bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5073: C5a receptor promotes invasive ability of gastric cancer
Authors: Kaida Takayoshi , Nitta Hidetoshi , Kitano Yuki , Yamamura Kensuke , Inoue Risa , Arima Kota , Higashi Takaaki , Taki Katunobu , Hayashi Hiromitsu , Imai Katsunori , Hashimoto Daisuke , Chikamoto Akira , Beppu Toru , Baba Hide 
Published: July 2016

Abstract
Background: C5a is one of the important factors produced via the complement pathway and a strong chemokine. The C5a receptor (C5aR) is expressed in various cancer cells and is linked to C5a-induced promotion of cancer cell invasion. However, the role of C5aR in gastric cancer (GC) is still mostly unknown.
Aim: To investigate the clinical role of C5aR-expression in human GC.
Method: 1) We investigated the C5aR expression for 237 GC patients who underwent gastrectomy from Jan. 2004 to Dec. 2011 by immunostaining using monoclonal human C5aR-antibody and analyzed the association between C5aR expression and clinicopathological factors. 2) We investigated the association between C5aR expression and invasiveness of GC cells, in vitro.
Result: 1) From immunostaining analysis, High-expression of C5aR was observed in 86 patients (36.8%) and was significantly related to depth of invasion, stage and vascular invasion. The 5-years RFS and OS rates of the patients with high-expression of C5aR were significantly worse than those of the patients with low-expression. 2) We found that several GC cell lines had high-expression of C5aR with western blotting. By using AGS and NUGC3 cell, the cell line which had low-expression of C5aR, We produced AGS (AGS/C5aR) and NUGC3 (NUGC3/C5aR) which had the overexpression of C5aR. Matrigel chamber assay revealed that C5a recombinant enhanced the cell invasion of AGS/C5aR and NUGC3/C5aR cell. Migration assay by using the timelapse imaging revealed that C5a recombinant enhanced the cell motility of AGS/C5aR and NUGC/C5aR cell. In addition, C5aR-antagont decreased the cell invasion and motility of those cell lines. The immunofluorescence microscopy revealed that C5a recombinant enhanced the cytoskeletal rearrangement, such as stress fiber, fillipdia and lamellipodia, in NUGC/C5aR cell. Then, C5a recombinant enhanced RhoA activity of NUGC3/C5aR.
Conclusions: The stimulation of C5a receptor may enhance the cell motility via RhoA activity, then it may enhance the cell invasion ability. In addition, High-expression of C5aR was associated with poor prognosis for GC patients. Therefore, C5a receptor might be a target of medical treatment.
Citation Format: Takayoshi Kaida, Hidetoshi Nitta, Yuki Kitano, Kensuke Yamamura, Risa Inoue, Kota Arima, Takaaki Higashi, Katunobu Taki, Hiromitsu Hayashi, Katsunori Imai, Daisuke Hashimoto, Akira Chikamoto, Toru Beppu, Hide Baba. C5a receptor promotes invasive ability of gastric cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5073.
Abstract 5077: The insulin-like growth factor-2 (IGF-2): A potential therapeutic target for triple-negative breast cancer metastasis
Authors: Hamilton Nalo , Marquez-Garban Diana , Pietras Richard 
Published: July 2016

Abstract
Introduction: Triple-negative breast cancers (TNBC) occur in 15-17% of patients, yet this subtype accounts for almost half of all breast cancer (BC) deaths. This breast cancer sub-type often occur in younger and African American (AA) women. TNBCs cannot be treated with current chemotherapies. Although initially responsive to chemotherapy, TNBCs tend to relapse and metastasize early. As there are no specific treatments for TNBCs, we aim to identify the therapeutic potential of insulin-like growth factor- 2 (IGF-2) in TNBC management.
Methods: Using immunohistochemistry archival breast tissue from women with metastatic TNBC was evaluated and scored for IGF-2 expression. To assess the ability of IGF-2 to stimulate cell proliferation and migration we used commercially available TNBC cell lines validated to be ER-alpha-negative (ER-), progesterone receptor-negative (PR-) and Her2 overexperssion-negative (HER2).
Results: We have found IGF-2 to be highly expressed archival breast tissue of women with metastatic TNBC. Using TNBC cell lines MDA-MB-231, HCC 38, HCC 1806 and HCC 1937, our in vitro studies demonstrate the ability of IGF-2 to stimulate TNBC proliferation and migration (P = 0.05). Further, the combination of NVP-AEW541, an insulin-like growth factor-1 receptor (IGF-1R) inhibitor, and BMS-754807, an inhibitor of IGF-1R and the insulin receptor (IR), cause a significant (P &lt; 0.05) reduction in TNBC proliferation and migration. Investigation into the cellular characteristics of the TNBC cell lines used, suggest that BRCA1 mutations increase cell susceptibility to IGF-1R inhibitors.
Conclusion: Our data indicate that IGF-2 plays a role in TNBC metastasis, an action that can be inhibited by targeting multiple IGF-2 mediated receptors.
Citation Format: Nalo Hamilton, Diana Marquez-Garban, Richard Pietras. The insulin-like growth factor-2 (IGF-2): A potential therapeutic target for triple-negative breast cancer metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5077.
Abstract 5081: hnRNP A18: an emerging novel target for cancer therapy
Authors: Parekh Palak R. , Chang Elizabeth , Yang Qingyuan , Carrier France 
Published: July 2016

Abstract
Heterogenous ribonucleoprotein A18 (hnRNP A18) increases de novo protein translation during cellular stress. Although hnRNP A18 has recently been associated with several cancers, the exact role of it during the multifactorial process of cancer growth and progression is still unknown. Accordingly, we examined the dependability of various malignant cancer cell lines on hnRNP A18. Down-regulation of hnRNP A18 impaired the proliferative, invasive and migratory properties of melanoma and triple negative breast cancer cell lines in vitro, while overexpression of hnRNP 18 caused an increase in invasiveness. Consistent with these observations, we detected remarkable reduction of tumor growth in two mouse xenograft models, melanoma and breast cancer. Moreover, down-regulation of hnRNP A18 increased the sensitivity of melanoma cells and breast cancer cells to paclitaxel and 5-fluoro uracil, respectively. In conclusion, hnRNP A18 plays a key role in tumor growth and progression. It may serve as a novel target for the treatment of cancer.
Citation Format: Palak R. Parekh, Elizabeth Chang, Qingyuan Yang, France Carrier. hnRNP A18: an emerging novel target for cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5081.
Abstract 5088: ACVRIB-dependent regulation of extracellular matrix protein in squamous cell carcinoma progression
Authors: Loomans Holli A. , Quast Laura L. , Andl Claudia A. 
Published: July 2016

Abstract
Squamous cell carcinomas (SCC) of the head and neck and esophagus pose a substantial public health risk globally. As SCC is often diagnosed in late stage, therapeutic options are limited. A more thorough understanding of the mechanisms involved their progression is needed. One potential mode by which SCCs progress is via Activin A signaling. The downstream effects of Activin A signaling have been primarily characterized as growth inhibiting and anti-angiogenic. However, Activin A is commonly overexpressed in SCC. Therefore, we hypothesized that SCC become insensitive to Activin A stimulation through the dysregulation of the signaling pathway. To model this dysregulation we utilized CRISPR-mediated regulation of ACVRIB (ACVRIB-kd), the necessary type IB receptor to transduce Activin A signaling in three SCC cell lines. Downregulation of ACVRIB enhanced invasiveness in the OSC19 SCC three-dimensional organotypic cultures. Additionally, ACVRIB-kd cells showed significant changes in protein expression, when compared to control. In particular, the correlative markers of SCC aggressiveness and putative downstream Activin A targets, podoplanin and fibronectin, were substantially altered in ACVRIB-kd cells. Integrin expression, particularly integrins β3, α5, and αv, was markedly changed in ACVRIB-kd cells, indicating additional ACVRIB-mediated effects to ECM proteins. We are currently analyzing ACVRIB-kd SCC tumor growth and metastasis in vivo using tongue orthotopic xenografts and subcutaneous flank injections. In conclusion, SCC-specific disruption of Activin A signaling promotes an aggressive phenotype. Re-activation of the canonical Activin A pathway may provide a novel therapeutic strategy to combat SCC.
Citation Format: Holli A. Loomans, Laura L. Quast, Claudia A. Andl. ACVRIB-dependent regulation of extracellular matrix protein in squamous cell carcinoma progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5088.
Abstract 5094: Acid-induced collagen remodeling promotes cancer progress as a result of niche engineering competition between cancer and stroma cells
Authors: Damaghi Mehdi , Chen Tinjan , Johnson Josef , Gillies Robert J. 
Published: July 2016

Abstract
Early carcinogenesis is an avascular and hypoxic disease that makes tumor cells export metabolically derived acid through glycolysis. Even in presence of oxygen cancer cells keep the glycolytic phenotype (Warburg effect) that acidifies the environment more and constantly. Hence the physical microenvironment of solid tumors is profoundly acidic. Pre-malignant cells within this niche must adapt to acidosis in order to survive this hostile microenvironment. We think pre-malignant cells adapt to acidosis to not only survive in this hostile microenvironment but also to acquire an advantage that helps them to outcompete the others and eventually help them to invade. Recently many evidences have been provided showing the collaboration of tumor associated stroma cells such as Fibroblasts (TAF) with tumor cells in cancer progress. Here we also show how these cells use acidification and acid adaptation as a strategy to construct and engineer their niche in their own favor for growth and proliferation. In this study we focused on collagen as major proteins of extra cellular matrix (ECM) and even arguably the most dominant one. The unique mechanical properties of fibrillar collagen are mainly controlled by its structure and any change in it can lead to ECM induced tumor growth. ECM unique compositions and topographies are generated through a dynamic biochemical and biophysical interplay between the various cells and the evolving microenvironment. In this study we developed the window chamber and intra vital microscopy to study the collagen remodeling lively. Later we used 3D cell culture and co-culture to validate our findings. Finally we used proteomics to understand molecular mechanism behind the changes in acid adapted versus non-adapted cancer cells and TAfs. We found cancer cells take different strategy than TAFs, although both changes promote cancer progression.
In conclusion, there are evolutionary advantages behind acid production and adapting to it for cancer and cancer associated cells. We discuss how acquiring these advantages can helps us to design new therapeutics against these unique phenotypes.
Citation Format: Mehdi Damaghi, Tinjan Chen, Josef Johnson, Robert J. Gillies. Acid-induced collagen remodeling promotes cancer progress as a result of niche engineering competition between cancer and stroma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5094.
Abstract 5100: Interplay between ECM stiffness, miR-203 and mammographic density
Authors: Dean Ivory , Acerbi Irene , Au Alfred , Chen Yunn-Yi , Hwang Shelley , Weaver Valerie 
Published: July 2016

Abstract
High mammographic density (MD) is associated with a greater risk of breast cancer and is characterized by high extracellular matrix (ECM) collagen. Elevated collagen increases ECM stiffness and can promote the malignant transformation of oncogenically-primed mammary epithelial cells in culture and in vivo. Whether or not high MD reflects a breast stroma that is stiff and if ECM stiffness accounts for the elevated breast cancer risk in high MD tissue has yet to be resolved. To address this question we are conducting a comprehensive biophysical and molecular analysis of BIRADS status in prophylactic mastectomies in women with low (BIRADS 1) versus high MD (BIRADS 4). Data revealed that the intra-lobular ECM associated with the terminal end-buds contains anisotropic compliant and relaxed collagen fibrils. By contrast, the inter-lobular ECM contains stiff, oriented collagen fibrils. Preliminary data suggest that the ECM associated with the terminal end-buds in the upper outer quadrant may be stiffer in women with high MD as compared to low MD. These same tissues also expressed lower levels of the microRNA miR-203, which has been implicated in epithelial-to-mesenchymal transition (EMT) inhibition. Consistently, in vitro studies revealed that miR-203 was repressed in MECs cultured on a stiff ECM. We also found that a stiffened mammary ECM decreased miR-203 expression and promoted an EMT. Additionally, inhibiting ECM stiffening restored miR-203 levels and reduced an EMT. Moreover and importantly, we showed that triple negative breast tumors that often express EMT markers have reduced miR-203 levels. Studies are underway to elaborate these preliminary findings and to assess their clinical relevance. (This work is supported by the: NIH NSRA T32 CA 108462-11 to Ivory Dean, Susan G Komen PDF12230246 to Irene Acerbi, W81XWH-13-1-0216, USMRAA DOD-BCRP BC122990, NIH R01 CA138818-01A1 and NIH R01 CA192914-01 to Valerie Weaver.)
Citation Format: Ivory Dean, Irene Acerbi, Alfred Au, Yunn-Yi Chen, Shelley Hwang, Valerie Weaver. Interplay between ECM stiffness, miR-203 and mammographic density. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5100.
Abstract 5101: Tumor-secreted acids alter macrophage phenotype
Authors: El-Kenawi Asmaa , Ibrahim-Hashim Arig , Luddy Kimberly , Ruffell Brian , Pilon-Thomas Shari , Gatenby Robert , Gillies Robert 
Published: July 2016

Abstract
Within tumors, tumor-associated macrophages (TAMs) usually adopt an M2 phenotype with tumor-promoting characteristics, as opposed to the M1 phenotype responsible for host protection. As acidic pH can affect the characteristics of immune cells, we aimed to test whether low pH as a common stress factor in the tumor microenvironment could be partially responsible for the phenotypic characteristics and/or functional activity of macrophages in prostate cancer. To test this hypothesis, we allowed TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate) mice to develop neoplastic lesions of variable histologic severity. Thereafter, we isolated tumor-associated macrophages from control tumors and analyzed their expression of the M1 and M2 markers; iNos, Il-6, Cd206 and Arg1. Gene expression analysis confirms previous studies which reported higher expression of both M1 and M2 markers in TAMs compared with peritoneal macrophages. Treatment of TRAMP mice with sodium bicarbonate to continuously buffer acids secreted by neoplastic cells, decreased TAMs infiltration into the stromal compartment of prostate. In addition, sodium bicarbonate decreased iNos, Arg1, and Cd206 but not Il-6 expression in TAMs isolated from subcutaneously growing TRAMP-C2 tumors, a TRAMP-derived prostate tumor cell line injected into syngeneic male hosts. Since decreased expression of Arg1 and iNos has been shown to mediate the suppressive activity of myeloid cells, tumor acidity might promote the suppressive microenvironment by upregulating both enzymes. In conclusion, extracellular acidosis increases the density of macrophages and their L-arginine metabolic potential; coincident with delayed tumor progression in prostate tumors.
Citation Format: Asmaa El-Kenawi, Arig Ibrahim-Hashim, Kimberly Luddy, Brian Ruffell, Shari Pilon-Thomas, Robert Gatenby, Robert Gillies. Tumor-secreted acids alter macrophage phenotype. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5101.
Abstract 5110: The role of autophagy in the tumor microenvironment
Authors: Dower Christopher M. , Wang Hong-Gang 
Published: July 2016

Abstract
The tumor microenvironment (TME) is a complex and dynamic breeding ground for the selection of aggressive tumor cells with an advantage of survival and metastatic potential. Autophagy has emerged as a powerful cellular process that can greatly influence how cancer cells respond to nutrient deprivation and hypoxic stress, the hallmarks of the TME. However, the physiological importance of hypoxia-regulated autophagy remains unknown. Here, we used a novel hypoxia-dependent reversible dominant-negative strategy, which allowed for physiological regulation of autophagy at the cellular level during tumor growth and metastasis and creates a heterogeneous population comprised of autophagy-competent and autophagy-deficient tumor cells. We demonstrate that the suppression of autophagy by HIF1-α dependent ULK1 inhibition within the hypoxic tumor microenvironment enhances the metastatic potential of breast cancer cells both in vitro and in vivo. Functional proteomic and transcriptome analysis indicated that the loss of hypoxia-regulated autophagy promotes metastasis through extracellular remodeling pathways, primarily through induction of the fibronectin-integrin signaling axis, along with LOX-mediated extracellular remodeling and pre-metastatic niche formation. In this way, the role of physiological hypoxia regulated autophagy was assessed for the first time in a triple negative breast cancer model. Currently, we are exploring the interplay between autophagy-competent and autophagy-deficient tumor cells within the TME, and how it relates to metastasis. Although the importance of autophagy in tumor-stromal interactions has recently become appreciated, the role autophagy plays in tumor cell-tumor cell interactions remains unknown. Through investigation of these intra-tumor cell networks, we can elucidate the precise mechanism of how physiologically-regulated autophagy in tumor cells influences the surrounding TME and tumor progression.
Citation Format: Christopher M. Dower, Hong-Gang Wang. The role of autophagy in the tumor microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5110.
Abstract 5115: Pre-clinical development of next generation inhibitors of the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase as cancer immunotherapies
Authors: Wise Alan , McGuinness Barry E. , Trewick Sarah C. , Brown Thomas J. , Cowley Phillip M. 
Published: July 2016

Abstract
The enzymes tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO1) catalyse oxidation of the essential amino acid tryptophan (Trp) leading to the formation of immunosuppressive kynurenine (Kyn) pathway metabolites that dampen the immune response in the tumor microenvironment. Both IDO1 and TDO have been shown to be up-regulated in a variety of cancers and blockade of their activity has been shown to stimulate the anti-tumour immune response in pre-clinical animal models. We have discovered and optimized multiple novel chemical series of both highly selective and dual-acting inhibitors of IDO1 and TDO. We describe the characterization of molecules that we are progressing into the clinic.
We have characterized the IDO1 and TDO-selective inhibitors and dual-acting inhibitors which demonstrate nM potencies. In IFNγ-stimulated A172 glioblastoma cells expressing both enzymes, the dual-acting molecules fully inhibit Kyn production, whilst selective inhibitors yield only a partial response, demonstrating the utility of dual enzyme blockade in cancer cells. The compounds also relieve inhibition of T-cell proliferation in cancer cell conditioned media/T-cell co-culture assays and demonstrate highly favourable physico-chemical and pharmacokinetic properties. These properties translate to superior PK/PD effects following oral dosing in rodents with profound and sustained modulation of plasma Kyn levels, combined with an exceptional safety profile. In a mouse model of LPS-induced IDO1 activation, our IDO1 inhibitors fully ablate elevation of Kyn in both plasma and lung in a dose-dependent manner. Following oral administration, the IOmet IDO1 inhibitors provide excellent single-agent tumor growth control in PAN02 pancreatic adenocarcinoma syngeneic models. In addition, combining IOmet IDO1 inhibitors with standard-of-care chemotherapy (gemcitabine/abraxane) in the PAN02 model completely inhibits tumor growth.
In summary, we describe the characterization of novel potent, selective and dual-acting IDO1 and TDO inhibitors. These candidate molecules demonstrate excellent rodent in vivo PK/PD, safety and anti-tumor profiles, supporting their progression into the clinic.
Citation Format: Alan Wise, Barry E. McGuinness, Sarah C. Trewick, Thomas J. Brown, Phillip M. Cowley. Pre-clinical development of next generation inhibitors of the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase as cancer immunotherapies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5115.