bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4100: Stromalcell suppression of estrogen receptor in growth-arrested breast cancer cellsand promotion of outgrowth of estrogen-independent clones
Authors: Steinman Richard , Huang Jingjing , Woods Paul , Normolle Daniel , Goff Julie , Stehle Christine 
Published: July 2016

Abstract
Breast cancers have a poorer prognosis if estrogen receptor expression was lost during recurrence. It is unclear whether this conversion is cell autonomous or whether it can be promoted by the microenvironment during cancer dormancy. Bone marrow is the most common site for luminal breast cancer recurrence. We explored whether the HS5 bone marrow stromal cell line that is known to arrest co-cultured breast cancer cells could suppress estrogen receptor alpha (ER) expression during arrest, and whether it could prime the emergence of estrogen-independent breast cancer clones. We demonstrated that paracrine signaling from HS5 cells downregulated ER at the mRNA level and also decreased ER protein stability in T47D and MCF7 breast cancer cells. Conditioned medium (CM) from HS5 arrested the cells in G0/G1 in part through interleukin-1 (IL1), inhibiting mammosphere formation and 2D-growth despite activation of proliferative pathways (Erk and AKT) by the CM. Reversal of stromal-induced growth arrest by blockade of signaling by IL1 in HS5-CM enabled the outgrowth of ER-negative breast cancer cells that were fulvestrant-resistant and estrogen-independent. Outgrowth depended on AKT signaling. Our results describe pro- and anti-proliferative paracrine signals arising from a bone marrow stromal cell line. Blockade of the growth suppressive signaling unmasked stromal facilitation of ER conversion and anti-estrogen resistance in breast cancer cells.
Citation Format: Richard Steinman, Jingjing Huang, Paul Woods, Daniel Normolle, Julie Goff, Christine Stehle. Stromalcell suppression of estrogen receptor in growth-arrested breast cancer cellsand promotion of outgrowth of estrogen-independent clones. [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 4100.
Abstract 411: Sensitive detection of BRAF V600E mutation by bridged nucleic acid (BNA)-mediate real-time PCR assay
Authors: Liu Xiaoyun , Loredo Leticia , Dai Houquan , Castro Aaron , Zhao Yuewei , Kim Sung Kun , Dinkel Austin , Castro Miguel 
Published: July 2016

Abstract
BRAF is a human gene encoding a serine/threonine protein kinase in the RAS-RAF-MEK-ERK signal pathway, which is important in regulating cellular responses to extracellular signals. Frequent mutations on BRAF gene have been detected in various types of human cancer, including malignant melanoma, non-small cell lung cancer, colorectal cancer, papillary carcinoma of the thyroid, ovarian cancer and hairy cell leukemia. Among all, a single point 1799T&gt;A (V600E) transversion, the most common mutation on BRAF, results in increased kinase activity. It serves as a driver mutation in several types of cancer and confers increased sensitivity to tyrosine kinase inhibitors. Thus, detecting the BRAF V600E mutation may offer valuable information for cancer diagnosis, treatment selection, and prognosis. Here we report a rapid, highly sensitive method for the detection of BRAF V600 mutation using a bridged nucleic acid (BNA) clamp technology associated with quantitative PCR (qPCR). Due to the feature of enhanced affinity for hybridization template, BNA clamp is able to selectively block PCR reactions on the perfect match DNA sequence, while leaves the mismatch template unaffected. In this study several BNA clamps that bind to BRAF V600 wild-type (WT) template was designed, synthesized, and characterized. As compared to DNA clamp counterparts, these BNA clamps increased Tm values for the BRAF V600 WT by greater than 30°C. In addition, BNA clamps efficiently distinguished BRAF WT (perfect match) from V600E (mismatch) templates (deltaTm &gt;12°C). In qPCR assays BNA clamps could suppress amplification of WT by &gt;1,000-fold, while had little or no effects on the V600E mutant. Such BNA clamps allowed us to detect 1.0% or lower levels for the BRAF V600E mutant in a wild-type background. These results indicate that BNA clamp-based qPCR technology offers a new tool for rapid, sensitive detection of BRAF V600E mutation. The technology may be adapted for detection of mutations of a variety of biomarker genes.
Citation Format: Xiaoyun Liu, Leticia Loredo, Houquan Dai, Aaron Castro, Yuewei Zhao, Sung Kun Kim, Austin Dinkel, Miguel Castro. Sensitive detection of BRAF V600E mutation by bridged nucleic acid (BNA)-mediate real-time PCR assay. [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 411.
Abstract 4111: Imaging of colon cancer-cell mitosis within liver metastasis in nude mice
Authors: Hasegawa Kosuke , Suetsugu Atsushi , Nakamura Miki , Matsumoto Takuro , Aoki Hitomi , Kunisada Takahiro , Shimizu Masahito , Hoffman Robert M. 
Published: July 2016

Abstract
Colon cancer frequently results in metastasis to the liver, when it becomes the main cause of death. The tumor cell cycle in primary tumors and metastases are poorly understood. We developed a liver metastasis mouse model using a human colon cancer cell line (HCT-116), which expresses GFP in the nucleus and RFP in the cytoplasm (HCT-116-GFP-RFP). HCT-116 GFP-RFP (2.0 × 106) cells were injected in the spleen of a BALB/c nude mouse. The cells subsequently formed tumor colonies in the liver and retroperitoneum 28 days after cell transplantation. Using an Olympus FV1000 confocal microscope, mitosis of the dual-colored colon cancer cells could be clearly imaged in the liver and other metastases. Multi-nucleated cancer cells, in addition to a mononuclear cancer cells and their mitosis, were observed in the primary tumor and metastasis. Multi-nuclear cells were also observed in cell culture of HCT-116 GFP-RFP cells. Multi-nuclear HCT-116 cells may participate in the tumor growth in vivo. A significant difference in mitotic cells count in the primary tumor and metastasis was not observed.
Citation Format: Kosuke Hasegawa, Atsushi Suetsugu, Miki Nakamura, Takuro Matsumoto, Hitomi Aoki, Takahiro Kunisada, Masahito Shimizu, Robert M. Hoffman. Imaging of colon cancer-cell mitosis within liver metastasis in nude mice. [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 4111.
Abstract 4119: Inhibition of PORCN prolongs metastasis free survival in a mouse model of Ewing sarcoma
Authors: Hayashi Masanori , Baker Alissa C. , Goldstein Seth D. , Albert Catherine M. , Jackson Kyle W. , Loeb David M. 
Published: July 2016

Abstract
Metastatic disease is the most important factor in determining the survival of patients with Ewing sarcoma (ES). Although intensive cytotoxic chemotherapy has improved the survival of patients with localized disease, the survival rate for patients with metastatic disease remains dismal, and the most pressing unmet need in ES is to prevent and treat metastasis better. The Wnt signaling pathway is a key regulator of a number of cellular functions associated with metastasis, including proliferation, motility, and stem cell self-renewal. A single enzyme, Porcupine (Porcn), mediates post-translational palmitoylation of Wnt ligands, and it's activity is required for secretion of all 17 Wnt ligands, making it an attractive target for a pan-Wnt inhibitor. We have studied the effect of LGK974, a potent, selective, Porcn inhibitor, on Ewing sarcoma metastasis. In vitro, we have observed that LGK974 does not affect proliferation or sarcosphere formation, but inhibits migration of ES cell lines through the suppression of expression of multiple transcriptional regulators of Epithelial-Mesenchymal Transition (EMT). In our orthotopic implantation/amputation mouse model, single agent LGK974 treatment leads to significant delay in formation of lung metastasis following amputation of the affected leg, without a significant effect on primary tumor growth. This delay leads to a significant post-amputation survival benefit in multiple xenografts. In LGK974 treated xenografts, the expression of multiple EMT related transcription factors were observed to be suppressed. Furthermore, in tail vein injection models, LGK974 did not produce a survival benefit, suggesting that LGK974 effects Ewing sarcoma metastasis by inhibiting early steps in the metastatic cascade, such as migration and invasion. Our findings strongly implicate Wnt signaling in the early steps of ES metastasis and demonstrate that LGK974 has the potential to significantly improve the survival of ES patients through the specific inhibition of metastasis.
Citation Format: Masanori Hayashi, Alissa C. Baker, Seth D. Goldstein, Catherine M. Albert, Kyle W. Jackson, David M. Loeb. Inhibition of PORCN prolongs metastasis free survival in a mouse model of Ewing sarcoma. [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 4119.
Abstract 4120: c-Met inhibition blocks MEK-induced tumor cell invasion in uveal melanoma
Authors: Surriga Oliver , Smith Bryan D. , Ambrosini Grazia , Flynn Daniel L. , Carvajal Richard D. , Schwartz Gary K. 
Published: July 2016

Abstract
Uveal melanoma is the most common primary intraocular malignant tumor in adults. About half of patients with uveal melanoma will develop metastatic disease to the liver and the lung. These tumors are characterized by mutations in G-proteins (GNAQ and GNA11), activation of MAPK, and over-expression of c-Met. We have previously reported that c-Met inhibition inhibits tumor cell invasion and metastasis formation in uveal melanoma. Altiratinib is a selective inhibitor for c-Met as well as TIE2, VEGFR2 and TRK kinases. We found that this agent had no effect on inhibiting cell growth, consistent with our previous findings with crizotinib. However, it did inhibit invasion of uveal melanoma cells through matrigel in a concentration dependent fashion (25 nM to 250 nM) with inhibition of phospho-Met noted at concentrations as low as 25 nM. Selumetinib, a MEK inhibitor, is currently in clinical trial in patients with this disease. We found that treatment with 250 nM selumetinib inhibited cell proliferation but unexpectedly induced a marked increase in cell invasion of GNAQ and GNA11 mutant cell lines. This was associated with an increase in c-Met RNA and protein expression, as well as receptor phosphorylation, after 24 hours of selumetinib treatment. Combining selumetinib with altiratinib inhibited cell invasion to the level of altiratinib alone and continued to inhibit cell proliferation to the level of selumetinib alone. This effect was recapitulated by the knockdown of c-Met by siRNA prior to treatment with selumetinib. In a uveal melanoma xenograft model, the combination treatment of 15 mg/kg altiratinib and 25 mg/kg selumetinib significantly delayed tumor growth compared to vehicle control, altiratinib and selumetinib alone. Western blot analysis of tumor tissue confirmed target inhibition of p-Met and p-ERK in animals treated with altiratinib and selumetinib, respectively. Furthermore, tumor metastasis was inhibited by altiratinib, selumetinib and combination treatments in a uveal melanoma mouse model. These results indicate that the combined inhibition of MEK and c-Met by selumetinib and altiratinib, respectively, may be sufficient to suppress uveal melanoma tumor growth and metastasis. This strategy can potentially be used as therapy for patients with primary uveal melanoma who are at high risk for the development of metastatic disease.
Citation Format: Oliver Surriga, Bryan D. Smith, Grazia Ambrosini, Daniel L. Flynn, Richard D. Carvajal, Gary K. Schwartz. c-Met inhibition blocks MEK-induced tumor cell invasion in uveal melanoma. [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 4120.
Abstract 4128: Anti-angiogenic and anti-metastatic activities of juglone in pancreatic cancer cells
Authors: Karki Namrata , Greenway Frank , Hansel William , Aggarwal Sita , Losso Jack N. 
Published: July 2016

Abstract
Pancreatic cancer is the fourth leading cause of cancer related deaths in the US. The late diagnosis, early metastasis and poor survival rate make this disease lethal. This current study was designed to examine the effect of juglone, 5 hydroxy-1, 4-naphthoquinone in modulating the angiogenic and metastatic potential of pancreatic cancer cells in vitro, using the MIA Paca-2 human pancreatic cancer cell line. Juglone is a natural quinoid abundantly found abundantly in plants of Juglandacea family. To understand the anti-angiogenic and anti-metastatic properties of juglone, expression of markers related to angiogenesis were measured by Western blot or ELISA and the effect on ability of cancer cells to migrate and invade after treatment was analyzed by transwell invasion and migration assay, wound healing assay, and in vitro tube formation assay in human umbilical vein endothelial cells. The Akt pathway is highly upregulated and is responsible for the regulation of various biological processes in pancreatic cancer cells including proliferation, growth, survival and angiogenesis. Akt activation is also associated with regulation of key angiogenic markers such as, VEGF (Vascular Endothelial Growth Factor) and HIF-1 (Hypoxia Inducible Factor). Upon treatment of pancreatic cancer cells with juglone, reduced expression of serine-phosphorylated Akt expression was observed. Juglone inhibited metastasis of pancreatic cancer cells as indicated by the results of cell migration, invasion and wound healing assay. Juglone treatment also downregulated the levels of VEGF and HIF-1α. Significantly, it was found that juglone inhibited pancreatic cancer cell motility, migratory and invading capabilities. These findings suggest that Akt inhibitors such as juglone possess ability to attenuate the aggressiveness of pancreatic cancer cells and can be used as a novel anti-cancer agent to prevent metastasis of highly invasive pancreatic adenocarcinomas.
Citation Format: Namrata Karki, Frank Greenway, William Hansel, Sita Aggarwal, Jack N. Losso. Anti-angiogenic and anti-metastatic activities of juglone in pancreatic cancer 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 4128.
Abstract 4138: Immunological profile of metastatic or recurrent breast cancer patients
Authors: Imoto Shigeru , Ueno Takayuki , Isaka Hirotsugu , Ito Hiroki , Miyamoto Kaisuke , Chiba Tomohiro , Kamma Hiroshi 
Published: July 2016

Abstract
Background: We previously reported about immune suppression in breast cancer patients at this meeting. In brief, tumor tissue specimens and peripheral blood mononuclear cells (PBMC) were analyzed in 50 early or advanced breast cancer (BC) patients. To compare between 38 early and 12 advanced BC cases, CD163-positive tumor cells and CCR4-positive tumor cells were detected more frequently in advanced cases than in early cases. Regulatory T (Treg) cells in PBMC significantly increased in percentage of the population in 37 BC patients than in 21 healthy volunteers (AACR 2011). In addition, several cytokines were examined in that cohort and plasma IL-17A had significantly higher levels in early BC than in advanced BC (AACR 2013). Then, we examined their prognosis and immunological profile.
Patients and methods: Treg cells were examined by counting CD4+CD25highCD127low/-cells in PBMC with flow cytometry analysis. Immunohistochemical evaluation of tumor specimens was performed with monoclonal antibodies of HLA-ABC and DR, CD56, CD68, CD83, CD163 and CCR4. The number of stained cells was analyzed using a semiquantitative ordinal scale ranging from 0 to 3 (0, +/-, ++, +++). Human IL-2, IL-4, IL-6, IL-10, TNF, INFγ and IL-17A were measured using cytometric beads array system. Most patients received chemotherapy, hormonal therapy, and/or anti-HER2 therapy on the basis of intrinsic subtype and breast irradiation after breast-conserving surgery.
Results and discussions: At the median follow-up of 7 years after blood sample collection, only 2 operable patients relapsed and 3 patients including 2 cases of stage IV died of disease. Of 5 cases of stage IV or recurrent BC, CD163 and/or CCR4 were strongly stained positive in tumor cells. There were significant differences of staining intensity in CD163 and CCR4-positive tumor cells between those cases and the rest 45 cases (p&lt;0.01 at Chi-square test). However, other immune cell profiles, Treg cells in PBMC and cytokines in plasma had no trend between them. Several reports demonstrated that cancer patients with CD163-positive tumor-infiltrating macrophages and CD163-positive tumor cells had poor prognosis due to tumor-associated macrophage. Phenotypic macrophage traits in cancer cells, like CD163 expression, may be explained by heterotypic cell fusion between monocytes/macrophages and cancer cells.
Conclusion: Targeted therapy against M2 macrophage or CCR4 is considered as a promising strategy of advanced breast cancer.
Citation Format: Shigeru Imoto, Takayuki Ueno, Hirotsugu Isaka, Hiroki Ito, Kaisuke Miyamoto, Tomohiro Chiba, Hiroshi Kamma. Immunological profile of metastatic or recurrent breast cancer patients. [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 4138.
Abstract 4154: Neuropilin-1 expressing macrophages promote neuropilin-1 expression on lymphocytes by direct interaction and exert antitumor activity in HER2 positive breast cancer
Authors: Kawaguchi Kosuke , SUzuki Eiji , Inoue Masashi , Kii Isao , Karaoke Tatsuki R. , Hiram Masahiro , Iwaisako Keiko , Fengling Pu , Niche Mariko , Yamaguchi Ayane , Haga Hironori , Hagiwara Masatoshi , Toi Masakazu 
Published: July 2016

Abstract
Tumor-infiltrating immune cells (TIIs) in HER2+ breast cancer (BC) play an important role in treatment with anti-HER2 therapy. However, the precise mechanisms of how TIIs exert anti-tumor activity remain unclear. Neuropilin-1 (NRP-1) on macrophages regulates immune functions in various cancers and thus we explored the role of NRP-1 expressing macrophages in anti-tumor activity in HER2+ BC. We show that NRP-1 on macrophages regulated the migration of and chemokine secretion from macrophages in vitro. Furthermore, in vivo studies using a humanized mouse model showed that NRP-1 knockdown of macrophages in adoptively transferring peripheral blood mononuclear cells (PBMCs) suppressed anti-tumor activity and infiltration of CD45+ immune cells into tumors. Interestingly, NRP-1 expressing TIIs were mainly CD4+ T cells, despite little expression of NRP-1 on CD4+ T cells in PBMCs. We found that NRP-1 expression on CD4+ T cells was induced by NRP-1 transfer from macrophages to T cells. In HER2+ BC patients, NRP-1 expressing TIIs correlated with better clinical outcomes. These results demonstrate that NRP-1 expressing macrophages are key subsets of immune cells in trastuzumab-mediated anti-tumor activity and may predict better outcomes for HER2+ BC patients. In conclusion, NRP-1 expression is required for differentiation and activation of macrophages. NRP-1 expressing macrophages promote NRP-1 expression on CD4+ T cells by direct interaction and contribute to anti-tumor immune responses in HER2+ BC.
Citation Format: Kosuke Kawaguchi, Eiji SUzuki, Masashi Inoue, Isao Kii, Tatsuki R. Karaoke, Masahiro Hiram, Keiko Iwaisako, Pu Fengling, Mariko Niche, Ayane Yamaguchi, Hironori Haga, Masatoshi Hagiwara, Masakazu Toi. Neuropilin-1 expressing macrophages promote neuropilin-1 expression on lymphocytes by direct interaction and exert antitumor activity in HER2 positive breast 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 4154.
Abstract 4161: Bortezomib enhances expression of effector molecules in antitumor CD8+ T lymphocytes by modulating Notch-NF-kB-miR-155 crosstalk
Authors: Renrick Ariana N. , Thounaojam Menaka C. , Dudimah Duafalia F. , Thomas Portia , Pellom Samuel T. , Uzhachenko Roman V. , Shanker Anil 
Published: July 2016

Abstract
The immunosuppressive tumor microenvironment usurps host antitumor immunity by multiple mechanisms including interference with the Notch system, which is important for various metazoan cell fate decisions and hematopoietic cell differentiation and function. We observed that treatment with the proteasome inhibitor bortezomib in mice bearing various solid tumors resulted in an upregulated expression of various Notch signaling components in lymphoid tissues, thereby increasing CD8+T-lymphocyte IFNγ secretion and expression of effector molecules, perforin and granzyme B, as well as the T-box transcription factor eomesodermin. Bortezomib also neutralized TGFβ-mediated suppression of IFNγ and granzyme B expression in activated CD8+T-cells. Of note, bortezomib reversed tumor-induced downregulation of Notch receptors, Notch1 and Notch2, as well as increased the levels of cleaved Notch intracellular domain (NICD) and downstream targets Hes1 and Hey1 in tumor-draining CD8+T-cells. Moreover, bortezomib promoted CD8+T-cell nuclear factor-κB (NF-κB) activity by increasing the total and phosphorylated levels of the IκB kinase and IκBα as well as the cytoplasmic and nuclear levels of phosphorylated p65. Even when we blocked NFκB activity by Bay-11-7082, or NICD cleavage by γ-secretase inhibitor, bortezomib significantly increased expression of Notch Hes1 and Hey1 genes as well as perforin, granzyme B and eomesodermin in activated CD8+T-cells. Data suggest that bortezomib can rescue tumor-induced dysfunction of CD8+T-cells by its intrinsic stimulatory effects promoting NICD-NFκB crosstalk. We are also elucidating components of microRNA regulation affecting NICD-NFκB crosstalk. Our preliminary data suggest that miR-155 plays a role in bortezomib-induced regulation of T cell function. These findings provide novel insights on using bortezomib not only as an agent to sensitize tumors to cell death, but also to provide lymphocyte-stimulatory effects, thereby overcoming immunosuppressive actions of tumor on anti-tumor T-cell functions.
Citation Format: Ariana N. Renrick, Menaka C. Thounaojam, Duafalia F. Dudimah, Portia Thomas, Samuel T. Pellom, Roman V. Uzhachenko, Anil Shanker. Bortezomib enhances expression of effector molecules in antitumor CD8+ T lymphocytes by modulating Notch-NF-kB-miR-155 crosstalk. [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 4161.