bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2394: A flexible micro spring array (FMSA) device for the high throughput enrichment of viable CTCs
Authors: Harouaka Ramdane , Zhou Ming-Da , Khan Waleed , Yeh Yin-Ting , Zheng Si-Yang 
Published: August 2012

Abstract
The ability of metastatic cancer to release cells that travel through the circulatory system and invade different parts of the body accounts for over 90% of cancer related deaths. The fundamental challenge with detecting these circulating tumor cells (CTCs) in blood samples is the fact that they are so rare, with only a few tumors cells occurring among billions of blood cells. Size based separation has been demonstrated to be an effective method for CTC capture and enrichment. While useful for detection, size based techniques apply concentrated stresses that affect the viability of captured cells. We have incorporated a novel micro spring array to mitigate the stresses experienced by CTCs during filtration to encourage their health and proliferability. The geometric design and filtration pressures have been optimized to maximize capture efficiency, enrichment against leukocytes, and tumor cell viability. The FMSA device can process 7.5 mL of whole blood in approximately 10 minutes, while still preserving cell viability. The successful enrichment and primary culture of viable CTCs from clinical samples will allow unprecedented analysis and genetic testing amounting to a minimally invasive biopsy that may be repeated often to monitor tumor progression. This can also provide the basis for externally testing tumor cell response to a variety of anticancer drugs without having to expose a patient to the unnecessary cost and toxic effects of chemotherapy, thereby improving patient outcomes through the development of personalized treatment plans.
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 2394. doi:1538-7445.AM2012-2394
Abstract 2400: Epithelial-mesenchymal transition in hepatocellular carcinoma leads to downregulation of adaptive immunity via COX-2 pathway
Authors: Ogunwobi Olorunseun O. , Liu Chen 
Published: August 2012

Abstract
The immune system targets pre-malignant and malignant cells and can attenuate or eliminate carcinogenesis. Epithelial-mesenchymal transition (EMT) is known to promote tumor progression in hepatocellular carcinoma (HCC). It is, however, unknown whether EMT promotes HCC by dysregulating the immune system. A clear understanding of the mechanisms underlying immune evasion in HCC may reveal targets that can be exploited for immunotherapy. In this study, we have used the murine HCC cell line 1MEA that we have successfully used to establish a syngeneic mouse model of aggressive HCC. The cells were exposed to TGFβ-1 (2ng/ml) and EGF (50ng/ml), two well-established inducers of EMT in HCC. Induction of EMT was confirmed by analysis of the gene expression profiles of E-cadherin, albumin, fibronectin and collagen I. Effects on clonogenicity were analyzed using colony formation assays. Effects on adaptive immunity were examined by analyzing gene and protein expression of major histocompatibility complexes I and II (MHC I and MHC II). The role of cyclooxygenase-2 (COX-2) was determined by examining the effect of the selective COX-2 inhibitor, celecoxib (1μM). Exposure to TGFβ-1 and EGF led to downregulation of E-cadherin and albumin and upregulation of fibronectin and collagen I. TGFβ-1 and EGF both promoted increased clonogenicity. Interestingly, exposure to TGFβ-1 and EGF both resulted in significant downregulation of both gene and protein expression of MHC I and MHC II. However, pre-treatment of cells with celecoxib significantly reversed these effects. Consequently, we conclude that EMT induction in HCC is associated with downregulation of adaptive immunity in a manner dependent on the COX-2 pathway. Immunotherapeutic targeting of COX-2 may, therefore, be a useful strategy for HCC management.
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 2400. doi:1538-7445.AM2012-2400
Abstract 241: A novel function of thyroid hormone receptors in promoting metastasis of human hepatoma cells via regulation of TRAIL
Authors: Chi HsiangCheng , Tseng YiHsin , Tsai Chung-Ying , Chung I-Hsiao , Lin Kwang-Huei 
Published: August 2012

Abstract
Thyroid hormone (T3) and its binding receptors (TRs) are potent regulators mediating cell metabolism, proliferation, and differentiation. Accumulating evidence has confirmed an important role of TRs in tumor progression. However, the specific functions of TRs in carcinogenesis have yet to be clarified. Experiments from the present study have shown that tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is upregulated by T3 in TR-overexpressing hepatoma cell lines. The T3-responsive element of the TRAIL promoter was localized to nucleotides at positions −1967 to −1977 upstream of the transcription start site. Interestingly, TRAIL acts as an apoptosis inducer in several cancer cell types, but also triggers non-apoptotic signals favoring tumorigenesis in apoptosis-resistant cancer cells. In our experiments, TR-overexpressing hepatoma cells treated with T3 were apoptosis-resistant, even under conditions where TRAIL was upregulated. This finding may be attributed to the simultaneous upregulation of Bcl-xL, an anti-apoptosis gene, by T3. Thus, overexpression of Bcl-xL in hepatoma cells possibly protects against apoptotic death triggered by TRAIL, consequently leading to TRAIL-promoted metastasis in hepatoma cells. Moreover, T3-enhanced metastasis was repressed by the treatment of TRAIL-blocking antibody. Notably, TRAIL was highly expressed in tumor cells of HCC patients, and this high expression was significantly correlated with the high TR expression as examined in 65 HCC tissues. Collectively, our findings indicate that TR directly binds to the TRAIL promoter to induce TRAIL expression, which acts in concert with the simultaneously activated anti-apoptotic factor, Bcl-xL, to promote metastasis, rather than apoptosis. Our findings provide a novel mechanistic link for increased TR and TRAIL in HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 241. doi:1538-7445.AM2012-241
Abstract 2410: Reduced expression of DDB2 promotes epithelial to mesenchymal transition in colon cancer
Authors: Roy Nilotpal , Raychaudhuri Pradip 
Published: August 2012

Abstract
Invasion and metastasis are the hallmarks of malignant tumor progression and the principal cause of death related to solid tumors. Epithelial to mesenchymal transition (EMT) is intricately associated with cancer progression, as it confers cancer cells the ability to invade and metastasize to a distant organ. Here we identify a novel function of nucleotide excision repair protein DDB2 as an important antagonist of the EMT in colon carcinoma through its maintenance of epithelial phenotype. In human colon carcinoma samples, loss of DDB2 expression is highly correlated with the aggressiveness of the disease. Moreover, stimuli (TGF-beta and hypoxia) that induce EMT inhibit expression of DDB2; and loss of DDB2 is sufficient to promote EMT of colon cancer cells. The mechanism involves DDB2 mediated transcriptional repression of VEGF and MMP3. DDB2 represses these genes by histone deacetylation. We also observed that loss of DDB2 results in resistance to anoikis, an important barrier to metastasis. The lack of anoikis response is associated with increased Akt and ERK activity. Furthermore, treatment with Phenethyl Isothiocyanate (PEITC), a promising cancer chemopreventive component, augmented E-cadherin expression that is related to an increase in DDB2 expression. The present study suggests that anti-metastatic effect of PEITC involves important role of DDB2. Together, our results show that loss of DDB2 expression is both necessary and sufficient for EMT during colon carcinoma progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2410. doi:1538-7445.AM2012-2410
Abstract 2458: The expression of hyaluronan and hyaluronidases in cutaneous melanoma
Authors: Siiskonen Hanna , Poukka Mari , Tyynelä Kristiina , Tammi Raija H. , Sironen Reijo , Pasonen-Seppänen Sanna M. 
Published: August 2012

Abstract
Aberrant hyaluronan expression implicates aggressive disease progression and metastatic potential in many cancers. In tumors originating from simple epithelium, hyaluronan amount is increased both in the epithelial and stromal component and it correlates with patient's poor overall prognosis. The role of hyaluronan degrading enzymes (hyaluronidases, HYAL1-2) in cancer progression is controversial. Hyaluronidases are proposed to be both tumor suppressors and tumor promoters. In this retrospective study, we characterized the expression levels of HYAL1 and HYAL2 and correlated their expression to hyaluronan in the different stages of primary skin melanoma as well as in metastatic melanoma. Superfically (pT1) and deeply (pT4) invasive melanoma (Breslow &lt; 1mm (n=18) and Breslow &gt; 4mm (n=18)), in situ melanoma (n=17), lymph node metastasis (n=19), dysplastic nevi (n=28) and benign nevi samples (n=29) were analyzed for hyaluronan staining and HYAL1 and HYAL2 immunoreactivity (ABCAM antibodies) in paraffin tissue sections. Stainings were evaluated for their intensity and coverage. The tissue area for hyaluronan and HYAL1/HYAL2 positive staining was estimated with a five-level scoring from 0-4 and the staining intensity of melanocytic cells was evaluated with a four-level scoring (0-3; no color, weak, moderate and strong) by two independent observers. Compared to benign nevi and in situ melanoma, the cell-associated hyaluronan staining coverage and intensity were clearly reduced in the invasive part of melanoma with advanced Breslow depth. Strong hyaluronan staining intensity was detected in 36% of in situ melanoma cases and in 21% of superficial melanoma (Breslow &lt; 1mm) cases, while in the deeply invasive melanoma group (Breslow &gt; 4mm), only 6% of cases showed strong hyaluronan staining intensity. In addition, in lymph node metastases the melanoma cells showed low hyaluronan staining intensity or were totally hyaluronan negative. However, the tumor stroma was highly hyaluronan positive in all groups. HYAL1 immunoreactivity was found in melanocytic cells both in benign nevi and melanoma samples while the tumor stromal cells were negative. The coverage of HYAL2 immunoreactivity was parallel to HYAL1, although its staining intensity was lower than that of HYAL1. Our results suggest that hyaluronan content is clearly decreased in invasive primary and metastatic melanoma compared to benign nevi. The results from hyaluronan stainings will be compared with clinical follow-up data to study the prognostic value of hyaluronan in melanoma.
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 2458. doi:1538-7445.AM2012-2458
Abstract 246: Calmodulin binding to death receptor-5 regulates pancreatic cancer apoptosis
Authors: Yuan Kaiyu , Zhou Tong , McDonald Jay , Chen Yabing 
Published: August 2012

Abstract
Targeting the extrinsic apoptosis pathway initiated by death receptors has been shown to be a promising therapy for pancreatic cancer. TRA-8, a humanized activating antibody for the death receptor 5 (DR5), is a potent therapeutic reagent for pancreatic cancer. However, several pancreatic cell lines are resistant to TRA-8-induced cell death. We have previously demonstrated that calmodulin (CaM) is recruited into the death-inducing signaling complex (DISC) by Fas death receptor activation, and that antagonists of CaM regulate DISC formation. Therefore, we determined the function of CaM in DR5-induced apoptosis of pancreatic cancer cells. We found that trifluoperazine (TFP), a CaM antagonist, enhanced TRA-8-induced cell death of pancreatic cells, PANC-1 and S2VP10, by 55% and 45% respectively. Consistent with the increased apoptosis, TFP increased TRA-8-induced activation of caspase 8 and caspase 3 in these cells. To determine the underlying molecular mechanisms, we analyzed the DR5-induced DISC. Interaction of CaM and DR5 was demonstrated by co-immunoprecipitation by using DR5 antibody. Activation of DR-5 by TRA-8 increased recruitment of CaM into the DISC which was inhibited by treatment with TFP. In addition, TFP decreased recruitment of the adaptor protein, FADD, and recruitment of other DISC proteins that regulate cell survival, including Src and FLICE-like inhibitory protein (FLIP), an inhibitor of caspase-8. These results suggest an important role for CaM in DR5-induced DISC formation in pancreatic cancer cells, regulating DR5-mediated survival and apoptotic signaling. In summary, we have demonstrated that CaM antagonism sensitizes pancreatic cancer cell to TRA 8-induced cell death, and that CaM binding to DR5 regulates DR5-induced DISC formation. Defining the function of CaM in regulating DR5-induced signaling pathways may lead to novel therapeutic strategies for pancreatic cancer therapy including possible combination therapy with TRA-8 and calmodulin antagonists.
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 246. doi:1538-7445.AM2012-246
Abstract 2460: Extracellular matrix protein expression is associated with chemotherapy resistance in breast cancer
Authors: Wang Tingting , Guo Tiannan , Sze Siu Kwan , Hartman Mikael , Buhari Shaik Ahmad , Chan Ching-Wan , Iau Philip , Khin Lay Wai , Saxena Nakul , Wong Andrea , Tan Sing-Huang , Goh Boon-Cher , Lee Soo-Chin 
Published: August 2012

Abstract
Extracellular matrix protein expression is associated with chemotherapy resistance in breast cancer Purpose: Biomarkers to predict sensitivity and resistance to chemotherapy are still lacking. A recent study reported that stromal gene signatures in breast cancer may predict chemoresistance. We aim to determine the changes of 5 extracellular matrix (ECM) proteins in response to neoadjuvant chemotherapy in breast cancer. Experimental design: 100 female patients with locally advanced or metastatic breast cancer were treated with 6 cycles of pre-operative alternating sequential doxorubicin and docetaxel. Immunohistochemistry staining for thrombospondin 1 (THBS1), tenascin C (TNC), fibronectin (FN), smooth muscle actin-α (α-SMA) and secreted protein acidic and rich in cysteine (SPARC) was performed on pre- and post-treatment core biopsies, and correlated with estrogen receptor status, intrinsic chemotherapy response, pathological lymph node involvement and survival. Changes in THBS1 and TNC in relation to chemoresponse was additionally evaluated with mass spectrometry, and further validated with immunohistochemistry in an independent cohort of 31 breast cancer patients. Results: High baseline THBS1 and SPARC and high post-treatment α-SMA expression were associated with poor overall survival (p&lt;0.05 for each marker). High expression of combined baseline ECM proteins was an independent predictor for poor progression-free survival (HR 2.22, 95% CI 1.06-4.64, p=0.034) and overall survival (HR 5.94, 95% CI 2.25-15.71, p&lt;0.001). After 1-2 cycles of chemotherapy, increased expression of THBS1 and TNC compared to baseline was seen in intrinsically resistant tumors (p&lt;0.05 for both), and in patients with pathological lymph node involvement (p&lt;0.05 for both), but not in sensitive ones. Mass spectrometric analyses revealed &gt;2 fold increase in THBS1 and TNC expression compared to baseline in tumors that were intrinsically resistant to doxorubicin relative to sensitive ones. The association between THBS1 and TNC immunohistochemistry changes and chemotherapy resistance was confirmed in the validation cohort. Conclusions: Up-regulation in ECM proteins after chemotherapy was associated with clinical and pathological response to doxorubicin- and docetaxel-based neoadjuvant chemotherapy in breast cancer. Assessment of these proteins may uncover strategies to overcome drug resistance. Key words: ECM proteins, neoadjuvant chemotherapy, breast cancer, drug resistance
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 2460. doi:1538-7445.AM2012-2460
Abstract 2463: Protease nexin 1 modulates prostate adenocarcinoma by regulating the Hedgehog pathway in humans and mice
Authors: McKee Chad , Xu Danmei , Kabraji Sheheryar , Allen Danny , Kersemans Veerle , Beech John , Smart Sean , Hamdy Freddy , Lam Wan , van der Kwast Theodorus , Bristow Robert , Muschel Ruth 
Published: August 2012

Abstract
Prostate adenocarcinoma is the most frequent cancer and is the second leading cause of cancer death of men in the Western world. Aberrant activation of the Hedgehog (Hh) pathway is implicated in the growth and progression of prostate cancer. We show that the Hh pathway is inhibited by the serine protease inhibitor, protease nexin 1 (PN1), an extracellular matrix (ECM) protein highly expressed in normal prostate. We demonstrate here that PN1 regulates Hh signalling by reduction of the Hh ligand, Sonic (SHH), and its downstream effectors in tissue culture and in vivo. Conversely, matrix metalloproteinase 9 (MMP9) enhances Hh signalling through degradation of PN1. MRI imaging was used to determine variation in tumour formation in an orthotopic prostate tumour model using PN1 and MMP9 knock-out mice. In PN1-/- animals, SHH was increased and tumor growth was stimulated. In contrast, PN1 levels were elevated in MMP9-/- mice while Hh signalling was reduced with concomitant decreased tumor growth. Finally, genetic alterations in Hh pathway genes identified by comparative genomic hybridization (CGH) from intermediate risk prostate cancer patients correlated with a worse clinical outcome (HR=2.67, p=0.00067), indicating the importance of this pathway in human cancer. Our data identify PN1 as a novel regulator of SHH and its downstream targets allowing PN1 levels to influence prostate tumor growth. Regulation of the PN1-Hh pathway could constitute a significant therapeutic advance in treating cancers that exhibit high expression of Hh markers. These data also provide a mechanism through which MMP-9 can regulate hedgehog pathway signalling in tissues rich in PN1.
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 2463. doi:1538-7445.AM2012-2463
Abstract 2465: Matrix metalloproteinase 9 promotes breast cancer through regulation of insulin-like growth factor-binding proteins
Authors: Park Jae-Hyun , Rasch Morten Grønbech , Qiu Jing , Lund Ida Katrine , Werb Zena , Egeblad Mikala 
Published: August 2012

Abstract
The matrix metalloproteinase (MMP) family is a large family of extracellularly acting proteases. MMP9 is expressed by tumor infiltrating myeloid cells and promotes tumor progression in animal models of cancer. Yet, the identities of the in vivo MMP9 substrates are not well established. Furthermore, clinical trials with broad-spectrum MMP inhibitors have shown no therapeutic benefit. We compared the effects of deleting Mmp9 between the luminal mouse mammary tumor virus (MMTV)-Neu model of breast cancer, driven by expression of rodent HER2/ErbB2, and the basal-like C3(1) SV40 large T antigen (Tag) model, driven through inactivation of p53 and Rb by Tag. Interestingly, absence of MMP9 delayed tumor-onset in C3(1)-Tag mice, but had no effect in the MMTV-Neu mice. In line with these data, we found that low MMP9 expression indeed predicts good prognosis for breast cancer patients with mutant p53, but does not influence prognosis for patients with wild type p53. The insulin-like growth factor-binding protein-1 (IGFBP-1) is an established in vitro MMP9 substrate. IGFBP-1 sequesters IGF in the extracellular matrix, leading to reduced IGF receptor activity and thereby cancer cell proliferation. Proteolysis of IGFBP by MMP9 releases IGF from the matrix. Interestingly, the protein levels of IGFBP-1 were significantly increased in the C3(1)-Tag;Mmp9−/− compared to C3(1)-Tag;Mmp9+/+ tumors. In contrast, IGFBP-1 protein levels were low in the MMTV-Neu model regardless of MMP9 status. Human breast tumors did not express IGFBP-1 but instead the other family members, IGFBP-2, -3, and -4, which all are substrates for MMP9 in vitro. We found that low levels of MMP9 were a good prognostic factor only for patients with high mRNA expression levels of the IGFBPs, and not for patients with low levels of the IGFBPs. Our findings from mouse models and human patients suggest that MMP9 promotes tumor progression in breast cancer via proteolysis of IGFBPs. Furthermore, a lack of stratification of patients based on both MMP9 and IGFBPs levels might explain why MMP inhibitors showed no clinical benefit against breast 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 2465. doi:1538-7445.AM2012-2465