mice. Chronic inflammation triggered by Helicobactor infection played a major role in CD44v related gastric carcinogenesis. CD44v expression and nuclear factor-kappa B (NF-κB) activation were promoted by inflammatory cytokines, IL-1α and TNF-α, in gastric cancer cell lines. Thus, CD44v+ tumor cell expansion induced by inflammation via NF-κB pathway might contribute to tumor development. Finally, an xCT inhibitor sulfasalazine treatment significantly suppressed tumor growth in K19-Wnt1/C2mE mice. These findings suggest a significant role of CD44v in inflammation-mediated gastric carcinogenesis via ROS defense.

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 4436. doi:1538-7445.AM2012-4436
Abstract 4437: Subsquamous extension of Barrett epithelium is a regular event
Authors: Marx Andreas H. , Rösch Thomas , Sauter Guido
Published: August 2012

Endoscopic resection and/or ablation of Barrett esophagus (BE) is directed by the endoscopic visual impression of pinkish Barrett versus whitish esophageal mucosa; microscopically however, BE may extend underneath squamous epithelium. Aim of the present study is to evaluate subsquamous BE extension in a large cohort of patients with endoscopically resected neoplastic BE. Resection specimens of 97 patients treated by endoscopic mucosal resection (EMR) for suspected or confirmed neoplastic BE (83 men, 14 women, mean age 65 years) were retrospective reanalyzed by two experienced GI histopathologists. Orientation of resected specimens pinned on cork was done prior to histopathological workup with squamous epithelium oriented proximally. Subsquamous extension was measured in all specimens containing squamous epithelium. Endoscopic and other histopathologic data were also analyzed. 442 specimens of the 97 study cases were analyzed and subsquamous BE was found in 42.5% of specimens or 97.9% of patients. Mean length of subsquamous BE extension was 3.5 mm (0.0-9.6 mm) with 27.8% of cases measuring 5 mm or more. In 56 cases (57.7%), subsquamous BE consisted entirely or partially of neoplasia (42 cancers, 12 HGIN, 2 LGIN) with a mean subsquamous tumor extension of 1.2 mm mm (range 0.0-5.2 mm). Subsquamous extension of BE including all forms of neoplasia is a regular event. A minimal safety margin of 1 cm has to be kept with Barrett ablation techniques in order to avoid BE and/or tumor recurrence.

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 4437. doi:1538-7445.AM2012-4437
Abstract 4443: Body weight status predicts pre-treatment risk of PSA failure in men with clinically localized prostate cancer
Authors: Freeman Vincent L. , Flanigan Robert C. , Hollowell Courtney M. , Branch Jeffrey , Deane Leslie , Quek Marcus , Vidal Patricia P. , Friedman Nicholas , Cintron Daisy , Dabbous Firas , Millbrandt Linda , Garabedian Anne , Cleofe Jasmine , Gomez Sandra L.
Published: August 2012

Introduction and Objective: Obesity/excessive adiposity in men with clinically organ-confined prostate cancer is of growing concern, because it associates with an increased risk of cancer recurrence after definitive therapy based on post-treatment prognostic parameters. The objective of this study was to evaluate whether body weight status associates with pre-treatment predictors of cancer recurrence in this patient population. Methods: We performed a cross-sectional study of body weight status and pre-treatment risk of PSA failure in 119 men awaiting radical prostatectomy for clinically localized prostate cancer in four urologic clinics in the Chicago area. Body weight status was assessed using the body mass index (BMI) and dual-energy x-ray absorptiometry (DXA). D'Amico risk scores, which are based on clinical tumor stage, biopsy Gleason sum, and pre-treatment PSA, were used to rank each patient's 5-year risk of PSA failure as low, intermediate, or high. Ordinal logistical regression analyzed the association between BMI quartile and D'Amico risk scores after accounting for age, race, total grams of body fat, and study site. Results: The risk of PSA failure increased with increasing quartile of BMI. Relative to the lowest BMI quartile, the cumulative odds of an intermediate or higher D'Amico risk score vs. a low risk score (the “cumulative odds ratio”) for patients in the second BMI quartile (mean BMI = 27.8 kg/m2) was 3.51 (95% CI = 1.07 to 11.5, p = .038). For patients in the third quartile (mean BMI = 32.0 kg/m2) and forth quartile (mean BMI = 37.0 kg/m2), the cumulative OR was 6.52 (95% CI = 1.72 to 24.6, p = .0057) and 7.74 (95% CI = 1.18 to 50.9, p = .033), respectively (OR trend = 1.98, 95% CI = 1.09 to 3.59, p = .0254). Conclusions: Body weight status predicts pre-treatment risk of PSA failure in men with clinically localized prostate cancer. This provides further support for a mechanistic link between body weight status, which reflects energy balance, and prostate cancer prognosis. The results also highlight the potential for using body weight status and other lifestyle-related factors pertinent to prostate cancer to identify men who are at high risk for unfavorable treatment outcomes.

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 4443. doi:1538-7445.AM2012-4443
Abstract 445: Has k-Ras predictive influence on the kind of metastasis in patients with colon carcinoma
Authors: Falch Claudius , Strohäker Jens , Hann-von-Weyhern Claus , Adam Patrick , Königsrainer Alfred , Fend Falko , Brücher Björn LDM
Published: August 2012

Background: The k-Ras-protein shows in regard to its mutations status a predicitvity of the response after Cetuximab in patients with colon carcinoma. To our knowledge, not much is known, if k-RAS has also a predictivity in regard to different ways of metastasis. The goal of our investigations was the evaluation of k-Ras on primary non-metastatic colon cancer compared to lymphatic, hepatic and peritoneal metastasis. Methods: 98 patients with adenocarcinom of the colon and a postoperative pT2/3-status, who underwent surgical resection between 2006 and 2008 at the University of Tübingen had been included within the study collective. 53 patients had no metastasis (control group), while 45 patients revealed primary metastasis: lymphatic metastasis (n=20), hepatic spread (n=20) and multiple metastasize (n=5). After DNA-extraction, an amplification by ARMS-PCR was performed and the analysis of the mutation status was done by melting point analysis by Light-Cycler. Additionally sequencing of Exons 12 and 13 was performed in individual cases. Results: 29/98 (=30%) revealed a k-Ras-mutation. Out of these, 12 (=41%) had metastasis: 9 hepatic (=75%), 2 lymphatic (=17%) and 1 (=8%) multiple metastasis. Patients with k-Ras-mutation (n=29) showed a significant lower rate of lymphatic metastasis. (90% vs. 10%, p=0.031). The survival in accordance to the k-Ras mutation was not statistically significant (p=0.415). Conclusion: Patients with mutated k-Ras-gene in out patient population revealed no significant higher rate of metastasis (p=0.558), nor in regard to hepatic (p=0.090) or multiple locations (p=0.629). Our preliminary data assume, that the k-Ras mutation status has a predictive function on the rate of lymphatic metastasis in patients suffering from colon carcinoma (p=0.031). Follow-up-studies are demanded, if single mutations status might have an additional influence.

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 445. doi:1538-7445.AM2012-445
Abstract 446: Protein kinase Ciota is a new prognostic factor in gastric cancer
Authors: Kashihara Hideya
Published: August 2012

Background: Protein kinase Ciota (PKCiota) have been reported to be an important effector of oncogenic K-ras. Furthermore, PKCiota is correlated with tumor angiogenesis. The role of PKCiota in gastric cancer remains unclear. The aim of this study is to clarify the role of PKCiota in human gastric cancer. Methods: Twenty-eight patients with gastric cancer who underwent gastrectomy were enrolled. The expression of PKCiota mRNA was determined in clinicopathological factors. Next, the patients were divided into two groups: the PKCiota high expression group (n = 14) and low expression group (n = 14). 5-year survival rate, ERK mRNA, which was the gene of downstream K-ras, and VEGF mRNA were compared between the two groups. The prognostic factors were investigated by multivariate analysis. Results: High expressions of PKCiota mRNA were observed in undifferentiation, deeper tumor invasion (MP≤), advanced stage (Stage III, IV) and peritoneal dissemination (+). The 5-year survival rate in the PKCiota high expression group were lower than that in the PKCiota low expression group. The multivariate analysis revealed that high expression of PKCiota mRNA was an independent prognostic factor. The expressions of ERK mRNA and VEGF mRNA in the PKCiota high expression group were higher than that in the PKCiota low expression group. Conclusion: Our results indicate that PKCiota was correlated with tumor progression and angiogenesis. PKCiota may be a new prognostic factor in gastric cancer.

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 446. doi:1538-7445.AM2012-446
Abstract 4464: Genetic variants at chromosome 8q24, colorectal epithelial cell proliferation, and risk for incident, sporadic colorectal adenomas
Authors: Yang Baiyu , Thyagarajan Bharat , Gross Myron D. , Goodman Michael , Sun Yan V. , Bostick Roberd M.
Published: August 2012

Three polymorphic sites at chromosome 8q24 (rs7837328, rs10808555, and rs6983267) have been associated with risk for colorectal adenomas. It was also previously reported that the rs6983267 single nucleotide polymorphism (SNP) may enhance Wnt signaling, which regulates cell proliferation. To investigate associations between the 8q24 variants and colorectal epithelial cell proliferation in the normal-appearing colorectal mucosa, as well as risk for colorectal adenoma, we analyzed data from a previously conducted pilot, colonoscopy-based case-control study of incident, sporadic colorectal adenoma among the White participants (n = 90 cases, 132 controls). Proliferation was measured in biopsies of the normal-appearing mucosa of the rectum, sigmoid colon, and cecum using immunohistochemistry for proliferating cell nuclear antigen (PCNA) and calculated as a labeling index averaged across all three colorectal sites. Each SNP was associated with risk for colorectal adenoma in the same direction as previously reported; the odds ratios (ORs) for those homozygous for the rs7837328, rs10808555, and rs6983267 risk alleles relative to those heterozygous or homozygous for the non-risk alleles combined were, respectively, 2.07 (95% confidence interval [CI] 1.07-3.97), 2.37 (CI 0.97-5.76), and 1.55 (CI 0.86-2.79). Colorectal epithelial cell proliferation tended to be higher among those homozygous for the risk alleles (alleles A, G, and G for SNPs rs7837328, rs10808555, and rs6983267, respectively) compared to those heterozygous or homozygous for the non-risk alleles combined; in the cases and controls combined, for those with the rs7837328 AA genotype proliferation was 6.7% higher (p = 0.40), for those with the rs10808555 GG genotype it was 16.5% higher (p = 0.12), and for those with the rs6983267 GG genotype it was 1.2% higher (p = 0.87). These preliminary findings, which are consistent with previously reported direct associations between genetic variants at chromosome 8q24 and risk for colorectal adenoma, suggest that the genetic variants may also be associated with higher levels of colorectal epithelial cell proliferation in humans, thus providing support for the hypothesis that 8q24 variants may increase risk via enhanced Wnt signaling.

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 4464. doi:1538-7445.AM2012-4464
Abstract 4467: Gene-specific methylation of leukocyte DNA in relation to colorectal cancer among male smokers from a nested case-control study in the ATBC Study
Authors: Gao Ying , Caporaso Neil
Published: August 2012

Gene-specific methylation of Leukocyte DNA in relation to colorectal cancer among male smokers from a nested case-control study in the ATBC Study Recent data suggest a link between leukocyte DNA methylation and cancer risk. However, data on DNA methylation from a prospective study, which may provide evidence for causality, are sparse. We explored the association between methylation in leukocyte DNA and colorectal cancer (CRC) risk in male smokers using the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study. 221 incident CRC cases, and 219 controls, frequency-matched on age and smoking intensity were included. DNA methylation of 1505 CpG sites selected from 807 genes were evaluated using Illumina GoldenGate Methylation Cancer Panel I in pre-diagnostic blood leukocytes of study subjects. Tertiles of methylation level classified according to the distribution in controls for each CpG site were used to analyze the association between methylation level and CRC risk with logistic regression. The time between blood draw to cancer diagnosis (classifying cases according to latency) was incorporated in further analyses using proportional odds regression. We found that methylation changes of 30 CpG sites were associated with CRC risk at P<0.01 level. Taking the latency information into account strengthened some associations, suggesting that the methylation levels of corresponding sites might change over time with tumor progression. This is the first prospective study for CRC risk focusing on gene-specific DNA methylation to date. The results suggest that the methylation level of some genes were associated with cancer susceptibility and some were related to tumor development over time. Further studies are warranted to confirm and refine our results.

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 4467. doi:1538-7445.AM2012-4467
Abstract 4535: CENP-E and c-Myc expression identifies a sensitive population of gastric cancer
Authors: Li Gang , Fan Conglin , Deng Shibing , Xu Jiangchun , Shi Stephanie , Wang Kai , Pascual Bernadette , Kung Pei-Pei , Leung Suet Yi , Yue Siu Tsan
Published: August 2012

Centromere-associated protein E (CENP-E) is expressed during mitosis and plays an essential role in establishing and maintaining stable connections between mitotic chromosomes and the microtubules of the spindle. Previous preclinical studies have shown that inhibition of CENP-E function by small interfering RNA, blocking antibodies or small molecule inhibitors arrested cell cycle before metaphase, and could lead to cell death. In a number of cancers, CENP-E is frequently overexpressed in tumor tissues compared with their normal counterparts. In this study, we showed that CENP-E is overexpressed in about 60% of gastric cancer (intestinal and diffuse-type) tissues. In addition, c-Myc up-regulation was observed in more than 50% of the same samples. Overall, about 40% of all gastric tumor samples harbor both CENP-E and c-Myc upregulation. Using a panel of small molecule inhibitors of CENP-E, we evaluated in vitro anti-proliferation effect in a panel of gastric cancer cell lines. Our data suggested that cells with higher levels of c-Myc transcript were more sensitive to CENP-E inhibition. This preliminary study indicated that c-Myc amplification and/or over-expression could be a potential biomarker for selecting gastric cancer patients more likely to respond to CENP-E inhibition.

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 4535. doi:1538-7445.AM2012-4535
Abstract 454: Glucocorticoids enhance metastatsis and tumorigenicity in a triple negative breast cancer cell line
Authors: Lu Yen-Shen , Gao Ming , Wu Pei-Fang , Lin Ching-Hung , Yeh Ling-Chun , Chen Chun-Wei , Cheng Ann-Lii
Published: August 2012

Glucocorticoid (GC) is commonly co-administered with chemotherapy to prevent drug-induced allergic reaction, nausea, and vomiting. We have previously reported that GC may affect growth and chemosensitivity of carcinoma cells via diverse mechanisms (Lung Cancer 2006, 53:303-10; J Endocrinol 2006,188:311-9; World J Gastroenterol. 2005, 28:6373-80). Along this line, we further explored the effect of GC on breast cancer cells. Treatment of dexamethasone (DEX) resulted in early axillary lymph node metastases, and increased the number of lung and liver metastases in an orthotopic xenograft model of a triple negative breast cancer cell line (MDA-MB-231) in nude mice (BALB/cAnN.Cg-Foxn1nu/CrlNarl). In tail vein injection assay of cancer metastasis, treatment of DEX dramatically enhanced the lung metastatic potential of a lung-seeking sub-clone, MDA-MB-231-Lu2 (derived from lung metastasis of MDA-MB-231 cells after two in vivo passages in nude mice using intracardiac injection). To explore the mechanism of GC-induced metastasis of breast cancer cells, we performed several in vitro studies. While DEX does not affect the proliferation rate of MDA-MB-231 cells according to MTT assay, treatment of DEX enhanced the tumorigenicity of the cells according to soft agar tumor sphere formation assay. On the other hand, treatment of DEX decreased tumorigenicity in two non-TNBC cell lines, MCF7 and T47D cells. Using quantitative polymerase chain reaction and Western blots assay, we found that treatment of DEX increased the expression of Slug, an epithelial-to-mesenchymal transition (EMT) related gene, and angiopoietin-like 4 (ANGPTL4), an important lung metastasis related gene, in MDA-MB-231 cells, but not in MCF7 and T47D cells. Using transwell migration/invasion assay (with or without matrigel above the membrane), we found that the conditioned medium of DEX-treated lung and liver tissues of mice attracted the MDA-MB-231 cells and promote migration/invasion. In conclusion, GC enhances metastasis and tumorigenicity in MDA-MB-231 cells, a triple negative breast cancer cell line. Whether GC may have a detrimental clinical effect on this subtype of breast cancer patients need to be verified.

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 454. doi:1538-7445.AM2012-454
Abstract 4540: Pyruvate kinase M2 (PKM2) associated with poor prognosis in gastric signet ring cell carcinoma
Authors: Lim Jae Yun , Yoon Sun Och , Hong Soon Won , Kim Jong Won , Choi Seung Ho , Cho Jae Yong
Published: August 2012

Background: PKM2 (M2 isoform of pyruvate kinase) was identified as a driver of aerobic glycolysis, leading to cell growth and tumor development. PKM2 is usually known to overexpress in cancer, however, there are still remaining questions about the function and the potential as anti-cancer treatment target. We investigated the expression status of PKM2 in gastric cancer tissues and evaluated the possibility of biomarker and anticancer target. Methods: Paraffin-embedded tissue microarray blocks of gastric adenocarcinoma tissue specimens were obtained from 363 gastric cancer patients. All patients underwent curative gastric resection from 1999 to 2007 and distributed from stage I to IV and their clinical characteristics were collected. IHC (Immunohistochemical) assay was performed to evaluate PKM2 expression levels. The correlation of PKM2 expression level with gastric cancer prognosis / stage / histology was evaluated. Results: In our previous microarray study using 60 gastric cancer tissues, we identified PKM2 mRNA overexpressed in cancer tissue than non-cancer tissue (P<0.01). In IHC assays, PKM2 expression level was classified to score 0 (negative, n=185), 1 (weak positive, n=136), and 2 (strong positive, n=42). 49% of gastric cancer tissues presented PKM2 expression (weak or strong positive). PKM2 expression had no relation with prognosis (p=0.913, recurrence free survival) and TNM stage (p=0.825). Intestinal and diffuse type cancer manifested different PKM2 expression pattern and signet ring cell carcinoma manifested 26.6% PKM2 expression. Within same Lauren classification, there was no significant difference of prognosis according to PKM2 expression except signet ring cell carcinoma. In signet ring cell cancer (n=78), PKM2 expression was related to poor overall survival (p=0.029) Conclusion: PKM2 protein expression was not correlated with gastric cancer prognosis. Only in signet ring cell gastric cancer, overexpressed PKM2 was associated with poor overall survival. The role of PKM2 should be further verified in signet ring cell gastric cancer model to find clinical significance in this subtype of gastric cancer.

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 4540. doi:1538-7445.AM2012-4540
Abstract 4541: Metabolomic diagnosis of prostate cancer from urine
Authors: McDunn Jonathan , Whitaker Hayley , Li Zhen , Adam Klaus-Peter , Milburn Michael , Neri Bruce , Neal David
Published: August 2012

There is a critical unmet need for new diagnostic tests to both determine if a patient has prostate cancer and whether that cancer is aggressive and therefore requires aggressive management. In this study we performed global metabolomic profiling on the post-DRE urine sediments of twenty-four men referred to the urologist with concern of prostate cancer. Eight of these men presented with benign prostatic conditions leading to a raised PSA while the remaining sixteen patients had clinical T3 prostate cancer. Global metabolomic profiling was carried out on methanolic extracts of these urine sediments. The resulting data sets were found to contain 256 metabolites based on spectral comparison against an in-house chemical reference library of over 2500 authentic standards. A subset of prostate cancer patients, but no patients with benign prostatic conditions, had elevated sarcosine abundance in their urine sediments. Patients with elevated sarcosine had a distinct metabolic signature that included sixty-five other differentially abundant metabolites, predominantly amino acids and their catabolites, differentiating these patients from the rest. The remaining prostate cancer patients could be differentiated from the patients with benign prostatic conditions based on their abundance profiles of acyl carnitines (increased) and uridine (reduced). Stable isotope dilution assays for select analytes confirmed these results, and several multianalyte algorithms were found to have good performance for the diagnosis of prostate cancer (AUROC > 0.8). Both metabolic presentations of prostate cancer exhibited biochemical hallmarks of multiple acyl-coA dehydrogenase deficiency, an inborn error of metabolism that can be due to impaired activity of the mitochondrial electron transfer flavoprotein/quinone oxidase complex. These data indicate that post-DRE urine sediment profiling could provide valuable information regarding the need to refer the urologic patient for prostate biopsy and may hold additional insight into the molecular pathogenesis of prostate cancer.

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 4541. doi:1538-7445.AM2012-4541
Abstract 4545: Positron emission tomography (PET) of TSPO expression in preclinical models of human cancer
Authors: Tang Dewei , Hight Matthew R. , Mckinley Eliot T. , Fu Allie , Buck Jason R. , Smith Adam , Tantawy Mohammed Noor , Colvin Daniel , Ansari Mohammad S. , Nickels Mike , Manning Henry C.
Published: August 2012

There is a critical need to develop and rigorously validate molecular imaging biomarkers to aid diagnosis and characterization of human cancer. Elevated expression of translocator protein (TSPO) has been shown to predict disease progression and aggressive, invasive behavior in a variety of solid tumors. Thus, noninvasive molecular imaging of TSPO expression could form the basis of a novel, predictive cancer imaging biomarker. In quantitative preclinical PET studies, we have evaluated a high-affinity pyrazolopyrimidinyl TSPO imaging ligand ([18F]DPA-714) and an aryloxyanilide-based TSPO imaging ligand ([18F]PBR06), as translational probes for quantification of TSPO levels in glioma, breast cancer, and colorectal cancer. In these studies, glioma-bearing rats or genetically engineered mice bearing spontaneously arrising breast or colorectal cancers were imaged with TSPO PET ligands in a microPET system. Dynamic images were acquired simultaneously upon injection of radioactive TSPO PET ligands. Arterial blood was collected to derive the input function (AIF), with HPLC radiometabolite analysis performed upon select samples for AIF correction. Compartmental modeling was performed using the corrected AIF. Immediately following imaging, tumor and healthy surrounding tissues were harvested for validation by western blotting and immunohistochemistry. Our results illustrate the feasibility of using TSPO PET ligands for visualization of TSPO-expressing tumors of the brain, breast and colon. Importantly, both [18F]DPA-714 and [18F]PBR06 appear suitable for quantitative assay of tumor TSPO levels in vivo. Given the relationship between elevated TSPO levels and poor outcome in oncology, these studies suggest the potential of these imaging agents to serve as a novel predictive cancer imaging biomarkers.

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 4545. doi:1538-7445.AM2012-4545