bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5047: Exosomes derived from HIV-1-infected T cells activate ERK 1/2 through EGFR and TLR3 in cancer cells
Authors: Feng Zhimin , Chen Lechuang , Yue Hong , Wang Bingcheng , Jin Ge 
Published: August 2018

Abstract
Exosomes secreted from HIV-1-infected T cells play important roles in coordinating the immune responses and disease processes in HIV-infected people who are treated with antiretroviral therapy. We hypothesize that exosomes from HIV-infected T cells can promote growth and progression of non-AIDS-defining cancer cells. Activation of the MAPK ERK 1/2 is important for cancer cell survival, proliferation and invasion. We investigated the ability of exosomes from HIV-1-infected T cells to activate ERK 1/2 in head neck squamous cell carcinoma (HNSCC) and lung cancer cells for cancer cell proliferation and progression. Exosomes were isolated from Jurkat and J1.1, a latently HIV-1-infected Jurkat cells, using differential ultracentrifugation and quantified by acetylcholinesterase (AchE) activity. HNSCC cell line HSC3 and lung cancer cell lines NCI-H1299 and NCI-H1437 cells were treated with exosomes. To test the involvement of EGFR and TLR3 in ERK 1/2 activation by exosomes, EGFR neutralizing antibody Cetuximab or the TLR3/dsRNA inhibitor complex was added to cancer cells 30 min prior to adding exosomes. To test the entry of exosomes into cells, HEK293 cells were transiently transfected with EGFR-GFP, and seeded into glass bottom 35 mm dishes, time lapse Z-stacking imaging was performed and deconvolution was used to remove out of focus signals. By using Western blotting, we found that exosomes from J1.1 cells (HIV-1-infected), but not those from HIV-negative Jurkat cells, constantly induced ERK 1/2 phosphorylation in HNSCC and lung cancer cells. Cetuximab dramatically decreased ERK activation by exosomes from J1.1 cells, suggesting an EGFR-dependent ERK activation. While EGF induced a whole series of EGFR phosphorylation, exosomes from J1.1 cells failed to do so, suggesting that exosomes from J1.1 cells trigger ERK activation through a non-canonical EGFR pathway. Furthermore, ERK activation was significantly reduced in TLR3/dsRNA inhibitor pretreated cancer cells in response to exosomes from J1.1 cells, indicating exosomes triggered ERK activation is also TLR3 dependent. Time lapse imaging showed that exosomes quickly entered into cells within two minutes; however, Cetuximab greatly delayed exosome entry. To conclude, we found that exosomes from HIV-infected T cells can induce ERK activation in HNSCC and lung cancer cells through interaction with EGFR and TLR3.
Citation Format: Zhimin Feng, Lechuang Chen, Hong Yue, Bingcheng Wang, Ge Jin. Exosomes derived from HIV-1-infected T cells activate ERK 1/2 through EGFR and TLR3 in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5047.
Abstract 5050: Molecular heterogeneity in HPV-dependent and -independent vulvar carcinogenesis: Chromosome 1 gain reflects the cancer risk in vulvar intraepithelial neoplasia
Authors: Bleeker Maaike CG , Swarts Dorian RA , Voorham Quirinus JM , Wilting Saskia M. , Beurden Marc van , Steenbergen Renske DM 
Published: August 2018

Abstract
Vulvar squamous cell carcinoma (VSCC) and precancerous high-grade vulvar intraepithelial neoplasia (VIN) can develop through human papillomavirus (HPV)-dependent and -independent pathways, indicating a heterogeneous disease. Only a minority of VIN progress, but current clinical and histological classifications are insufficient to predict the cancer risk. Here we analyzed copy number alterations (CNA) to assess the molecular heterogeneity of vulvar lesions in relation to HPV and cancer risk. HPV-status and CNA by means of whole-genome next-generation shallow-sequencing were assessed in 24 VSCC and 41 VIN lesions. The latter included VIN of women with associated VSCC (VINVSCC) and women who did not develop VSCC during &gt;10 year follow-up (VINnoVSCC). HPV-testing resulted in 41 HPV-positive lesions (16 VINVSCC, 14 VINnoVSCC and 11 VSCC) and 24 HPV-negative lesions (11 VINVSCC and 13 VSCC). HPV-positive and -negative VSCC showed a partially overlapping pattern of recurrent CNA, including frequent gains of 3q and 8q. In contrast, amplification of 11q13/cyclinD1 was exclusively found in HPV-negative lesions. HPV-negative VINVSCC had less CNA than VSCC (P = 0.009), mainly 8q gains and 8p losses. In HPV-positive lesions, CNA frequencies were lower in VINnoVSCC than in VINVSCC (P = 0.022) and VSCC. Interestingly, a 1pq gain was detected in 81% of VINVSCC and only 29% of VINnoVSCC. In conclusion, HPV-dependent and -independent vulvar carcinogenesis is characterized by distinct CNA patterns at the VIN stage, while more comparable patterns are present at the cancer stage. Progression risk in VIN is reflected by the extent of CNA, in particularly chromosome 1 gain.
Citation Format: Maaike CG Bleeker, Dorian RA Swarts, Quirinus JM Voorham, Saskia M. Wilting, Marc van Beurden, Renske DM Steenbergen. Molecular heterogeneity in HPV-dependent and -independent vulvar carcinogenesis: Chromosome 1 gain reflects the cancer risk in vulvar intraepithelial neoplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5050.
Abstract 5056: HPV, HIV and male gender as major risk factors for anal neoplastic transformation in African Americans
Authors: Brim Hassan , Afsari Ali , Atefi Nazli , Retland Nicole , Abbas Muneer , Naab Tammey , Shokrani Babak , Laiyemo Adeyinka O. , Lee Edward L. , Nouraie Seyed M. , Ashktorab Hassan 
Published: August 2018

Abstract
Background: Human Papilloma Virus (HPV) is the most common sexually transmitted infectious agent. The incidence HPV-related anal cancers increased among HIV infected people. Aim: To assess risk factors of anal lesions among African Americans in an inner city hospital. Methods: We reviewed medical records of 370 African-Americans with anal lesions at Howard University Hospital from Jan. 2007 to Dec. 2015. Demographic, clinical and pathological data including; HPV, HIV, HCV (hepatitis C virus), diabetes mellitus (DM), hypertension (HTN) and body mass index (BMI) were collected. Statistical analysis was performed using Chi-square and Student's t-test. Results: 276 (75%) patients were male, with median age of 44 years and BMI of 25.8 kg/m2. The frequency of condyloma, high grade dysplasia, squamous cell carcinoma (SCC) and adenocarcinoma was 191 (52%), 26 (7%), 31 (8%) and 8 (2%), respectively. The frequency of HPV, HIV, and HCV was 231 (68%), 147 (43%) and 42 (12%), respectively. HPV and HIV were risk factors for condyloma and dysplasia (P&lt;0.05). Forty two percent of patients had diabetes (DM) and hypertension (HTN). Conclusion: Our results shows that majority of patients with condyloma are male and young with HPV and HIV infection. A clinical utility of HPV as risk factor may be use for prediction of anal lesions.
Citation Format: Hassan Brim, Ali Afsari, Nazli Atefi, Nicole Retland, Muneer Abbas, Tammey Naab, Babak Shokrani, Adeyinka O. Laiyemo, Edward L. Lee, Seyed M. Nouraie, Hassan Ashktorab. HPV, HIV and male gender as major risk factors for anal neoplastic transformation in African Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5056.
Abstract 5059: Comprehensive molecular profiling of HPV-induced transformation over time
Authors: Babion Iris , Miok Viktorian , Jaspers Annelieke , Wieringen Wessel N. van , Steenbergen Renske D. , Wilting Saskia M. 
Published: August 2018

Abstract
Although persistent infection with high-risk human papillomavirus (HPV) is generally acknowledged as necessary cause for cervical cancer, additional molecular changes are required for the development of cancer. Those changes include chromosomal aberrations that result in deregulated expression of coding and non-coding RNAs. In this study we performed a comprehensive and longitudinal molecular characterization of HPV-transformed keratinocyte cell lines, to identify the sequential order and relevance of these molecular alterations for HPV-induced transformation. Genome-wide chromosomal, mRNA and miRNA expression profiles were generated from 4 HPV-transformed keratinocyte cell lines at 8 different passages representing progressive stages of transformation. Unsupervised hierarchical clustering of DNA copy number, mRNA and miRNA profiles revealed that in all 4 cell lines most pronounced changes were associated with the acquisition of anchorage independence, a hallmark of transformation. Approximately one third of differentially expressed mRNAs and miRNAs was directly attributable to DNA copy number alterations. Focal adhesion, TGF-β signalling and mTOR signalling pathways were enriched among these genes. In addition, longitudinal analysis identified more than 600 potential miRNA-mRNA interactions that were negatively correlated during passaging. Four interactions were also predicted by 3 independent prediction algorithms, and have in part already been functionally validated, thereby demonstrating the validity of our approach. In conclusion, integrated longitudinal analysis of our HPV-induced transformation model enabled us to pinpoint relevant interconnected molecular changes and affected signalling pathways. Increased understanding of the interplay between different molecular alterations and affected pathways will be of importance for the clinical management of patients diagnosed with HPV-induced (pre)cancerous lesions.
Citation Format: Iris Babion, Viktorian Miok, Annelieke Jaspers, Wessel N. van Wieringen, Renske D. Steenbergen, Saskia M. Wilting. Comprehensive molecular profiling of HPV-induced transformation over time [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5059.
Abstract 5073: Involvement of TGFa-EGFR-Akt axis on enhanced proinflammatory chemokines in triple-negative breast cancer cells
Authors: Ignacio Rosa Mistica Coles , Gibbs Carla , Lee Eunsook , Son Deok-Soo 
Published: August 2018

Abstract
Triple-negative breast cancer (TNBC) is aggressive, leading to poorer outcomes. Chemokines have chemoattractive potential for cancer metastasis. We investigated the signature of chemokine network between TNBC and non-TNBC cells followed by underlining mechanisms on enhanced proinflammatory chemokines in TNBC. Analysis from microarray dataset revealed that basal-like BC subtype representing TNBC expressed dominantly proinflammatory chemokines, such as CXCL1 and 8, compared to non-TNBC. Chemokine PCR array confirmed the dominant proinflammatory chemokines in TNBC cells. As a driving factor for proinflammatory chemokines in TNBC cells, we checked expression profiles for epidermal growth factor receptor (EGFR) family and its downstream signaling. TNBC cells showed higher expression levels of EGFR and phosphorylated Akt compared to non-TNBC cells. In addition, EGF enhanced the proinflammatory chemokines in TNBC cells. Knockdown of Akt reduced the CXCL2 promoter activity, while overexpression of Akt enhanced the activity. MKK2206, an Akt inhibitor, abrogated the CXCL2 promoter activity, but targeting Erk using inhibitor and knockdown did not reduce the activity. As a driving factor for EGFR-mediated Akt activation in TNBC cells, we found transforming growth factor alpha (TGFα) among ligands of EGFR family. MK2206 decreased the TGFα promoter activity, while overexpression of Akt significantly increased the activity in TNBC cells. MK2206 abrogated TGFα protein released by TNBC cells. MK2206 downregulated CXCL2 mRNA, while TGFα upregulated the CXCL2 expression. Taken together, higher expression of proinflammatory chemokines in TNBC involves TGFα-EGFR-Akt axis, probably contributing to the inflammatory burden followed by promoted cancer progression and higher mortality in TNBC.
Citation Format: Rosa Mistica Coles Ignacio, Carla Gibbs, Eunsook Lee, Deok-Soo Son. Involvement of TGFa-EGFR-Akt axis on enhanced proinflammatory chemokines in triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5073.
Abstract 51: Role of hematopoietic cell kinase (HCK) in breast cancer dormancy
Authors: Khiste Sachin , Eton Elliot , Hodgetts Kevin , Lusic Hrvoje , Gopinath Kodaganur , Krishnamurthy S , Sengupta Shiladitya , Goldman Aaron 
Published: August 2018

Abstract
Background: Triple negative breast cancer (TNBC) is an aggressive basal-like malignancy, which recurs more frequently than any other subtype of breast cancer. We recently discovered that TNBC can overcome drug pressure by switching to a hybrid basal-like (CD44Hi) and epithelial-like (CD24Hi) cell state, which is accompanied by a transient period of quiescence, or dormancy. These dormant, ‘hybrid' cells highly express the phosphorylated SRC family kinase, hematopoietic cell kinase (HCK). Methods: Here, we used a panel of novel HCK inhibitors to study the effect of signaling-disruption in drug tolerance and tumor cell dormancy. Using flow cytometry and immunofluorescent microscopy we examined how HCK inhibition perturbs common features associated with dormancy such as proliferation and cell cycle status, intracellular levels of reactive oxygen species, and state of glucose metabolism. Finally, we validated the results using an ex-vivo human tumor model that predicts clinical response and recreates the native tumor microenvirnoment, CANscriptTM. Results: We determined that targeted inhibition of HCK down-regulates the features of tumor cell dormancy and drug tolerance, eliminating cells with a hybrid mesenchymal-epithelial phenotype, diminishing polyploidy and hyper-G2 endoreduplication, and suppressing features of a dysregulated glycolytic state. Conclusion: Expression of HCK drives cancer cells to a quiescent cancer cells subpopulation, resulting in tolerance to chemotherapy. Targeted disruption of HCK overcomes these features of dormancy. HCK inhibitors could emerge as a novel treatment for chemotherapy-induced breast cancer dormancy.
Citation Format: Sachin Khiste, Elliot Eton, Kevin Hodgetts, Hrvoje Lusic, Kodaganur Gopinath, S Krishnamurthy, Shiladitya Sengupta, Aaron Goldman. Role of hematopoietic cell kinase (HCK) in breast cancer dormancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 51.
Abstract 5111: Gene editing in the NSG mouse strain and its genetic derivatives
Authors: Grass David S. , Buaas F William , Wiles Michael V. , Low Benjamin E. , Kutny Peter 
Published: August 2018

Abstract
Mouse models continue to be powerful tools in preclinical oncology and immuno-oncology studies. The development of the inbred highly immunocompromised mouse strain NSG (NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ) has dramatically improved the ability to work with human tumors in an organismal context using xenograft approaches. Furthermore, technical innovations have expanded the utility of this personalized tumor platform via the reconstitution of parts of the human immune system. An example of this is the NSG-SGM3 inbred mouse strain, in which transgenes expressing human IL3, GMCSF and SCF have been stably integrated into the NSG background. This NSG “derivative” strain can effectively support the stable engraftment of human myeloid lineages and the regulatory T cell populations. Direct genetic modification of the NSG genome in mouse embryos was a key technical capability to attain this NSG “derivative” strain rapidly and avoid extensive breeding. Modification of NSG and derivative strains represent an opportunity to optimize the engraftment of other human lineages. The ability to apply modern genome modification technology to different inbred mouse strains is highly desirable but must overcome two major technical hurdles - 1) Reproductive biology constraints that prevent live born progeny after reagent delivery methods such as microinjection or electroporation and 2) Cell intrinsic DNA-repair processes that are a prerequisite enabling gene editing tools. Given the SCID mutation (Prkdcscid) in the NSG background compromises some DNA repair pathways, it was not clear whether nuclease assisted recombination technologies would be a robust tool to modify NSG (and derivatives) genomes at the zygote stage. Here, we demonstrate that CRISPR-Cas9 is an effective tool for introducing genome modifications in NSG and present a specific example using the Hprt locus. Furthermore, we will present general experience with genomic modifications using NSG, and its derivatives, to emphasize direct modification of these genomes is technically feasible and is enabling the rapid sequential genetic tailoring in this high value cancer model strain.
Citation Format: David S. Grass, F William Buaas, Michael V. Wiles, Benjamin E. Low, Peter Kutny. Gene editing in the NSG mouse strain and its genetic derivatives [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5111.
Abstract 5119: In vivo characterization of the Duffy Antigen Receptor for Chemokines (DARC) in the breast cancer microenvironment
Authors: Martini Rachel , Manley Nancy , Davis Melissa 
Published: August 2018

Abstract
Chemokines are small inflammatory molecules that, in combination with their receptors, recruit lymphocytes to influence immune and inflammatory responses. This work specifically follows an atypical chemokine receptor, known as the Duffy Antigen Receptor for Chemokines (DARC). DARC is a non-signaling receptor able to bind both the CC and CXC chemokine classes, and mainly functions to regulate homeostatic levels of chemokines in circulation, and aid in chemokine transcytosis from sites of inflammation to mediate immune response. DARC serves as a portal of entry for the malaria-causing parasite Plasmodium vivax. In Sub-Saharan Africa, where malaria is endemic, a regulatory variant arose removing DARC expression from red blood cells (RBCs). This mutation, known as the Duffy-Null allele, was highly beneficial in this population, as removal of DARC from RBCs conferred immunity to Duffy-Null individuals. The Duffy-Null allele quickly rose to fixation in this population, and today recent decedents of Sub-Saharan Africans carry this allele. In the context of breast cancer (BCa) we are particularly interested in how Duffy-Null status impacts the tumor microenvironment. In clinic, we observe that pre-menopausal women of African descent have higher incidence rates of BCa, and that regardless of age, these women are disproportionately diagnosed with the most aggressive molecular subtype of BCa, triple-negative BCa. Knowing the important role that DARC plays in immune response, and that the Duffy-Null allele is prevalent in this population of women, we aim to investigate how Duffy-Null status impacts the tumor microenvironment in vivo through establishment of mouse models that depict Duffy-Null status in the BCa environment. To do this, we are using the C3(1)-TAg BCa transgenic mouse, alongside a DARC-KO mouse to characterize cancer progression and aggressiveness in BCa transgenic mice with varying global DARC expression. At 6 and 12 week time points, mice were sacrificed and the following information was obtained: total number of tumors, tumor location, tumor size and weight, and hematoxylin and eosin staining of tumor sections. Removal of DARC could lead to an excess of chemokines in the tumor microenvironment, promoting processes of tumor progression and metastasis, leading to the more aggressing tumor phenotypes we observe in women of African descent in clinic.
Citation Format: Rachel Martini, Nancy Manley, Melissa Davis. In vivo characterization of the Duffy Antigen Receptor for Chemokines (DARC) in the breast cancer microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5119.
Abstract 5121: Obesity and prostate cancer progression: Role of the chemokine CXCL12
Authors: Ahn Songyeon , Saha Achinto , Kolonin Mikhail G. , DiGiovanni John 
Published: August 2018

Abstract
Prostate cancer (PCa) is the third leading cause of cancer in men in the United States. Many epidemiologic studies suggest that obesity increases PCa progression and mortality. However, the mechanistic relationship between PCa progression and obesity is very complex and not fully understood. In previous studies, we have shown that obesity enhances PCa growth and progression in the HiMyc mouse model of PCa by changing the surrounding tumor microenvironment, especially in white adipose tissue (WAT). WAT consists of many cells including mature adipocytes, adipose stromal cells (ASCs) and inflammatory cells, which secrete chemokines, cytokines and proinflammatory molecules. ASCs are an important component of the stromal vascular fraction (SVF) from WAT that secretes such factors. In this study, we evaluated the role of ASCs and ASC-derived CXCL12 in driving PCa progression in obesity. We observed upregulation of mRNA expression of CXCL12 in the SVF of the periprostatic WAT from obese HiMyc mice. In HMVP2 cells, a PCa cell line derived from HiMyc mice expressing high levels of CXCR4 and CXCR7, CXCL12 treatment increased activation of MAPKs (JNK and ERK), AKT, STAT3 and NFkB. In further studies, HMVP2 cells were treated with the CXCR4 antagonist, AMD3100, alone or together with CXCL12 and the CXCL12-induced signaling was abolished in AMD3100-treated cells. Similar results were observed in CXCR4 knockdown cells and CXCR7 knockdown cells. In addition, knockdown of CXCR4 and CXCR7 significantly decreased migration and invasion of the HMVP2 cells. Lastly, a tumor study was performed by injecting HMVP2 cells into the flank of FVB/N mice, which were fed either a control diet or obese diet. AMD3100 significantly inhibited the growth of HMVP2 tumors in both obese and control diet groups. AMD3100 also inhibited proliferation and epithelial-mesenchymal transition (EMT) in both obese and control diet groups. In conclusion, this study provides evidence that the CXCL12/CXCR4/CXCR7 signaling pathway is important for obesity-driven PCa progression in HiMyc mice. Furthermore, this pathway may represent a novel therapeutic target for inhibiting obesity-driven PCa growth and progression.
Citation Format: Songyeon Ahn, Achinto Saha, Mikhail G. Kolonin, John DiGiovanni. Obesity and prostate cancer progression: Role of the chemokine CXCL12 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5121.