tbuckley/cabot-search huggingface dataset:
Abstract 239: Associations of polyunsaturated fat, bile acids, and gut microbiota on colorectal adenoma risk
Authors: Tengteng Wang, Nicole M. Brown, Amber N. McCoy, Robert S. Sandler, Temitope O. Keku
Journal: Cancer Research (2017)

Abstract Background: Intestinal microbiota, and their metabolites are increasingly recognized as important players in the genesis of colorectal adenomas and cancer. Epidemiological studies have also shown that polyunsaturated fat intake is associated with decreased risk of colorectal adenomas. This study examined the association between adherent gut microbiota and mucosal bile acids, and total polyunsaturated fat intake in relation to colorectal adenomas in a case-control study. Methods: Participants were 217 adenoma cases and 218 adenoma-free controls who underwent screening colonoscopies and completed food frequency questionnaires. The mucosal adherent microbiota was characterized by bacterial 16S rRNA sequencing. Global metabolomics of colonic mucosal tissue was conducted by gas chromatography and mass spectrometry on a subset of samples. Genus level microbiota and bile acids were compared between cases and controls using t-test with correction for multiple comparison. Logistic regression and Pearson correlations were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs), and correlation coefficients for the association among microbiota abundance, bile acids concentration, and total polyunsaturated fat intake. Results: Adenoma subjects had a significantly higher bacterial abundance of Sphingomonas, Marinomonas and Ralstonia, but lower abundance of Adlercreutzia compared to controls. The concentration of eleven bile acids (Chenodeoxycholate, Cholate, Deoxycholate, Glycochenodeoxycholate, Glycocholenate sulfate, 7-ketodeoxycholate; 12-dehydrocholate, Taurochenodeoxycholate, Taurocholate, Taurodeoxycholate, Taurolithocholate 3-sulfate, and Tauroursodeoxycholate) were significantly elevated in cases compared to controls. Subjects with increased abundance of Sphingomonas and Ralstonia were significantly more likely to have adenomas (OR 2.17, 95% CI 1.31-3.57; OR 1.19, 95% CI 1.02-1.38) respectively. Subjects with increased abundance of Adlercreutzia were less likely to have adenomas (OR 0.44, 95% CI 0.21-0.93). The multivariable adjusted OR for those in the high relative to the low level of total polyunsaturated fat intake was 0.46 (95% CI 0.27-0.80). The correlations between bacterial diversity and eleven bile acids also significantly differed by case control status. Conclusion: The interactions of the gut microbiota, bile acids and consumption of polyunsaturated fat are associated with colorectal adenoma risk. Citation Format: Tengteng Wang, Nicole M. Brown, Amber N. McCoy, Robert S. Sandler, Temitope O. Keku. Associations of polyunsaturated fat, bile acids, and gut microbiota on colorectal adenoma risk [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 239. doi:10.1158/1538-7445.AM2017-239
Abstract 3211: Inhibition of autophagy potentiates cytotoxicity of CX-5461 treatment in chemoresistant epithelial ovarian cancer
Authors: Robert Cornelison, Danielle C. Llaneza, Yulia Petrova, Zachary C. Dobbin, David A. Schneider, Charles N. Landen
Journal: Cancer Research (2017)

Abstract Epithelial ovarian cancer remains a deadly diagnosis with poor prognosis and patients succumbing to chemoresistant disease in 80% of cases. Mechanisms of chemoresistance are numerous, but we have identified ribosomal biogenesis basal machinery as being a common upregulated signaling network in response to chemotherapeutic insult. Tumors treated with chemotherapy showed dramatic increases in size and morphology of nucleoli, suggesting global changes in ribosomal synthesis with stress. We next sought to use the RNA Polymerase I inhibitor CX-5461 to identify biologic changes in targeting ribosomal machinery that may allow resensitization to chemotherapy. CX-5461 induced autophagy, senescence and mitotic catastrophe in ovarian cancer cell lines Overall, 13 ovarian cancer lines examined were highly sensitive to Pol I inhibition by MTT, with IC50s ranging from 25nM to 2μM, and chemoresistant lines were generally more sensitive to CX-5461. In p53 mutant cells CX-5461 appears to be primarily cytostatic with mitotic catastrophe being a relatively rare event accompanying cytokinesis failure. This could be indicative of the cells successfully using autophagy to decrease ribosome requirements and evade treatment. When treated in combination with chloroquine as an autophagy inhibitor IC50s decreased to 550nM in HeyA8 (from 2μM), 70nM for HeyA8MDR (from 191nM), 110nM in SKOV3 (from 595nM) and 60nM for SKOV3TR-ip2 (from 109nM) with abundant multinucleated cells, suggesting synergy between ribosomal synthesis and autophagy inhibitors in vitro. Chloroquine administration appears to push cell to mitotic catastrophe after co-administration with CX-5461, thereby enhancing cytotoxicity over cytostatic endpoints after treatment, even in multi-drug resistant cell populations. Inhibition of autophagy appears to enhance efficacy of RNA Polymerase I inhibition in both sensitive and chemoresistant populations, prompting a potential new approach to chemoresistant disease. Citation Format: Robert Cornelison, Danielle C. Llaneza, Yulia Petrova, Zachary C. Dobbin, David A. Schneider, Charles N. Landen. Inhibition of autophagy potentiates cytotoxicity of CX-5461 treatment in chemoresistant epithelial ovarian 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 3211. doi:10.1158/1538-7445.AM2017-3211
Abstract LB-175: Gender and racial disparities in incidence trends of tobacco-related cancers from 2010 to 2013
Authors: Danyell S. Wilson, Alice Parish, Yi Guo
Journal: Cancer Research (2017)

Abstract Over one in three cancer-related deaths are associated with tobacco use. Although the overall incidence trend of tobacco-related cancers (TRCs) has been decreasing in the past a few decades, evidence suggests that not all TRCs have decreasing incidence and there exists gender and racial disparities in the TRC trends. Prior studies of TRC incidence have used the Surveillance, Epidemiology, and End Results Program (SEER) database. However, the SEER database includes limited information regarding the United States southeastern region and has been shown not to be representative of the US. In this study, we analyzed TRC incidence trends from 2010 to 2013 using the Florida cancer registry data, collected from a large ethno-racially diverse state. We computed annual age-adjusted incidence rates and annual percentage change (APC) to characterized the incidence trends of the following cancers: oral cavity, cervical, respiratory (lung, bronchitis, and larynx), urinary (bladder, kidney, and renal pelvis), digestive (esophagus, stomach, and pancreas), non-Hodgkin’s lymphoma, and pharyngeal. All incidence trends were also evaluated stratifying by gender (men and women) and race (Non-Hispanic (NH) Whites, NH Blacks, and Hispanics). Overall, all TRCs had a significant decrease in age-adjusted incidence rates for the study period, except for non-Hodgkin’s lymphoma and pharyngeal cancer for which the incidence remained unchanged. Oral cavity cancer had the biggest decline in age-adjusted incidence rates (APC= −2.5; 95% CI= −3.4, −1.6), while cancers of the digestive system had the smallest decline in incidence rates (APC= −0.6; 95% CI= −1.0, −0.2). When broken down by gender, males have a greater decrease in incidence rates than women for urinary and respiratory cancers. In addition, while pharyngeal cancer incidence rate stayed unchanged overall, there was a significant increase in the rate among male (APC= 1.0; 95% CI= 0.3, 1.7), but not female. When broken down by race and ethnic groups, NH Blacks and Hispanics had greater decline in cancer incidence for cervical cancer, oral cavity cancer, and respiratory cancer. For pharyngeal cancer, there was a significant decrease in incidence among NH Blacks (APC= −3.7; 95% CI= −5.5, −1.9), while the incidence significantly increased among NH Whites (APC= 1.6; 95% CI= 0.7, 2.5). In summary, there was an overall decreasing trend of TRC incidence. However, increasing incidence of pharyngeal cancer was observed for male and NH Whites. Citation Format: Danyell S. Wilson, Alice Parish, Yi Guo. Gender and racial disparities in incidence trends of tobacco-related cancers from 2010 to 2013 [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 LB-175. doi:10.1158/1538-7445.AM2017-LB-175
Abstract 2881: CXCL1 and CCL5, induced by ionizing radiation, reprogram nontumorigenic cancer cells into cancer stem cells in breast cancer
Authors: Justine Bailleul-Dubois, Nadège Bidan, Raphaëlle Mouttet-Audouard, Mélanie Arcicasa, Karine Hannebicque, Yuki Takayama, Samuel Meignan, Xuefen Le Bourhis, Chann Lagadec
Journal: Cancer Research (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 5877: The functional role(s) of <i>serum amyloid A1 (SAA1)</i> polymorphisms in integrin-mediated cell adhesion in nasopharyngeal carcinoma (NPC) cells
Authors: On Ying Man, Hong Lok Lung
Journal: Cancer Research (2017)

Abstract Serum amyloid A1 (SAA1) was previously identified as a tumor suppressor gene with anti-angiogenic activities in nasopharyngeal carcinoma (NPC). Three SAA1 isoforms (SAA1.1, 1.3, and 1.5) were observed with disproportionate frequencies among the NPC patients and healthy people. SAA1.1 and 1.3 are the functional isoforms to inhibit angiogenesis whereas SAA1.5 was the defective gene. Our immunohistochemical results showed that the loss of SAA1 staining in the metastatic NPC tissues was significantly associated with tumor progression. We aim to investigate the functional roles of the three SAA1 isoforms in NPC metastasis in the present study. We want to investigate whether the functional SAA1.1 and 1.3 isoforms can suppress tumor metastasis by antagonizing the integrin-FAK signaling pathway in the NPC tumor cells. The focal adhesion assay was performed by seeding the tumor cells with or without the integrin alphaVbeta3/beta5 ligand vitronectin. Both the vector-alone control and the SAA1.5-expressing NPC cells began to spread out and adhered to the bottom of the culture dish in the presence of vitronectin from 7 to 9 hours, whereas the SAA1.1 and SAA1.3-cells remained in the round-up morphology with minimal attachment. Interestingly, after 48 hours the SAA1.1 and SAA1.3-expressing cells formed adherents junction among the cells. In order to study the viability of the effects of the three SAA1 isoforms on NPC cells, MTT viability assay was performed. The results showed that the viability of the SAA1.1 and SAA1.3-expressing cells were around 50 % lower than both the vector-alone and the SAA1.5-expressing cells. It is likely that the loss of focal adhesion after seeding of the SAA1.1 and SAA1.3-expressing cells will affect the survival of NPC cells. Furthermore, we found that the presence of the recombinant SAA1.1 and SAA 1.3 proteins could reduce the number of viable NPC cells compared with the solvent control and the SAA1.5 protein. We previously reported that the SAA1 proteins can physically interact with the integrin alphaVbeta3. Taken together, we suggested that the secreted SAA1 proteins from the NPC cells could directly affect the NPC focal adhesion as well as the cell viability by blocking the integrin on the NPC cell surface. We acknowledge the financial support of the General Research Fund (grant number HKBU17115114 to HLL) of the Research Grants Council of the Hong Kong Special Administrative Region. Citation Format: On Ying Man, Hong Lok Lung. The functional role(s) of serum amyloid A1 (SAA1) polymorphisms in integrin-mediated cell adhesion in nasopharyngeal carcinoma (NPC) 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 5877. doi:10.1158/1538-7445.AM2017-5877
Abstract 2090: Targeting estrogen receptor negative breast cancer cells using diarylthiourea analogs of SHetA2
Authors: Hongye Zou, Emily Ginn, Sabah M. Francis, Shengquan Liu, Maggie Louie
Journal: Cancer Research (2017)

Abstract Breast cancer is one of the most common cancers that occur in women in the United States. Depending on the expression of estrogen receptor α (ERα), breast cancer can be classified as ER-positive or negative. ER-negative (ER-) breast cancers are often more aggressive and have poorer prognosis compared with the ER-positive (ER+) subtype. Consequently, there is a great need to develop more targeted therapeutic options for ER- breast cancer. One such compound is SHetA2, a flexible heteroarotinoid (flex-hets) that has been shown to inhibit growth of multiple cancer types including breast cancer. However, the clinical utility of SHetA2 is limited by its high lipophilicity (LogP). The goal of this study is to screen eleven 2nd generation analogs of SHetA2 with lower LogP values— SL1-22, 24, 27, 29, 30, 32, 36, 37, 38, 39, and 40— on different breast cancer cell lines to identify potential lead compounds that show the highest anti-growth activities against ER- breast cancer cells and further delineate the mechanism by which these compounds affect breast cancer cell growth. Results from this study demonstrate that SL1-38 [1-(3-chloro-4-methylphenyl)-3-(4-nitrophenyl)thiourea] and SL1-39 [1-(4-chloro-3-methylphenyl)-3-(4-nitrophenyl)thiourea], inhibit ER-negative breast cancer cells (MDA-MB-231, MDA-MB-453 and MDA-MB-468) effectively at micromolar concentrations. In order to understand the mechanisms of action, we evaluated the effects of SL1-38 and 39 on the expression of key cell cycle regulators. Our results show that these two analogs down-regulate the expression of cyclin A, cyclin B, cyclin D1, cyclin E and cdk2 and block S-phase progression. Taken together, these preliminary results suggest that SL1-38 and 39 may be further developed as anti-cancer agents for treating ER-negative breast cancer. Citation Format: Hongye Zou, Emily Ginn, Sabah M. Francis, Shengquan Liu, Maggie Louie. Targeting estrogen receptor negative breast cancer cells using diarylthiourea analogs of SHetA2 [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 2090. doi:10.1158/1538-7445.AM2017-2090
Abstract 2357: CDK4/6 inhibition in early stage triple negative breast cancer
Authors: William B. Kietzman, Virginie Ory, Fransisco Saenz, Ghada Sharif, Anton Wellstein, Anna T. Riegel
Journal: Cancer Research (2017)

Abstract Palbociclib (PD), a CDK4/6 inhibitor, has recently been approved for use in advanced ER positive breast cancer, demonstrating significant benefit in combination with endocrine therapies. Ductal carcinoma in situ (DCIS) is an inobligate precursor to invasive ductal carcinoma with anywhere from 14-53% of cases progressing. Progression is unpredictable and driven by poorly understood mechanisms. In this study, we assess the efficacy of PD in the context of this early stage disease using a triple negative DCIS model(MCF10DCIS), not only in inhibiting cell cycle but also in hindering the progression from in situ to invasive lesion. We demonstrate similar efficacy of PD in 2D on MCF10DCIS and immortal mammary epithelial cells (MCF10As) in preventing proliferation, inhibiting phosphorylation of RB and stopping cell cycle progression. Yet in 3D, MCF10DCIS cells form smaller, more organized spheres in the presence of drug while MCF10As appear unaffected, highlighting potential disease selectivity in vivo. Interestingly, when a cDNA array is performed on MCF10DCIS cells grown in 3D +/- PD, the most regulated genes are not well characterized cell cycle genes as one might predict based on previously published data and 2D response to treatment, suggesting alternative CDK4/6 targets may be responsible for the phenotype observed in 3D. We also demonstrate in a nude mouse xenograft model of MCF10DCIS that PD is able to significantly reduce overall tumor burden while simultaneously delaying the progression of lesions to invasive disease. Though the growth of PD treated MCF10DCIS lesions is delayed we demonstrate that proliferation is unaffected in vivo by the presence of the drug, based on equivalent Ki67 signal within the lesions. This reiterates the possibility that in 3D and in vivo contexts PD targets mechanisms outside of cell cycle regulation in order to slow tumor growth and delay invasive transition. We believe that investigation into alternative targets of CDK4/6 altered by PD in 3D and in vivo may provide insights on important mechanisms of DCIS progression in DCIS models and human patients. Citation Format: William B. Kietzman, Virginie Ory, Fransisco Saenz, Ghada Sharif, Anton Wellstein, Anna T. Riegel. CDK4/6 inhibition in early stage triple negative 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 2357. doi:10.1158/1538-7445.AM2017-2357
Abstract 1981: Tissue-engineered bone for longitudinal intravital microscopy of solid tumor growth and therapy response
Authors: Eleonora Dondossola, Stephanie Alexander, Boris Holzapfel, Christopher J. Logothetis, Dietmar W. Hutmacher, Peter Friedl
Journal: Cancer Research (2017)

Abstract Bone metastases are the initial site of progression and account for many of the complications experienced by men with metastatic prostate cancer (PCa), including therapy resistance. Besides cell intrinsic mechanisms, the interaction between PCa cells and the bone microenvironment critically contributes to lesion expansion and drug sensitivity. We here developed a mouse model amenable to intravital multiphoton microscopy (iMPM) to longitudinally study PCa-stromal cell interactions and therapy response in a partially humanized neobone, established in the dermis of the mouse. Tissue engineered bone constructs, TEBCs, were generated by functionalizing polymeric polycaprolactone scaffolds with human mesenchymal stem cells (hMSCs) differentiated to osteoblasts followed by cell-derived calcification of the inter-scaffold space. 30 days after implantation of functionalized scaffolds under the skin of the mouse, bone and bone marrow maturation resulted in a 30mm3 cavity surrounded by optically transparent cortical bone of 50-60 μm thickness, as monitored by microCT and iMPM. Intra-bone tumor growth and osteolysis dynamics caused by human fluorescent PCa cells (PC3) were three-dimensionally reconstructed by multi-parameter detection through a body window, including collagen and bone matrix (SHG), calcified bone (fluorescent bisphosphonates), osteoclasts (cathepsin K), bone surface (THG), blood vessels and stromal phagocytes (fluorescent dextran), and PC3 cells (nuclear H2B/eGFP, cytoplasmatic DsRed2). As a proof of concept, the efficacy to halt bone remodeling during bisphosphonate therapy was detected, revealing the composition and kinetics of the bone-tumor interface. Combining engineered neobone with an optical window is suited to detail the 3D organization and dynamics of cancer lesions in bone and provides mechanistic insight and efficacy predictions for therapy response. Thus, this strategy will be implied to dissect the therapeutic effect of radium 223, a radioisotope with bone seeking properties, and the first agent that improves the duration and quality of life of advanced metastatic PCa patients. By using this model we will test the hypothesis that 223Ra alters stromal niches, structurally and molecularly, in a manner that accounts for the clinical observations in established macroscopic lesions. Citation Format: Eleonora Dondossola, Stephanie Alexander, Boris Holzapfel, Christopher J. Logothetis, Dietmar W. Hutmacher, Peter Friedl. Tissue-engineered bone for longitudinal intravital microscopy of solid tumor growth and therapy response [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 1981. doi:10.1158/1538-7445.AM2017-1981