bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1075: Molecular determinants of colon and renal cancers' immune contextures
Authors: Becht Etienne , Giraldo Nicolas A. , Remark Romain , Reynies Aurelien de , Lacroix Laetitia , Damotte Diane , Sautès-Fridman Catherine , Fridman Wolf-Herman 
Published: May 2015

Abstract
In the vast majority of cancer types, as demonstrated and exemplified in colorectal cancer (CRC), a high density of CD8+ T cells in the tumor microenvironment correlates with a good prognosis for the patient. However, an opposite correlation has been reported in primary clear cell renal cell carcinoma (RCC) tumors. Our team studied the immune infiltrates of pulmonary metastases from CRC and RCC. We reported that despite the advanced stage of the disease in these patients, the immune infiltrate of pulmonary metastases remained a prognostic factor. As in the primary tumors, a high density of CD8+ T cells correlated with good prognosis for CRC metastases while it correlated with a bad prognosis for RCC metastases. These results suggest that the identity of the tumor cell is critical in shaping the immune contexture of a given tumor. We therefore investigated the molecular characteristics of the tumor cells which could be responsible for this opposite clinical impact in RCC versus CRC. First, we assessed the prognostic value associated with the expression of genes specific for different immune populations in several cohorts of primary CRC (n=177) and RCC tumors (n=72 and n=479), and confirmed the opposite impact of infiltrating lymphocyte densities on patient survival. In addition, RCC tumors showed a higher expression of genes related to inflammation, immunosuppression and angiogenesis. By comparing transcriptomic data from RCC and CRC cell lines, we observed that RCC tumor cells also expressed a significantly higher amount of these transcripts when compared to CRC tumor cells. Altogether, these results support the hypothesis that RCC malignant cells produce factors which are able to modify and determine the functional orientation of their immune microenvironment. Identifying which factors and pathways are critical for the RCC-related detrimental impact of CD8+ T cells on prognosis will be a major breakthrough, enabling the identification of new immunomodulatory drug targets and guide researchers and clinicians in immunotherapy protocols.
Citation Format: Etienne Becht, Nicolas A. Giraldo, Romain Remark, Aurelien de Reynies, Laetitia Lacroix, Diane Damotte, Catherine Sautès-Fridman, Wolf-Herman Fridman. Molecular determinants of colon and renal cancers' immune contextures. [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 1075. doi:10.1158/1538-7445.AM2014-1075
Abstract 1078: Cancer-associated fibroblasts promote endometrial cancer cell proliferation in vitro and in vivo
Authors: Chung Ivy , Subramaniam Kavita S. , Tham Seng Tian , Mohamed Zahurin , Adenan Noor Azmi Mat , Woo Yin Ling 
Published: May 2015

Abstract
Cancer-associated fibroblasts (CAFs) recently demonstrated tumor-promoting roles in various cancer types, yet their implication in endometrial cancer (EC) has not been fully explored. We isolated fibroblasts (CAFs) and its epithelial counterpart from human EC tissues using CD90- and CD326-antibodies conjugated magnetic beads, respectively. We collected CAFs secretion by concentrating spent supernatants from cells growing in media containing 2% fetal bovine serum. Both human EC cell lines and primary EC epithelial cells showed increased cell proliferation in a dose-dependent manner, following treatment with CAFs secretion. This was in contrast to the growth inhibitory effects shown with secretions from normal endometrial fibroblasts. EC cells also demonstrated increased cell motility and invasiveness in response to CAFs secretion. Using cytokine array and ELISA, we further identified several cytokines which were overexpressed in CAFs compared to normal endometrial fibroblasts: macrophage chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), growth regulated oncogene (GRO), regulated on activation, normal T cell expressed and secreted (RANTES) and vascular endothelial growth factor (VEGF). These cytokines may activate MAPK/Erk and/or PI3K/Akt pathways to promote EC cell proliferation, as shown by immunoblotting and ELISA. Indeed, CAFs-mediated EC proliferation was suppressed independently by specific inhibitors for PI3K/Akt (LY294002) and MAPK/Erk (U0126). To determine if CAFs promote EC tumor proliferation in vivo, we inoculated fluorescently labeled-epithelial cell and CAFs subcutaneously at the flank of nude mice in the ratio of 1:2 and 1:4. Tumor sizes were measured twice a week using calipers and monitored weekly using in vivo imaging. Inoculation of CAFs and normal fibroblasts alone did not induce any tumor growth; however, co-injection of EC with CAFs (1:4) showed approximately 3 times higher growth rate when compared to EC alone. More interestingly, there was no sign of tumor growth in mice inoculated with combination of EC and normal fibroblasts (1:4) at the end of experiment. Taken together, our data suggests that CAFs exert tumor-promoting effects both in vitro and in vivo partly via specific cytokines-mediated activation of MAPK/Erk and PI3K/Akt pathways. Delineating the roles of CAFs in EC tumor microenvironment may provide potential therapeutic targets for the treatment of EC.
Citation Format: Ivy Chung, Kavita S. Subramaniam, Seng Tian Tham, Zahurin Mohamed, Noor Azmi Mat Adenan, Yin Ling Woo. Cancer-associated fibroblasts promote endometrial cancer cell proliferation in vitro and in vivo. [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 1078. doi:10.1158/1538-7445.AM2014-1078
Abstract 1079: COX-2 blockade immunologically suppresses brain metastasis of lung cancer
Authors: Fujita Mitsugu , Nakata Susumu , Okuda Takeshi , Kato Amami , Yoshie Osamu 
Published: May 2015

Abstract
Epidemiological studies have highlighted associations between the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) and reduced cancer risks in human. In addition, NSAIDs reduce VEGF-D production levels, which in turn inhibit lymphatic vessel dilation and eventually cancer metastasis. Most NSAIDs function as cyclooxygenase-2 (COX-2) inhibitors that prevent the production of prostaglandin E2 (PGE2). The PGE2 induces myeloid-derived suppressor cells (MDSCs) in the bone marrow of cancer-bearing hosts, which is known to be responsible for T-cell suppression in chronic inflammation. Based on these findings, we hypothesized that COX-2 blockade would suppress brain metastasis of cancers by inhibiting MDSC development and their chemokine-mediated accumulation in the tumor microenvironment (TME). In both mouse and human brain metastasis cases, the expression levels of COX-2 and CCL2, a chemokine primarily attracting MDSCs, were increased in the brain tumor tissues compared with normal brain or peripheral bloods. Concomitantly, the infiltration of MDSCs (CD11+Gr-1+ for mice and CD14-CD15+HLA-DRlow for human, respectively) was observed at high levels in the tumor tissues. In the mouse brain tumor models using LL/2 murine lung cancer cell line, treatment with NSAIDs inhibited the PGE2 production levels and the formation of brain metastases. Furthermore, the NSAID treatment reduced the CCL2 in the TME, which was associated with a reduction in Ly6ChighLy6Glow monocytic and Ly6ClowLy6Ghigh granulocytic MDSCs in both the bone marrow and the TME. Mice genetically deficient for CCR2, a receptor for CCL2, exhibited low penetration of brain metastases along with reduced infiltration of MDSCs. Collectively, our findings show that the COX-2 pathway promotes brain metastases of lung cancers by supporting systemic development of MDSC and their accumulation in the TME mediated by the CCL2-CCR2 chemokine axis.
Citation Format: Mitsugu Fujita, Susumu Nakata, Takeshi Okuda, Amami Kato, Osamu Yoshie. COX-2 blockade immunologically suppresses brain metastasis of lung 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 1079. doi:10.1158/1538-7445.AM2014-1079
Abstract 11: Absence of TGFBI favors tumor angiogenesis
Authors: Seo Jun-Young , Jung Hae Uk , Son Hye-Nam , Kim Soyoun , Jun Eunsung , Nam Ju-Ock , Kim Jung-Eun , Kim In-San 
Published: May 2015

Abstract
TGFBI, a circulating extracellular matrix protein, modulates several integrin-mediated cellular functions. The protein contains an N-terminal EMI domain, four consecutive FAS1 domains, and the RGD motif in the C-terminal domain. The fourth FAS1 domain of TGFBI exerts anti-angiogenic activity through interactions with αvβ3 integrin. Here, we used TGFBI-deficient mice and TGFBI transgenic mice to investigate the role of TGFBI in tumor growth in vivo. The absence of TGFBI led to enhanced tumor angiogenesis and a 3.6-fold increase in tumor growth. In contrast, a 1.7-fold increase in circulating levels of TGFBI in TGFBI transgenic mice induced a 2.4-fold decrease in tumor growth. We found that the binding affinity (Kd) of TGFBI for αvβ3 integrin was approximately 3.8 × 10 8 M, a value ∼2300-fold higher than that of a single FAS1 domain, and demonstrated that this greater affinity was due to the cooperative action of four FAS1 domains and the RGD motif. Moreover, TGFBI exhibited potent anti-angiogenic and anti-tumorigenic activities and specifically targeted the tumor vasculature and accumulated at the tumor site. Collectively, our results support the theory that TGFBI acts as a potent endogenous anti-tumor and anti-angiogenic molecule by targeting αvβ3 integrin, and highlight the importance of physiological circulating TGFBI levels in inhibiting tumor growth.
Citation Format: Jun-Young Seo, Hae Uk Jung, Hye-Nam Son, Soyoun Kim, Eunsung Jun, Ju-Ock Nam, Jung-Eun Kim, In-San Kim. Absence of TGFBI favors tumor angiogenesis. [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 11. doi:10.1158/1538-7445.AM2014-11
Abstract 1103: MDSC targeting therapy for uterine cervical cancer displaying TRL
Authors: Matsumoto Yuri , Kawano Mahiru , Sasano Tomoyuki , Mabuchi Seiji 
Published: May 2015

Abstract
Objectives: The aim of this study was to investigate the clinical implications and underlying mechanism of tumor-related-leukocytosis (TRL) in cervical cancer. Methods: The clinical data of cervical cancer patients who were treated with definitive radiotherapy were analyzed to investigate the association between TRL and treatment outcome in retrospective and prospective settings. Clinical samples, cervical cancer cell lines, and a mouse model of cervical cancer were employed to examine the mechanisms responsible for TRL in cervical cancer, focusing on the myeloid-derived suppressor cell (MDSC) and tumor-derived granulocyte colony-stimulating factor(G-CSF). Results: TRL was significantly associated with shorter survival. The TRL-positive patients displayed upregulated tumor G-CSF expression and elevated serum G-CSF levels and increased MDSC frequencies in the blood compared with the TRL-negative patients. In vitro and in vivo investigations revealed that tumor-derived G-CSF is involved in the underlying causative mechanism of TRL and that the increase in the number of MDSC induced by tumor-derived G-CSF is responsible for the rapidly progressive nature of TRL-positive cervical cancer. The administration of anti-Gr-1 antibody or the depletion of MDSC by splenectomy significantly inhibited tumor growth in TRL-positive cervical cancer. Conclusion: TRL is an indicator of a poor prognosis in cervical cancer patients treated with definitive radiotherapy. MDSC induced by tumor-derived G-CSF is responsible for the rapidly progressive nature of TRL-positive cervical cancer. MDSC-targeting treatments might have therapeutic potential in TRL-positive cervical cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Yuri Matsumoto, Mahiru Kawano, Tomoyuki Sasano, Seiji Mabuchi. MDSC targeting therapy for uterine cervical cancer displaying TRL. [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 1103. doi:10.1158/1538-7445.AM2014-1103
Abstract 1110: Colorectal liver metastases induce a systemic phase shift of the biological clock
Authors: Huisman Sander A. , Tamanini F. , Ahmadi A. , IJzermans J.N.M. , Horst G.T.J. van der , Bruin R.W.F. de 
Published: May 2015

Abstract
Circadian clock genes drive cyclic expression of 10-15% of the transcriptome. Disruption of the circadian clock may deregulate the cell's normal functions and can lead to carcinogenesis, indicating that clock genes also act as tumor suppressor genes. In previous work, we have shown that circadian rhythmicity is disrupted in C26 colon carcinoma cell-derived hepatic metastases, as compared to the non-cancerous tissue of the liver. It has been suggested that neoplastic tissue can influence the circadian clock of adjacent tissues, causing a tissue specific phase shift. A better understanding of how tumors affect the circadian system may help elucidate the role of the clock in cancer patients suffering from fatigue and sleep disorders. Therefore, we have examined the circadian clock in liver and kidney tissue of mice carrying hepatic C26 colon carcinoma cell metastases.
Male BALB/c mice were divided into two groups. In group 1, hepatic metastases were induced by injecting C26 colorectal carcinoma cells into the spleen. Group 2 was sham operated. Three weeks after (sham) surgery, animals were sacrificed over a 24-hour period (6 time points, n=4 per time point) and liver and kidneys were collected to compare circadian rhythmicity in control and tumor bearing animals. RNA was isolated and qRT-PCR was performed to determine the expression levels of 5 clock genes (Rev-Erbα, Per1, Per2, Bmal1, Cry1) and 3 clock controlled genes (Dbp, p21 and Wee1).
Liver and kidney tissue of healthy control mice showed normal 24-hour oscillations of all clock genes, consistent with normal circadian rhythmicity. Liver and kidney tissue of tumor-bearing mice, as compared to control mice, showed a marked phase difference in clock rhythms. In the liver we observed a 4-hour phase advance for Bmal1, Rev-Erbα and Dbp. In contrast in the kidney, there was a 4-hour phase delay for Bmal1, Rev-Erbα, Cry1 and DBP, and a 8 hour delay for Per2.
These data show that colorectal liver metastases induce a phase advance in the liver, and a phase delay in the kidney . This suggests a systemic effect of the tumor on peripheral clocks. This difference in clock phase between tumor-bearing mice and healthy controls may provide new clues to further understand the role of the clock for fatigue and sleep problems in cancer patients, but may also give opportunities to administer chemotherapeutic treatment in a chronotherapeutical setting .
Citation Format: Sander A. Huisman, F. Tamanini, A. Ahmadi, J.N.M. IJzermans, G.T.J. van der Horst, R.W.F. de Bruin. Colorectal liver metastases induce a systemic phase shift of the biological clock. [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 1110. doi:10.1158/1538-7445.AM2014-1110
Abstract 1112: Role of osteoprotegerin in inflammatory and invasive breast cancer
Authors: Goswami Sudeshna , SHARMA-WALIA NEELAM 
Published: May 2015

Abstract
Inflammatory breast cancer (IBC) is a highly aggressive and angioinvasive form of breast cancer associated with a high incidence of early nodal and systemic metastasis. A proactive, complex and dynamic tumor microenvironment of IBC adds to the grim scenario of the disease by accumulating inflammatory and angiogenic growth factors and creating a niche for the growth and metastasis of tumor cells. The secretions from the primary inflammatory ductal carcinoma of the breast (SUM149PT), and highly invasive ductal carcinoma cells (SUM1315MO2) secrete unusually high levels of osteoprotegerin (OPG) as compared to those obtained from the primary human mammary epithelial cells (HMEC). OPG, which plays a pivotal role in bone remodeling by regulating osteoclast formation, is a multifaceted molecule, and has been found to be involved in multiple myeloma and prostate cancers. This prompted us to examine the role of OPG in the aggressive breast cancers, which has not been deciphered till date. For a better understanding of the OPG functions, apart from using adherent cells, we used in vitro ‘sphere culture’ as our working model. We studied the functional significance of OPG in aggressive breast cancer biology by utilizing well standardized techniques such as OPG staining (immunohistochemistry, immunofluorescence), OPG secretion (ELISA), angiogenesis (in vitro tube formation), proliferation (MTT), and cell cycle/aneuploidy analysis (PI staining). We demonstrated that (1) OPG secretion as well as protein level is upregulated in IBC (SUM149PT) and highly Invasive ductal carcinoma cells (SUM1315MO2), and their spheres compared to those of normal human mammary epithelial (HMEC); (2) OPG stained specifically in patient breast cancer tissue samples when compared to the uninvolved tissue from the same patient; (3) OPG rich secretions from IBC and highly invasive breast cancer were highly angiogenic; (4) OPG enriched culture medium induced proliferation of the control HMEC spheres; (5) the presence of OPG triggered the onset of aneuploidy in the control HMEC adherent cells as well as spheres. The functional studies showing the biological significance of OPG (i,e its effect on proliferation, angiogenesis, and aneuploidy) were confirmed using recombinant human OPG and OPG rich/depleted medium obtained from breast cancer cells. Overall our studies highlight the link between OPG and aneuploidy in aggressive breast cancer cells, and opens up avenues for new therapeutic targets for treating IBC.
Citation Format: Sudeshna Goswami, NEELAM SHARMA-WALIA. Role of osteoprotegerin in inflammatory and invasive 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 1112. doi:10.1158/1538-7445.AM2014-1112
Abstract 1117: Platelet interaction induces Tissue Factor and a pro-metastatic phenotype in ovarian cancer cells
Authors: Orellana Renan F. , Oliva Barbara , Kato Sumie , Bravo Loreto , Gonzalez Pamela , Panes Olga , Mezzano Diego , Cuello Mauricio , Owen Gareth 
Published: May 2015

Abstract
Introduction: An increase in circulating platelets, or thrombocytosis, is recognized as an independent risk factor correlated with bad prognosis and metastasis, however the exact role that platelets play in tumor progression has not been fully elucidated. The expression of Tissue Factor (TF) protein by cancer cells has been shown to correlate with Hypercoagulable state and metastasis. It is speculated that cancer cells need to acquire a “Metastasis Initiating Cell (MIC)” phenotype. To achieve this, cells may suffer an Epithelial to Mesenchymal Transition (EMT) coupled with stem-like protein expression in which E-cadherin is lowered, while CD44 and N-cadherin are increased. Ovarian cancer patients develop ascitis, a build up of peritoneal fluid that contains cancerous and serum derived cells. After the surgical removal of the primary and visible tumors, these ascitic borne cells form peritoneal tumors and thus make a good model to study platelet/cancer cells interaction in metastasis. The aim of this work was determine the effect of platelet-cancer cell interaction on TF and EMT marker levels and cancer cell migration in ascites-derived cancer cells. Material and Methods: Ovarian ascitic-isolated cancer cells and cell lines were co-cultivated with human washed platelets (from healthy donors). TF and EMT marker levels were determined by Western blotting. Cancer cell migration was determined by Boyden chambers and the scratch assay. Results: The co-culture of ovarian cancer cells with platelets causes: 1) a phenotypic change in cancer cells, 2) increases TF protein levels and activity, 3) induces EMT markers, 3) promotes chemoattraction and cancer cell migration. Conclusion: We present evidence that platelet-cancer cell interaction promotes a Metastasis Initiating Cell phenotype and enhanced migration. We speculate that platelet-cancer cell interaction may promote the formation of metastatic foci worsening the patient prognosis.
Fundings: FONDECYT 1120292, 3120003, 1100870, CORFO 13IDL2-18608, BMRC 13CTI-21526-P6
Citation Format: Renan F. Orellana, Barbara Oliva, Sumie Kato, Loreto Bravo, Pamela Gonzalez, Olga Panes, Diego Mezzano, Mauricio Cuello, Gareth Owen. Platelet interaction induces Tissue Factor and a pro-metastatic phenotype in ovarian cancer 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 1117. doi:10.1158/1538-7445.AM2014-1117