bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 411: 1,25(OH)2D3 deficiency accelerates colon cancer progression via microenvironmental regulation
Authors: Yuan Xiaoqin , Liu Yun , Chen Lulu , Miao Dengshun 
Published: August 2015

Abstract
Epidemiologic studies have revealed that low serum vitamin D levels are associated with an increased risk of colon cancer and inflammatory diseases such as inflammatory bowel disease (IBD) while underlying biological mechanisms remain largely unknown. It is also well established that tumor microenvironment plays an essential role in tumor progression. In this study, we sought to determine whether 1,25(OH)2D3 deficiency has a direct impact on colon cancer by using 25-hydroxyvitamin D 1-hydroxylase knockout [1α(OH)ase−/−] mice that had been fed with a rescue diet (high calcium, phosphate and lactose) from weaning. We injected CT26.WT cells (a murine colon cancer cell line) into 1α(OH)ase−/- and wild-type (WT) mice repectively and found that 1,25(OH)2D3 deficiency accelerated the growth of xenografted colon tumors. In the AOM/DSS model, heterozygous 1α(OH)ase+/− mice increased the multiplicity and size of colon tumors. Compared to WT mice, 1α(OH)ase−/− mice exhibited an increase of DNA damage, cellular senescence and the production of senescence-associated inflammatory cytokines in their colon stromal cells. These results suggest that 1,25(OH)2D3 deficiency may have a direct effect on colon cancer development, at least in part, by influencing tumor microenvironment.
Note: This abstract was not presented at the meeting.
Citation Format: Xiaoqin Yuan, Yun Liu, Lulu Chen, Dengshun Miao. 1,25(OH)2D3 deficiency accelerates colon cancer progression via microenvironmental regulation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 411. doi:10.1158/1538-7445.AM2015-411
Abstract 4112: Mechanisms of transendothelial migration by invasive breast carcinoma cells from patients
Authors: Pignatelli Jeanine , Jones Joan , Chen Xiaoming , Smith Bryan , Flynn Daniel , Condeelis John , Oktay Maja 
Published: August 2015

Abstract
The majority of breast cancer related deaths are not due to the primary tumor, but rather to the dissemination of metastatic tumor cells from it to distant sites. Our lab has previously identified the tumor microenvironment of metastasis (TMEM) in mouse and human mammary tumors, sites where transendothelial migration, intravasation and dissemination occur. The constituent cells of TMEM are an endothelial cell, a perivascular TIE2-expressing macrophage (TEM) and an invasive Mena-over expressing tumor cell in direct contact. TMEM are present in human invasive breast tumors and the density of TMEM is positively associated with the risk of developing metastases.
Using invasive ductal carcinoma cells of the breast obtained from patients by fine needle aspiration (FNA), we demonstrated that intravasation-directed transendothelial migration (iTEM) of these cancer cells requires macrophages and, depending on clinical subtype, involves either paracrine (macrophage CSF1-R; tumor cell EGFR), or both paracrine and autocrine (tumor cell EGFR + CSF1-R) signaling. Compared to the total population of primary breast cancer cells assayed, cells capable of transendothelial migration expressed relatively high MenaINV and low Mena11a levels, independently of clinical subtype. MenaINV and Mena11a are functionally distinct isoforms of Mena, a key regulator of motility and invasion. Depletion of MenaINV using siRNA showed that MenaINV is required for efficient macrophage-dependent iTEM of tumor cells. Furthermore, relative MenaINV expression correlated with the density of TMEM, which were previously shown to correlate with risk of metastasis in patients. From these observations we have identified the signaling pathways involved in macrophage-dependent tumor cell iTEM. Two novel small molecule inhibitors, Rebastinib (Tie2 inhibitor) and Altiratinib (c-MET inhibitor), have been identified that show great promise in preventing key steps in iTEM.
Our data reveal targetable signaling events required for transendothelial migration of human breast cancer cells, and indicate that relative MenaINV levels and TMEM frequency are correlated prognostic markers of metastasis and therapeutic targets for most human breast cancers.
Citation Format: Jeanine Pignatelli, Joan Jones, Xiaoming Chen, Bryan Smith, Daniel Flynn, John Condeelis, Maja Oktay. Mechanisms of transendothelial migration by invasive breast carcinoma cells from patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4112. doi:10.1158/1538-7445.AM2015-4112
Abstract 4117: Syk is a candidate kinase target for the treatment of advanced prostate cancer
Authors: Danen Erik 
Published: August 2015

Abstract
Improved targeted therapies are needed to combat metastatic prostate cancer. Here we report the identification of the spleen kinase SYK as a mediator of metastatic dissemination in zebrafish and mouse xenograft models of human prostate cancer. While SYK has not been implicated previously in this disease, we found that its expression is upregulated in human prostate cancers and associated with malignant progression. RNAi-mediated silencing prevented invasive outgrowth in vitro and bone colonization in vivo, effects that were reversed by wild-type but not kinase-dead SYK expression. In the absence of SYK expression, cell surface levels of the progression-associated adhesion receptors integrin α2β1 and CD44 were diminished. RNAi-mediated silencing of α2β1 phenocopied SYK depletion in vitro and in vivo, suggesting an effector role for α2β1 in this setting. Notably, pharmacological inhibitors of SYK kinase currently in Phase I-II trials for other indications interfered similarly with the invasive growth and dissemination of prostate cancer cells. Our findings offer a mechanistic rationale to reposition SYK kinase inhibitors for evaluation in patients with metastatic prostate cancer.
Citation Format: Erik Danen. Syk is a candidate kinase target for the treatment of advanced prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4117. doi:10.1158/1538-7445.AM2015-4117
Abstract 412: Phytochemical pterostilbene suppresses lung cancer stem cell generation via modulating tumor-associated macrophages
Authors: Huang Wen-Chien 
Published: August 2015

Abstract
Tumor associated macrophages have been shown to play key roles in tumor progression in different cancer types including lung. Here we investigated the role of M2-tumor associated macrophages (TAMs) in the generation of lung cancer stem cells (LCSCs) and the potential of modulating TAMs to inhibit the generation of LCSCs. Elevated Muc1 expression has been reported in inflammatory lung macrophages and associated with lung cancer development. We first found that Muc1 is overexpressed in lung cancer patients and associated with poor survival rates from public database; importantly, we showed that when co-cultured with TAMs, the level of Muc1 along with stemness genes significantly increased in lung cancer cells. Pterostilbene dose-dependently suppressed self-renewal ability in TAMs-cocultured lung cancer cells via downregulating Muc1, NF-kB, CD133, β-catenin and Sox2 expression. Subsequently, we demonstrated Muc1-silenced TAMs exhibited a significantly lower ability to promote the generation of LCSCs and a decreased level of NF-kB, CD133 and Sox2. Collectively, we demonstrated that Muc1 played an important role in TAMs-induced LCSC generation and pterostilbene treatment inhibited this phenomenon. Modulation of TAMs using pterostilbene may be of future clinical use for treating lung cancer patients.
Note: This abstract was not presented at the meeting.
Citation Format: Wen-Chien Huang. Phytochemical pterostilbene suppresses lung cancer stem cell generation via modulating tumor-associated macrophages. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 412. doi:10.1158/1538-7445.AM2015-412
Abstract 4124: Potent anti-tumor and metastatic breast cancer efficacy of bevacizumab with CRLX101, an investigational chemotherapy nanoparticle-drug conjugate that secondarily suppresses HIF-1α
Authors: Pham Elizabeth , Lee Christina R. , Xu Ping , Man Shan , Yin Melissa , Foster F. Stuart , Peters Christian G. , Lazarus Douglas , Eliasof Scott , Kerbel Robert S. 
Published: August 2015

Abstract
Despite the approval of seven different VEGF-pathway targeting agents, such as bevacizumab, for ten different cancer types, VEGF inhibition has shown only modest survival benefits - especially in breast cancer. One hypothesis for this is the adaptive resistance that emerges, such as increased tumor hypoxia and elevated hypoxia-inducible factor 1α (HIF-1α), which up-regulates genes causing tumor angiogenesis, resistance and metastasis. Here we evaluated bevacizumab paired with a potent cytotoxic investigational drug called CRLX101, a nanoparticle-drug conjugate containing the payload camptothecin that secondarily suppresses HIF-1α. In a preclinical mouse model of primary human breast tumor xenografts grown in the mammary fat pad after cell-line implantation, CRLX101 monotherapy was highly efficacious. More importantly, CRLX101 with bevacizumab resulted in dramatic primary tumor shrinkages and greatly improved mice survival, despite bevacizumab alone having no activity in this model. This potent anti-tumor efficacy was further confirmed in a patient-derived xenograft (PDX) model, where again CRLX101 and bevacizumab led to obvious shrinkage of established primary tumors. HIF-1α suppression was confirmed by immunohistochemistry while changes in tumor hypoxia and perfusion were evaluated using photoacoustic imaging and contrast-enhanced ultrasound, respectively. To better reflect the clinical treatment setting, the combination was next evaluated in our preclinical model of post-surgical, overt metastatic disease. Both CRLX101 monotherapy and CRLX101 in combination with bevacizumab showed shrinkage of existing metastatic masses and prevented the emergence of new metastases. In conclusion, we showed that pairing an anti-angiogenic agent with a potent chemotherapy backbone that is able to suppress HIF-1α up-regulation induced by anti-angiogenic therapy greatly improve efficacy in both primary and metastatic breast cancer models. The data from these preclinical experiments demonstrate that further research of the combination of bevacizumab and other anti-angiogenic drugs with CRLX101 is warranted in solid tumors.
Citation Format: Elizabeth Pham, Christina R. Lee, Ping Xu, Shan Man, Melissa Yin, F. Stuart Foster, Christian G. Peters, Douglas Lazarus, Scott Eliasof, Robert S. Kerbel. Potent anti-tumor and metastatic breast cancer efficacy of bevacizumab with CRLX101, an investigational chemotherapy nanoparticle-drug conjugate that secondarily suppresses HIF-1α. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4124. doi:10.1158/1538-7445.AM2015-4124
Abstract 4141: Hypoxia-induced transition from collective to amoeboid single cell dissemination in epithelial cancer cells
Authors: Lehmann Steffi , te Boekhorst Veronika A M , Odenthal Julia , Jiang Liying , van Helvert Sjoerd , Friedl Peter 
Published: August 2015

Abstract
Tumor hypoxia, by elevating hypoxia-inducible factors (HIFs), is an established inducer of epithelial-to-mesenchymal transition (EMT) and subsequent cancer cell invasion and metastasis. Using epithelial carcinoma spheroids in 3D fibrillar collagen, we characterized the invasion patterns as well as cellular and molecular mechanisms of hypoxia-induced cancer cell migration modes. While epithelial cancer cells show collective invasion under normoxic conditions, hypoxia or pharmacological stabilization of HIF-1 using the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG) induced EMT-like detachment and migration of single cells. Besides mesenchymal movement, most epithelial cells converted to amoeboid migration with characteristic actin-rich filopodal or distinctive blebby protrusions towards the direction of migration. Whereas mesenchymal migrating cells moved with low velocities in a directionally persistent manner, amoeboid migrating cells generated a broad spectrum of low to high velocities, but with less persistent invasion paths. Sub-cellular molecular analysis showed typical amoeboid features particularly in hypoxic blebby single cell migration, including low to lacking collagen degradation along the migration path and insensitivity to broad-spectrum matrix metalloproteinase (MMP)-inhibitor GM6001, non-focalized cortical actin cytoskeleton within blebs that interacted with collagen structures and low-beta1 integrin expression with lack of integrin focalization. Thus, tumor hypoxia induces a diversity of single-cancer cell invasion modes, including blebby amoeboid migration, thereby enhancing predominantly MMP- and integrin-independent amoeboid dissemination in parallel to EMT induction.
Citation Format: Steffi Lehmann, Veronika A M te Boekhorst, Julia Odenthal, Liying Jiang, Sjoerd van Helvert, Peter Friedl. Hypoxia-induced transition from collective to amoeboid single cell dissemination in epithelial cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4141. doi:10.1158/1538-7445.AM2015-4141
Abstract 4166: Targeting NF-κB by the curcumin and its analogs EF-31 and UBS-109 decreases growth and angiogenesis of colon cancer
Authors: Nagaraju Ganji Purnachandra , Shoji Mamoru , Rayes Bassel El 
Published: August 2015

Abstract
Purpose/Objective:
NF-κB plays an essential role in cancer cell growth and metastasis by stimulating angiogenesis. Curcumin decreases the activity of several oncogenic transcriptional factors including NF-κB and HIF-1α, thus we investigated whether curcumin and its analogs EF-31 and UBS-109, could disrupt angiogenesis using colorectal cancer cells (CRC).
Methods:
HCT-116 and HT-29 cells were used in these experiments. HUVEC tube formation assay, Matrigel plug assay, Western blotting, and VEGF activity assay were carried out to determine the curcumin, EF-31 and UBS-109 role in angiogenesis. A subcutaneous xenograft mouse model was used to evaluate the in vivo effects of curcumin analogues.
Results:
Conditioned medium from HCT-116 or H-T29 cells exposed to curcumin, EF-31 and UBS-109 in vitro significantly blocked HUVEC tube assembly in comparison to control. In vivo, EF-31 and UBS-109 blocked the vascularization of subcutaneous matrigel plugs and the growth of CRC xenografts. We observed significant inhibition of VEGF synthesis and secretion in both colon cell lines treated with curcumin, EF-31 and UBS-109 in concert with the loss of HIF-1α expression, of which transcriptionally regulated by NF-κB. Similar effects were observed in tumors from animals treated with EF-31 and UBS-109. Further, EF-31 and UBS-109 treatment significantly decreased the tumor growth compared to untreated tumors. These results suggesting that curcumin, EF-31 and UBS-109 inhibits VEGF production in part through the degradation of HIF-1α and increased the cytoplasmic accumulation of NF-κB.
Conclusion:
Taken together, destabilization of HIF-1α and inhibition of NF-κB from cytoplasm to nuclear translocation may be important contributing factors to the antiangiogenic action of curcumin, EF-31 and UBS-109 in CRC.
Note: This abstract was not presented at the meeting.
Citation Format: Ganji Purnachandra Nagaraju, Mamoru Shoji, Bassel El Rayes. Targeting NF-κB by the curcumin and its analogs EF-31 and UBS-109 decreases growth and angiogenesis of colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4166. doi:10.1158/1538-7445.AM2015-4166
Abstract 4176: The homeobox gene DLX4 stimulates inducible nitric oxide synthase-mediated angiogenesis in ovarian cancer
Authors: Trinh Bon Q. , Ko Song Yi , Haria Dhwani , Barengo Nicolas , Naora Honami 
Published: August 2015

Abstract
Increasing evidence indicates that the free radical gas nitric oxide plays an important role in stimulating angiogenesis. However, the mechanisms that control nitric oxide-mediated angiogenesis in tumors are poorly understood. We previously identified that DLX4, a transcription factor encoded by a homeobox gene, stimulates ovarian tumor progression and correlates with poor outcomes of ovarian cancer patients. In this study, we identified that high DLX4 expression in ovarian cancer specimens is strongly associated with elevated expression of inducible nitric oxide synthase (iNOS), an enzyme that generates nitric oxide. DLX4 induced iNOS expression in ovarian cancer cells in vitro and in xenograft models. We identified that DLX4 interacts with STAT1 and induces iNOS expression in a STAT1-dependent manner. In in vitro studies, inhibition of iNOS abrogated the stimulatory effects of DLX4 on nitric oxide production, vascular endothelial growth factor expression and endothelial cell growth. Furthermore, inhibition of iNOS abrogated the stimulatory effects of DLX4 on tumor microvessel density and ascites formation in ovarian cancer xenograft models. Collectively, our findings indicate that DLX4 contributes to ovarian tumor progression in part by promoting nitric oxide-mediated angiogenesis. This is the first report that functionally links the aberrant expression of a developmental patterning gene in tumors with free radical gas generation.
Note: This abstract was not presented at the meeting.
Citation Format: Bon Q. Trinh, Song Yi Ko, Dhwani Haria, Nicolas Barengo, Honami Naora. The homeobox gene DLX4 stimulates inducible nitric oxide synthase-mediated angiogenesis in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4176. doi:10.1158/1538-7445.AM2015-4176
Abstract 4198: mTORC2 directs breast morphogenesis through Rictor-dependent PKCα/Rac1 signaling independent of Akt
Authors: Brantley-Sieders Dana M. , Morrison Meghan M. , Hicks Donna J. , Cook Rebecca S. 
Published: August 2015

Abstract
Akt phosphorylation is a major driver of cell survival, motility, and proliferation in development and disease, causing increased interest in upstream regulators of Akt like mTOR complex 2 (mTORC2). We used genetic disruption of Rictor to impair mTORC2 activity in mouse mammary epithelia, which decreased Akt phosphorylation, ductal length, secondary branching, cell motility, and cell survival. These effects were recapitulated with a pharmacological dual inhibitor of mTORC1/mTORC2, but not upon genetic disruption of mTORC1 function via Raptor knock-out. Surprisingly, Akt re-activation was insufficient to rescue survival, branching, or motility of mTORC2-impaired mammary epithelial cells (MECs). However, activation of the mTORC2 substrate protein kinase C (PKC)-α fully rescued branching, invasion, and survival of MECs after genetic or pharmacological mTORC2 inhibition. PKCα-mediated signaling through the small GTPase Rac1 was necessary for mTORC2-dependent mammary morphogenesis, revealing a novel role for Rictor/mTORC2 in survival and motility of untransformed MECs through an Akt-independent, PKCα/Rac1-dependent mechanism. Ongoing analyses of mammary specific Rictor-deletion in genetically engineered mouse models of breast cancer support a key role for mTORC2 in tumor progression and metastasis.
Citation Format: Dana M. Brantley-Sieders, Meghan M. Morrison, Donna J. Hicks, Rebecca S. Cook. mTORC2 directs breast morphogenesis through Rictor-dependent PKCα/Rac1 signaling independent of Akt. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4198. doi:10.1158/1538-7445.AM2015-4198
Abstract 4203: Retinoic acid signal and annexins: A vicious circle of breast tumorigenesis
Authors: Rossetti Stefano , Bshara Wiam , Reiners Johanna , Corlazzoli Francesca , Miller Austin , Sacchi Nicoletta 
Published: August 2015

Abstract
Physiological retinoic acid (RA), the bioactive derivative of Vitamin A, is a signal necessary for epithelial cell morphogenesis. During acinar morphogenesis of normal breast epithelial cells in three dimensional (3D) culture, physiological RA activates in a spatiotemporal fashion both genomic and non-genomic RA receptor alpha (RARA) signalings, thus leading to growth-arrested acini with a lumen lined by a layer of polarized cells. In contrast, lack of activation of genomic RARA by physiological RA results in the formation of 3D amorphous acini without lumen and with uncontrolled proliferation of the luminal cells. This is similar to what is observed in early in situ breast cancer lesions, such as ductal carcinoma in situ (DCIS). Different factors that, directly or indirectly, affect genomic RARA in normal breast epithelial cells and, consequently, the morphogenetic action of RA signal, lead to deregulation of members of the Annexin family, including Annexin A8 (ANXA8). Interestingly, upregulation of ANXA8 is sufficient to affect the genomic RARA-mediated RA signaling with consequent development of 3D amorphous acini. Thus, ANXA8 upregulation consequent to functional inhibition of genomic RARA by different factors seems to reinforce through a feedback loop the extent of functional inhibition of genomic RARA itself. It is of significance that ANXA8 upregulation in DCIS does correlate with tumor grade and stage.
Acknowledgements: Funding for this study was provided by the NCI R01 CA127614 grant, the Susan Komen Foundation, the Breast Cancer Coalition of Rochester, the Friends for an Earlier Breast Cancer Test, the Terri Brodeur Breast Cancer Foundation.
Citation Format: Stefano Rossetti, Wiam Bshara, Johanna Reiners, Francesca Corlazzoli, Austin Miller, Nicoletta Sacchi. Retinoic acid signal and annexins: A vicious circle of breast tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4203. doi:10.1158/1538-7445.AM2015-4203