bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1529: Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor.
Authors: Cavel Oren , Wong Richard J. , Shomron Olga , Amit Moran , Gil Ziv 
Published: August 2014

Abstract
Perineural invasion of cancer cells (CPNI) is found in most patients with pancreatic adenocarcinomas (PDAs), prostate or head and neck cancers. These patients undergo palliative rather than curative treatment due to dissemination of cancer along nerves, well beyond the extent of any local invasion. Although CPNI is a common source of distant tumor spread and a cause of significant morbidity, its exact mechanism is undefined. Immunohistochemical analysis of specimens excised from patients with PDAs showed a significant increase in the number of endoneurial macrophages (EMΦs) which lie around nerves invaded by cancer compared to normal nerves. Video microscopy and time-lapse analysis revealed that EMΦs are recruited by the tumor cells in response to colony stimulated factor-1 secreted by invading cancer cells. Conditioned medium (CM) of tumor-activated EMΦs (tEMΦs) induced a 5-fold increase in migration of PDA cells compared to controls.
Compared to resting EMΦs, tEMΦs secreted higher levels of glial-derived neurotrophic factor (GDNF), inducing phosphorylation of RET and downstream activation of extracellular signal-regulated kinases (ERK) in PDA cells. Genetic and pharmacologic inhibition of the GDNF receptors GFRA1 and RET abrogated the migratory effect of EMΦ-CM and reduced ERK phosphorylation. In an in-vivo CPNI model, CCR2-deficient mice which have reduced macrophages recruitment and activation showed minimal nerve invasion, while wild-type mice developed complete sciatic nerve paralysis due to massive CPNI. Taken together, our results identify a paracrine response between EMΦs and PDA cells which orchestrates the formation of cancer nerve invasion.
Citation Format: Oren Cavel, Richard J. Wong, Olga Shomron, Moran Amit, Ziv Gil. Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1529. doi:10.1158/1538-7445.AM2013-1529
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1601: Paclitaxel potentiates212Pb-radioimmunotherapy-induced cell killing efficacy by perturbing mitotic spindle checkpoint.
Authors: Yong Kwon Joong , Milenic Diane E. , Baidoo Kwamena E. , Brechbiel Martin W. 
Published: August 2014

Abstract
We have recently reported on the potentiation of high-LET radiation 212Pb-TCMC-trastuzumab targeting HER2 in combination with paclitaxel. To elucidate mechanisms associated with this therapy, mice bearing human colon cancer LS-174T i.p. xenografts were pre-treated with paclitaxel, followed by treatment with 212Pb-TCMC-trastuzumab and compared to groups treated with paclitaxel alone, 212Pb-TCMC-HuIgG, 212Pb-TCMC-trastuzumab and 212Pb-TCMC-HuIgG with paclitaxel pre-treatment. 212Pb-TCMC-trastuzumab with paclitaxel given 24-30 h earlier, induced mitotic catastrophe and increased apoptosis. The combined modality of paclitaxel and 212Pb-TCMC-trastuzumab markedly reduced DNA content in the S-phase of the cell cycle with a concomitant increase observed in the G2/M-phase. This treatment regimen also resulted in reduced phosphorylation of histone H3, accompanied by an increase in multimicronuclei, or mitotic catastrophe in nuclear profiles and positive stained γH2AX foci. This data suggests possible effects on the mitotic spindle checkpoint by the paclitaxel and 212Pb-TCMC-trastuzumab treatment. Consistent with this hypothesis, 212Pb-TCMC-trastuzumab treatment in response to paclitaxel reduced expression and phosphorylation of BubR1, which is likely attributable to disruption in a functional survivin/Aurora B complex, leading to impairment of the mitotic spindle checkpoint. In addition, the reduction of BubR1 expression may be mediated by the association of a repressive transcription factor, E2F4, on the promoter region of BubR1 gene. Taken together, these findings suggest that paclitaxel pre-treatment sensitizes 212Pb-TCMC-trastuzumab induced cell killing, leading to cell death by mitotic catastrophe followed by apoptosis.
Citation Format: Kwon Joong Yong, Diane E. Milenic, Kwamena E. Baidoo, Martin W. Brechbiel. Paclitaxel potentiates 212Pb-radioimmunotherapy-induced cell killing efficacy by perturbing mitotic spindle checkpoint. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1601. doi:10.1158/1538-7445.AM2013-1601
Abstract 1617: Chebulagic acid can inhibit vascular endothelial growth factor-A mediated angiogenesis.
Authors: Lu Kai , Basu Sujit 
Published: August 2014

Abstract
Background: Angiogenesis or new blood vessel formation is essential for the growth, progression and metastasis of malignant tumors. Among the several pro-angiogenic factors, vascular endothelial growth factor-A (VEGF-A) plays a critical role in this process of angiogenesis. However, the current anti-VEGF-A agents in the clinics are not only expensive, but also have serious side effects. Therefore it is essential to identify newer, effective, less toxic and inexpensive anti-VEGF-A agents for the treatment of cancer. We have recently demonstrated the anti-VEGF-A actions of Triphala churna (THL), a natural medicinal product prepared from three myrobalan fruits. Because chebulagic acid (CA), a bioactive tannin present in THL has been reported to inhibit tumor growth, we therefore investigated the effect of CA on VEGF-A mediated angiogenesis.
Method: Human umbilical vein endothelium cells (HUVECs) were cultured in vitro, and pre-treated with different doses of CA for 24hrs. Thereafter, we examined the proliferation migration and tube formation abilities of these cells. In addition we also determined the effects of CA on HUVEC cell permeability and on new blood vessel formation utilizing CAM assay. Finally, the effect of CA on VEGFR-2 phosphorylation was investigated.
Results: 5uM CA can significantly inhibit VEGF-A induced cell proliferation, migration and permeability of HUVECs. Besides it can also inhibit formation of tube-like structures by these cells. In vivo CAM assay also suggested that 5uM CA can suppress VEGF-A stimulated new vessel formation. Western blot confirmed that CA inhibits VEGF-A actions by suppressing phosphorylation of VEGFR-2.
Conclusion: Our findings suggest that CA can significantly inhibit VEGF induced angiogenesis.
Citation Format: Kai Lu, Sujit Basu. Chebulagic acid can inhibit vascular endothelial growth factor-A mediated angiogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1617. doi:10.1158/1538-7445.AM2013-1617
Abstract 2053: F-XA7, a novel derivative of vinca alkaloid with potent antitumor activity, efficiently overrides P-glycoprotein-mediated drug resistance both in vitro and in vivo.
Authors: Quan Haitian , Xu Yongping , Hu Lihong , Lou Liguang 
Published: August 2014

Abstract
Vinorelbine, a semi-synthetic vinca alkaloid, is widely used for the treatment of non-small cell lung cancer, metastatic breast cancer and ovarian cancer by inhibiting microtubule assembly. However, drug resistance mediated by P-glycoprotein (P-gp) and neurotoxic side effect possibly caused by microtubule paracrystal are major obstacles to vinorelbine application in clinic. Here, we describe a vinorelbine derivative F-XA7 as a novel microtubule-disrupting agent. F-XA7 inhibits microtubule assembly by binding to tubulin at the same site as vinorelbine and thus inhibiting the proliferation of cultured tumor cells. In vivo, F-XA7 exhibits potent antitumor activity against human tumor xenografts in nude mice. More importantly, F-XA7 is active against vinorelbine-resistant tumor cells mediated by P-gp-overexpression and significantly suppresses the growth of P-gp-overexpressing tumor xenograft in vivo, indicating that F-XA7 efficiently overrides P-gp-mediated drug resistance. In addition, the activity of F-XA7 to induce microtubule paracrystal is much weaker than that of vinorelbine in cultured cells, suggesting it may have less neurotoxic side effect. Collectively, these results indicate that F-XA7 is a novel and promising microtubule-disrupting agent for cancer therapy.
Citation Format: Haitian Quan, Yongping Xu, Lihong Hu, Liguang Lou. F-XA7, a novel derivative of vinca alkaloid with potent antitumor activity, efficiently overrides P-glycoprotein-mediated drug resistance both in vitro and in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2053. doi:10.1158/1538-7445.AM2013-2053
Abstract 2129: Aplidin triggers the activation of molecular components of the UPR as part of its pro-apoptotic program in tumor cells.
Authors: Losada Alejandro , Martínez-Leal Juan F. , Bejarano Alberto , Cuevas Carmen , Garcia-Fernández Luis F. , Galmarini Carlos M. 
Published: August 2014

Abstract
Aplidin (APL), a cyclic depsipeptide originally isolated from the marine tunicate Aplidium albicans and currently under phase II/III clinical trials for cancer therapy, induces oxidative stress, activation of Rac1 and phosphorylation of JNK1, which together trigger a rapid apoptotic program in tumor cells. A previously generated APL-resistant HeLa cell line (APL-R) allowed us to find out differences in protein expression with the parental HeLa cells. Among the proteins differentially expressed, several endoplasmic reticulum (ER) stress-related proteins were observed. We found decreased basal levels of BiP in HeLa APL-R, while the levels of Ero1a and phospho-eIF2a were slightly increased when compared to parental HeLa cells, indicative of a higher basal ER stress. In this work, we investigated if APL was inducing a bona fide ER stress in HeLa cells and whether this process was essential in the mechanism of action of the compound. Similarly to that observed with thapsigargin and tunicamycin, two well known ER stress inducing agents, APL triggered the activation of several key molecular components of a classical ER stress induced unfolded protein response (UPR), including the phosphorylation of eIF2a and JNK1, the proteolitic processing of ATF6 and the alternative splicing of XBP1, but not others, such as the accumulation of noxa or the proteolitic activation of caspase 4. Interestingly, although the eIF2a phosphorylation induced by APL in HeLa wt cells correlated with a strong inhibition of protein synthesis, it did not elicit an increased expression of CHOP, a transcription factor involved in the launch of UPR mediated apoptosis. Actually, it was observed a clear reduction of CHOP protein levels after the treatment of HeLa cells with APL, most probably due to its rapid degradation by the proteasome machinery. In summary, as a part of the proapoptotic program triggered by APL in HeLa cells, we observed the induction of ER stress and the activation of several endpoint executioners of the UPR apoptotic branch.
Citation Format: Alejandro Losada, Juan F. Martínez-Leal, Alberto Bejarano, Carmen Cuevas, Luis F. Garcia-Fernández, Carlos M. Galmarini. Aplidin triggers the activation of molecular components of the UPR as part of its pro-apoptotic program in tumor cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2129. doi:10.1158/1538-7445.AM2013-2129
Abstract 2326: S6K activation is essential for the development of follicular thyroid cancer.
Authors: Antico Arciuch Valeria Gabriela , Di Cristofano Antonio 
Published: August 2014

Abstract
The PI3K signaling cascade is frequently activated in follicular and anaplastic thyroid tumors. Mice in which the PI3K pathway is constitutively activated through loss of Pten (PtenL/L;TPO-Cre mice) develop thyroid hyperplasia that progresses to thyroid follicular carcinoma.
The wide range of downstream targets of this pathway raises the question of the relative role and relevance of its multiple effectors. This issue has important therapeutic implications, since it would be ideal to only target molecules directly involved in the transformation process, thus reducing the toxicity associated with wide-range inhibitors.
PDK1 plays a central role in the PI3K cascade, acting as a master regulator of both AKT and S6K. Notably, PDK1 possesses a substrate docking site named “PIF pocket” that is required to phosphorylate and activate S6K but not AKT.
In order to define the relative contribution of Akt and S6k to the development of thyroid lesions and to their progression to follicular carcinoma, we have generated a compound mouse strain in which, in addition to thyroid-specific Pten loss, the PIF-pocket site of Pdk1 can be conditionally disrupted by the L155E mutation, resulting in constitutive activation of Akt and mTor, but not of S6k.
We have found that young double mutant mice display a significant reduction in thyroid size, compared to PtenL/L;TPO-Cre mice, and that such rescue is associated with a marked decrease in the thyrocytes proliferation rate. More strikingly, while 60% of Pten mutants develop adenomas and carcinomas by one year of age, none of the age-matched double mutant mice displays neoplastic lesions, indicating that Akt activation, in the absence of S6k activation, is completely unable to drive transformation.
Furthermore, we have identified STAT3 as a molecule that is selectively activated downstream of S6k, and that is inactive in double mutants. Pharmacological STAT3 inhibition drastically reduces the proliferation rate of thyroid cancer cell lines, suggesting that STAT3 may be one key conduit of S6k oncogenic activity.
Citation Format: Valeria Gabriela Antico Arciuch, Antonio Di Cristofano. S6K activation is essential for the development of follicular thyroid cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2326. doi:10.1158/1538-7445.AM2013-2326
Abstract 2561: MiRNA-related SNPs and risk of esophageal adenocarcinoma and Barrett's esophagus: post genome-wide association analysis in the BEACON consortium.
Authors: Buas Matthew F. , Onstad Lynn , Levine David , Vaughan Thomas L. , Whiteman David C. ,   BEACON Consortium Investigators
Published: August 2014

Abstract
The incidence of esophageal adenocarcinoma (EA) has increased significantly in recent decades. Although several major risk factors have been identified for EA and its precursor, Barrett's esophagus (BE), including reflux, Caucasian race, male gender, obesity, and smoking, only limited knowledge exists regarding the role of inherited genetic variation and its interplay with environmental factors. The Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) recently completed a genome-wide association study (GWAS) of 1,517 EA cases, 2,416 BE cases, and 2,187 controls. Using this dataset, we examined single nucleotide polymorphisms (SNPs) that potentially affect the biogenesis or biological activity of microRNAs (miRNAs), a class of small non-coding RNAs that regulate post-transcriptional gene expression and are deregulated in many cancers, including EA. Polymorphisms in three classes of genes were evaluated for their association with risk of EA or BE: 1) miRNA biogenesis genes (157 SNPs), 2) miRNA gene loci (234 SNPs), and 3) miRNA-targeted mRNAs (179 SNPs). 28 SNPs were significantly associated (P&lt;0.05) with EA, and 34 with BE. A polymorphism located in a predicted miRNA-138 binding site of the DNA repair gene XRCC1 (rs1799782) was associated with &gt;30% reduced risk of EA (OR 0.68, 95% CI 0.55-0.83), which remained significant after correction for multiple comparisons (adjusted P=0.04). This inverse association became more pronounced with increasing pack-years (P-interaction=0.02). Alterations in disease risk associated with other polymorphisms ranged from 10-40%. This study provides the most extensive assessment to date of miRNA-related SNPs in relation to risk of EA and BE and suggests that genetic variation in this pathway may influence disease susceptibility and interact with known risk factors.
Citation Format: Matthew F. Buas, Lynn Onstad, David Levine, Thomas L. Vaughan, David C. Whiteman, BEACON Consortium Investigators. MiRNA-related SNPs and risk of esophageal adenocarcinoma and Barrett's esophagus: post genome-wide association analysis in the BEACON consortium. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2561. doi:10.1158/1538-7445.AM2013-2561
Abstract 2575: Differential anti-tumor activities of curcumin against apoptosis and cell Cycle progression in Src- and Ras-activated human gallbladder carcinoma cells.
Authors: Ono Misaki , Higuchi Takako , Takeshima Mikako , Chen Chen , Nakano Shuji 
Published: August 2014

Abstract
Curcumin, a phytochemical in turmeric, has been studied as a potential anticancer drug targeting multiple signaling molecules. However, the role of Src and Ras signaling pathways in curcumin sensitivity remains unknown. We investigated therefore the molecular mechanism of anti-proliferative and apoptosis-inducing activities of curcumin in HAG-1 human gallbladder adenocarcinoma cells transfected with either activated Src (HAG/src3-1) or Ras (HAG/ras5-1). Effects of curcumin on proliferation, apoptosis, cell cycle perturbation, and signal proteins for survival, proliferation, and apoptosis were evaluated by WST-1 assay, FACS analyses and Western blotting. Activation of either Src or Ras did not confer resistance to curcumin compared to HAG/neo3-5 vehicle-transfected cells, producing similar IC50 concentrations of curcumin among these 3 cell lines. Upon treatment with curcumin, constitutive activities of Erk1/2 were enhanced, but those of Akt were significantly inhibited in these three cell lines, with subsequent reductions of activities of downstream mTOR and S6K1. The sub-G0/G1 apoptotic cell populations were substantially increased in all cell lines with demonstrable cleavage of PARP, but this increase was most prominent in Src-activated cells. Reduced expression and phosphorylation of Bcl-2 and enhanced expression of Bax were demonstrated to have a causative role for the curcumin-induced apoptosis in Src-driven, but not Ras-driven cells. By contrast, drastic increases of the proportion of cells in a G2/M phase were seen in Ras-activated cells, suggesting a potential role of Ras/Erk1/2 activation in curcumin-induced G2/M cell cycle arrest. These data indicate that curcumin-induced growth declines would be mediated mainly by G2/M arrest of the cell cycle in Ras-driven cells but by apoptosis induction in Src-driven cells. Taken together, the results indicate that curcumin exhibits differential activities against apoptosis and cell cycle progression, depending on activation mechanisms of signal transduction, and that curcumin can overcome Src- and Ras-driven activation of downstream signaling pathways, thus providing evidence of potential application of curcumin for the treatment of human cancers with activated Src or Ras.
Citation Format: Misaki Ono, Takako Higuchi, Mikako Takeshima, Chen Chen, Shuji Nakano. Differential anti-tumor activities of curcumin against apoptosis and cell Cycle progression in Src- and Ras-activated human gallbladder carcinoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2575. doi:10.1158/1538-7445.AM2013-2575
Abstract 3264: AZD8186: a potent selective inhibitor of PI3Kβ targeting PTEN-deficient tumours dependent on dysregulated PI3Kβ signalling.
Authors: Hancox Urs , Cosulich Sabina , Dry Hannah , Hanson Lynsey , Crafter Clare , Barlaam Bernard , Fitzek Martina , Ward Lara , Cumberbatch Marie , Powell Steve , Ellston Rebecca , Lawson Mandy , Wedge Steve , Harrington Liz , Green Stephen , Barry Simon T. 
Published: August 2014

Abstract
AZD8186 is a novel potent small molecule that targets the lipid kinase PI3Kβ with selectivity vs PI3Kα. AZD8186 reduces pAKT-S473 in the PTEN deficient MDA-MB-468 cell line with an IC50 &lt;5nM, while in the PI3Kα-dependent PIK3CA mutant line BT474 it is 200 fold less potent. AZD8186 also demonstrates cellular activity versus PI3Kβ, inhibiting IgM-dependent pAKT-S473 with an IC50 of 15nM. In cell line panels, sensitivity to AZD8186 is associated in part with loss of PTEN function suggesting that targeting tumours that have lost normal levels of PTEN function through deletion, mutation or down regulation might enrich for sensitivity to AZD8186. Deficiencies in PTEN are described in a number of tumour types such as prostate, squamous lung, breast, renal and glioblastoma. AZD8186 has single anti-tumour activity in pre-clinical models representing each of these settings, which is associated with dynamic regulation of a number of key pathway biomarkers. Clinically, agents such as AZD8186 are likely to be used in combination. The use of AZD8186 in conjunction with either androgen therapy or docetaxol has been explored in cell lines and pre-clinical disease models. Combining AZD8186 with MDV-3100 resulted in synergistic inhibition of LNCAP prostate tumour cell growth, demonstrating the potential to combine with androgen therapy. Moreover in HCC70 (breast) and PC3 (prostate) tumour xenografts AZD8186 shows increased benefit in combination with docetaxel, demonstrating the ability to combine with cytotoxic chemotherapy. Exploration of dose and schedule revealed that efficacy can be maintained in combination with docetaxol at a lower dose of AZD8186 than required for monotherapy activity. Moreover efficacy was maintained when the frequency of AZD8186 dosing was reduced using a shorter intermittent schedule. Understanding how AZD8186 combines with standards of care for PTEN null disease segments provides important insight into how agents targeting PI3Kβ-dependent tumours may be used most effectively in the clinic.
[Current affiliation for S. Cosulich is Novartis, Basel, Switzerland.]
Citation Format: Urs Hancox, Sabina Cosulich, Hannah Dry, Lynsey Hanson, Clare Crafter, Bernard Barlaam, Martina Fitzek, Lara Ward, Marie Cumberbatch, Steve Powell, Rebecca Ellston, Mandy Lawson, Steve Wedge, Liz Harrington, Stephen Green, Simon T. Barry. AZD8186: a potent selective inhibitor of PI3Kβ targeting PTEN-deficient tumours dependent on dysregulated PI3Kβ signalling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3264. doi:10.1158/1538-7445.AM2013-3264