bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1484: Functional and molecular characterization of macrophage-tumor cell communication
Authors: Schmall Anja , Herold Susanne , Vipotnik Natasha , Al-tamari Hamza M , Pullamsetti Soni Savai , Grimminger Friedrich , Seeger Werner , Savai Rajkumar 
Published: August 2012

Abstract
Lung Cancer is the leading cause of cancer deaths worldwide. It is increasingly appreciated that the tumor stroma, consistent of a heterogeneous population of non-neoplastic host cells, is an essential part of cancer initiation, growth and progression. Tumor-associated macrophages (TAMs) can influence cancer progression and metastasis, but the responsible mechanisms remain unclear. Here, we focus on the involvement of bone-marrow derived macrophages (BM- MM) and two of their major chemotactic pathways (CX3CR1-CX3CL1 and CCR2-CCL2 axis) in cancer proliferation and migration. We demonstrate that conditioned medium (CM) derived from co-cultures of lewis lung carcinoma (LLC1) cells with BM- MM (purity &gt;99%) enhances proliferation of LLC1-cells significantly from 1.79±0.1717 to 2.43±0.2067 in an absorbance based BrdU-Assay and a higher colony-number was found in a colony-formation-assay compared to control. In addition LLC1-migration in presence of CM was 5 fold increased compared to controls (172.9±2.18 versus 33.93±2.29). Further, analysis of the cytokine profile of co-culture-derived CM showed regulation of pro-inflammatory cytokines (Interleukin-6 and Interleukin-1α), anti-inflammatory cytokines (Interleukin-10 and Interleukin-1RA) and several chemokines (CCL5 and CCL2). Importantly, evaluation of tumor growth in chemokine receptor knockout mice, CX3CR1-KO and CCR2-KO demonstrated reduced tumor size compared to wild type mice. CX3CR1-KO and CCR2-KO tumor showed reduced in vivo proliferation as assessed by PCNA immunostaining (12.46%±3.188 versus 46.45%±2.922). Further analysis of the tumor microenvironment in CX3CR1-KO and CCR2-KO demonstrated a significant decrease in monocyte/ macrophage accumulation compared to control tumors as assessed by FACS. Compared to the percentage of macrophages in control tumor (7.518±0.78%), a significant decrease was observed in CCR2-KO (2.96± 0.233%) and CX3CR1-KO (3.975±0.6019%) tumors. Based on these findings, we conclude that macrophage plays a crucial role in lung cancer progression and the knowledge of tumor-host interactions can provide novel therapeutic approaches for lung cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1484. doi:1538-7445.AM2012-1484
Abstract 1487: Tumor-derived microvesicles induce proangiogenic phenotype in endothelial cells via endocytosis
Authors: Kawamoto Taisuke , Ohga Noritaka , Akiyama Kosuke , Hirata Naoya , Maishi Nako , Osawa Takahiro , Yamamoto Kazuyuki , Kondoh Miyako , Shindoh Masanobu , Hida Yasuhiro , Hida Kyoko 
Published: August 2012

Abstract
Background: Increasing evidence indicates that tumor endothelial cells (TEC) differ from normal endothelial cells (NEC). Our previous reports also showed that TEC were different from NEC. For example, TEC have chromosomal abnormality and proangiogenic properties such as high motility and proliferative activity. However, the mechanism by which TEC acquire a specific character remains unclear. To investigate this mechanism, we focused on tumor-derived microvesicles (TMV). Recent studies have shown that TMV contain numerous types of bioactive molecules and affect normal stromal cells in the tumor microenvironment. However, most of the functional mechanisms of TMV remain unclear. Methodology/Principal Findings: Here we showed that TMV isolated from tumor cells were taken up by NEC through endocytosis. In addition, we found that TMV promoted random motility and tube formation through the activation of the phosphoinositide 3-kinase/Akt pathway in NEC. Moreover, the effects induced by TMV were inhibited by the endocytosis inhibitor dynasore. Our results indicate that TMV could confer proangiogenic properties to NEC partly via endocytosis. Conclusion: We for the first time showed that endocytosis of TMV contributes to tumor angiogenesis. These findings offer new insights into cancer therapies and the crosstalk between tumor and endothelial cells mediated by TMV in the tumor microenvironment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1487. doi:1538-7445.AM2012-1487
Abstract 1499: Periprostatic fat from obese patients promotes prostate cancer growth
Authors: Venkatasubramanian Palamadai N. , Crawford Susan E. , Fitchev Philip S. , Brendler Charles B. , Plunkett Beth A. , Abroe Betsy , Mafi Massa , Morgan Gina , Cornwell Mona L. , O'Leary Judy , Pruitt Jacklyn , Stadnik Agnieszka , Burright Marna J. , McGuire Michael S. , Wyrwicz Alice M. , Doll Jennifer A. 
Published: August 2012

Abstract
Background: Obesity, particularly visceral obesity, increases the risk of prostate cancer (PCa) progression. However, the mechanism of this remains unclear. Here, we hypothesized that the visceral periprostatic fat (PPF) from obese PCa patients stimulates progression as compared to subcutaneous fat (SQF) or PPF from lean patients. Methods: PPF and SQF were collected from PCa patients. MTT assays were performed on endothelial and PC-3 PCa cells to test proliferative activity in explant culture tissue conditioned media (CM). Angiogenesis was evaluated ex vivo using MR to generate T2 relaxation times from a series of T2-weighted spin-echo images (Bruker 14.1 T imager). Results: PPF CM from an obese patient increased endothelial cell proliferation ∼5 times that of PPF CM from a lean patient (P&lt;0.01). In contrast, SQF CM, from lean or obese patients, showed only minimal activity. When tested on PC-3 cells, SQF CM from obese or lean patients only weakly promoted proliferation. In contrast, PPF CM significantly induced proliferation; however, obese PPF CM was significantly higher than that of lean PPF CM (P&lt;0.05). Interestingly, the MR data revealed key differences between PPF and SQF and between lean and obese fat (Table 1). In all patients, the PPF T2 was lower than that of the SQF (P&lt;0.01). And, the PPF T2 from obese patients was lower than that of lean patients. A lower T2 reflects elevated hemoglobin levels and thus could serve as an indirect measure of vascularity. And, our data suggest that vascularity is increased in obese PPF as compared to SQF and lean PPF tissues. Conclusions: Our data reveal that PPF has increased angiogenic and tumorigenic capacity as compared to SQF and this potential is markedly increased by the presence of obesity. Adipokines and/or other molecules expressed by the PPF may modify the PCa microenvironment to potentiate tumor growth. Our results also support the potential use of MR clinically as a non-invasive test of the angiogenic potential of PPF in PCa patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1499. doi:1538-7445.AM2012-1499
Abstract 1513: Functional analysis of TGFBR1 mutations in breast cancer associated fibroblasts
Authors: Moore-Smith Lakisha D. , Manne Kanika , Caldwell Charisma , Frost Andra , Pasche Boris 
Published: August 2012

Abstract
The TGFBR1*6A variant consists of a GCG repeat deletion resulting in a three-alanine deletion in the TGFBR1 coding region which has been linked to breast cancer risk. We have screened 30 breast cancer cell lines including: 20 epithelial (2 from normal breast) and 10 CAFs (2 from normal breast) for the presence of this mutation. Initial screening indicates that 45% of the epithelial cell lines screened harbor the *6A mutation. Of the 8 fibroblast screened 67% harbored TGFBR1*6A. The following CAF cell lines were used for the remainder of our functional studies: Hs748 (9A/9A), Hs841.T (9A/6A) and Hs742.T (6A/6A) genotypes. CAFs were treated with 100pM TGF-β resulting in decreased growth inhibitory response of 20% for Hs742.T (*6A/*6A) cells when compared to Hs841.T (9A/*6A) cells with 42% inhibition. Invasion assays, using a matrigel-coated Boyden Chamber, indicated a higher invasive capacity for Hs841.T (9A/6A) fibroblast cell line than in the Hs742.T (6A/6A) or Hs748.T (9A/9A). Western blot analysis was used to determine cell differentiation status. Cells which harbor TGFBR1*6A showed an increased expression of α-sma when compared to the WT fibroblasts indicating progression to a more aggressive myofibroblast phenotype. Studies are underway to reproduce these data in additional CAF cell lines, however, this preliminary data suggest that TGFBR1*6A enhances breast cancer development by enhancing tumor-associated fibroblast oncogenic properties in addition to its direct effect on breast tumor cells. TGF-β signaling was altered in TGFBR1*6A cells which may alter normal tumor-stromal signaling pathways. Future studies, using primary cell lines derived from a transgenic mouse model harboring the TGFBR1*6A allele will provide an optimal system to dissect the functional effects of this mutation in tumor and stromal cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1513. doi:1538-7445.AM2012-1513
Abstract 1518: Multiple myeloma cells cross talk with bone marrow stroma lead to induction of DKK1 expression and produce bortezomib resistance
Authors: Ryu Jiyeon , Jung Woo-june , Lee Chansu , Park Soyoung , Park Juwon , Bae Eunkyung , Ahn Kwang-Sung , Yoon Sung-Soo 
Published: August 2012

Abstract
The importance of the micro-environment in tumor progression is now well established. Dynamic interaction between multiple myeloma (MM) cells and bone marrow stromal cells (BMSCs) plays critical role in the progression of MM including drug response and bone erosion. Firstly, we found that DKK1 expression was statistically increased in MM cells (MOLP8, KMS12BM, KMS12PE, NCIH929, LP1, MOLP2, EJM, U266, RPMI8226, and 536MM, respectively) co-cultured with BMSCs obtained from MM patients when compared to MM cells alone (p&lt;0.05). Also, MM cells co-cultured with BMSCs were significantly more resistant against 25 nM bortezomib than MM cells alone (p&lt;0.05). We, therefore, established a bortezomib-resistant cell line using U266 cells (U266/velR), and explored the characteristics of U266/velR cells. Cytotoxic effect of bortezomib in U266/velR was 1.5 folds lower than U266 cells, and the cross-resistance against thalidomide was observed. DKK1 expression in U266/velR was higher than that in parental cells. We found that elevated levels of p-p65 were detected in U266/velR, and the degree of p65 and I-κB expression levels reduced by bortezomib was different between U266/velR and U266. Elevated levels of p-p65/p65 were effectively suppressed by treating with NF-κB activator inhibitor (6-aminoquinazoline). Also, combined treatment of bortezomib and 6-aminoquinazoline reduced the expression of DKK1 in co-culture of U266 cells and BMSCs. The expression of HGF in CD138− fractions of MM bone marrow cells was higher than that in its CD138+ fractions. Whereas, IL-6 and OPN in CD138+ fraction of MM bone marrow cells was higher compared to its CD138− fractions. In co-culture of U266 and BMSCs, IL-6, OPN and HGF was dramatically increased compared to U266 alone and BMSC alone (p&lt;0.01; p&lt;0.05). Taken together, cytokines and growth factor regulated by dynamic interplay between MM cells and BMSCs contributes the bortezomib response and bone erosion.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1518. doi:1538-7445.AM2012-1518
Abstract 1556: α-mannosylceramide, a new NKT cell agonist, induces tumor immunity without anergy induction in NKT cells
Authors: O'Konek Jessica , Takao Satomi , Izhak Liat , Illarinov Petr , Besra Gurdyal , Berzofsky Jay , Terabe Masaki 
Published: August 2012

Abstract
NKT cells are CD1d-restricted T cells recognizing lipid antigens. When NKT cells are activated with a prototypic antigen, α-galactosylceramide (α-GalCer), they induce strong tumor immunity. Strong preclinical evidence for α-GalCer's ability to induce tumor immunity through NKT cell-activation led to translation into therapy of cancer patients. However, so far minimal success has been achieved in patients. We reasoned that having an α-linked sugar moiety in the structure of α-GalCer can be a target for anti-α-linked galactose natural antibodies, which are a cause of acute xenograft rejection, and which might abrogate the biological activity of α-GalCer. After testing multiple glycosylceramides with potential agonistic activity for NKT cells, we discovered that α-mannosylceramide (α-ManCer) has strong activity to induce tumor immunity through a TNF-α- and NOS-dependent mechanism that is distinct from the IFN-γ dependent protection induced by α-GalCer. Another downside of α-GalCer treatment is induction of long-lasting anergy in activated NKT cells. Since we did not observe massive cytokine production with α-ManCer, in contrast to α-GalCer, we asked whether this new compound activates NKT cells without inducing long-lasting anergy in vivo. In contrast to α-GalCer, α-ManCer did not induce long-lasting anergy of activated NKT cells. This was correlated with the observation that α-ManCer induced only a short term expression of PD-1 on activated NKT cells, which has been reported to be responsible for α-GalCer-induced long-term anergy. Furthermore, while prior treatment with α-GalCer abrogated the protective effect of either α-GalCer or α-ManCer against CT26 colon carcinoma tumor challenge for at least two months, the pre-treatment with α-ManCer had no effect on the protection induced by either NKT cell agonist. Since α-ManCer can activate human NKT cells, this new NKT cell agonist may provide a better opportunity for NKT cell targeted immunotherapy in cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1556. doi:1538-7445.AM2012-1556
Abstract 1557: High mobility group box 1 secretion supports tumor progression of human malignant mesothelioma
Authors: Jube Sandro , Rivera Zeyana , Bianchi Marco , Powers Amy , Wang Ena , Pagano Ian , Pass Harvey I. , Gaudino Giovanni , Carbone Michele , Yang Haining 
Published: August 2012

Abstract
Human malignant mesothelioma (MM) is an aggressive and highly lethal cancer, often associated with exposure to asbestos and erionite. Prognosis is poor, due to late-stage diagnosis and resistance to current conventional therapies. We previously showed that high-mobility group box-1 protein (HMGB1), a damage-associated molecular pattern (DAMP) protein, is involved in the early stages of mesothelial cell transformation. Here we show that HMGB1 establishes an autocrine circuit in MM cells influencing tumor cell proliferation and survival. MM cells express HMGB1 at high levels and secrete HMGB1 into the extracellular space. Accordingly, HMGB1 levels in MM patients’ sera are significantly higher than in those of healthy individuals. In addition, motility, survival and anchorage-independent growth of HMGB1-secreting MM cells were inhibited in vitro by a monoclonal antibody (mAb) against HMGB1, by the recombinant HMGB1 competitive antagonist BoxA and by antibodies against the receptor for advanced glycation end products (RAGE). Inhibition of HMGB1 reduced the growth of MM xenografts in SCID mice and extended survival. Our findings indicate that MM cells become “addicted” to HMGB1 and that targeting HMGB1 can be a promising novel therapeutic approach for MM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1557. doi:1538-7445.AM2012-1557
Abstract 1813: Evaluation of TBK1 as a novel cancer target in the K-Ras pathway
Authors: Vangamudi Bhava , Ayres Aimee E. , Burke Jason P. , Waterson Alex G. , Rossanese Olivia W. , Fesik Stephen W. 
Published: August 2012

Abstract
TBK1 (TANK-binding kinase 1) is a serine/threonine kinase best known for its role in mediating the innate immune response through modulation of the interferon and NF-kB pathways. TBK1 has also been implicated in supporting cancer cell survival and transformation as the downstream effector of the small GTPase RalB, and is overexpressed in lung, breast and colon tumors. Recently, a high-throughput RNAi screen identified TBK1 as a synthetic lethal partner of oncogenic K-Ras, suggesting that small molecule inhibition of TBK1 may provide a novel therapeutic strategy for K-Ras mutant tumors. Given the high tractability of kinases as drug targets, we sought to confirm that kinase inhibition recapitulated the synthetic lethal effects observed with shRNA silencing. We examined two small molecule inhibitors of TBK1, BX795 (6 nM) and GSK2292978A (4 nM), in a panel of lung, pancreas and colon cancer cell lines. We found only a small subset of lines that were sensitive to TBK1 inhibition and this sensitivity did not correlate with K-Ras dependence. We then used K-Ras and TBK1 siRNA in a similar panel of cell lines. As anticipated, knockdown of K-Ras using siRNA produced significant growth and signaling defects in K-Ras dependent cell lines. In contrast, knockdown of TBK1 did not result in a significant alteration of growth in any of our cell lines. Neither TBK1 siRNA nor TBK1 inhibitors revealed a sensitivity that correlated with K-Ras dependence in our lung, pancreatic, or colorectal cancer cell lines. Our data disputes the proposed synthetic lethal relationship of oncogenic K-Ras and TBK1 and does not support development of TBK1 inhibitors for treatment of K-Ras driven tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1813. doi:1538-7445.AM2012-1813
Abstract 1818: The Aurora B inhibitor ABT-348 is not susceptible to known resistance mechanisms of other Aurora B inhibitors
Authors: Guo Jun , Curtin Michael L. , Heyman Robin , Anderson Mark G. , Marcotte Patrick A. , Tapang Paul , Palma Joann , Rodriguez Luis E. , Niquette Amanda , Bouska Jennifer J. , Albert Daniel H. , Donawho Cherrie K. , Frey Robin R. , Michaelides Michael , Tse Chris , Glaser Keith B. , Shah Omar J. 
Published: August 2012

Abstract
The Aurora kinases (Aurora A, B, and C) play essential roles in regulating cell division in mammalian cells and their over-expression in diverse tumor types makes them appealing oncology targets. ABT-348 is a novel, ATP-competitive, multi-targeted kinase inhibitor that exhibits potent activity in multiple solid tumor-derived and leukemia cell lines. ABT-348 is active against Aurora B (IC50 7 nM) and Aurora C (IC50 1 nM), Aurora A (IC50 120 nM). The activity against Aurora B is demonstrated by inhibition of histone H3 phosphorylation and induction of polyploidy. ABT-348 is also active against Aurora-B Y156H, a mutant resistant to other Aurora-B inhibitors. In addition, ABT-348 potently inhibits most members of the VEGFR and PDGFR family of receptor tyrosine kinases, which play a critical role in stromal angiogenesis. In contrast to other Aurora kinase inhibitors, the cellular efficacy of ABT-348 is retained in cells over-expressing P-glycoprotein (Pgp) or breast cancer resistant protein (BCRP), indicating that ABT-348 is not a substrate for these commonly upregulated ATP-binding cassette drug transporters. Consistent with these in vitro studies, ABT-348 was broadly efficacious as a single agent against a wide range of tumor types in vivo, including 3 multi-drug resistant xenograft models. In summary, the potent activity and unique kinase selectivity of ABT-348 against the Aurora kinases and VEGF and PDGF receptor tyrosine kinases, engender its ability to block multiple mechanisms of tumor progression. In addition, our data provide evidence that ABT-348 may be active in tumors resistant to other well-characterized inhibitors targeting Aurora-B. ABT-348 is presently under clinical evaluation in adult patients with advanced solid and hematological neoplasms.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1818. doi:1538-7445.AM2012-1818
Abstract 1827: Developing chemotherapeutics which selectively disable the actin cytoskeleton of tumor cells
Authors: Stehn Justine R. , Haass Nikolas K. , Desouza Melissa , Kottyan Gregg , Treutlein Herbert , Zeng Jun , Nascimento Paula R. , Han Min Hi , Hill Timothy A. , McCluskey Adam , Palmer Stephen , Hardeman Edna C. , Weninger Wolfgang , Cripe Timothy P. , Gunning Peter 
Published: August 2012

Abstract
The actin cytoskeleton is an important regulator of a variety of cellular functions making it an ideal chemotherapeutic target. Despite this promise no anti-actin compounds are used in current chemotherapy, primarily due to the inability of existing anti-actin agents to discriminate between the actin cytoskeleton of tumor cells and that of the muscle sarcomere. We have previously shown that tropomyosin, an integral component of the actin cytoskeleton, defines functionally distinct actin filament populations. We have designed a new class of compounds which target a specific cancer associated tropomyosin isoform, Tm5NM1. Anti-tropomyosin (Tm) compounds were selected based on ability to target the actin cytoskeleton and efficacy against a panel of neuroblastoma and melanoma cell lines. The lead compound, TR100, was shown to be effective against a panel of tumor cell lines (average EC50 3µM). Preliminary studies demonstrate that TR100 induces cell death via the intrinsic (mitochondrial) apoptotic pathway and the mechanism appears to be independent of the pro apoptotic factors BAX and BAK. In 3D melanoma spheroid models, which more accurately mimic the tumor microenvironment, TR100 inhibited cell growth and motility. This translated to a reduction in tumor cell growth in neuroblastoma and melanoma xenograft models. Analysis of drug treated animals showed no evidence of cardiac damage as measured by blood Troponin I levels and the intraventricular septum thickness of isolated hearts. These results demonstrate the possibility of targeting distinct actin filament populations based on tropomyosin composition. Next generation anti-Tm compounds with improved efficacy and specificity have now been developed. Preliminary data demonstrate that these compounds exhibit increased selectivity for transformed cells. Taken together, our findings suggest that the anti-Tm compounds show a significant improvement in the therapeutic window compared to existing anti-actin agents. This novel approach and the development of the new class of anti-Tm compounds may be the key for disabling a long sought after target, the actin cytoskeleton, and may lead to a new class of chemotherapeutics active against a broad range of cancer types.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1827. doi:1538-7445.AM2012-1827