bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3187: Ex vivo characterization of CTCs isolated using the FMSA device
Authors: Cheng Hairong , Gallant Jean-Nicolas , Harouaka Ramdane , Zheng Siyang , El-Deiry Wafik 
Published: August 2012

Abstract
Although technological advances in recent years have enabled isolatation of circulating tumor cells (CTCs), only the VeridexCellSearch System has been approved by the FDA for assessment of patient prognosis in metastatic breast, colon, and prostate cancers. A fundamental challenge with the CellSearch System is that the technique it uses to enrich and detect CTCs, EpCAM-basedimmunomagnetic isolation, fixates captured cells and prevents further molecular characterization by functional assays and primary cell culture. Progress in addressing these issues may help with progress with a variety of clinical needs including further characterization of the biology of individual patient tumors as well as their potential response top various therapeutics. In this study, we use the Flexible Micro Spring Array (FMSA) Device —a novel portable microfluidic device that captures and isolates viable CTCs by two physical parameters: size and flexibility—to capture, culture, and further characterize CTCs.GFP-labeled HCT-116 cells were spiked into healthy samples of donor blood to mimic blood samples of metastatic cancer patients. This spiked blood was filtered using the FMSA device, and the recovered cells were expanded in cell culture. A series of experiments were carried out to characterize these cells and investigate the effect of chemotherapy on the resulting cultures. Studies are ongoing to evaluate the potential of using this model to culture CTCs from patients and to evaluate the response of these cells to chemotherapies using high-throughput methodologies. The isolation of viable CTCs from human blood using the FMSA device provides a novel means for studying viable CTCs and for testing drug efficacy ex vivo. The analysis and identification of CTC-specific characteristics and their relation to chemotherapy susceptibility suggests a potential paradigm shift toward personalized and targeted cancer therapy based on the specific genetic defects of each patient's malignancy and CTCs.
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 3187. doi:1538-7445.AM2012-3187
Abstract 3266: Interaction of MCM7 and RACK1 for activation of MCM7 and cell growth
Authors: Luo Jian-Hua , Zhang Xi-Yue , Yu Yan Ping 
Published: August 2012

Abstract
MCM7 is one of the pivotal DNA replication licensing factors in controlling DNA synthesis and cell entry into S phase. Its expression and DNA copy number are some of the most predictive factors for the growth and behavior of human malignancies. In this study, we identified that MCM7 interacts with receptor for activated protein kinase C 1 (RACK1), a protein kinase C (PKC) adaptor in vivo and in vitro. The RACK1 binding motif in MCM7 is located at the amino acid 221-248. Knocking down of RACK1 significantly reduced MCM7 chromatin association, DNA synthesis and cell cycle entry into S phase. Activation of PKC by 12-O-tetradecanoylphorbol-13-acetate dramatically decreased MCM7 DNA replication licensing and induced cell growth arrest. Activation of PKC induced redistribution of RACK1 from nucleus to cytoplasm, and decreased RACK1-chromatin association. MCM7 mutant that does not bind RACK1 has no DNA replication licensing nor oncogenic transformation activity. As a result, this study demonstrates a novel signaling mechanism that critically controls DNA synthesis and cell cycle 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 3266. doi:1538-7445.AM2012-3266
Abstract 3273: A robust transgenic mouse model to study male breast cancer
Authors: Krause Silva , Tobin Heather , Lurvey Heidi L. , Ingber Donald E. 
Published: August 2012

Abstract
Male breast cancer accounts for about 1% of all breast cancers and even though it is a rare disease, the incidence rate has increased steadily during the past 20 years. Study of the male form of the disease has been hampered by a lack of relevant animal models as it is commonly believed that male mammary glands do not contain ducts. Female FVB C3(1)-SV40Tag transgenic mice spontaneously develop hyperplastic mammary lesions that progress to invasive mammary tumors, whereas most of the transgenic males develop prostatic hyperplasia that progresses to adenocarcinoma. However, upon closer examination, we discovered that approximately 55% of transgenic males develop mammary tumors by 40 weeks of age, often prior to developing prostate tumors. The course of male mammary development is similar to that observed in the females but with a later onset. Hyperplastic ducts form as early as 15 weeks of age and progress into DCIS-resembling tumors before developing into invasive tumors that invade locally into adipose tissue and muscle and occasionally form metastases to lung and other organs. We then examined male mammary development in the FVB background strain (wild type) and showed that all males develop mammary ducts that continue to grow and branch throughout adulthood. The morphology of these ducts was similar to that of females with a central lumen surrounded by concentric layers of luminal epithelium, myoepithelium, a basement membrane and surrounding stroma. A study of CD1 male mice confirmed that male mammary development was not specific to the FVB strain but that CD1 males showed similar mammary ductal development. Male mammary development in FVB wild type animals and tumor progression in the transgenic males was characterized in terms of cell proliferation, apoptosis and expression of various markers of differentiation including hormone receptor status. In summary, our results demonstrate that FVB C3(1)-SV40Tag transgenic males represent a highly robust and reproducible model for the study male breast cancer. Our long-term goal is to leverage the information we uncovered through this effort to design novel therapies for breast cancer treatment in men.
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 3273. doi:1538-7445.AM2012-3273
Abstract 3277: Increased mitogen-activated protein kinase kinase 4 (MEK4) induces metastasis in an orthotopic murine model of prostate cancer
Authors: Pavese Janet M. , Ogden Irene , Huang Xiaoke , Bergan Raymond 
Published: August 2012

Abstract
Mitogen-activated protein kinase kinase 4 (MEK4) is a dual-specificity kinase that has been implicated in prostate cancer (PCa) progression. Increased MEK4 expression is observed in invasive cancer lesions in human prostate tissue. We have demonstrated the clinical importance of this in vitro, as MEK4 increases human PCa invasion. This phenotype is driven by increased protease production, and not via changes in cell migration. However, it is not known whether MEK4 regulates human PCa metastasis. This is of high importance as MEK4 has shown differential effects in various cancer models in a cell type specific fashion, and may therefore represent an important human PCa specific target. To emulate the situation of sustained altered MEK4 expression in humans, we engineered MEK4 clonal variant cell lines, generating multiple clones each for vector control (VC), increased wild type (WT), and increased constitutively-active mutant MEK4 (CA). Using a murine orthotopic implantation model designed to characterize in vivo behavior, we implanted 75 mice with these clones and demonstrated that both WT and CA MEK4 increase human PCa metastasis to the lung, a clinically relevant site in humans. In the primary tumor, interestingly, WT tumors were not increased compared to VC, while CA tumors were. Additionally, increased MMP-2 and MMP-10 were observed in both WT and CA tumors. However, MMP-9 was increased in WT tumors only, and MMP-13 in CA tumors only. Currently, we are expanding our efforts at characterizing additional molecular changes in primary tumor between these groups. Outside of the primary tumor, we isolated circulating tumor cells in the blood and bone marrow. We are currently characterizing their relevant cellular and molecular parameters. Using a clinically relevant murine model we have shown that increased MEK4 increases human PCa metastasis to the lung and protease production within the primary tumor. Further, a constitutively active phenotype drives tumor growth and circulating tumor cell formation.
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 3277. doi:1538-7445.AM2012-3277
Abstract 3280: Loss of the tumor suppressor APC in cells expressing lysozyme M results in murine endometrial hyperplasia
Authors: Kitchen-Goosen Susan M. , Sternberger Sarah C. , Alberts Arthur S. 
Published: August 2012

Abstract
The Adenomatous polyposis coli (APC1) tumor suppressor is a multi-function protein that is involved in both the Wnt signaling cascade and cytoskeletal remodeling. Mutations or loss of APC1 can result in defects in cell migration, proliferation, and differentiation. APC frequently collaborates with the canonical Diaphanous-related formin, mDia1 (DIAPH1), which also functions to regulate cytoskeletal dynamics. APC1 and DIAPH1 are genetically linked on Chromosome 5q in a region frequently disrupted in myeloproliferative neoplasms (MPNs). Mice lacking mDia1 (Drf1) and the Apc min mice develop myelodysplastic phenotypes. The physical and functional linkage of APC and mDia1 as 5q tumor suppressors and in cytoskeletal remodeling led us to explore the role of APC in tumor suppression in myeloid-derived cell lineages. We created a mouse which lacks APC in myeloid lineage cells by breeding Apc-flox mice with mice expressing Cre recombinase under the control of lysozyme M (LyzsM) gene promoter. Lysozyme M is expressed in myeloid lineage cells including monocytes, macrophages and granulocytes. Surprisingly, the female mice develop cystic endometrial hyperplasia and are unable to sustain pregnancy. Lysozyme M expression appears to be limited to tissue resident macrophages within the uterus and was not detected in uterine epithelial cells. However, there is a small subset of uterine epithelial cells with increased β-catenin expression, suggesting that these cells lack APC. This subset of cells has elevated expression of cyclin D1, a regulator of cell cycle progression and a downstream effector of Wnt signaling, resulting in increased proliferation. Interestingly, the uterine epithelial cells with increased β-catenin expression also have increased estrogen receptor ≤ (ERα) expression. Estrogen stimulates uterine growth and unopposed estrogen signaling is a hallmark of Type I endometrial cancer. It is unclear if the endometrial hyperplasia seen in these mice is due to lysozyme M expression early on in uterine epithelial cell development or perhaps in a progenitor cell population. A second alternative is that loss of APC in tissue resident myeloid cells residing in the uterine stroma affects epithelial morphology. Regardless, these data suggest that APC plays a role in uterine tissue homeostasis, perhaps even regulating ERα expression.
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 3280. doi:1538-7445.AM2012-3280
Abstract 3289: Tissue specific expression of the PI 3-kinase mutation Pik3caH1047R induces hyperplasia and tumorigenesis in a mouse model
Authors: Kinross Kathryn M. , Tikoo Anjali , Hare Lauren , Montgomery Karen G. , Phillips Wayne A. 
Published: August 2012

Abstract
Mutations in the p110α subunit of phosphoinositide 3-kinase (PI3K) (encoded by the gene PIK3CA) are frequent in human cancers. To better understand the role of mutant PIK3CA in the initiation or progression of tumorigenesis in vivo, we generated a conditional (Cre recombinase-inducible) knock-in mouse model of the common activating mutation, Pik3caH1047R, expressed from the endogenous locus. We have then targeted the mutation to specific tissues by crossing our mouse to mice expressing Cre under the control of tissue-specific promoters. The mouse mammary gland was targeted using a transgenic mouse expressing Cre under the control of the mouse mammary tumor virus promoter (MMTV-Cre). To target the gastrointestinal tract, we used the A33CrePR2 mouse, expressing Ru486-inducible version of Cre under the control of the gpa33 promoter. Tumors were formed in both these models but only following a long latency (&gt;15 months) suggesting that a ‘second-hit’ may be necessary for tumor development. Similarly, activation of this mutation in the mouse ovary, by injection of an adenovirus expressing Cre into the ovarian bursa, revealed that Pik3caH1047R alone is a weak activator of AKT capable of inducing premalignant hyperplasia in ovarian surface epithelium. Interestingly, we found that combining Pik3caH1047R mutation with deletion of Pten in the mouse ovary resulted in robust epithelial AKT signaling and progression to ovarian serous adenocarcinomas and granulosa cell tumors within 6 months. Therapeutic inhibition of PI3K/mTOR in these mice delayed tumor growth and prolonged survival. This novel mouse is proving to be a fascinating model with which to explore the biological consequences and clinical significance of Pik3caH1047R mutation in diverse tissue types and a valuable tool for the preclinical evaluation of PI3K pathway inhibitors.
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 3289. doi:1538-7445.AM2012-3289
Abstract 329: Downregulation of PKC∈/par3/par6 polarity complex is critical for hypoxia-induced epithelial-mesenchymal transition, migration, and invasion in lung cancer cells
Authors: Zhou Qiyuan , Chen Tianji , Ibe Joyce Christina F. , Raj J. Usha , Zhou Guofei 
Published: August 2012

Abstract
Rationale: We have previously reported that hypoxia induces epithelial-mesenchymal transition (EMT) in lung cancer cells. EMT has been known to contribute to tumor cell invasion and metastasis. Recent evidence suggests that loss of cell polarity complex, which consists of atypical protein kinase C ≤ (PKC∈), Par (partitioning defective) 3, and Par6, is strongly correlated with malignancy. However, it is unknown whether hypoxia-induced cancer cell migration, invasion, and metastasis are caused by the loss of PKC∈/Par3/Par6 polarity complex and subsequent EMT. Methods: We incubated A549 in hypoxic conditions (1.5% O2) for a period of time and assessed the protein abundance of α-SMA, vimentin, E-cadherin, PKC∈, Par3, and Par6 as well as PKC∈ ubiquitination. Next we knocked down PKC∈/Par3/Par6 by siRNAs and determined the abundance of α-SMA, vimentin, and E-cadherin. We also measured cell migration and invasion after knockdown of PKC∈/Par3/Par6 in vitro. In addition, we established A549 cells with knockdown of Par3 and determined cell proliferation rate and lung colonization in a mouse tail-vein injection model, in which lung cancer cells were injected intravenously into the tail vein of mice and lung metastatic foci were quantified in five weeks. Furthermore, we obtained human lung adenocarcinoma tissue samples and self-matched adjacent normal tissues as well as unmatched normal tissues and detected the expression levels of PKC∈/Par3/Par6 polarity complex. Results: We found that A549 cells exposed to hypoxia expressed decreased PKC∈/Par3/Par6 polarity complex and E-cadherin and increased expression of α-SMA and vimentin, suggesting that loss of PKC∈/Par3/Par6 polarity complex is associated with the induction of EMT. We also showed that hypoxia increased ubiquitination of PKC∈. Our results also showed that loss of either of PKC∈, Par3, or Par6 resulted in EMT, elevated migration and invasion, and increased the numbers of metastatic foci in the lungs. Moreover, we show that human lung adenocarcinoma tissues express less Par6 protein than the adjacent normal tissues. Conclusions: These results suggest that in lung cancer cells hypoxia downregulates PKC∈/Par3/par6, leading to EMT and increased cancer cell migration, invasion, and colonization. Support: UIC Faculty Scholarship Support Program and the University of Illinois Cancer Center Pilot Subsidy Program.
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 329. doi:1538-7445.AM2012-329
Abstract 3305: The role of carbonic anhydrase IX in tumor hypoxia, metastasis and the cancer stem cell niche
Authors: Lock Frances E. , McDonald Paul C. , Lou Yuanmei , Supuran Claudiu T. , Dedhar Shoukat 
Published: August 2012

Abstract
Carbonic anhydrase IX (CAIX) is a hypoxia and HIF-1 inducible protein that regulates intra- and extracellular pH under hypoxic conditions, and promotes tumor cell survival and invasion in hypoxic microenvironments. shRNA-mediated depletion of CAIX expression in mouse and human metastatic breast cancer cells, capable of inducing CAIX in hypoxia, resulted in regression of orthotopic mammary tumors and inhibition of spontaneous lung metastasis formation. CAIX depletion led to caspase-independent cell death and reversal of extracellular acidosis under hypoxic conditions in vitro. In addition, the CD44+/CD24-/low “cancer stem cell” compartment, which exhibited hallmarks of EMT (E-cadherin low/SMA high) was significantly enhanced in hypoxia, but was severely depleted in shRNA-CAIX knock-down cells as well as in cells treated with CAIX small molecule inhibitors. CAIX depletion or inhibition of its activity prevented mesenchymal conversion of the stem cells and also resulted in the suppression of expression of several EMT and “stemness” regulator genes. Treatment of mice harboring CAIX-positive 4T1 and MDA-MB-231/LM2 mammary tumors with novel CAIX-specific small molecule inhibitors that mimicked the effects of CAIX depletion in vitro resulted in significant inhibition of tumor growth and metastasis formation in both spontaneous and experimental models of metastasis, without any inhibitory effects on CAIX negative tumors, or any adverse toxic effects. This was associated with significant depletion of cells expressing “cancer stem cell” markers. Furthermore, interrogation of 3,630 human breast cancers revealed CAIX to be an independent poor prognostic biomarker for distant metastases and survival. Our findings demonstrate that CAIX is vital for the survival of “cancer stem cells” in hypoxic niches as well as for the growth and metastasis of hypoxic breast tumors. It is a specific, targetable biomarker for breast cancer 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 3305. doi:1538-7445.AM2012-3305
Abstract 3307: Improved survival in AML by in vivo drug targeting of conserved regulatory pathways in phenotypically distinct tumor-initiating compartments
Authors: Gibbs Kenneth D. , Jager Astraea , Crespo Oliver , Goltsev Yury , Tejo Angelica , Richard Chase , Nolan Garry 
Published: August 2012

Abstract
Increasing evidence suggests tumors are maintained by cancer stem cells, however their nature remains controversial. In a HoxA9-Meis1 (H9M) driven model of acute myeloid leukemia (AML), we found that tumor-initiating activity existed in three, immunophenotypically distinct compartments, corresponding to disparate lineages on the normal hematopoietic hierarchy–stem/progenitor cells (Lin−kit+), and committed progenitors of the myeloid (Gr1+kit+) and lymphoid lineages (Lym+kit+). Each compartment clonally recapitulated the original range of tumor cell immunophenotypes in vivo, including cells with a less-differentiated immunophenotype. These distinct populations largely shared signaling networks, and in vivo pharmacologic targeting of shared pathways (DNA methyltransferase and MEK phosphorylation) significantly increased survival. Collectively, these data show that H9M AML is organized as an atypical hierarchy that defies the strict lineage marker boundaries and unidirectional differentiation of normal hematopoiesis. Moreover, in some malignancies, tumor-initiation ability (or “cancer-stemness”) can represent a targetable, cellular state that can exithat exists independently of distinct immunophenotypic definition.
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 3307. doi:1538-7445.AM2012-3307
Abstract 331: Epithelial-mesenchymal transition confers resistance to complement-dependent cytotoxicity in lung cancer cells
Authors: Goswami Moloy T. , Reka Ajaya K. , Kurapati Himabindu , Kaza Viritha , Keshamouni Venkateshwar G. 
Published: August 2012

Abstract
Recent studies have implicated Epithelial-mesenchymal transition (EMT) in conferring several clinically relevant properties to cancer cells, in addition to initiating tumor metastasis. These include stem-cell like properties, resistance to targeted therapies and ability to evade immune surveillance. Pathway analysis of gene expression changes in TGF-β induced EMT identified the complement cascade as one of the significantly enriched pathway. Further analysis of the genes in the complement pathway revealed EMT-induced expression of complement inhibitors and decrease in expression of proteins essential for complement activity, suggesting resistance to complement dependent cytotoxicity (CDC) during EMT. We found lung cancer cells that undergo EMT showed marked decrease in C3 deposition and concomitant resistance to apoptosis by CDC as measured by 7-Aminoactinomycin D staining. Flow cytometric and RT-PCR analysis showed a significant increase in the CD59 expression on the surface of cells undergoing EMT, which is a potent inhibitor of formation of membrane attack complex that mediates complement dependent cell lysis. Furthermore, CD59 inhibition by siRNA mediated knock-down overcame the EMT-induced resistance to anti-EGFR antibody (Cetuximab) mediated CDC. The increase in CD59 was abrogated on disruption of TGF-β signaling as revealed by TGF- β Receptor kinase inhibitor and is dependent on Smad3 signaling. Chromatin immunoprecipitation analysis revealed increased occupancy of Smad3 on CD59 promoter, suggesting a direct regulation by Smad3. These results demonstrate that TGF-β-induced EMT confers another novel immune evasive mechanism to tumor cells that facilitates tumor progression and CD59 as a potential therapeutic target for enhancing the efficacy of anti-EGFR Antibody therapies and against 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 331. doi:1538-7445.AM2012-331