bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 430: MiRNA profiling of prostate cancer cell-derived large oncosomes identifies a signature of invasion and metastasis
Authors: Morello Matteo , Dudley Andrew C. , Schow Peter , Adam Rosalyn M. , Morley Samantha , Mulholland David , Insabato Luigi , Wu Hong , Klagsbrun Michael , Bhowmick Neil A. , Rubin Mark A. , D'Souza-Schorey Crislyn , Freeman Michael R. , Vizio Dolores Di 
Published: August 2012

Abstract
Introduction: We recently demonstrated that amoeboid prostate cancer (PCa) cells shed large (1-10µm diameter), bioactive membrane particles, representing a new class of tumor microvesicles termed large oncosomes (LO). LO can transfer oncogenic signals horizontally within the tumor microenvironment, as demonstrated by activation of phospho-tyrosines and Akt in recipient cells. Methods: We used differential ultracentrifugation and immuno-flow cytometry with size beads to isolate oncosomes in the 1-10µm diameter range. The method was applied to culture medium as well as to the plasma of mice with prostate cancer. In order to identify oncosome miRNAs relevant to metastasis, we performed a GeneChip® miRNA 2.0 Array screen of oncosomes shed by tumorigenic RWPE-2 PCa cells. Non-tumorigenic RWPE-1 cells were also analyzed. Results: LO contained protease and significantly stimulated migration of tumor and endothelial cells. LO also contained Caveolin-1, the GTPase ARF6 and other proteins that we used as markers to identify them in the circulation of mice with PCa, and in murine and human tissues with metastatic disease. Oncosomes also contained RNA. The miRNA profile of the oncosomes was compared to the miRNA profile of the cells of origin. While the miRNA profile of RWPE-2 almost completely matched the profile of RWPE-1 cells, the profiles differed significantly between LO isolated from the two cell lines. In particular, RWPE-2-derived LO contained miR-1228*, miR-150*, miR-373*, miR-135a*, miR-34b and miR-491-3p, which have been implicated in cancer cell proliferation and migration. In particular, the miRNAs miR-135a* and miR-373* target and inhibit the focal adhesion kinase (FAK), which plays a role in promoting a mesenchymal to amoeboid transition. miR-135a* and miR-373* have also been demonstrated to stimulate cell invasion, and are up-regulated in metastatic prostate and breast cancer. Target prediction analysis identified members of pathways involved in metabolic deregulation, and in oncogenic intercellular signaling and cell-cell interaction specifically in the LO purified from the tumorigenic cell line. Conclusions: Collectively, our results indicate that tumor cells can use oncosome formation to actively export pro-oncogenic miRNAs and that oncosomes therefore serve as a potential source of biomarkers of tumor 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 430. doi:1538-7445.AM2012-430
Abstract 4304: A microfluidic invasion assay to investigate the mechanisms involved in prostate cancer metastasis to bone
Authors: Bischel Lauren L. , Casavant Benjamin P. , Beebe David J. 
Published: August 2012

Abstract
Background: The majority of cancer patient mortality can be attributed to the spread of the cancer to secondary sites. Bone represents one of the most preferential sites for metastases from prostate and other cancers. While there has been much investigation into the underlying mechanisms involved in the homing of prostate cancer metastases to bone, there is still much that remains to be elucidated. Methods: We present a microfluidic invasion assay that can be used to investigate the mechanisms by which prostate cancer cells metastasize to bone. The assay uses a controlled microenvironment with a simple readout to observe the formation of cellular protrusions during invasion. By flowing fluid through an extracellular matrix (ECM) hydrogel in a microfluidic channel, an ECM hydrogel with a continuous lumen patterned through the microfluidic channel can be formed. Cancer cells can then be seeded into the lumen and invasion of the cells into the ECM hydrogel can be quantitatively analyzed using microscopy after 24 hours. The assay can be altered to model invasion in different microenvironments by altering the ECM hydrogel composition and pre-seeding the channels with cell representative of a secondary site before the ECM coating is formed. Results: In cocultures of LNCaPs (a prostate cancer cell line) or C4-2B (a bone metastatic LNCaP derived prostate cancer cell line) in the lumen with MC3T3s (osteoblast cell line) pre-seeded on the side of the microchannel, the C4-2Bs invaded more readily than LNCaPs. When C4-2Bs in the lumen are cultured with MC3T3-E1s on the side of the microchannel an 8-fold increase in the percentage of invasive C4-2Bs was observed compared to C4-2B alone. A 5-fold increase in invasiveness was observed when C4-2Bs were cultured with conditioned media from a mixed culture of C4-2Bs and MC3T3-E1s. Conclusions: These results indicate that cross-talk between prostate cancer cells and osteoblasts could play a role in the targeting of prostate cancer metastases to bone. This assay offers several advantages over traditional macroscale invasion assays (e.g. transwell assays) including the capability to control and vary the matrix composition and to perform the assay with a smaller number of cells. The microchannels can be arrayed allowing many different conditions to be tested in a single platform. Additionally, the assay set-up can be performed with automated liquid handling systems further increasing the ability to assay different conditions in a high-throughput manner. These capabilities will allow in vitro studies not previously possible which could yield new insights into the mechanisms controlling prostate cancer cell homing to bone.
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 4304. doi:1538-7445.AM2012-4304
Abstract 4306: Lack of TGF-β signaling induces a switch from single to collective cell migration in vivo
Authors: Matise Lauren A. , Palmer Trenis D. , Ashby William J. , Nashabi Abudi , Chytil Anna , Aakre Mary , Gorska Agnieszka , Pickup Michael W. , Zijlstra Andries , Moses Harold L. 
Published: August 2012

Abstract
Transforming growth factor-beta (TGF-β) has a dual role during tumorigenesis initially as a suppressor and then as a promoter. In stromal fibroblasts, TGF-β signaling suppresses tumorigenesis in adjacent epithelia, while its ablation potentiates tumor formation. Concurrently, epithelial TGF-β signaling regulates fibroblast recruitment and activation. Yet, the role of TGF-β in stromal-epithelial migration during tumorigenesis is unknown. We hypothesize that TGF-β is a critical regulator of tumor-stromal interactions that promote mammary tumor cell migration and invasion. We are using the chicken embryo chorioallantoic membrane (CAM) model to study this interplay by grafting both breast cancer epithelial cells, isolated from either TGF-β receptor II knockout (TβRII-deficient) or TβRII floxed (control) mice, and fibroblasts onto the CAM. Intravital microscopy revealed fibroblast stimulation of either a single cell/strand migration of control cells or collective migration of TβRII-deficient cells, both along the vasculature. Epithelial clusters at the epithelial-stromal boundaries of TβRII-deficient tumors express E-cadherin, p120, and β-catenin, while control epithelia in these regions express αSMA. TβRII-deficient tumors also exhibit a two-fold greater local CAM metastasis than control tumors. Epithelial tumor RNA isolated by laser capture microdissection was analyzed on a qPCR array. In TβRII-deficient epithelium compared to control epithelium, we found upregulation of Igfbp4 and Tspan13 and downregulation of Col1α2, Bmp7, Wnt11, Gng11, Vcan, Tmeff1, and Dsc2. Western and qPCR analyses validated these targets in vitro. For current and future studies determining the relevance of these targets to migration patterning, we achieved Wnt11 overexpression in TβRII-deficient cells, as well as knockdown of Wnt11 and Tmeff1 in control cells. Our findings about TGF-β signaling in stromal-epithelial interactions are important in identifying migratory mechanisms that can be targeted as recourse for breast cancer treatment.
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 4306. doi:1538-7445.AM2012-4306
Abstract 4307: The effect of ablating ADF/cofilin pathway during skin homeostasis and tumorigenesis
Authors: Zhou Jing , Patel Hitesh , Brunton Valerie G. , Frame Margaret C. 
Published: August 2012

Abstract
Proteins of the cofilin pathway are key regulators of actin dynamics. There are three cofilin isoforms encoded by human and mice. Of these, ADF-cofilin(ADF) and cofilin1(COF) are expressed in most epithelial tissues while muscle-cofilin is not. Recent data has indicated that components of the cofilin pathway(ADF, COF) are frequently mis-regulated in cancer cells, but there are conflicting reports on how these cofilins and the upstream regulatory LIM kinases contribute to the malignant phenotype by their over-expression, or suppression. The data suggest that it is the balance of the cofilin pathway regulators, and the cofilin pathway “output” which determines the invasiveness of tumor cells. The cofilin pathway must therefore be considered as a whole. Therefore, we will address the role of the cofilin pathway in skin homeostasis and cancer by deletion of ADF and COF in the skin. We generated K14-Cre-ER/ADF(-/-)/COF(fl/fl) mice, which are nullizygous for ADF and have floxed COF under control of keratin14 Cre recombinase, as ubiquitous cofilin deletion is embryonic lethal. After 4-OHT-induced COF deletion, we examined the effects on skin homeostasis and skin tumorigenesis. However, the homozygous ADF and COF knockout mice died within a few days following induction of Cre. There was a thickening of the epidermis due to hyperplasia of the spinous layer of cells. A marked increase in apoptosis of epithelial cells was also evident, predominantly affecting cells of the basal layer, resulting in ulceration of the skin and oral mucosa. These animals become acutely sick due to the oral ulceration leading to reduced food and water intake. Immunohistochemical analysis showed that the “stress inducible” keratin6, which is usually observed in hyperproliferative conditions, was aberrantly expressed in the epidermis of the homozygous ADF and COF knock out mice. Both in vitro and in vivo experiments indicated that E-cadherin was lost from cell-cell contacts in double ADF/COF knockout keratinocytes. In addition, the double ADF/COF knockout keratinocytes migrated in a mesenchymal manner and their movement was 4 times faster than wild type keratinocytes, which retained cell-cell contacts and moved in collective manner. All these data indicate that the output of the cofilin pathway is likely to be involved in cancer cell processes, including migration, proliferation, differentiation and apoptosis. We are currently generating tumor-derived cell lines from invasive squamous cell carcinomas in which both ADF and COF have been deleted and analyzing cancer-associated behaviour both in vitro and in vivo.
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 4307. doi:1538-7445.AM2012-4307
Abstract 4321: EGFR signaling in glioblastoma regulates the expression of a brain specific isoform of alphaPIX/Arhgef6 to promote invasion
Authors: Babic Ivan , Gini Beatrice , Tanaka Kazuhiro , Jacobs Carolina , Yong William H. , Cloughesy Timothy F. , Mischel Paul S. 
Published: August 2012

Abstract
The gene Arhgef6 encodes the protein alphaPIX/Cool-2, a guanine nucleotide exchange factor specific for the Rho GTPases Rac1 and Cdc42. AlphaPIX is a protein of 90 kDa predominantly expressed in haemopoietic cells where it has been shown to have a role in cytoskeletal reorganization. However, Arhgef6 is also expressed in the brain and mutations in Arhgef6 have been linked to intellectual disability (ID) in humans. AlphaPIX mRNA was reported to be upregulated in glioblastoma multiforme (GBM), the most lethal form of brain cancer. We examined alphaPIX expression in several glioma cell lines and observed a smaller isoform migrating at 72 kDa. To characterize this isoform we performed 5′RACE from several glioma cell lines and show the smaller isoform is an amino-terminal truncated form of alphaPIX lacking the calponin homology (CH) domain. We demonstrate this isoform is expressed during post-natal brain development and its expression coincides with activation of mTOR. Examination of glioblastoma from both autopsy and biopsy clinical samples shows alphaPIX expression correlates with EGFR/PI3K/Akt/mTOR activation. EGF stimulation is shown to upregulate alphaPIX, and pharmacological inhibition of Akt inhibits alphaPIX expression. To examine the function of alphaPIX in glioblastoma we performed siRNA-mediated knockdown and demonstrate increased cell adhesion upon alphaPIX loss. In addition, knockdown of alphaPIX in glioma cells decreases invasive capacity and decreases the formation of invadopodia. These data demonstrate a previously uncharacterized isoform of alphaPIX is expressed during post-natal brain development, and is highly upregulated in GBM with activated EGFR signaling. A functional consequence of EGFR-mediated alphaPIX expression in glioma is increased invasion as a result of dysregulated cytoskeletal organization.
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 4321. doi:1538-7445.AM2012-4321
Abstract 4323: MED28 (magicin/EG-1) modulates MEK1 (MAP2K1)-dependent cellular migration in human breast cancer cells
Authors: Huang Chun-Yin , Hsieh Nien-Tsu , Chou Yu-Hsuan , Lee Ming-Fen 
Published: August 2012

Abstract
The objective of this study is to understand the role of MED28 (magicin/EG-1) in the aspect of cellular migration in human breast cancer cells. MED28 exhibits several cellular roles, including a mammalian Mediator subunit (MED28), a Grb2 and cytoskeleton-associated protein, a repressor of smooth muscle cell differentiation, and an endothelial-derived gene (EG-1). The association of MED28 with multiple proteins, including Grb2, Src, merlin, and actin, strongly suggests that MED28 is involved in many cellular signaling pathways. Specifically, several tumors, including breast cancer, highly express MED28; however, the fundamental mechanism is unclear at present. Using RNA interference (RNAi) technology, we found that suppression of MED28 blocked cellular migration and invasion with concomitant reduced expression levels of matrix metalloproteinase-2 (MMP2) and mitogen-activated protein kinase kinase 1 (MEK1; MAP2K1). In contrast, overexpression of MED28 enhanced cellular migration and up-regulated MMP2 and MEK1 expression. Moreover, MEK1 knockdown blocked MED28-induced MMP2 activation, cellular migration, and invasion as shown by gelatin zymography, wound-healing, and Matrigel invasion assays. Our data indicate that MED28 modulates cellular migration in a MEK1-dependent manner in human breast cancer cells, reinforcing the important cellular function of MED28. Funding: This work was supported by the National Science Council grant, NSC 98-2320-B-309-002-MY3, to M.-F.L.
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 4323. doi:1538-7445.AM2012-4323
Abstract 4326: The potential role of IMP-3 and PDPN in invadopodia formation and collective cancer invasion: Anti-invadopodia therapy as a therapeutic target
Authors: Hwang Young Sun , Park Kwang-Kyun , Chung Won-Yoon 
Published: August 2012

Abstract
Better understanding the mechanisms underlying the metastatic process is essential to developing novel targeted therapeutics. Recently, invadopodia have been increasingly recognized as important drivers of local invasion in metastasis. Invadopodia are actin-rich structures that have the ability to degrade the underlying extracellular matrix (ECM) and promote cell invasion. However, many questions concerning the mechanisms of invadopodia formation, regulation and function remain open to debate. Meanwhile, invasion of cells into the surrounding tissue and destruction of normal tissue architecture are two hallmarks of malignant tumors. Morphologically, two patterns of tumor invasion can be distinguished; single cell and collective cell invasion. The invasion of single cells and collective cells is often correlated with dramatic changes in the expression and function of adhesive and regulatory proteins. These changes are reminiscent of early developmental processes when cells acquire a migratory, mesenchymal phenotype. Currently, the role of invadopodia in collective cancer invasion is completely unknown. In the present study, we reveal that insuline-like growth factor-II mRNA-binding protein-3 (IMP-3) associated with invadopodial infiltration and collective cancer invasion through podoplanin (PDPN) mRNA stabilization as a component of invadopodia, suggesting that invadopodia plays a pivotal role in invasive front of collective cancer invasion and thereby involved the cancer metastasis. This finding, combined with other investigations into the mechanisms of invadopodia formation, reveal clinically-relevant targets for intervention in invadopodia, including IMP-3 and PDPN.
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 4326. doi:1538-7445.AM2012-4326
Abstract 4336: Macrophage migration inhibitory factor (MIF) plays roles in proliferation, survival and migration of Ewing tumor cells by activation of a CD74-CD44 receptor complex
Authors: Kang Hyung-Gyoo , Triche Timothy J. 
Published: August 2012

Abstract
The deregulated expression of cytokines and the aberrant activation of their downstream signaling pathways would give tumor cells the abnormal proliferation and survival. Therefore identification and understanding of deregulated cytokines in certain tumor would provide an opportunity of better targeted therapies of the cancer. MIF, a proinflammatory cytokine has been known to play a role in proliferation, survival and apoptosis in several tumors. In our studies it was found that MIF expression in Ewing tumors is pretty high and it is secreted out of the cells. Ewing tumor cell lines deficient of MIF showed morphological change, deregulation of differentiation, decrease of proliferation and increase of apoptosis. Through the investigation of several signaling pathways it was found that JAK2/STATs pathways are involved in the MIF dependent survival and proliferation of Ewing tumors and in addition, MIF is involved in the autophagy of Ewing tumors through the activation of AMPK. It has been reported that CD74 is the main receptor of MIF and in our study it was found that CD74 is expressed in Ewing tumors even though the expression is much less than MIF. The decreased expression of CD74 in Ewing tumor cell lines caused the morphological change and inhibition of proliferation, which are the similar phenotypes of MIF deficient Ewing tumor cell lines. It is known that CD74 is associated with CD44 which is involved in the signaling pathways of cellular survival and proliferation. In our study it was found that decreased expression of CD44 in Ewing tumor cell lines caused the inhibition of cell survival and proliferation. In conclusion, our data implies that MIF and its downstream signaling pathways such as JAK/STATs, AMPK, CD74 and CD44 might be involved in growth, survival, proliferation and metastasis of Ewing tumors. Therefore MIF and its downstream signaling pathways could be promising targets of Ewing tumors therapy.
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 4336. doi:1538-7445.AM2012-4336
Abstract 4341: A novel sonodynamic therapy using hydroxyl radical generated from ultrasound activated TiO2 for human epithelial carcinoma cells
Authors: Itano Osamu , Onishi Tatsuya , Matsuda Sachiko , Fujimura Tomonori , Jinno Hiromitsu , Kitagou Minoru , Shinoda Masahiro , Kawachi Shigeyuki , Tanabe Minoru , Ogino Chiaki , Shimizu Nobuaki , Katagawa Yuko 
Published: August 2012

Abstract
&lt;Background and Objective&gt; Radical oxygen species, which are produced by the action of some chemotherapy drugs, radiation and some types of anticancer agent, are known to mediate cytotoxic activity by modifying the cellular homeostatic redox balance. Photodynamic therapy uses photosensitizers activated by light to induce cell death via formation of free radicals and is actually used in clinical setting. However the limited tissue penetrability of light has been a crucial problem because most of cancers often develop in deep tissue. The generation of hydroxyl radical was investigated during ultrasonic (US) irradiation and in the presence of titanium dioxide (TiO2) (Shimizu, et al. Ultrason. Sonochem. 2008). In this study, the effect of US combined with TiO2 particles on human epithelial carcinoma cell (A431) was investigated in vitro and in vivo. &lt;Methods&gt; TiO2 nanoparticles used were uniform in size of about 200 nm in diameter. A431 (1.0x106) were irradiated with US in the various density of TiO2 particles (0 to 10mg/ml). Cell viability was measured immediately after US irradiation (1 MHz, 2.0 W/cm2 for 30, 60, 120 and 300 sec) by using trypan blue exclusion assay. The effect of the combination of TiO2 particle injection (0.1, 1.0 and 10mg, day5) and US exposure (1 MHz, 2.0 W/cm2, 5 min duration, day 5, 7, 9, 11, 13) on subcutaneously implanted A431 solid tumors in female BALB c nu/nu mice were investigated by measuring tumor volume. &lt;Results&gt; The cell viability was significantly decreased after US irradiation in the presence of high dose of TiO2. In vivo results also showed significant inhibition of tumor growth in groups treated with high dose of TiO2 particles and US. The efficacies of US could not be demonstrated combined with low dose of TiO2 particles.&lt;Conclusion&gt; Our results demonstrate the potent toxicity of TiO2 combined with US irradiation against tumor in vitro and also the growth inhibition of tumors in a mouse xenograft model. Moreover the cytotoxic efficacy of TiO2 was dependent on the amount of TiO2 particles attaching to cancer cells. These results suggest that the effective and low toxic method for accumulation of TiO2 in the tumor (injection, arterial injection, DDS, etc.) should be necessary for clinical use.
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 4341. doi:1538-7445.AM2012-4341