bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3777: Low physiological fluid shear exposure induces metastatic potential of chondrosarcoma cells via MMP-12 activation.
Authors: Chen Shih-Hsun , Wang Pu , Hung Wei-Chien , Konstantopoulos Konstantinos 
Published: August 2014

Abstract
Interstitial flow in and around tumor tissue affects the mechanical microenvironment to modulate tumor cell metastasis. We investigated the roles of flow-induced shear stress in modulating chondrosarcoma cell metastatic potential such as cell invasiveness and motility, and the underlying mechanisms. Using human chondrosarcoma cell lines as a model system, we demonstrated that low fluid shear (2 dyn/cm2), but not high fluid shear (20 dyn/cm2), exposure for 48 h remarkably induced MMP-12 mRNA by ∼35-fold and significantly triggered it proteolytic activity among all MMP members. The molecular basis of the shear effect was further analyzed, and our data revealed that low fluid shear stress induces the rapid synthesis of VEGF-B, VEGF-D and IGF-2, which in turn transactivates MMP-12 expression via PI3K and p38 MAPK-dependent pathways. Furthermore, highly induced MMP-12 markedly enhanced chondrosarcoma cell invasion and motility by using chemtaxis transwell chambers in conjunction with time-lapse micro-channel assays. Collectively, our data suggest that the induction of IGF-2, VEGF-B, and VEGF-D under low fluid shear, which in turn upregulates MMP-12 via PI3K and p38 MAPK signaling pathways, leading to the enhanced invasive and migratory capabilities of chondrosarcoma cells. Our findings provide insights into the mechanism by which shear stress induces chondrosarcoma metastatic potential and demonstrate the importance of mechanical environments in modulating molecular signaling, gene expression and functions in tumor cells.
Citation Format: Shih-Hsun Chen, Pu Wang, Wei-Chien Hung, Konstantinos Konstantopoulos. Low physiological fluid shear exposure induces metastatic potential of chondrosarcoma cells via MMP-12 activation. [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 3777. doi:10.1158/1538-7445.AM2013-3777
Abstract 3782: NEDD9 promotes cell invasion through modulation of Arf6-dependent endocytic recycling.
Authors: Loskutov Yuriy , McLaughlin Sarah , Kozyulina Polina , Kozyreva Varvara , Ice Ryan , Rajulapati Anuradha , Culp Mark , Wysolmerski Robert , Ivanov Alexey , Weed Scott , Pugacheva Elena 
Published: August 2014

Abstract
The adaptor protein, NEDD9, is an established pro-metastatic trigger in several cancers but the molecular mechanisms behind NEDD9-driven invasion remain unclear. Here we show that expression of NEDD9 protein tightly correlates with the transition of breast cancer to invasive stages. Overexpression of NEDD9 is critical for the invasion of cancer cells but depletion of NEDD9 is sufficient to block invasion. It is also well established that invadopodia are important for cell invasion. We demonstrate that NEDD9 localizes to invadopodia and its depletion leads to a deficiency in matrix degradation. NEDD9 depletion was also accompanied by an increase in surface levels of inactive proteases (MT1-MMP) and adhesion receptors (integrins). In addition, depletion of NEDD9 induced an increase in recycling and early endosomes via activation of Arf6. NEDD9 binds to the Arf6 specific GAP, ASAP3, which explains NEDD9 modulation of Arf6 activity. Inhibition of Arf6 or re-expression of NEDD9 rescue in NEDD9-deficient cells is sufficient to restore proper recycling rates and invasive properties of breast cancer cells. These results reveal the mechanism behind NEDD9-driven migration and tumor invasion.
Citation Format: Yuriy Loskutov, Sarah McLaughlin, Polina Kozyulina, Varvara Kozyreva, Ryan Ice, Anuradha Rajulapati, Mark Culp, Robert Wysolmerski, Alexey Ivanov, Scott Weed, Elena Pugacheva. NEDD9 promotes cell invasion through modulation of Arf6-dependent endocytic recycling. [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 3782. doi:10.1158/1538-7445.AM2013-3782
Abstract 3787: ERK and AKT signaling cooperate to translationally regulate survivin expression for promotion of cell motility and metastasis in colorectal cancer.
Authors: Ye Qing , Cai Weijia , Zheng Yongbin , Evers B. Mark , She Qing-Bai 
Published: August 2014

Abstract
The MEK/ERK and PI3K/AKT pathways are often concurrently activated by separate genetic alterations in colorectal cancer (CRC), which is associated with CRC progression and poor survival. However, how activating both pathways is required for CRC metastatic progression remains unclear. Our recent study showed that both ERK and AKT signaling are required to activate eIF4E-initiated cap-dependent translation via convergent regulation of the translational repressor 4E-BP1 for maintaining CRC transformation. Here, we identified that the activation of cap-dependent translation by cooperative ERK and AKT signaling is critical for promotion of CRC motility and metastasis. In CRC cells with coexistent mutational activation of ERK and AKT pathways, inhibition of either MEK or AKT alone showed limited activity in inhibiting cell migration and invasion, but combined inhibition resulted in profound effects. Genetic blockade of the translation initiation complex by eIF4E knockdown or expression of a dominant active 4E-BP1 mutant effectively inhibited migration, invasion and metastasis of CRC cells, whereas overexpression of eIF4E or knockdown of 4E-BP1 had the opposite effect and markedly reduced their dependence on ERK and AKT signaling for cell motility. Mechanistically, we found that these effects were largely dependent on the increase in mTORC1-mediated survivin translation by ERK and AKT signaling. Despite the modest effect of survivin knockdown on tumor growth, reduction of the translationally-regulated survivin profoundly inhibited motility and metastasis of CRC. These findings reveal a critical mechanism underlying the translational regulation of CRC metastatic progression, and suggest that targeting cap-dependent translation may provide a promising treatment strategy for advanced CRC.
Citation Format: Qing Ye, Weijia Cai, Yongbin Zheng, B. Mark Evers, Qing-Bai She. ERK and AKT signaling cooperate to translationally regulate survivin expression for promotion of cell motility and metastasis in colorectal 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 3787. doi:10.1158/1538-7445.AM2013-3787
Abstract 3788: Alpha-2 Heremans Schmid glycoprotein (AHSG) promotes migration in head and neck squamous cell carcinoma (HNSCC) cell lines.
Authors: Thompson Pamela D. , Watson Kurt , Sakwe Amos , Ochieng Josiah , Marshall Dana 
Published: August 2014

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the eighth most common tumor in the world. Approximately 30,000 new cases of HNSCC are reported each year and 8,000 related deaths, in the United States. HNSCC of the oral cavity is highly metastatic and has a recurrence rate of 20%-50%, with a dismal 5-year survival rate of ∼50%. African-American males have a 5-year survival rate of ∼42% while the survival rate for Caucasian males is 52%. To date, there is no consistent means for early detection or a reliable biomarker for HNSCC, thus perpetuating the lack of improvement in mortality despite advances in delivery of treatment and surgical reconstruction. In a proteomic study seeking possible biomarkers for HNSCC, AHSG was detected at elevated levels in serum. Interestingly, we have found that some HNSCC cell lines synthesize and secrete AHSG. We have also shown in earlier studies, that the lack of AHSG reduces mammary tumor incidence and prolongs tumor latency in a mouse model for breast cancer. Together, this suggests that this hepatocellular glycoprotein that is found in most body fluids including serum could be a potential biomarker for HNSCC. AHSG is a negative acute phase response protein, which makes the findings of elevated levels of AHSG in the proteomic study most intriguing. In order to evaluate the role of AHSG in HNSCC progression (proliferation and metastatic properties) in vitro, we depleted AHSG in the HNSCC cell lineSQ20B. Thus far, we show that depletion of AHSG does not affect the proliferation of SQ20B cells. However, the depletion of AHSG mediates a decrease in migration and invasion of SQ20B cells. We are currently elucidating the molecular mechanisms of AHSG-mediated motility.
This work was supported by grants from the NIH-NCI-Score 1 SC1 CA134018-01 (JO); DOD W81XWH-07-1-0254 (J.O); 5 T32 HL007735-15 (SA) and U54 CA091408 (subproject, DM).
Citation Format: Pamela D. Thompson, Kurt Watson, Amos Sakwe, Josiah Ochieng, Dana Marshall. Alpha-2 Heremans Schmid glycoprotein (AHSG) promotes migration in head and neck squamous cell carcinoma (HNSCC) cell lines. [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 3788. doi:10.1158/1538-7445.AM2013-3788
Abstract 3807: Integrative genomic profiling of pilocytic astrocytomas reveals location specific differential methylation and expression of brain developmental genes.
Authors: Lambert Sally R. , Witt Hendrik , Hovestadt Volker , Zucknick Manuela , Kool Marcel , Pearson Danita , Korshnov Andrey , Pfister Stefan , Collins V. Peter , Jones David T. W. 
Published: August 2014

Abstract
Pilocytic astrocytomas (PA) are the most common brain tumor in pediatric patients and cause significant morbidity, particularly related to chronic neurological deficiencies. They are characterized by activating alterations in the mitogen activated protein kinase (MAPK) pathway, but little else is known about their development. To map the methylation profile of these tumors, we have performed a global DNA methylation analysis on 62 PAs and 7 normal cerebellum samples using Illumina 450K microarrays. Based on these data we have found two subgroups of PA that separate according to tumor location (infratentorial versus supratentorial), and have identified key neural developmental genes that are differentially methylated between the two groups, including NR2E1 and EN2. Integration with gene expression microarray data revealed significant expression differences that were typically associated with a strong positive correlation between methylation and expression. Differential methylation was most commonly identified within the gene body and/or 10 kb upstream/downstream of the gene body, and was, in part, accounted for by differences in the level of 5-hydroxymethylcytosine. We also identified a large number of differentially methylated genes between cerebellar PAs and normal cerebellum, which were again enriched for developmental genes. In addition, we found a significant association between differential methylation and SUZ12 binding sites, suggesting potential disruption of the polycomb repressor complex 2 (PRC2) in PA development. Taken together these data suggest the methylation profile of PA may reflect the cell of origin from which the tumors are derived, and highlights the potential disruption of key developmental regulators during tumorigenesis. These findings have implications for future clinical trials, as they suggest drug sensitivity and response may differ according to tumor location.
Citation Format: Sally R. Lambert, Hendrik Witt, Volker Hovestadt, Manuela Zucknick, Marcel Kool, Danita Pearson, Andrey Korshnov, Stefan Pfister, V. Peter Collins, David T. W. Jones. Integrative genomic profiling of pilocytic astrocytomas reveals location specific differential methylation and expression of brain developmental genes. [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 3807. doi:10.1158/1538-7445.AM2013-3807
Abstract 381: VEGF-A and VEGF-C: potential coregulators in angiogenic event in thyroid cancer.
Authors: Salajegheh Ali , Smith Robert A. , Pakneshan Sahar , Gopalan Vinod , Lam Alfred KY 
Published: August 2014

Abstract
Vascular endothelial growth factor (VEGF) promotes growth of blood or lymphatic vessels, termed angiogenesis and lymphangiogenesis. These share several basal mechanisms, including cross-talk between VEGF-A, C and their receptors, which may be important in the development of malignancies. Study aimed to identify relationships between VEGF-A, VEGF-C and their impact in angiogenesis and metastases in thyroid cancers.We studied VEGF-A and VEGF-C mRNA expression in 123 thyroid cancers, 40 lymph node metastases and 7 non-malignant thyroid control tissues using qPCR. Protein expressions for both VEGFs were determined by immunohistochemistry.VEGF-A and VEGF-C mRNA over-expression was noted in 51% (n=62) and 27% (n=33) of the thyroid cancers respectively. VEGF-A and VEGF-C protein over-expression was also identified in 70% (n=86) and 62% (n=76) of the thyroid cancers. ANOVA showed significant expression differences for VEGF-A and VEGF-C in subtypes of thyroid carcinoma, lymph node metastasis and normal controls (P=1x10-6 and 1x10-5 respectively). VEGF-A mRNA was significantly higher in cancers with lymph node metastases compared to non-metastatic cancers (p=0.001) however, most metastatic tumors under-expressed VEGF-C (p=0.0002). Similarly, VEGF-A protein expression was higher in metastases and VEGF-C protein was higher in non-metastatic lesions, though not significantly. Finally, we used linear regression analysis to test previous proposals about physiological interactions of VEGF-A and VEGF-C expression. Our model indicated that in metastatic cancers, 32% of the expression of VEGF-A could be predicted by a positive influence of VEGF-C production (model p=0.0002). These findings add weight to previous hypotheses concerning VEGF-A and C interaction. Early lymphangiogenic events were proposed to regulate angiogenesis, and changes to VEGF expression in this cancer population bear this out, with VEGF-C in early tumors giving way to VEGF-A in metastases. The commonality of local metastasis in thyroid cancer makes it a useful model to further examine mechanisms of angiogenesis and lymphangiogenesis in cancer metastasis. Keywords: thyroid cancer, VEGF-A, VEGF-C
Citation Format: Ali Salajegheh, Robert A. Smith, Sahar Pakneshan, Vinod Gopalan, Alfred KY Lam. VEGF-A and VEGF-C: potential coregulators in angiogenic event in 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 381. doi:10.1158/1538-7445.AM2013-381
Abstract 3812: Target identification in rhabdomyosarcomas induced in mouse skeletal muscle.
Authors: Hettmer Simone , Schinzel Anna , Hahn William C. , Wagers Amy 
Published: August 2014

Abstract
Soft-tissue sarcomas are a group of cancers arising in non-hematopoietic, mesodermal tissues. Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children and adolescents, represents a biologically heterogeneous category of mesodermal, non-hematopoietic malignancies, which exhibit evidence of skeletal muscle differentiation. This study builds on the premise that ex-vivo induction of sarcomas by cell-specific activation of sarcoma-relevant pathways can be used to model biologically distinct sarcoma categories in mice and identify novel downstream targets. Up to 35% of human RMS tumors carry Ras mutations, and we have demonstrated Ras/ Raf/ Mek/ Erk pathway activation in approximately 50% of human RMS tumors surveyed. We showed that Kras-expressing; p16p19null muscle satellite cells gave rise to mouse pleomorphic RMS, whereas Kras-expressing; p16p19null non-myogenic progenitors typically induced pleomorphic non-myogenic sarcomas (NMS). Transcriptional profiling demonstrated that myogenic and non-myogenic Kras; p16p19null sarcomas recapitulate gene expression signatures of human RMS and share a cluster of concordantly upregulated genes (many associated with Ras pathway activation) with human RMS. We used a customized RT² Profiler™ PCR Array (SA Biosciences) to confirm that 105 out of these 141 candidate genes were indeed upregulated in Kras;16p19null sarcomas compared to mouse skeletal muscle. The functional contributions of individual candidate genes to sarcoma proliferation were evaluated using a customized shRNA-based proliferation screen in cell lines established from Kras; p16p19null sarcoma explants. These comprehensive experiments identified a small group of high-priority candidates that contributed significantly to the growth of Kras; p16p19null NMS (n=11 genes) and RMS (n=10 genes) (q&lt;0.05). The effects of shRNA mediated silencing of selected candidate genes in human sarcoma cells were verified using human sarcoma cell lines. We conclude that these genes have potential broad importance in sarcoma biology and anti-sarcoma therapy. Future studies will help to illuminate their roles in promoting RMS growth and may suggest new approaches for therapeutic intervention.
Citation Format: Simone Hettmer, Anna Schinzel, William C. Hahn, Amy Wagers. Target identification in rhabdomyosarcomas induced in mouse skeletal muscle. [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 3812. doi:10.1158/1538-7445.AM2013-3812
Abstract 3863: Transgenic model for early prostate metastasis to the lymph nodes.
Authors: Ko Hyun-Kyung , Akakura Shin , Peresie Jennifer , Goodrich David W. , Foster Barbara A. , Gelman Irwin H. 
Published: August 2014

Abstract
Background: The emergence of recurrent, metastatic prostate cancer following the failure of androgen-deprivation therapy represents the lethal phenotype of this disease. However, little is known regarding the genes and pathways that regulate this metastatic process, and moreover, it is unclear whether metastasis is an early or late event. The SSeCKS/Gravin/AKAP12 (“SSeCKS”) gene, previously shown to suppress prostate cancer metastasis upon re-expression (1,2), as well as the tumor suppressor gene, Rb, are either transcriptionally downregulated or deleted in human prostate cancers (3,4). Mouse models deficient in either SSeCKS or Rb exhibit prostatic hyperplasia (5,6). Moreover, SSeCKS-null fibroblasts as well as SSeCKS-null prostates display Rb-dependent premature senescence markers (7). Methods: In order to determine whether the combined loss of AKAP12 and Rb in the prostate synergizes to induce oncogenic progression, Akap12-/- mice were crossed with Pb4-Cre;RbloxP/loxP mice to generate Akap12-/-;RbPE-/− progeny, with the Probasin-Cre passed only through males. Results: The combined loss of SSeCKS and Rb results in prostatic intraepithelial neoplasia (PIN) starting at 6 months of age that fails to progress to malignancy (adenocarcinoma) after 18 months. The PIN lesions were marked by increased Ki-67 proliferation of cytokeratin 8 (CK8), p63-negative luminal cells as well as p63-positive basal cells. Interestingly, these lesions also had increased numbers of androgen-receptor (AR)-positive, p63-positive, CK5-negative cells. There was evidence of reactive stroma including mural hyperplasia and inflammatory cell infiltration. Strikingly, 83% of mice with PIN lesions exhibited metastases to draining lymph nodes (LN), marked by well-differentiated tumors cells expressing markers of basal (p63, CK14) and luminal (CK8 and AR) epithelial cells, although none expressed the basal marker, CK5. PCR-based tests for the deleted floxed Rb allele from laser capture microdissected LN lesions confirmed the prostatic origin of these metastatic cells. The LN lesions showed very limited inflammation, based on very few cells staining with the histiocyte marker, CD68. Conclusions: Taken together, these data suggest that in the context of Rb loss, SSeCKS suppresses the oncogenic proliferation and early metastatic spread of transitional, basal-luminal prostate tumor cells.
Citation Format: Hyun-Kyung Ko, Shin Akakura, Jennifer Peresie, David W. Goodrich, Barbara A. Foster, Irwin H. Gelman. Transgenic model for early prostate metastasis to the lymph nodes. [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 3863. doi:10.1158/1538-7445.AM2013-3863
Abstract 387: Intermittent hypoxia stimulates capillary growth and branching in an in vitro model of tumor angiogenesis.
Authors: Ehsan Seema M. , Mendoza Nicole L. , George Steven C. 
Published: August 2014

Abstract
Introduction: The complex heterogeneity of the tumor microenvironment, including a structurally and functionally abnormal vasculature, impacts oxygen tension leading to intermittent hypoxia (IH). While it is known that chronic hypoxia modulates tumor development in vivo, including mechanisms of angiogenesis and resistance to radiotherapy, our understanding of IH remains limited. We hypothesized that IH would stimulate vasculogenesis and lead to a larger and more branched network of vessels consistent with the vessel network in tumors. Using a fabricated oxygen control system, we explored the effects of chronic and intermittent hypoxia on in vitro vascularized tissues.
Materials and Methods: A co-culture of endothelial colony forming cell-derived endothelial cells (ECFC-ECs) from cord blood and normal human lung fibroblasts was distributed in a fibrin gel, and incubated for 7 days at constant 20% O2 (ambient condition), constant 5% O2 (physiological condition), constant 1% O2 (hypoxia conditions), and multiple IH conditions all of which had a mean value of 5% O2. The resulting vessel networks were quantified for total vessel network length and number of junctions. Vascular endothelial growth factor (VEGF) production was measured over the course of the 7 days.
Results and Discussion: Decreasing oxygen tension from 20% to 5% O2 limits vessel formation in vitro, and 1% O2 stopped vessel formation completely. Tissues exposed to IH, however, exhibited significantly more developed and branched vascular networks compared to the constant 5% O2 counterparts (total vessel network length: 5%: 5.4 ± 0.8 mm, IH: 10.7 ± 1.6 mm; (number of junctions: 5%: 32.7 ± 10.6 mm, IH: 99.2 ± 23.1), suggesting a role in tumor angiogenesis. Indeed, VEGF production was upregulated as well in the IH conditions, which may contribute to the enhanced blood vessel formation. We conclude that IH conditioning generates vascular networks in vitro that more structurally and functionally resemble tumor vascular networks in vivo.
Citation Format: Seema M. Ehsan, Nicole L. Mendoza, Steven C. George. Intermittent hypoxia stimulates capillary growth and branching in an in vitro model of tumor 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 387. doi:10.1158/1538-7445.AM2013-387