bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3860: Furin is required for processing KISS1 to kisspeptins.
Authors: Harihar Sitaram , Pounds Keke M. , Iwakuma Tomoo , Seidah N G. , Welch Danny R. 
Published: August 2014

Abstract
KISS1 is a broadly functional metastatic suppressor that is secreted and processed in the extracellular milieu into small peptides (called kisspeptins (KP)). The enzyme(s) responsible for generation of KP from nascent KISS1 is unknown, although sequence analysis (cleavage at KR or RR dibasic sites) suggests that members of the proprotein convertase family may be involved. We, therefore, hypothesized that enzyme(s) belonging to the proprotein convertase family process KISS1 to generate kisspeptins. To this end, we treated multiple melanomas and breast carcinoma cells overexpressing KISS1 with the proprotein convertase inhibitor Dec-RVKR-CMK and found that KISS1 processing was completely inhibited, strongly consistent with a role for proprotein convertases. To identify specific proprotein convertases responsible for KISS1 processing, we systematically analyzed the mRNA expression of the nine members of this family across numerous cell lines. We found a consistent expression of the three proteases - furin, PC5 and PC7 -suggesting one or combination of these three enzymes to be involved in KISS1 processing. shRNA-mediated knockdown of furin, PC5 and PC7 (individually and in combination) resulted in complete loss of KISS1 processing only in furin knockdown cells; whereas, no effect on processing was observed in PC5 or PC7 knockdown cells. Thus, when combined with previous studies showing post-secretion processing, extracellular furin was identified as the essential enzyme responsible for KISS1 proteolytic cleavage into kisspeptins. [Support: CA134981, Komen SAC110037, National Foundation for Cancer Research, Steiner Family Fellowship in Metastasis Research]
Citation Format: Sitaram Harihar, Keke M. Pounds, Tomoo Iwakuma, N G. Seidah, Danny R. Welch. Furin is required for processing KISS1 to kisspeptins. [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 3860. doi:10.1158/1538-7445.AM2013-3860
Abstract 3864: Blocking hypoxia-induced tumor cell migration by p16/INK4A.
Authors: Lu Yi 
Published: August 2014

Abstract
One general characteristic of fast-growing solid tumors including breast cancer is the development of intratumoral hypoxia. The activation of hypoxia-inducible factor-1α (HIF-1α) by intratumoral hypoxia stimulates a group of downstream genes including vascular endothelial growth factor (VEGF) that are responsible for tumor malignant progression. Loss of p16 expression occurs in many cancers including breast cancer. Our studies showed that, by ectopic expression via adenoviral-mediated gene transfer, p16 downregulates VEGF gene expression by neutralizing the transactivation of HIF-1α, and suppresses breast cancer angiogenesis and metastasis. To investigate whether p16 directly affects one or more aspects of the metastatic cascade, MDA-MB-231 cells infected with lentivirus expressing Tet-on inducible p16 were used to study the p16 effects on growth, adhesion and migration of the breast cancer cells. We found that p16 inhibits MDA-MB-231 cell proliferation (45.6% inhibition) and hypoxia-induced cell migration (36% inhibition), but has no apparent effect on cell adhesion. The p16-mediated inhibition of hypoxia-induced cell migration parallels with p16’s inhibition of HIF-1α transactivation activity. These results indicate that p16’s ability to suppress breast tumor metastasis may result from a combined p16-mediated actions including inhibition of cell proliferation, migration, and angiogenesis. This study suggests that p16 gene therapy may have clinical potentials to treat breast cancer due to p16’s multiple-level anti-cancer capabilities: inhibiting proliferation, inducing apoptosis, blocking tumor angiogenesis, inhibiting cell migration and suppressing metastasis.
Citation Format: Yi Lu. Blocking hypoxia-induced tumor cell migration by p16/INK4A. [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 3864. doi:10.1158/1538-7445.AM2013-3864
Abstract 3867: Novel mouse models to investigate the molecular pathogenesis of metastatic osteosarcoma.
Authors: Zhao Shuying , Kurenbekova Lyazat , Donehower Lawrence A. , Yustein Jason T. 
Published: August 2014

Abstract
Background: Osteosarcoma (OS) is the primary bone tumor in the pediatric population with the main determinant for patient prognosis being the presence of metastatic disease. Approximately 25-30% of patients will present with metastatic osteosarcoma. Patients with metastatic disease have long-term survival rates often &lt;20%.
Objectives: We hypothesize that the molecular pathogenesis of metastatic osteosarcoma is different from localized disease. We intend this work to provide a relevant, endogenous model of metastatic OS that can be utilized to advance our understanding of the molecular pathogenesis of the disease, insights into novel therapeutic targets and as a pre-clinical model for investigating the efficacy of novel therapies.
Design: We have developed a tissue-specific alteration of the p53 status by using osteoblast specific Cre-recombinase expressing mice to generate progeny that spontaneously form endogenous osteosarcomas. Through the use of a mutated, gain of function form of p53, shown previously to be associated with metastatic disease, we have developed a novel immunocompetent model that significantly enhances the endogenous development of metastatic OS.
Results: Tumor analysis has revealed genetic insights in the metastatic progression of osteosarcoma. These include the significant downregulation of Wnt-signaling inhibitors, such as NKD2, APCDD1 and Wnt5a in the metastatic tumors. Functional studies have determined that overexpression of NKD2, also downregulated in several human OS metastatic cell lines, in metastatic mouse OS cell lines leads to a significant decrease in metastatic lung lesions upon transplantation into immunodeficient mice. Possible NKD2-dependent functions include regulation of not only the Wnt signaling pathway, but also blood vessel formation, regulation of cell migration and cell adhesion.
We have also noted the dysregulation of several critical microRNAs in metastatic OS, including the upregulation of mir-130b in the metastatic lesions. This particular microRNA has recently been shown to have clinical correlation in Ewing's sarcoma, with higher levels of tumor mir-130b having a significantly poorer outcome. We are actively pursuing the role of this (and other) microRNA(s) in the molecular pathogenesis of metastatic osteosarcoma.
Conclusion: This novel model has enabled valuable molecular insights into the development and progression of metastatic OS that can lead to the identification of novel therapeutic targets.
Citation Format: Shuying Zhao, Lyazat Kurenbekova, Lawrence A. Donehower, Jason T. Yustein. Novel mouse models to investigate the molecular pathogenesis of metastatic osteosarcoma. [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 3867. doi:10.1158/1538-7445.AM2013-3867
Abstract 3868: Identification of PHLPP1 as a novel metastasis suppressor in melanoma .
Authors: Yu Yanlin , Lu Andrew , Dai Meng , Merlino Glenn 
Published: August 2014

Abstract
Metastatic dissemination is the cause of nearly all melanoma-related deaths. Despite an improving understanding of genetic lesions present in human melanomas, how these alternations relate to the metastatic process is not well understood. Previously, we found that activation of the PI3K/Akt pathway is a driving force in metastatic melanomas. Here we identify PHLPP1 as a novel metastasis suppressor in melanoma. PHLPP1 was recently identified as a Ser/Thr-specific phosphatase, belonging to pleckstrin homology (PH) domain leucine-rich repeat protein phosphatase family. The two isoforms of this family, PHLPP1 and PHLPP2 control kinase signaling in the AKT family by catalyzing the dephosphorylation of the hydrophobic phosphorylation motif. PHLPP1 can specifically dephosphorylate AKT2 and AKT3, whereas PHLPP2 dephosphorylates AKT1 and AKT3. To study the role of PHLPPs in metastatic melanoma, we first examined the expression of PHLPPs in 30 melanoma metastases, 30 primary melanomas, and 9 normal skin tissues using tissue microarray analysis. We found that PHLPP1 was significantly downregulated or lost in metastatic melanoma samples, but not PHLPP2. Moreover, analysis of various human melanoma cell lines (12 highly metastatic, 14 poorly metastatic melanoma cell lines and 1 normal melanoctye cell line) demonstrated that PHLPP1 expression correlated with metastatic behavior, supporting the notion that PHLPP1 is involved in the metastatic regulation of melanoma. To confirm a functional role for PHLPP1 in metastasis, we forced the expression of PHLPP1 and PHLPP2 in B16 and A375sm melanoma cell lines. Overexpression of PHLPP1 dramatically inhibited metastasis in both cell lines. Unexpectedly, the PHLPP2 isoform had little influence on metastatic ability in both cell lines in vivo, despite the fact that both PHLPP1 and PHLPP2 were able to inhibit in vitro cell proliferation, motility, migration as well as colony formation in soft agar. Notably, introduction of PH mutant forms of PHLPP1 still blunted the metastatic potential of both cell lines, whereas a phosphatase-deficient C-terminal mutant did not affect metastasis. Interestingly, transfected AKT2 active form could rescue PHLPP1-mediaed inhibition of metastasis. Our data demonstrate at the first time that PHLPP1 plays a critical role in inhibiting metastasis through its phosphatase activity, and suggest that PHLPP1 could be a diagnostic marker and therapeutic target for metastatic melanoma.
Citation Format: Yanlin Yu, Andrew Lu, Meng Dai, Glenn Merlino. Identification of PHLPP1 as a novel metastasis suppressor in melanoma . [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 3868. doi:10.1158/1538-7445.AM2013-3868
Abstract 3870: Overexpression of SPARC represses MMP-9 mediated metastasis in neuroblastoma.
Authors: Velpula Kiran Kumar , Gorantla Bharathi , Asuthkar Swapna , Bhasin Arnima , Gogineni Venkateswara Rao , Chetty Chandramu , Rao Jasti S. 
Published: August 2014

Abstract
Neuroblastoma (NB) is the most common pediatric solid tumor and arises from defective neural crest cells. NB is characterized by local invasion and metastasis, which is partly regulated by the proteins matrix metalloprotease-9 (MMP-9) and secreted protein acidic and rich in cysteine (SPARC). Although the pleiotropic anti-cancer role of SPARC and its effect on metastasis has been shown in a variety of cancers, the mechanism by which it acts is not very clear. In the present study, we found that the overexpression of SPARC in NB-1649 and SK-AS cell lines downregulated MMP-9 protein and inhibited the expression of other metastasis promoting molecules such as N-cadherin, β-Catenin and FAK. Moreover, SPARC overexpression significantly suppressed MMP-9-mediated migration, invasion and proliferation of NB cells. Interestingly, immunohistochemistry analysis of 36 human NB paraffin-embedded specimens showed that higher expression of MMP-9 was associated with lower levels SPARC. All these data suggest that SPARC and MMP-9 negatively associate to regulate the various stages of tumor progression. Furthermore, computational docking studies showed the existence of structural and physical interaction between SPARC and MMP-9 proteins. This SPARC-MMP-9 interaction was validated by immunoprecipitation and immunohistochemistry analysis in NB-1649 and SK-AS cells. Consistent with the above results, we observed a similar MMP-9-SPARC interaction in intracranial NB tumors of mice and found that the expression of MMP-9 was higher in control mice when compared to SPARC-treated mice. Taken together, our results demonstrate the role of SPARC in negative regulation of MMP-9 and MMP-9-mediated migration, invasion and metastasis of NB cells.
Citation Format: Kiran Kumar Velpula, Bharathi Gorantla, Swapna Asuthkar, Arnima Bhasin, Venkateswara Rao Gogineni, Chandramu Chetty, Jasti S. Rao. Overexpression of SPARC represses MMP-9 mediated metastasis in neuroblastoma. [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 3870. doi:10.1158/1538-7445.AM2013-3870
Abstract 3873: MMP9 processing of HSBP1 regulates tumor metastases.
Authors: Choi Seo-Hyun , Lee Hae-June , Jin Yeung Bae , Lee Minyoung , Kim Joon , Yoon Sam S. , Lee Yun-Sil , Lee Yoon-Jin 
Published: August 2014

Abstract
Matrix metalloproteinases regulate pathophysiological events by processing matrix proteins and secreted proteins. Previously, we demonstrated that soluble heat shock protein B1 (HSPB1) is released primarily from endothelial cells (ECs) and regulates angiogenesis via direct interaction with vascular endothelial growth factor (VEGF). Here we report that MMP9 can cleave HSPB1 and release anti-angiogenic fragments, which play a key role in tumor metastasis. We mapped the cleavage sites and explored their physiological relevance during these processing events. HSPB1 cleavage by MMP9 inhibited VEGF-induced ECs activation and the C-terminal HSPB1 fragment exhibited more interaction with VEGF than did full-length HSPB1. HSPB1 cleavage occurs during B16F10 lung metastases in wild-type mice and is decreased in B16F10 lung metastases of MMP9-null mice. Finally, we confirmed that secretion of C-terminal HSPB1 fragment was significantly inhibited lung metastases of B6F10 melanoma cells, compared to full-length HSPB1. These data suggest that in vivo MMP9-mediated processing of HSPB1 acts to maintain an angiogenic balance against tumor metastases. Moreover, these findings potentially explain an anti-target effect for the failure of MMP inhibitors in clinical trials, suggesting that MMP inhibitors may have pro-tumorigenic effects by reducing HSPB1 fragmentation.
Citation Format: Seo-Hyun Choi, Hae-June Lee, Yeung Bae Jin, Minyoung Lee, Joon Kim, Sam S. Yoon, Yun-Sil Lee, Yoon-Jin Lee. MMP9 processing of HSBP1 regulates tumor metastases. [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 3873. doi:10.1158/1538-7445.AM2013-3873
Abstract 3875: Effect of Nutlin and E3 ligase inhibitor on p53 and p21 levels in HDM2 expressing LNCaP cells.
Authors: Shaikh Saamia , Reddy Melanie , Dhandayuthapani Sivanesan , Alagarsamy Karthikeyan , Schmitt Emily , Rathinavelu Appu 
Published: August 2014

Abstract
HDM2 is a human homologue of murine double minute 2 protein (MDM2), which is also a negative regulator for p53 mediated tumor suppressor mechanisms. The latter is involved in regulating cell proliferation and induction of apoptosis as a means of controlling tumor growth. HDM2 can directly bind to p53 and neutralize its ability to induce p21 transcription. HDM2 also contains E3 ligase activity that is responsible for p53 ubiquitination and proteosomal degradation. Hence, compounds that inhibit E3 ligase activity of HDM2 are expected to lead to elevated p53 levels via inhibition of ubiquitination-mediated degradation. Similarly, blocking HDM2 by Nutlin was also expected to restore the levels of p53. According to existing literature, up-regulation of p53 should lead to activation of downstream pathways, such as induction of p21 protein. To confirm this hypothesis the prostate cancer cell line (LNCaP) was treated with HDM2-E3 ligase inhibitor and Nutlin for a 24-hour time period. The levels of p53 and p21 proteins were measured by Western Blot analysis and the mRNA levels were measured by RT-PCR amplification. Our preliminary results showed that HDM2-E3 ligase inhibitor increased p53 levels in LNCaP cells. The increase in p53 levels was greater in Nutlin treated samples compared to E3 ligase inhibited treated samples. In addition, we suspect that induction of p53 expression may also activate downstream pathways that will eventually lead to inhibition of cyclin-dependent kinases (CDKs) and phospho-retinoblastoma (pRB) protein mediated cell proliferation. To confirm our hypothesis further studies will be conducted. (The financial support from the Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida is gratefully acknowledged).
Citation Format: Saamia Shaikh, Melanie Reddy, Sivanesan Dhandayuthapani, Karthikeyan Alagarsamy, Emily Schmitt, Appu Rathinavelu. Effect of Nutlin and E3 ligase inhibitor on p53 and p21 levels in HDM2 expressing LNCaP cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3875. doi:10.1158/1538-7445.AM2013-3875
Abstract 3876: TRIM16 is a prognostic marker for patients with lymph node metastatic melanoma.
Authors: Cheung Belamy B. , Sutton Selina K. , Tan Owen , Koach Jessica , Liu Bing , Liu Tao , Scolyer Richard A. , Zhang Xu Dong , Marshall Glenn M. 
Published: August 2014

Abstract
The family of tripartite-motif (TRIM) proteins is involved in diverse cellular processes, ranging from innate immunity, oncoprotein, and tumor suppressor roles. TRIM16 overexpression confers retinoid sensitivity in retinoid-resistant cancer cells. Previously, we found a strong correlation between loss of TRIM16 expression and disease progression in two human cancers: neuroblastoma and squamous cell carcinoma of skin. Moreover, TRIM16 acted as a tumor suppressor in both cancers through effects on cell cycle and migration. Here we examined the potential role of TRIM16 as a tumor suppressor in melanoma.
We found that the endogenous TRIM16 expression level in seven melanoma cell lines was significantly lower than in normal human melanocytes. Overexpression of TRIM16 reduced cell viability and proliferation in multiple melanoma tumor cell lines assessed by the Alamar Blue assay, compared to empty vector controls (P &lt; 0.01). Overexpression of TRIM16 also decreases cell migration and induces apoptosis in melanoma cells. Immunohistochemical analysis demonstrated that TRIM16 expression is decreased in human metastatic melanoma tissue samples (Stage 3 and 4) compared to dysplastic compound nevi and primary melanomas (n=91). Most importantly, we have demonstrated that high TRIM16 expression is a favourable prognostic marker of survival (P=0.025) in a cohort of 170 melanoma patients with lymph node metastases. Median survival was 59 months in the high TRIM16 expression group (n=64), compared to 16 months in the low TRIM16 expression group (n=106). We also show overexpression of TRIM16 in melanoma cells lines induced interferon-beta 1 (IFNB1) mRNA expression, and IFNB1 expression is required for inhibition of cell proliferation by TRIM16. IFNB1 expression was also reduced in human metastatic melanoma tissue samples (n=91), and positively correlated with TRIM16 expression in patient samples. Our in vitro and in vivo data suggest that TRIM16 is a prognostic marker for patients with lymph node metastatic melanoma and may play an important role in melanoma tumor metastasis.
Citation Format: Belamy B. Cheung, Selina K. Sutton, Owen Tan, Jessica Koach, Bing Liu, Tao Liu, Richard A. Scolyer, Xu Dong Zhang, Glenn M. Marshall. TRIM16 is a prognostic marker for patients with lymph node metastatic melanoma. [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 3876. doi:10.1158/1538-7445.AM2013-3876
Abstract 388: Morphological assessment of tumor-associated vessels: Automated image processing of whole tumor sections in invasive breast cancer.
Authors: Fakhrejahani Elham , Asao Yasufumi , Yamaga Iku , Torii Masae , Takada Masahiro , Kitai Toshiyuki , Sugie Tomoharu , Toi Masakazu 
Published: August 2014

Abstract
Clinical benefit of anti-angiogenic therapies in different cancers is a result of normalizing the tumor vasculature by these agents. However, tumor vascular imaging modalities in human cancers are in their early evaluating phases. Photoacoustic mammography (PAM) is a newly introduced technique which can image the hemoglobin distribution and oxygenation state inside breast tissue with high spatial resolution. We have previously presented the oxygenation data of our first study in breast cancers by PAM in European Congress of Radiology (ECR) 2011. Here we report the morphological assessment of tumor-associated vessels in 81 histological sections of 20 invasive breast carcinomas.
The histological slides were scanned with the magnification of 200 after CD31 immunohistochemical staining. For automated CD31 analysis, 105 jpeg files were extracted from each virtual slide and were changed to binary images with Image Pro-Plus 7.0 software. The optimal hue, saturation and intensity (HSI) of stained structures was selected for each virtual slide. Each binary file was divided into 16 squares of 0.84mm x 0.84 mm size. Total number, area and length of stained structures were calculated in each square.
Patients’ age ranged from 36 to 84 years.19 cases were invasive ductal carcinomas and 1 case was invasive lobular carcinoma. Nine cases were luminal A, 9 cases luminal B and 2 cases were HER-2 subtype. For Ki67 scoring ndex,5 cases had &lt;5%, 9 cases between 5-20% and 6 cases had more than 20%.
There was a wide heterogeneity among total of 2.95 x10 6 analyzed tumor-associated vessels in 81 histological sections.
Table-1 shows the characteristics and distribution pattern. Total number of vessels/mm2 of breast tissue Total area of vessels (μm2)/mm2 of breast tissue Total perimeter of vessels (μm)/mm2 of breast tissue Perimeter/vessel (μm) Area/vessel (μm2) Min 4.6 218.4 65.5 17.8 37.7 Max 87 4369.8 1274.5 45.4 139.3 Average (+SD) 30.7 (+19) 1573.9 (+1060.8) 448.3 (+286.7) 28.9 (+ 4.2) 71.6 (+ 17.9)
Additional analysis of shape and pericyte coverage in these vessels is on its way. In conjunction with oxygenation data obtained by PAM,this can be used as a tumor vessel normalization assessment tool which can be used as a biomarker in anti-angiogenic treatments in breast cancers.
Citation Format: Elham Fakhrejahani, Yasufumi Asao, Iku Yamaga, Masae Torii, Masahiro Takada, Toshiyuki Kitai, Tomoharu Sugie, Masakazu Toi. Morphological assessment of tumor-associated vessels: Automated image processing of whole tumor sections in invasive breast 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 388. doi:10.1158/1538-7445.AM2013-388