bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4807: Zoledronic acid overcomes the resistance to the anti-angiogenic therapy and normalizes tumor vessels by switching from a M2- to a M1-like macrophages phenotype in a mouse model of spontaneous cervical cancer
Authors: Capano Stefania , Maione Federica , Casanovas Oriol , Bussolino Federico , Giraudo Enrico 
Published: May 2015

Abstract
Recent studies described a resistance to the anti-angiogenic therapy both in pre-clinical and clinical settings. Several mechanisms that contribute to this resistance has been so far proposed and, among these, the recruitment of bone marrow-derived cells to the tumors, seems to be critical.
We have previously showed that an amino-bisphosphonate, Zoledronic acid (ZA), in a mouse model of spontaneous cervical carcinogenesis (HPV16/E2) by targeting MMP-9+ tumor-associated macrophages (TAM), strongly inhibited cancer progression and angiogenesis. Stemming from these data we sought to investigate whether ZA by acting on TAM, was able to overcome the resistance to anti-angiogenic treatments.
We treated tumor-bearing HPV16/E2 mice with ZA alone or combined with the small molecule tyrosine kinase inhibitor Sunitinib or with an anti-VEGFR-2 antibody, DC101, to assess the ability of ZA to block metastasis dissemination. Notably ZA synergized with Sunitinib and DC101 to inhibit primary tumor growth. Interestingly, while these compounds increased the incidence and the number of liver and lung metastasis, ZA alone inhibited basal tumor metastasis in parallel to angiogenesis inhibition. ZA combined with Sunitinib or DC101 showed a greater effect in impairing liver and lung metastasis formation. Confocal analysis of the vasculature revealed that while Sunitinib- or DC101-treated cancers displayed poorly functional vessels, both ZA alone or combined with Sunitinib or DC101 efficiently induced a normalized vasculature highly covered by pericytes and better perfused. Remarkably, gene and protein expression analysis of FACS-sorted macrophages derived from tumors of the different treatment groups, showed that ZA alone or combined with Sunitinib or DC101 inhibited the expression of M2-markers such as MRC-1, Il-10, CCL22 and MMP-9 and simultaneously enhanced the levels of M1-markers such as Il12 and CXCL9 in these cells.
We conclude that ZA, by promoting a M1-like macrophages phenotype in HPV16/E2 cervical cancers and consequently inducing a normalized vasculature, efficiently overcomes the resistance to angiogenesis inhibition by blocking metastasis dissemination.
Citation Format: Stefania Capano, Federica Maione, Oriol Casanovas, Federico Bussolino, Enrico Giraudo. Zoledronic acid overcomes the resistance to the anti-angiogenic therapy and normalizes tumor vessels by switching from a M2- to a M1-like macrophages phenotype in a mouse model of spontaneous cervical cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4807. doi:10.1158/1538-7445.AM2014-4807
Abstract 4832: Isolation and molecular characterization of circulating melanoma cells
Authors: Luo Xi , Mitra Devarati , Sullivan Ryan J. , Wittner Ben S. , Kimura Anya M. , Pan Shiwei , Hoang Mai P. , Brannigan Brian W. , Lawrence Donald P. , Flaherty Keith T. , Sequist Lecia V. , Stott Shannon L. , Ting David T. , Ramaswamy Sridhar , Toner Mehmet , Fisher David E. , Maheswaran Shyamala , Haber Daniel A. 
Published: May 2015

Abstract
Melanoma is a highly invasive malignancy frequently presenting with blood-borne metastases, in which recent breakthroughs in targeted and immunological therapies highlight the need for both early detection of invasion and monitoring of drug responses. We adapted a microfluidic device to capture circulating tumor cells (CTCs) in patients with melanoma and in a mouse model. In eight patients followed longitudinally, CTC numbers were correlated with response and progression on B-RAF/MEK, CDK4/6 and PDL1 inhibitors. Consistent with this trend, in a mouse model of tamoxifen-inducible B-RAF/PTEN-driven melanoma, CTCs declined within four days of treatment with a B-RAF inhibitor. In this model, CTCs are shed very early in tumorigenesis, and a four week course of B-RAF inhibition after resection of the primary tumor is sufficient to prevent the subsequent development of cutaneous metastases. Whereas primary and metastatic mouse melanomas are highly similar, RNA sequencing of CTCs identifies significant differences in expression, generating a signature that is correlated with invasiveness and motility in human melanoma.
Citation Format: Xi Luo, Devarati Mitra, Ryan J. Sullivan, Ben S. Wittner, Anya M. Kimura, Shiwei Pan, Mai P. Hoang, Brian W. Brannigan, Donald P. Lawrence, Keith T. Flaherty, Lecia V. Sequist, Shannon L. Stott, David T. Ting, Sridhar Ramaswamy, Mehmet Toner, David E. Fisher, Shyamala Maheswaran, Daniel A. Haber. Isolation and molecular characterization of circulating melanoma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4832. doi:10.1158/1538-7445.AM2014-4832
Abstract 4887: Omentin: A novel adipokine in the omental microenvironment associated with ovarian cancer progression
Authors: Yeung Chi Lam Au , Co Ngai Na , Onstad Michaela , Yeung Tsz-Lun , Leung Cecilia S. , Schmandt Rosemarie , Lu Karen H. , Mok Samuel C. 
Published: May 2015

Abstract
Advanced stage serous ovarian cancer metastasizes preferentially to the omentum, which is a well-vascularized fold of peritoneal tissue and is a major site of intra-abdominal fat accumulation, suggesting that the omental microenvironment is a favorable niche for ovarian cancer cells. The 5-year survival drops to below 50% for the cancer cases that spread beyond the pelvis to the omentum. It has also become apparent that obesity contributes to a poor clinical outcome. The mechanisms by which omental adipose tissue promotes tumor growth and disease progression are not entirely clear.
Using transcriptome profiling analysis on the microdissected adipose tissue from patients with benign gynecologic diseases and from patients with advanced high-grade serous ovarian cancer (HGSOC), we identified a gene signature for ovarian cancer associated omental adipose tissue, suggesting that alteration of these genes in the ovarian cancer associated omental adipose tissue may generate a permissive microenvironment to support ovarian cancer growth. Among genes that are significantly up- or down-regulated in ovarian cancer associated adipose tissue compared with the normal adipose tissue, we seek to focus on evaluating the role of omentin (Intestinal Lactoferrin Receptor ITLN1) in ovarian cancer progression since it is a novel adipokine that is predominantly expressed and secreted by visceral adipose tissue and is barely detectable in subcutaneous fats. Our data showed for the first time that omentin was expressed predominantly by the mesothelial cells covering the visceral adipose tissue but not by other cell types in the omental adipose tissue. Interestingly, we showed that circulating omentin level is significantly lower in patients with HGSOC compared with those in the BMI matched healthy individuals. In addition, using monolayer culture models, we demonstrated that omentin suppressed ovarian cancer motility and invasion potential directly and ovarian cancer growth only in the presence of adipocytes. We also showed that omentin can increase insulin-dependent glucose up-take in adipocytes and omentin expression can be down-regulated by co-culturing with ovarian cancer cells and in the presence of TNF-α.
The study provides the first evidence that ovarian cancer cells modify the visceral adipose tissue through down-regulation of omentin to facilitate their growth in the omental microenvironment.
Citation Format: Chi Lam Au Yeung, Ngai Na Co, Michaela Onstad, Tsz-Lun Yeung, Cecilia S. Leung, Rosemarie Schmandt, Karen H. Lu, Samuel C. Mok. Omentin: A novel adipokine in the omental microenvironment associated with ovarian cancer progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4887. doi:10.1158/1538-7445.AM2014-4887
Abstract 4911: NSCLC cells demonstrate differential mode of cell death in response to the combined treatment of radiation and a DNA-PKcs inhibitor
Authors: Lan Yu , Shang Zengfu , Hsu Feng-Ming , Tumati Vasu , Chen Benjamin P. , Saha Debabrata 
Published: May 2015

Abstract
Introduction: Lung cancers demonstrate the highest number of p53 mutations of any cancer with 70% of small cell lung cancers and 33% of adenocarcinomas containing a mutation. Loss of p53 function has been correlated with therapeutic resistance and poor clinical outcomes. Therefore, developing therapeutic strategies that specifically target p53 loss-of-function mutants is of the utmost importance. The purpose of this investigation is to explore whether p53 status has impact on the radio-sensitizing effect of a DNA-PKcs inhibitor (NU7441).
Methods: Clonogenic surviving fraction analysis, DNA double strand break repair kinetics, cell cycle analysis, immunofluorescence, immunoblot, apoptosis and autophagy assays were used to investigate the mechanism of radiosensitization of NU7441 in NSCLC cell lines (A549, H1299, and H460) with differential levels of p53 expression.
Results: NU7441 substantially inhibited the repair of IR-induced DNA double strand break (DSB) in all three cell lines. Clonogenic surviving fraction analysis reveals that NU7441 is a better radio-sensitizer in p53-deficient cells (H1299) when compared to p53-wild type cells (A549, H460). Combination of ionizing radiation (IR) and NU7441 leads to a more robust G2 arrest in A549 and H460 cells when compared to radiation treatment only. However, NU7441 and radiation preferentially induced mitotic arrest in H1299 consequently leading to a significant increase in mitotic catastrophe. Furthermore, NU7441 led to an increase in apoptosis rather than autophagy as the predominant cell death pathway in p53-deficient cells. Moreover, knockdown of p53 using siRNA sensitized A549 to NU7441+IR treatment.
Conclusion: Our study clearly shows that NU7441, a novel DNA-PKcs inhibitor, is a potent radio-sensitizer in p53-dificient lung cancer cells and highlights the promise of NU7441 in targeted cancer treatment.
Citation Format: Yu Lan, Zengfu Shang, Feng-Ming Hsu, Vasu Tumati, Benjamin P. Chen, Debabrata Saha. NSCLC cells demonstrate differential mode of cell death in response to the combined treatment of radiation and a DNA-PKcs inhibitor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4911. doi:10.1158/1538-7445.AM2014-4911
Abstract 4914: AKT- and ERK signaling inhibition does not sensitize GBM cells to chemo-/radiation in vitro
Authors: Narayan Ravi , Dik Rogier , Berg Jaap van den , Stalpers Lukas J.A. , Baumert Brigitta G. , Slotman Ben J. , Sminia Peter 
Published: May 2015

Abstract
A common feature of Glioblastoma Multiforme (GBM) is an augmented RTK/RAS/PI3K pathway signaling. This pathway has been shown to be involved in DNA repair by both NHEJ and HR in various tumor types and is thought thereby to interfere with its chemo- and radioresistance. Targeting this pathway to sensitize GBM to chemo- and radiotherapy seems to be an attractive therapeutic approach.
Proliferation and clonogenic survival of U251, U87 and T98 GBM cells were assessed following exposure to, BKM120 (pan class I PI3K inhibitor), RAD001 (mTORC1 inhibitor), MK-2206 (AKT inhibitor) and/or MEK162 (ERK inhibitor) alone and in combination with either irradiation or Temozolomide (TMZ). Effectivity of each compound on its target pathway was assessed by westernblot. BEZ235 (PI3K/mTOR/DNA-PK inhibitor) was used as a positive control for radiosensitization.
Our data show BKM120 and MK-2206 to effectively inhibit AKT phosphorylation at 1 uM and leads to growth inhibition in all tested cell lines. However, these compounds are not toxic on clonogenic cell survival and do not sensitize the cells to TMZ or irradiation. Increasing the dose to 5 uM and 10 uM for BKM120 and MK-2206 respectively an antagonistic effect was found in the combination with TMZ and irradiation. Effectively inhibiting mTOR, the downstream effector of AKT, by 100 nM RAD001 also does not radiosensitize GBM cells.
Inhibiting the parallel ERK-pathway by 1 uM MEK162, dephosphorylates ERK1/2 and leads to a slight increase in AKT phosphorylation. Inhibiting both pathways with BKM120 and MEK162 resulted in a synergistic growth inhibition of U251 cells however no radiosensitizing effect was found in a clonogenic assay.
In conclusion, selective targeting of key components in the AKT- and/or ERK signaling pathway effectively inhibits proliferation of GBM cells yet does not sensitize them to either TMZ or radiotherapy, indicating that GBM does not depend on the RTK/RAS/PI3K pathway for its DNA-repair.
Citation Format: Ravi Narayan, Rogier Dik, Jaap van den Berg, Lukas J.A. Stalpers, Brigitta G. Baumert, Ben J. Slotman, Peter Sminia. AKT- and ERK signaling inhibition does not sensitize GBM cells to chemo-/radiation in vitro. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4914. doi:10.1158/1538-7445.AM2014-4914
Abstract 4919: Visible/NIR-activatable prodrug strategy for treating local tumors by the combination of photodynamic therapy and local chemotherapy
Authors: Rajaputra Pallavi , Bio Moses , Nkepang Gregory , You Youngjae 
Published: May 2015

Abstract
Photodynamic therapy (PDT) and neoadjuvant chemotherapy have been used for treating localized tumors. However, each has its shortcomings such as limited efficacy to larger tumors and systemic side effects. We proposed a novel prodrug strategy by combining PDT and localized chemotherapy, which overcomes the problems of PDT and chemotherapy. A prodrug is composed of a photosensitizer and an anticancer drug connected via singlet oxygen (SO)-cleavable linker. Thus, SO generated by the illumination (690 nm) of the prodrug will not only directly damage tumors but also release active drug to kill surviving cancer cells. In our recent paper, we demonstrated the concept of our visible/NIR-activatable prodrug expressing the combination effect of PDT and local chemotherapy. We prepared CMP-L-CA4 where CMP = core-modified porphyrin (photosensitizer), CA4 = combretastatin A-4 (anticancer drug), and L = aminoacrylate linker (SO-cleavable linker) and its pseudo-prodrug (CMP-NCL-CA4: NCL = non-cleavable linker). CMP-L-CA4 showed desirable characteristics such as &gt; 80% drug release in test tubes in 10 min, 6 times reduction in IC50 by illumination, and bystander effect. On the other hand, CMP-NCL-CA4 showed smaller increase in IC50 by illumination and did not show the bystander effect. Consistent with the in vitro results, CMP-L-CA4 showed significantly better antitumor effect than CMP-NCL-CA4. Recently, we developed improved prodrugs using phthalocyanine (Pc) as a photosensitizer. In our presentation, we will show our newer biological data with the prodrugs supporting our novel prodrug strategy.
Citation Format: Pallavi Rajaputra, Moses Bio, Gregory Nkepang, Youngjae You. Visible/NIR-activatable prodrug strategy for treating local tumors by the combination of photodynamic therapy and local chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4919. doi:10.1158/1538-7445.AM2014-4919
Abstract 4940: Perivascular macrophages induce localized, transient blood vessel permeability and tumor cell intravasation
Authors: Harney Allison S. , Arwert Esther N. , Entenberg David , Wang Yarong , Jones Joan G. , Condeelis John S. 
Published: May 2015

Abstract
Metastasis is a multistep process involving tumor and stromal cells. The microanatomical site consisting of a perivascular macrophage interacting with a Mena over-expressing tumor cell has been named the “tumor microenvironment of metastasis” (TMEM). TMEM density predicts distant metastatic recurrence in breast cancer patients making the study of TMEM function essential. In spontaneous orthotopic mouse mammary tumors (MMTV-PyMT), as the tumor progresses to malignancy tumor cells have increased Mena expression and assemble TMEM. TMEM assembly is correlated with elevated levels of circulating tumor cells and lung metastases, indicating a functional role for TMEM in tumor cell dissemination. High-resolution multiphoton-based microscopy at single cell resolution has revealed transient blood vessel permeability events at TMEM, marked by the extravasation of otherwise impermeable serum markers such as Qdots and fluorescent 155 kDa dextran. In proximity to sites of permeability there is increased tumor cell and macrophage motility towards the blood vessel, and local intravasation of tumor cells. Blocking macrophage function results in decreased blood vessel permeability and decreased numbers of circulating tumor cells. TMEM-associated macrophages produce VEGF-A, and blocking VEGF-A reduces blood vessel permeability and circulating tumor cells. The observation that TMEM mediates tumor cell intravasation through localized blood vessel permeability in live animals demonstrates that TMEM is a key metastatic microenvironment in the primary tumor, explains the prognostic value of TMEM density in predicting distant metastatic recurrence in breast cancer patients and suggests a potentially valuable re-tasking of existing anti-angiogenesis drugs.
This research is supported by the Department of Defense [Breast Cancer Research Program)] under award number BC120227 (ASH).
Note: This abstract was not presented at the meeting.
Citation Format: Allison S. Harney, Esther N. Arwert, David Entenberg, Yarong Wang, Joan G. Jones, John S. Condeelis. Perivascular macrophages induce localized, transient blood vessel permeability and tumor cell intravasation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4940. doi:10.1158/1538-7445.AM2014-4940
Abstract 4975: Identification of a novel interaction between EZH2 and p38 in triple negative breast cancer
Authors: Anwar Talha , Moore Heather , Gonzalez Maria E. , Kleer Celina 
Published: May 2015

Abstract
Background: Breast cancer accounts for more than 40,000 deaths yearly in the United States, the majority of which are due to metastatic disease. The histone methyltransferase EZH2 (Enhancer of Zeste Homolog 2) is a member of the polycomb repressive complex 2 (PRC2) responsible for transcriptional repression by trimethylation of histone H3 at lysine 27. EZH2 is an independent predictor of recurrence and mortality that is overexpressed in 55% of invasive breast carcinomas. We previously identified a novel link between EZH2 and the p38 mitogen-activated protein kinase, an important mediator of breast cancer progression and metastasis. EZH2 binds to p38, and overexpression of EZH2 leads to phosphorylation and activation of p38. Based on in vitro evidence and recent studies implicating EZH2 in the methylation of non-histone targets, we hypothesized that EZH2 may methylate p38 in breast cancer cells. We further hypothesized that this methylation event may be important for p38 activation or stability.
Methods: In order to test this hypothesis, we used stable shRNA knockdown of EZH2 in MDA-MB-231 and SUM149 breast cancer cell lines. We performed co-immunoprecipitation using p38 and pan-methyl lysine antibodies to assess changes in methylated p38 by immunoblot. We are currently performing LC MS/MS analysis to identify the specific residues that are methylated by PRC2 both in vitro and in vivo. Additionally, in order to localize this interaction, we performed co-immunoprecipitation experiments on fractionated MDA-MB-231 and SUM149 lysates.
Results: Stable knockdown of EZH2 resulted in reduced methylated p38 compared to vector controls, suggesting that EZH2 methylates p38 in vivo. We found that EZH2 and p38 interact in nuclear and, surprisingly, cytoplasmic fractions.
Conclusions. We provide evidence that in addition to being a nuclear protein, EZH2 can be found in the cytoplasm of TNBCs, where it is able to complex with p38. Taken together, our data suggest that p38 methylation may represent an additional mechanism by which EZH2 mediates breast cancer progression in TNBC.
Citation Format: Talha Anwar, Heather Moore, Maria E. Gonzalez, Celina Kleer. Identification of a novel interaction between EZH2 and p38 in triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4975. doi:10.1158/1538-7445.AM2014-4975
Abstract 503: Antioxidants markedly accelerate tumor growth and reduce survival in mice with KRAS- and BRAF-induced lung cancer by disrupting the ROS-p53 axis
Authors: Sayin Volkan I. , Ibrahim Mohamed X. , Larsson Erik , Nilsson Jonas A. , Lindahl Per , Bergö Martin O. 
Published: May 2015

Abstract
Antioxidants are widely used to protect cells from damage induced by reactive oxygen species (ROS). The concept that antioxidants can help fight cancer is deeply rooted in the general population, promoted by the food supplement industry, and supported by some scientific studies. However, clinical trials have reported inconsistent results. Here, we show that supplementing the diet with the antioxidants N-acetylcysteine (NAC) or vitamin E markedly increases tumor progression and reduces survival by 50-60% in mouse models of B-RAF- and K-RAS-induced lung cancer. RNA sequencing revealed that NAC and vitamin E, which are structurally unrelated, produce highly coordinated changes in tumor transcriptome profiles, dominated by reduced expression of endogenous antioxidant genes. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 increases tumor growth to a similar degree as antioxidants and abolishes the antioxidant effect. Thus, antioxidants accelerate tumor growth by disrupting the ROS-p53 axis. Because somatic mutations in p53 occur late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production.
Citation Format: Volkan I. Sayin, Mohamed X. Ibrahim, Erik Larsson, Jonas A. Nilsson, Per Lindahl, Martin O. Bergö. Antioxidants markedly accelerate tumor growth and reduce survival in mice with KRAS- and BRAF-induced lung cancer by disrupting the ROS-p53 axis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 503. doi:10.1158/1538-7445.AM2014-503