bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4030: Interactions between co-cultured myoblasts and prostate cancer cells kill myoblasts but promote cancer cell proliferation and fusion: implications for cachexia and metastasis to skeletal muscle
Authors: Uygur Berna , Leikina Evgenia , Chernomordik Leonid V. 
Published: August 2015

Abstract
Severe muscle loss (cachexia) is the major cause for the cancer related death and 70% prostate cancer patients suffer from cachexia. Multinucleated cells of skeletal muscles are generated and regenerated by cell-to-cell fusion. It has been suggested that cell-to-cell fusion also takes place during carcinogenesis and promotes tumor cell diversity, drug resistance and the ability to metastasize. However fusion between cancer cells has remained elusive due to a very low efficiency of this process in earlier studies. Here we explored interactions between cancer cells and muscle environment in vitro. Co-culturing cells of human prostate cancer line (PC3) with primary murine proliferating myoblasts (muscle stem cells) resulted in differentiation and then apoptosis in muscle stem cells. Conditioned medium from PC3 cells also caused 50% decrease in proliferation of muscle stem cells. On the other hand, fusion-committed myoblasts co-cultured with PC3 cells lost their characteristic shapes and went through apoptosis. In addition to these effects of PC3 cells on murine myoblasts, we observed striking effects of myoblasts on PC3 cells. Co-culturing of PC3 cells with either proliferating myoblasts or fusion-committed myoblasts resulted in a robust fusion between cancer cells that yielded PC3 syncytia with up to 5 nuclei. Fusion promotion between PC3 cells was accompanied by a 1.5-fold increase in expression of Annexin A5, a protein recently implicated in myoblast fusion. In contrast, the expression of Annexin A5 in myoblasts was halved. Both co-culturing and using conditioned medium from fusion-committed myoblasts also resulted in a 2-fold increase in cancer cells proliferation and a 3-fold increase in the expression of the phosphorylated protein kinase AKT (pAKT). pAKT activity is associated with proliferation, drug resistance and cancer stem cell phenotype generation. Therefore we examined cancer stem cell marker, CD133 expression in PC3 cells. Treatment with conditioned medium from either proliferating or fusion-committed myoblasts doubled a percentage of CD133-expressing cells. Our results suggest an intriguing interplay between prostate cancer and muscle cells that may contribute to the progression of cancer and potentially explain cachexia.
Citation Format: Berna Uygur, Evgenia Leikina, Leonid V. Chernomordik. Interactions between co-cultured myoblasts and prostate cancer cells kill myoblasts but promote cancer cell proliferation and fusion: implications for cachexia and metastasis to skeletal muscle. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4030. doi:10.1158/1538-7445.AM2015-4030
Abstract 4045: MRAS and SHOC2 interact with SCRIB and coordinate ERK pathway activation with polarity and tumorigenic growth
Authors: Young Lucy C. , Hartig Nicole , Munoz-Alegre Marta , Oses-Prieto Juan A. , Durdu Sevi , Bender Sabine , Vijakumar Vineetha , Vietri Rudan Matteo , Gewinner Christina , Jathoul Amit P. , Ghatrora Rupinder , Lythgoe Mark L. , Burlingame Alma L. , Rodriguez-Viciana Pablo 
Published: August 2015

Abstract
SHOC2 is mutated in Noonan syndrome and plays a key role in the activation of the ERK-MAPK pathway, which is upregulated in the majority of human cancers. SHOC2 functions as a PP1-regulatory protein and as an effector of MRAS. Here we show that SHOC2 and MRAS form a complex with SCRIB, a polarity protein with tumor suppressor properties. SCRIB functions as a PP1-regulatory protein and antagonizes SHOC2-mediated RAF dephosphorylation through a mechanism involving competition for PP1 molecules within the same macromolecular complex. SHOC2 function is selectively required for the malignant properties of tumor cells with mutant RAS, and both MRAS and SHOC2 play a key role in polarized migration. We propose that MRAS, through its ability to recruit a complex with paradoxical components, coordinates ERK pathway spatiotemporal dynamics with polarity and that this complex plays a key role during tumorigenic growth.
Citation Format: Lucy C. Young, Nicole Hartig, Marta Munoz-Alegre, Juan A. Oses-Prieto, Sevi Durdu, Sabine Bender, Vineetha Vijakumar, Matteo Vietri Rudan, Christina Gewinner, Amit P. Jathoul, Rupinder Ghatrora, Mark L. Lythgoe, Alma L. Burlingame, Pablo Rodriguez-Viciana. MRAS and SHOC2 interact with SCRIB and coordinate ERK pathway activation with polarity and tumorigenic growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4045. doi:10.1158/1538-7445.AM2015-4045
Abstract 4051: Protection from CTL mediated killing by iNOS expression in a mouse model of melanoma
Authors: Marvel Douglas M. , Gabrilovich Dmitry 
Published: August 2015

Abstract
The presence of peroxynitrite (PNT) in tumor tissue, as measured by its surrogate tissue marker, nitrotyrosine (NT), is correlated with poor clinical prognosis and poor response to immunotherapy. The production of PNT at the tissue can be attributed to multiple sources. For example, many tumors are characterized by extensive infiltration by immature myeloid cells with robust immuno-suppresive activity. These myeloid derived suppressor cells (MDSC) are known to produce high level of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and the reaction of these two species is a major source of PNT at the tumor site. In addition to MDSC, iNOS expression in tumor cells themselves can act as a major source of PNT. Here we show that B16 melanoma cells are protected from CTL mediated lysis via iNOS expression. This effect is independent of effects on the T cells themselves as ability to lyse iNOS expressing and non-expressing cells was assessed in the same culture. Previously it was shown that peroxynitrite treated cells bound certain exogenous MHC class I peptides with lower affinity than their non-treated counterparts. Using a system of endogenous iNOS expression, our data supports the existence of a similar phenomenon for endogenously processed and presented peptide antigens, suggesting that the repertoire of surface bound immunogenic peptides is different in tumors when compared to the presentation of those same antigens in the tumor draining lymph node, where PNT is less prevalent. As a result, immune responses generated in the lymph node are against antigens which are not relevant and will fail to control tumor growth. Additionally, our data suggests that pharmaceutical intervention to reduce intratumoral PNT levels may buoy concurrent immunotherapy.
Citation Format: Douglas M. Marvel, Dmitry Gabrilovich. Protection from CTL mediated killing by iNOS expression in a mouse model of melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4051. doi:10.1158/1538-7445.AM2015-4051
Abstract 4065: Delineating the role of epithelial-mesenchymal transition in the generation and maintenance of prostate cancer stem cells
Authors: Paranjape Anurag N. , Soundararajan Rama , Werden Steven J. , Joseph Robiya , Taube Joseph H. , Bhangre Neeraja , Liu Hui , Rodriguez-Canales Jaime , Wistuba Ignacio I. , Chang Jeffrey T. , Tang Dean G. , Mahajan Nupam , Mahajan Kiran , Miura Naoyuki , Mani Sendurai A. 
Published: August 2015

Abstract
Prostate cancer cells depend on androgens for growth and survival. While androgen-deprivation-therapy (ADT) results in regression of the tumor bulk, in many cases, the cancers recur in aggressive androgen-independent forms that are also resistant to standard-of-care therapies. The prevailing hypothesis is that pre-existing androgen-independent prostate cancer (PCa) stem-cells in the primary tumor are selectively enriched following therapy. However, we have previously shown that induction of epithelial-mesenchymal-transition (EMT) in differentiated breast epithelial cells can result in the generation of cells with stem-cell properties. In the current study, we investigated if induction of EMT in PCa promotes stem-cell features and androgen-receptor (AR) regulation, and if targeting EMT-promoting pathways renders PCa stem-cells sensitive to ADT.
We found that LNCaP-PSAlow cells, which were previously shown to represent the PCa stem-cell population, exhibit EMT properties. Induction of EMT through over-expression of EMT-inducing transcription factors or with TGFβ1 treatment, significantly stimulated stem-cell properties in the androgen-sensitive LNCaP cells, whereas inhibition of EMT in the androgen-insensitive DU145 cells using targeted shRNA or a specific TGFβ1-signaling inhibitor, resulted in markedly reduced stemness. We observed that FOXC2 expression consistently correlated with induction of EMT and androgen-insensitivity in PCa cells. Our study demonstrates that targeting EMT-inducing molecules and signaling pathways could represent a tangible approach to inhibiting the generation and maintenance of therapy-resistant PCa stem-cells, that are the prime harbingers of tumor recurrence.
Citation Format: Anurag N. Paranjape, Rama Soundararajan, Steven J. Werden, Robiya Joseph, Joseph H. Taube, Neeraja Bhangre, Hui Liu, Jaime Rodriguez-Canales, Ignacio I. Wistuba, Jeffrey T. Chang, Dean G. Tang, Nupam Mahajan, Kiran Mahajan, Naoyuki Miura, Sendurai A. Mani. Delineating the role of epithelial-mesenchymal transition in the generation and maintenance of prostate cancer stem cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4065. doi:10.1158/1538-7445.AM2015-4065
Abstract 4092: PDGFRα and β play critical roles in mediating Foxq1-driven breast cancer stemness and chemoresistance
Authors: Meng Fanyan , Speyer Cecilia , Zhang Bin , Zhao Yongzhong , Chen Wei , Gorski David , Miller Fred R. , Wu Guojun 
Published: August 2015

Abstract
Many epithelial-mesenchymal transition (EMT)-promoting transcription factors have been implicated in tumorigenesis and metastasis, as well as chemoresistance of cancer. However, the underlying mechanisms mediating these processes are unclear. Here we report that Foxq1, a forkhead box-containing transcription factor and EMT-inducing gene, promotes stemness traits and chemoresistance in mammary epithelial cells. Using an expression profiling assay, we identified Twist1, Zeb2, and PDGFRα and β as Foxq1 downstream targets. We further show that PDGFRα and β can be directly regulated by Foxq1 or indirectly regulated through the Foxq1/Twist1 axis. Knockdown of both PDGFRα and β results in more significant effects on reversing Foxq1-promoted oncogenesis in vitro and in vivo than knockdown of either PDGFRα or β alone. In addition, PDGFRβ is a more potent mediator of Foxq1-promoted stemness traits than PDGFRα. Finally, pharmacological inhibition or gene silencing of PDGFRs sensitizes mammary epithelial cells to chemotherapeutic agents in vitro and in vivo. These findings collectively implicate PDGFRs as critical mediators of breast cancer oncogenesis and chemoresistance driven by Foxq1, and may have important implications for the development of novel combinational therapeutics against breast cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Fanyan Meng, Cecilia Speyer, Bin Zhang, Yongzhong Zhao, Wei Chen, David Gorski, Fred R. Miller, Guojun Wu. PDGFRα and β play critical roles in mediating Foxq1-driven breast cancer stemness and chemoresistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4092. doi:10.1158/1538-7445.AM2015-4092
Abstract 4118: Near infrared photoimmunotherapy for lung metastases
Authors: Sato Kazuhide , Nagaya Tadanobu , Choyke Peter L. , Kobayashi Hisataka 
Published: August 2015

Abstract
Introduction and Purpose
Lung metastases are a leading cause of cancer related deaths. Current therapies include surgery, chemotherapy and radiotherapy but cause considerable side effects in the remaining normal lung, chest wall and heart. Therefore, a new-targeted therapy for lung metastases that results in minimal damage to adjacent structures, yet effectively treats lung metastases, is needed. Since one interesting property of the lung is that it transmits light better than other organs, light therapy is a viable alternative therapy. Near infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that combines the specificity of intravenously injected antibodies that target tumors with the toxicity induced by photosensitizers activated by NIR light. Herein, we demonstrate the efficacy of NIR-PIT in a mouse model of lung metastases.
Experimental Design
In vitro and in vivo experiments were conducted with a HER2, luciferase and GFP expressing cell line (3T3/HER2-luc-GFP). An antibody-photosensitizer conjugate (APC) consisting of trastuzumab and a phthalocyanine dye, IRDye-700DX, was synthesized. In vitro NIR-PIT cytotoxicity was assessed with dead staining, luciferase activity, and GFP fluorescence intensity. In vivo NIR-PIT was performed in a mouse model of lung metastases as well as a flank model, and assessed by tumor volume and/or bioluminescence (BLI).
Results
In vitro NIR-PIT-induced cytotoxicity was light dose dependent. In vivo anti-tumor effects of NIR-PIT included significant reductions in both tumor volume (p = 0.0141 vs. APC) and BLI (p = 0.0086 vs. APC) in the flank model, and prolonged survival (p &lt; 0.0001). BLI demonstrated a significant reduction in lung metastases volume (p = 0.0117 vs. APC). Multiple NIR-PIT doses significantly prolonged survival in the lung metastases model (p &lt; 0.0001).
Conclusions
NIR-PIT prolonged survival suggesting that NIR-PIT is a potential new therapy for the local control of lung metastases.
Citation Format: Kazuhide Sato, Tadanobu Nagaya, Peter L. Choyke, Hisataka Kobayashi. Near infrared photoimmunotherapy for lung metastases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4118. doi:10.1158/1538-7445.AM2015-4118
Abstract 4135: A polyclonal origin for pancreatic cancer metastases
Authors: Maddipati Ravikanth , Stanger Ben Z. 
Published: August 2015

Abstract
Cancer genome studies demonstrate that tumors are comprised of multiple sub-clones with varied genetic and phenotypic properties. Metastases are often depicted as arising from these subpopulations through seeding by single cells, leading to clonally-derived lesions at distant sites. Alternatively, it has been suggested that metastases can also arise from the collective migration of tumor cells, resulting in formation of polyclonal metastases. To better understand the dynamics of metastasis formation in native tumors, we employed the multi-color “Confetti” lineage tracing system, in an autochthonous mouse model of pancreatic ductal adenocarcinoma (PDAC). Through the stochastic expression of distinct fluorescent proteins in any given cell, we tracked the contribution of different tumor subpopulations to malignant progression. We find that early pre-malignant lesions exhibit significant clonal heterogeneity but this clonal diversity decreases during progression to frank carcinoma. Furthermore our data provide the first direct evidence for polyclonal metastasis in the context of a naturally-evolving tumor and suggest that seeding and colonization of metastatic sites involves interactions between at least two distinct tumor populations. We also observe that clonal evolution during metastatic growth varies significantly between the sites of metastatic invasion, resulting in either monoclonal or polyclonal outgrowth. These results provide and unprecedented window into the dynamic changes in clonality that accompany tumor progression and suggest that heterotypic interactions between tumor subpopulations and microenvironmental factors unique to each tissue site contribute to the clonal evolution of metastases.
Citation Format: Ravikanth Maddipati, Ben Z. Stanger. A polyclonal origin for pancreatic cancer metastases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4135. doi:10.1158/1538-7445.AM2015-4135
Abstract 4148: Tankyrase inhibition impairs directional migration and invasion of lung cancer cells by affecting microtubule dynamics and polarity signals
Authors: Lupo Barbara , Vialard Jorge , Bertotti Andrea , Lanzetti Letizia , Trusolino Livio 
Published: August 2015

Abstract
Tankyrases are poly(ADP)-ribose polymerases that contribute to biological processes as diverse as modulation of Wnt signaling, telomere maintenance, vesicle trafficking, and spindle pole assembly (1,2). Here we report a new function for tankyrases, namely, regulation of directional cell locomotion. Oriented migration is established by polarized reshaping of the microtubule network, which in turn is attained by phosphorylation-dependent inhibition of GSK3β at the leading edge, the ensuing association of APC with the plus end of microtubules at the cortex of cell membrane protrusions, and microtubule-based centrosome reorientation towards the migrating front (3,4).
Using a panel of lung cancer cell lines as a model system, we found that pharmacologic abrogation of tankyrase activity by two different, structurally unrelated small-molecule inhibitors weakened cell migration, invasion and directional movement induced by the motogenic cytokine HGF. Mechanistically, the anti-invasive outcome of tankyrase inhibition could be ascribed to sequential deterioration of the distinct events that govern cell directional sensing. In particular, tankyrase blockade negatively impacted: i) microtubule dynamic instability; ii) HGF-triggered GSK3β phosphorylation; iii) APC plasma membrane targeting; iv) centrosome reorientation. Collectively, these findings uncover an unanticipated role for tankyrases in influencing at multiple levels the interphase dynamics of the microtubule network and the activity and localization of related polarity signals. In perspective, these results pave the way for challenging tankyrase inhibitors as therapeutic tools to oppose dissemination and metastasis of cancer cells.
1. Riffell JL, Lord CJ, Ashworth A. Tankyrase-targeted therapeutics: expanding opportunities in the PARP family. Nat Rev Drug Discov 2012;11(12):923-36.
2. Haikarainen T, Krauss S, Lehtio L. Tankyrases: structure, function and therapeutic implications in cancer. Curr Pharm Des 2014;20(41):6472-88.
3. Etienne-Manneville S. Microtubules in cell migration. Annu Rev Cell Dev Biol 2013;29:471-99.
4. Etienne-Manneville S. Polarity proteins in migration and invasion. Oncogene 2008;27(55):6970-80.
Citation Format: Barbara Lupo, Jorge Vialard, Andrea Bertotti, Letizia Lanzetti, Livio Trusolino. Tankyrase inhibition impairs directional migration and invasion of lung cancer cells by affecting microtubule dynamics and polarity signals. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4148. doi:10.1158/1538-7445.AM2015-4148
Abstract 4179: Id3 generated cancer stem-like cells: A microvascular niche for the development of glioma
Authors: Das Jayanta , Felty Quentin H. 
Published: August 2015

Abstract
Pro-angiogenic vascular stem cells and angiogenesis are key events in the process of glioma formation. Vascular lesions that arise from a focal budding of endothelial cells have been associated with a poor prognosis in glioblastoma multiforme. Hyper-proliferative endothelial lesions are common in patients with severe brain tumors, however, little is known about the relevance of vascular stem cells in the development of these lesions. We tested the hypothesis that the overexpression of the inhibitor of DNA binding and differentiation protein 3 (ID3) reprograms the molecular signature of endothelial cells to stem-like cells; and we hypothesize that these stem-like cells participate in the development of vascular lesion formation in glioma. We generated ID3 overexpressing cells using the human cerebral microvascular endothelial cell line, hCMEC/D3; and determined the effect of ID3 on molecular stem-like signature and vascular lesion formation. ID3 overexpressing cells resided more in the G0/G1 phase and showed a significantly higher level of stem cell markers CD34, CD133, Oct-4, and Sox-2 than wild-type cells. ID3 overexpressing cells also showed a significant increase in VEGFR3, an endothelial growth factor receptor that has been previously reported to correlate with tumor grade of malignant gliomas. In addition, ID3 overexpressing cells showed increased levels of Pyk2, a kinase that has been shown to control glioma cell migration. In the 3-D culture model, we observed that ID3 was essential for the growth of endothelial spheroids. Our findings demonstrate that ID3 generated vascular stem-like cells have the capacity to participate in vascular lesion formation and that vascular stem-like molecular signatures are regulated in part by ID3. Furthermore, the correlation of ID3 overexpression with an increase in VEGFR3 and Pyk2 suggests the importance of ID3 in malignant glioma endothelium. Assessing ID3 in malignant gliomas on a functional level may enable a better understanding for how the microvascular niche contributes to the development of glioma. A better understanding of how microvascular lesions depend on ID3 may open new avenues for the prevention and treatment of glioma.
Citation Format: Jayanta Das, Quentin H. Felty. Id3 generated cancer stem-like cells: A microvascular niche for the development of glioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4179. doi:10.1158/1538-7445.AM2015-4179