bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2874: Inhibition of tumor angiogenesis by Salmonella typhimurium A1-R in the in vivo Gelfoam color-coded imaging assay
Authors: Kiyuna Tasuku , Tome Yasunori , Murakami Takashi , Zhao Ming , Kanaya Fuminori , Hoffman Robert M. 
Published: July 2017

Abstract
We previously demonstrated a color-coded angiogenesis imaging model using Gelfoam® implanted in nestin-driven green fluorescent protein (ND-GFP) nude mice in which nascent blood vessels express GFP. In this assay, we demonstrated osteosarcoma promotes angiogenesis. We report here that Salmonella typhimurium A1-R (S. typhimurium A1-R) inhibits angiogenesis of osteosarcoma cells in the Gelfoam® angiogenesis assay in ND-GFP mice. Gelfoam® was transplanted subcutaneously in the flank of transgenic ND-GFP nude mice. Seven days after transplantation, skin flaps were made and 143B human osteosarcoma cells, expressing red fluorescent protein (RFP), were injected in the transplanted Gelfoam®. After establishment of tumor in the Gelfoam®, the control group mice were treated with PBS by tail vein injection. The treated group was treated by S. typhimurium A1-R, also by tail vein injection. Skin flaps were made at days 14, 21, and 28 after transplantation of the Gelfoam® in order to allow imaging of vascularization. The OV100 variable magnification small animal imaging system and FV1000 confocal fluorescence microscope were used to visualize vascularization. Nascent blood vessels grew in the Gelfoam® in a time-dependent manner. A random 3 fields were quantified in each group. The mean length of ND-GFP-expressing blood vessels in the Gelfoam® in mice were treated with S. typhimurium A1-R was 9.40, 12.40, and 10.12 mm/mm2, at days 14, 21, and 28, respectively. The mean total length of ND-GFP-expressing blood vessels in the Gelfoam® in mice of the control group were 8.86, 14.50, and 15.81 mm/mm2 on day 14, 21, and 28, respectively. ND-GFP expressing blood vessels of the mice in the osteosarcoma cells treated with S. typhimurium A1-R had shorter vessels than the control group (on day-28, P&lt;0.05). There was not a significant difference in tumor size between the 2 groups, thereby indicating a specific inhibition of angiogenesis by S. typhimurium A1-R. In the present study, we reported that S. typhimurium A1-R inhibited angiogenesis of human osteosarcoma cells in the in vivo Gelfoam® color-coded imaging assay.
Citation Format: Tasuku Kiyuna, Yasunori Tome, Takashi Murakami, Ming Zhao, Fuminori Kanaya, Robert M. Hoffman. Inhibition of tumor angiogenesis by Salmonella typhimurium A1-R in the in vivo Gelfoam color-coded imaging assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2874. doi:10.1158/1538-7445.AM2017-2874
Abstract 2877: IKK-mediated signaling controls prostate tumor initiating cells
Authors: Conard Sara E. , Ebbs Aaron , Baldwin Albert S. 
Published: July 2017

Abstract
The heterogeneous nature of prostate cancer tumors is thought to play an important role in the decreased effectiveness of existing therapies. Tumor initiating cells (TICs) are capable of self-renewal and comprise a subset of the tumor mass. These cells are proposed to drive the growth and metastasis of tumors, and are considered to be resistant to traditional cytotoxic and targeted therapies. Several studies have shown that NF-κB signaling is increased in recurrent prostate cancer and enriched in prostate TICs. We sought to determine the potential of an IKK/NF-κB-driven mechanism for inherent or acquired resistance by IKK-mediated control of a subset of prostate tumor initiating cells. These studies were performed by using established prostate cancer cell lines, murine prostate organoids, and a murine prostate cancer animal model. We have found that inhibition of IKKα and IKKβ, upstream regulators of noncanonical and canonical NF-κB signaling, block self-renewal of several PTEN-deficient prostate cancer cell lines. Furthermore, we have also found that IKK is important for tumorigenicity and stemness seen in prostate cancer cells as measured by colony formation and extreme limiting dilution assays. Loss of canonical NF-κB (p65/RelA) decreased stemness while loss of noncanonical did not alter tumorsphere formation. Interestingly, Pten-/- tumors with loss of Ikkα or Ikkβ displayed decreased levels of self-renewing cells as measured by CD49fhigh expression, a known prostate basal cell marker. Isolated murine Pten-/- cells were 2x more efficient than Pten-/-Ikkα-/- or Pten-/-Ikkβ-/- cells in forming prostate organoids suggesting that loss of Ikk decreased the number of self-renewing cells needed for formation. Taken together, we conclude that IKK-mediated signaling is important for maintenance of prostate tumor initiating cells and further studies will address whether IKK-mediated signaling provides a mechanism for evading current therapies.
Note: This abstract was not presented at the meeting.
Citation Format: Sara E. Conard, Aaron Ebbs, Albert S. Baldwin. IKK-mediated signaling controls prostate tumor initiating cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2877. doi:10.1158/1538-7445.AM2017-2877
Abstract 2878: Anti-cancer effects of retinoic acid in CRC occurs via decreased growth of ALDH+ cancer stem cells and increased differentiation of stem cells to neuroendocrine cells
Authors: Modarai Shirin R. , Opdenaker Lynn M. , Gupta Anindita , Fields Jeremy Z. , Boman Bruce M. 
Published: July 2017

Abstract
Our studies on tissues from colon cancer patients show that in the development of colorectal cancer (CRC), stem cell (SC) overpopulation underlies tumor initiation and progression. Because aldehyde dehydrogenase (ALDH) is a marker for SCs in several tissues and is a key enzyme in retinoid acid (RA) signaling, we investigated the role of RA signaling in normal and malignant colonic SCs. Our overall hypothesis is that RA signaling regulates growth and differentiation of ALDH+ colonic SCs and dysregulation of RA signaling contributes to SC overpopulation in CRC development. To begin to investigate underlying mechanisms, we analyzed CRC cell lines/tissues to see if retinoid receptors RXR and RAR are exclusively expressed in ALDH+ SCs and if the RA pathway components change during CRC development. We determined whether RA signaling influences SC proliferation, differentiation, self-renewal, and SC population size. RXR & RAR were selectively expressed in ALDH+ colonic SCs, but not in MCM2+ proliferative cells, suggesting that RA signaling mainly occurs in SCs. Western blotting/immunostaining of CRCs revealed that RA signaling components, including RAR and RXR, become overexpressed in parallel with ALDH overexpression, which coincides with the known overpopulation of ALDH+ SCs that occurs during CRC development. Treatment of cells with RA ligands (ATRA, 9-cis RA) inhibited proliferation, reduced sphere formation, decreased ALDH+ SC population size, and induced differentiation along the neuroendocrine cell (NEC) lineage. Taken together, our findings indicate that: (1) retinoid signaling, by regulating ALDH+ colonic SCs, reduces SC proliferation, self-renewal and SC population size, and promotes SC differentiation to NECs, and (2) dysregulation of RA signaling in colonic SCs likely contributes to overpopulation of ALDH+ SCs and CRC growth. Thus, RA signaling, by inducing increased differentiation of the SC population, suggests a novel therapeutic target.
Citation Format: Shirin R. Modarai, Lynn M. Opdenaker, Anindita Gupta, Jeremy Z. Fields, Bruce M. Boman. Anti-cancer effects of retinoic acid in CRC occurs via decreased growth of ALDH+ cancer stem cells and increased differentiation of stem cells to neuroendocrine cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2878. doi:10.1158/1538-7445.AM2017-2878
Abstract 2880: GANT61-mediated constraint of Fibulin-5/prorenin receptor/BMI1 signaling impacts nasopharyngeal carcinoma stemness and metastasis
Authors: Tasi Hsin-Ting , Chen Chang-Han 
Published: July 2017

Abstract
Background: Cancer stem cells (CSCs) of NPC exhibit higher tumorigenesis and metastatic potential. Novel therapies based on molecular targets of CSCs have become the focus to cure NPC. GANT61, a GLI1 inhibitor, has been reported to exhibit potent anticancer effect on many cancers; here, we evaluated whether GANT61 has inhibitory effects on NPC-CSCs and further explored the possible mechanism.
Methods: Condition medium was used to enrich NPC stem-like cells. The NPC stem-like cells characteristics were examined by Q-RT-PCR, Western blotting, MTT, BudU, colony formation, sphere formation, and subcutaneous and metastatic xenograft models. Genetic, pharmacological and biochemical approaches were applied in NPC stem-like cells to investigate molecular signals, to assess the efficacies under the inhibitors treatment, and to examine the correlation among the molecules in vitro, in vivo and NPC specimens.
Results: In the present study, we had demonstrated that NPC tumorsphere cells (NPC-TCs) possess CSC properties. The proliferation, colony formation, spheroid formation, migration, and invasion of NPC-TCs were dramatic prevented in the presence of GANT61 in vitro and in vivo. ChIP reveals that Gli1 preferentially binds to the Fibulin-5 promoter, and Fibulin-5 transcriptional/post-transcriptional levels in NPC-TCs were regulated upon GANT61 treatment. However, ectopic expression of Fibulin-5 in NPC-TCs not only enhanced self-renewal and ALDH1 expression, but also reduced the effects of GANT61-eilicted anti-tumor in vitro and in vivo. We further identified that a novel signaling, prorenin receptor/BMI1 pathway was modulated by Fibulin-5 and involved in Fibulin-5-raised self-renewal capacity of NPC-TCs in vitro and in vivo. Notably, GANT61 inhibited NPC-TCs phenotypes was associated with suppression of Fibulin-5/prorenin receptor/BMI1 signaling. Finally, a significant correlation was observed among GLI1, Fibulin-5, AT1R and BMI1 in the specimens of NPC.
Conclusions: Our data highlight that Fibulin-5/prorenin receptor/BMI1 signaling has critical role in maintaining stem-like properties of NPC-CSCs and can be efficiently targeted by GANT61 representing a preclinical therapeutic strategy to repress NPC-CSCs.
Note: This abstract was not presented at the meeting.
Citation Format: Hsin-Ting Tasi, Chang-Han Chen. GANT61-mediated constraint of Fibulin-5/prorenin receptor/BMI1 signaling impacts nasopharyngeal carcinoma stemness and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2880. doi:10.1158/1538-7445.AM2017-2880
Abstract 2881: CXCL1 and CCL5, induced by ionizing radiation, reprogram nontumorigenic cancer cells into cancer stem cells in breast cancer
Authors: Bailleul-Dubois Justine , Bidan Nadège , Mouttet-Audouard Raphaëlle , Arcicasa Mélanie , Hannebicque Karine , Takayama Yuki , Meignan Samuel , Bourhis Xuefen Le , Lagadec Chann 
Published: July 2017

Abstract
Identification of cancer stem cells (CSC) in solid tumors - with self-renewal, multipotency, tumorigenesis, and therapy resistance capacities - has opened path to new targeting therapeutic approaches. However, CSC targeting alone might not be sufficient to eradicate a tumor. Indeed, recent studies showed that cancer cells are plastic, and conventional therapies, such as radiotherapy, can lead to cancer cells (non-CSC) reprogramming into iCSC (induced-CSC). The goal of our work is to identify the molecular mechanisms responsible for treatment-induced CSC emergence. First, we have shown that conditioned media from irradiated non-CSC is sufficient to induce iCSC reprogramming. These results suggest that cell plasticity might be actively regulated by diffusible factors secreted by irradiated cells. By using proteins arrays and ELISA, we demonstrated that the secretion of a specific cocktail of chemokines is induced by ionizing radiation, such as CXCL1 and CCL5. Interestingly, recombinant CXCL1 and CCL5 treatments increase the sphere forming capacity (SFC) of isolated non-CSC treated population. Concomitantly, treatment with neutralizing antibodies targeting CXCL1 and CCL5 leads to a decreased CSC number (ALDH+ cells). We also studied the expression of the corresponding chemokines receptors, by flow cytometry. First, we saw that reprogrammable ALDH- cells are enriched for CXCL1 and CCL5 receptors expressing cells compare to unsorted population or ALDH+ population (CSC). We analysed the reprogramming potential of isolated ALDH-/receptor-positive cells versus ALDH-/receptor-negative cells. The ALDH-/receptor-positive-derived cell population is more able to form spheres and overcomes the receptor-negative-derived population when the two populations are mixed and tested for their sphere forming capacity. The use of pharmacological inhibitors against the receptors induce a slight decrease of CSC. Taken together, our results indicate the involvement of chemokines, in particular CXCL1 and CCL5, in the reprogramming mechanism. To validate the implication of CXCL1 and CCL5 and in a pre-clinical perspective, we are currently beginning an in vivo experiment to study the effects of CXCL1 and CCL5 inhibition on tumor development and on CSC enrichment in vivo.
Citation Format: Justine Bailleul-Dubois, Nadège Bidan, Raphaëlle Mouttet-Audouard, Mélanie Arcicasa, Karine Hannebicque, Yuki Takayama, Samuel Meignan, Xuefen Le Bourhis, Chann Lagadec. CXCL1 and CCL5, induced by ionizing radiation, reprogram nontumorigenic cancer cells into cancer stem cells in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2881. doi:10.1158/1538-7445.AM2017-2881
Abstract 2887: Macrophage conditioned medium promotes colon cancer stem cell phenotype via the hedgehog signaling pathway
Authors: Fan Fan , Wang Rui , Boulbes Delphine R. , Zhang Huiyuan , Watowich Stephanie S. , Bhattacharya Rajat , Xia Ling , Ye Xiang-Cang , Ellis Lee M. 
Published: July 2017

Abstract
Background: Contradicting studies have shown that increased macrophages infiltration in colorectal cancer (CRC) could either result in anti-tumoral or in pro-tumoral effects. Because of these inconsistencies, we sought to determine the role of conditioned medium from macrophages, in particular classically activated macrophages, on the development of the CSC phenotype in CRC cells, which is believed to mediate tumor growth and chemoresistance.
Methods: Murine (CT26) and human (HCP-1) CRC cell lines were treated with conditioned media (CM) from lipopolysaccharide (LPS)-activated murine macrophages. Viability studies were performed using the MTT assay, annexin V-FITC assay, and Western blot analysis. The CSC population was assessed using the sphere-forming assay and aldehyde dehydrogenase assay.
Results: The results showed that 1) murine LPS-activated macrophage CM induced apoptosis in murine and human CRC cells, 2) murine and human LPS-activated macrophage CM secreted paracrine factors that promoted the CSC phenotype in murine and human CRC cells via the Sonic hedgehog (SHH)-Gli signaling pathway, which is known to drive self-renewal and 3) these effects were blocked by depletion of SHH in macrophage CM.
Conclusions: Our data show that LPS-activated macrophages play an active role in promoting the CSC phenotype through activation of the SHH-Gli signaling pathway.
Citation Format: Fan Fan, Rui Wang, Delphine R. Boulbes, Huiyuan Zhang, Stephanie S. Watowich, Rajat Bhattacharya, Ling Xia, Xiang-Cang Ye, Lee M. Ellis. Macrophage conditioned medium promotes colon cancer stem cell phenotype via the hedgehog signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2887. doi:10.1158/1538-7445.AM2017-2887
Abstract 2891: Retinoic acid directs breast cancer cell state changes through regulation of TET2-aPKC pathway
Authors: Wu Meng-Ju , Chang Chun-Ju 
Published: July 2017

Abstract
The key molecular mechanism governing the cancer cell state (stem cell-like state vs. differentiation state) to control the cancer stem cell (CSC) pool remains elusive. This study provides the first evidence showing that all-trans retinoic acid (ATRA) induces the interaction and chromatin recruitment of a novel RARB-TET2 complex to epigenetically activate a specific cohort of gene targets, including MiR-200c. TET2-activated miR-200c further targets and suppresses aPKC, a cell polarity protein that plays a pivotal role in directing asymmetric division of mammalian stem cells to sustain the stem cell pool. Our data reveals that pharmacological concentration of ATRA effectively down-regulates aPKC through activation of miR-200c, leading to a decrease of the stem cell-like populations from non-tumorigenic mammary epithelial cells and non-aggressive breast cancer cells. However, aggressive breast cancer cells that manifest TET2-miR200c dysregulation sustain a CSC pool highly resistant to ATRA, where inhibition of aPKC directs the resistant CSCs to the luminal cell-like state and sensitization to Tamoxifen, resulting in abrogation of mammary tumor growth and progression. Together, these findings elucidate a novel RARB-TET2-miR200c-aPKC signaling pathway that directs cancer cell state changes and also provide previously unidentified therapeutic implications for aPKC inhibitors in diminishment of breast CSCs to eradicate breast cancer.
Citation Format: Meng-Ju Wu, Chun-Ju Chang. Retinoic acid directs breast cancer cell state changes through regulation of TET2-aPKC pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2891. doi:10.1158/1538-7445.AM2017-2891
Abstract 2892: Oncostatin M elicits cellular plasticity through cooperative STAT3-SMAD3 signaling
Authors: Bryson Benjamin L. , Junk Damian J. , Smigiel Jacob , Parameswaran Neetha , Doherty Mary R. , Bartel Courtney A. , Jackson Mark 
Published: July 2017

Abstract
Increasing evidence suggests that tumor cell plasticity promotes metastasis and tumor recurrence, resulting in cancer patient mortality. While it is clear that the tumor microenvironment (TME) contributes to tumor cell plasticity, the specific TME factors that actively generate tumor cell plasticity are largely unknown. Here, we identify TME cytokines that promote epithelial-mesenchymal plasticity, and acquisition of cancer stem-cell (CSC) properties. A screen of 27 TME cytokines identified multiple Interleukin-6 family members as inducers of mesenchymal/CSC properties, with Oncostatin M (OSM) being the most potent. Importantly, OSM induced plasticity was mediated by STAT3, but also dependent on TGF-β signaling and downstream SMAD3. Inhibition of functional TGF-β/SMAD signaling by expressing a dominant-negative TGF-β receptor, treating with a TGF-β receptor inhibitor, or suppressing SMAD3 expression using a SMAD3-shRNA prevented the OSM-induced mesenchymal/CSC properties. OSM-activated STAT3 binds to SMAD3 and promotes SMAD3 nuclear localization and binding to the SNAIL promoter, increasing transcription of the SNAIL gene. The epithelial-mesenchymal transition induced by the STAT3/SMAD3 axis results in a highly invasive and metastatic phenotype and the emergence of CSC properties, including therapeutic resistance. Importantly, maintenance of the OSM-induced mesenchymal/CSC state requires sustained exposure to the cytokine, as removal of OSM results in a marked phenotypic reversion. A high-throughput screen for small molecule inhibitors of the OSM-induced mesenchymal/CSC phenotype has been performed and are currently being confirmed. We propose that, targeted blockade of the STAT3/SMAD3 axis in tumor cells may represent a novel therapeutic approach to prevent the plasticity associated with metastasis and tumor recurrence.
Citation Format: Benjamin L. Bryson, Damian J. Junk, Jacob Smigiel, Neetha Parameswaran, Mary R. Doherty, Courtney A. Bartel, Mark Jackson. Oncostatin M elicits cellular plasticity through cooperative STAT3-SMAD3 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2892. doi:10.1158/1538-7445.AM2017-2892
Abstract 2894: Epinephrine-induced gamma-secretase/Notch signaling in pancreatic cancer stem cells
Authors: Xu Xuemin , Hu Chen , Schuller Hildegard M. 
Published: July 2017

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths with 5-year survivals below 10%. Cancer stem cells represent a small population of cells in PDAC and are thought to drive the development, progression, metastasis and drug resistance of this cancer. The Notch pathway regulates the self-renewal of pancreatic cancer stem cells as well as angiogenesis and drug resistance. Gamma-secretase cleaves the Notch-1 receptor, resulting in release of the Notch intracellular domain (NICD) that then translocates to the nucleus and activates the transcription of target genes. Aberrant Notch signaling activated by γ-secretase activity is associated with progression, angiogenesis and drug resistance of PDAC and is being explored as a target for PDAC therapy. Smoking and psychological stress are risk factors for PDAC. However, the potential modulation of γ-secretase/Notch by these risk factors has not been investigated to date. Nicotine and psychological stress both cause hyperactivity of the sympathetic nervous system and adrenal glands, resulting in increased blood and organ levels of the stress neurotransmitters norepinephrine (NOR) and epinephrine (EPI), which are the physiological agonists of beta-adrenergic receptors (β-ARs). In turn, β-ARs are coupled to the stimulatory G-protein Gαs that stimulates the formation of intracellular cAMP, which activates multiple signaling pathways in a cell type-specific manner. Using spheroid formation assays and Western blotting, our data show, -for the first time,- that the stress neurotransmitter Epi significantly increases the self-renewal of pancreatic cancer stem cells by increasing the expression of the activated forms (c-terminal) of the γ-secretase component presenilin1 and of Notch1 (NICD). These responses were inhibited by the β-AR antagonist (beta-blocker) propranolol and by the inhibitory neurotransmitter γ-aminobutyric acid (GABA) that inhibits cAMP formation via activation of Gαi-coupled GABAB receptors. These findings suggest that the γ-sexretasesecretase/Notch pathway in pancreatic cancer stem cells is under regulatory control by neurotransmitters, with Epi as stimulator and GABA as inhibitor. These data could open up new avenues for the prevention and therapy of PDAC. Additional experiments are currently underway to further investigate mechanistic aspects of this novel concept. Supported by RO1CA042829 with NIH.
Note: This abstract was not presented at the meeting.
Citation Format: Xuemin Xu, Chen Hu, Hildegard M. Schuller. Epinephrine-induced gamma-secretase/Notch signaling in pancreatic cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2894. doi:10.1158/1538-7445.AM2017-2894