bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-31: Castration induces upregulation of intratumoral androgen biosynthesis and androgen receptor expression in orthotopic VCaP human prostate cancer xenograft model
Authors: Knuuttila Matias , Yatkin Emrah , Kallio Jenny , Savolainen Saija , Laajala Teemu Daniel , Aittokallio Tero , Oksala Riikka , Häkkinen Merja , Keski-Rahkonen Pekka , Auriola Seppo , Poutanen Matti , Mäkelä Sari 
Published: May 2015

Abstract
Androgens are key factors involved in the development and progression of prostate cancer (PCa), and the growth of PCa can be suppressed by androgen deprivation therapy (ADT). In a significant proportion of men receiving ADT, PCa progresses to castration-resistant prostate cancer (CRPC), which is a major challenge in the development of efficient therapies. The aim of the study was to characterize the cellular and molecular changes in tumors after ADT (castration), by using orthotopic VCaP human prostate cancer xenograft model. VCaP cells were inoculated in the dorsolateral prostate of immunodeficient mice, and tumor growth was followed by weekly serum PSA measurements. Mice with recurrent tumors after castration were randomized to treatment groups. Serum PSA concentrations showed significant correlation with the tumor volume, confirming that PSA is a reliable indicator of the tumor volume in the orthotopic VCaP xenograft model. Tumor and serum samples were collected and concentrations of androgens were measured by LC-MS/MS. Castration-resistant tumors retained their intratumoral androgen (androstenedione, testosterone, 5α-dihydrotestosterone) concentrations at levels similar to those in tumors growing in intact hosts. Accordingly, castration induced upregulation of enzymes involved in androgen biosynthesis (CYP17A1, AKR1C3 and HSD17B6), as well as expression of full-length androgen receptor (AR) and AR splice variants (AR-V1 and AR-V7). Furthermore, AR target gene expression was maintained in castration-resistant xenografts. AR antagonists, MDV3100 and ARN-509, suppressed the PSA production of castration-resistant tumors, confirming their androgen-dependency. In conclusion, we demonstrated that VCaP xenograft model exhibits the key characteristics of clinical CRPC, thus providing a valuable tool to identify druggable targets and for testing therapeutic strategies targeting AR signaling in CRPC.
Citation Format: Matias Knuuttila, Emrah Yatkin, Jenny Kallio, Saija Savolainen, Teemu Daniel Laajala, Tero Aittokallio, Riikka Oksala, Merja Häkkinen, Pekka Keski-Rahkonen, Seppo Auriola, Matti Poutanen, Sari Mäkelä. Castration induces upregulation of intratumoral androgen biosynthesis and androgen receptor expression in orthotopic VCaP human prostate cancer xenograft model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-31. doi:10.1158/1538-7445.AM2014-LB-31
Abstract LB-320: Systemic tumor-stroma interactions are prognostic indicators of breast tumor invasiveness
Authors: Bainer Russell , Frankenberger Casey , Rabe Daniel , Saleh Sadiq , Park Morag , Chada Kiran , Gilad Yoav , Rosner Marsha 
Published: May 2015

Abstract
Tumor invasiveness dysregulates homeostatic processes within tissues, driving both tumor and stroma cells to locally proliferate while also disrupting tissue boundaries and recruiting cells from distal sites to promote metastatic dissemination. Here, we use an RNA sequencing approach in mouse models of invasive and noninvasive breast cancer to directly test whether the transcriptional changes that occur as invasive tumors disrupt their microenvironment can be used to predict tumor subtype and patient outcomes. We find that tumor and stroma gene expression levels are largely synchronized within the tumor microenvironment, but that the expression levels of a subset of genes with high prognostic potential are strongly negatively correlated and may reflect opposing responses of tumor and normal stroma cells to tissue disruption. We clinically validate these observations in multiple human breast tumor gene expression datasets and demonstrate that stromal transcript levels enable superior classification of breast cancer subtypes relative to those expression changes observed between invasive and noninvasive tumor tissue. We show that local stromal remodelling is partially driven by differential recruitment of macrophages to invasive tumor sites by CCL5, and that invasion-specific gene expression changes that are prognostic for metastasis-free survival in human patients are detectable in stromal tissues far from the primary lesion. Our data indicate that dysregulation of tissue homeostasis by invasive tumors generates transcriptional changes both within the tumor microenvironment and in peripheral tissues that have significant diagnostic and prognostic potential and could facilitate novel patient therapeutic strategies.
Citation Format: Russell Bainer, Casey Frankenberger, Daniel Rabe, Sadiq Saleh, Morag Park, Kiran Chada, Yoav Gilad, Marsha Rosner. Systemic tumor-stroma interactions are prognostic indicators of breast tumor invasiveness. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-320. doi:10.1158/1538-7445.AM2014-LB-320
Abstract LB-33: Establishment and application of patient-derived xenograft models for translational research of personalized cancer therapeutics
Authors: Park Hyeji , Ju Eun Jin , Choi Jinhyang , Park Seok Soon , Park Jaesook , Lee Jae Hee , Shin Seol Hwa , Jeong Seong-Yun , Song Si Yeol , Choi Eun Kyung 
Published: May 2015

Abstract
Although there have been world-wide huge efforts in the field of cancer research to overcome cancer, the therapeutic influence is not satisfactory level yet, because of the diversity and complexity of cancers. The lack of preclinical models for translational research reliably predicting clinical activity of novel therapeutics is another obstacle in cancer research. Xenotransplantation of human cancer cell line into immunodeficient mice is very useful for studying human cancer therapy. However, these animal models have been limited to reflect a practical consideration of clinic and genetic diversity of patients. The creation of patient-derived xenografts (PDX) that carry partial or complete human physiological systems has been certainly accepted as a helpful tool to overcome these obstacles.
We have established total 339 cases in total (lung 79 cases, liver 109 cases, stomach 106 cases and colon 45 cases) up to date, and they were analyzed for the gene mutations by “Onco map” method, in order to compare to the original patient-tumor. As a result of cytogenetically homology comparison and finger printing, PDX tumors represent the same characteristics of the original PD tumors. These PDX models have been practically used for the translational research for personalized cancer therapeutics. This study represents new technologies for translational research platform of personalized cancer therapeutics. Additionally, these translational research platform promise the new access in many other studies such as a drug efficacy test, target discovery and co-clinical study.
Citation Format: Hyeji Park, Eun Jin Ju, Jinhyang Choi, Seok Soon Park, Jaesook Park, Jae Hee Lee, Seol Hwa Shin, Seong-Yun Jeong, Si Yeol Song, Eun Kyung Choi. Establishment and application of patient-derived xenograft models for translational research of personalized cancer therapeutics. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-33. doi:10.1158/1538-7445.AM2014-LB-33
Abstract LB-35: Living biobank of cancer organoids for drug development and screening
Authors: Vries Robert G.J. , Clevers Hans 
Published: May 2015

Abstract
Future cancer therapy will rely on treatment with drugs that are specific for individual tumours and patients. However, predicting clinical responses from genomic data remains highly challenging. Recently, systematic screens utilizing large panels of tumor cell lines have been used to correlate drug sensitivity with tumor genotype to identify predictive genomic markers of drug response. However, tumour cell lines have several drawbacks including being of limited genetic diversity; pre-clinical models that are more representative of the ‘natural’ mutational diversity of cancer are urgently required.
The Clevers lab recently developed methods for long-term culture of human primary tissues and cancers (‘organoids’). By establishing a large collection of tumour-specific organoids, the genetic spectrum of tumours can be captured as a pre-clinical model. This will allow stratification of tumours based on their genomic footprint and drug sensitivity, and may reveal correlations between drug sensitivity and this footprint. We have now established the organoid technology and the first biobank of Colon, Pancreas, and Lung primary carcinomas and metastasis. Importantly, whole genome sequencing of the initial tumour material and long term cultures demonstrate that, similar to healthy organoids, also tumour organoids are stable. The first screens with sets of drugs that are clinically available shows that the organoids respond as would be predicted by their sequence analysis, such as KRAS mutant organoids not responding to the EGFR inhibitor Cetuximab. We do however find patient specific differences which points to a promising role for organoids in drug development, patient stratification and possibly diagnosis. Finally, genetic analysis has indicated that we are efficiently generating organoids of the full range of genetic alterations previously identified in patients for these tumour types, including specific genotypes that are poorly or not represented in any other in vitro model at the moment.
Citation Format: Robert G.J. Vries, Hans Clevers. Living biobank of cancer organoids for drug development and screening. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-35. doi:10.1158/1538-7445.AM2014-LB-35
Abstract LB-5: Ultraviolet radiation inhibits murine mammary carcinogenesis at an early stage
Authors: Makarova Anastasia M. , Wang Grace , Libove Eileen , Khaimskiy Yefim , Epstein Ervin H. 
Published: May 2015

Abstract
Epidemiological studies of geographical variations in breast cancer mortality rates have found increased death rates at higher latitudes in USA and other countries. This breast cancer latitudinal gradient is hypothesized to be mediated by ultraviolet radiation (UVR) - produced vitamin D3. We have tested the effects of UVR in the well-described C3(1)/Tag transgenic mouse and have demonstrated that UVR started at age 6w and continued throughout the life of the mouse inhibits mammary carcinogenesis. Thus UVR prolongs palpable tumor - free survival (15±0.9 vs. 18±1.1 w; p=0.023) and delays the time of death (22±0.9 vs. 25±1.1 w; p=0.028).
To differentiate between an inhibitory effect of UVR on the processes leading to initial histologic changes vs. an effect on the later stage of progression from microscopic to palpable tumors we assessed the anti-carcinogenic effects of UVR given at different time points and for different intervals. UVR was given thrice weekly at 350mJ/cm2 per treatment to FVBN/J C3(1)-Tag females. Treatment groups: (1) No UVR, (2) UVR age 6 w until end of the study, (3) UVR age 6 w until the 1st palpable tumor, (4) UVR 1st palpable tumor until the end of the study, (5) UVR age 12 w (a time when histologic changes are present but no tumor has become palpable) until the 1st palpable tumor. Results: (1) UVR significantly delayed the onset of the first palpable tumor when started at age 6 w (12 days delay, p=0.005, two-tailed t-test) but not when started at age 12 w. (2) UVR started after the 1st tumor became palpable did not reverse already-existing histological changes and did not prolong overall survival, thus confirming that UVR's effects occur at an early, pre-palpable stage of carcinogenesis. (3) UVR was sufficient to delay the first palpable tumor and to prolong overall survival (21±1.0 vs. 23±0.9 w; p=0.002, compared to untreated group) even at short-term exposure from age 6 w until the 1st palpable tumor. Furthermore, UVR reduces the percentage of glands with DCIS changes appreciable histologically by 82, 55, 66, 20 and 19% at ages 9, 11, 13, 14 and 15 weeks). Thus UVR is able to delay the appearance of early stages of breast carcinogenesis but is unable to reverse already-present histologic changes and their progression to more advanced cancer.
Garland, F. C. et all. Prev Med 1990, 19, 614-22.; Green, J. E. et all. Oncogene 2000, 19, 1020-7.
Citation Format: Anastasia M. Makarova, Grace Wang, Eileen Libove, Yefim Khaimskiy, Ervin H. Epstein. Ultraviolet radiation inhibits murine mammary carcinogenesis at an early stage. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-5. doi:10.1158/1538-7445.AM2014-LB-5
Abstract LB-50: TRIM3, the human homolog of Drosophila Brat, is a tumor suppressor that regulates asymmetric cell division (ACD) in glioblastoma stem cells
Authors: Mukherjee Subhas , Chen Gang , Anand Monika , Kong Jun , Tucker-Burden Carol , Rong Yuan , Rahman Fahmia , Moreno Carlos , Meir Erwin Van , Hadjipanayis Constantinos , Brat Daniel 
Published: May 2015

Abstract
Cancer stem cells, capable of self-renewal and multipotent differentiation, influence tumor behavior through a complex balance of symmetric and asymmetric cell divisions. Mechanisms regulating the dynamics of stem cell and their progeny in human cancer are poorly understood. In Drosophila, mutation of brain tumor (brat) leads to loss of normal asymmetric cell division by developing neural cells and results in a massively enlarged brain composed of neuroblasts with neoplastic properties. Brat promotes asymmetric cell division and directs neural differentiation at least partially through its suppression on Myc. We identified TRIM3 (11p15.5) as a human ortholog of Drosophila brat and demonstrate its regulation of asymmetric cell division and stem cell properties of glioblastoma (GBM), a highly malignant human brain tumor. TRIM3 gene expression is markedly reduced in human GBM samples, neurosphere cultures and cell lines and its reconstitution impairs growth properties in vitro and in vivo. TRIM3 expression attenuates stem-like qualities of primary GBM cultures, including neurosphere formation and the expression of stem cell markers CD133, Nestin and Nanog. In GBM stem cells, TRIM3 expression leads to a greater percentage dividing asymmetrically rather than symmetrically. As with Brat in Drosophila, TRIM3 suppresses c-Myc expression and activity in human glioma cell lines. We also demonstrate a strong regulation of Musashi-Notch signaling by TRIM3 in GBM neurospheres and neural stem cells that may better explain its effect on stem cell dynamics. We conclude that TRIM3 acts as a tumor suppressor in GBM by restoring asymmetric cell division.
Citation Format: Subhas Mukherjee, Gang Chen, Monika Anand, Jun Kong, Carol Tucker-Burden, Yuan Rong, Fahmia Rahman, Carlos Moreno, Erwin Van Meir, Constantinos Hadjipanayis, Daniel Brat. TRIM3, the human homolog of Drosophila Brat, is a tumor suppressor that regulates asymmetric cell division (ACD) in glioblastoma stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-50. doi:10.1158/1538-7445.AM2014-LB-50
Abstract LB-63: Cell ground state dictates cancer susceptibility across organs
Authors: Zhu Liqin , Poppleton Helen , Neale Geoffrey , Onar-Thomas Arzu , Pounds Stanley , Bahrami Armita , Utley Sarah , Wang Kasper S. , Lopez-Terrada Dolores H. , Ellison David W. , Gilbertson Richard J. 
Published: May 2015

Abstract
Cancers are distributed unevenly across the body, suggesting that cell context dictates susceptibility to transformation. To test this hypothesis, we mapped cellular susceptibility to tumor initiation across all organs in adult mice. Ten combinations of potent oncogenic mutations, including activating mutations of Kras, Notch1, Ctnnb1 and deletions of tumor suppressors Tp53,Pten and Cdkn2a, were targeted by conditional recombination into Prom1+ (CD133+) cells in the organs of &gt;800 Prom1-Cre/+ mice. Life time clinical surveillance, necropsy and gene expression profiling of over 250 animals, across all genotypes, identified extensive tumor formation that was biased to certain organs including small intestine, stomach, liver, skin, prostate and uterus. Extensive histology and cross-species genomics confirmed these tumors recapitulated &gt;250 tissue-matched human cancers. Detailed mapping of the number and proliferative activity of Prom1+ cells in organs demonstrated that these variables did not dictate cancer incidence. Rather, parallel, life-long linage tracing of Prom1+ populations showed that the capacity of these cells to repair and regenerate their host organ is directly correlated with their tumorigenic capacity. Only Prom1+ cells capable of long-term tissue renewal generated cancers; quiescent and differentiated Prom1+ cells rarely formed tumors regardless of targeted oncogenic mutation. The repair/regeneration capacity of Prom1+ populations also dictated developmental and damage-response patterns of tumorigenesis. Normally quiescent and tumor-resistant Prom1+ cells in the adult liver became highly regenerative upon liver damage, dramatically increasing their tumorigenic capacity. Conversely, Prom1+ cells are highly proliferative in the neonatal liver - driving the development of this organ - and were highly susceptible to transformation without inducing liver damage. Remarkably, neonatal Prom1+ cells formed hepatoblastoma, the pediatric form of liver cancer. Our large-scale, comprehensive mapping of tumor susceptibility shows that cell ground-state, and specifically the capacity to repair and regenerate organs, is a common determinant of cancer susceptibility across all major organs.
Citation Format: Liqin Zhu, Helen Poppleton, Geoffrey Neale, Arzu Onar-Thomas, Stanley Pounds, Armita Bahrami, Sarah Utley, Kasper S. Wang, Dolores H. Lopez-Terrada, David W. Ellison, Richard J. Gilbertson. Cell ground state dictates cancer susceptibility across organs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-63. doi:10.1158/1538-7445.AM2014-LB-63
Abstract LB-65: Bevacizumab fate in glioblastoma: Mechanism of internalization by endothelial cells and glioma stem cells
Authors: Muller-Greven Gaelle M. , Carlin Cathleen , Rich Jeremy , Hamerlik Petra , Gladson Candece L. 
Published: May 2015

Abstract
Antiangiogenic therapy shows great promise for treatment of cancer. Bevacizumab is a humanized mAb that blocks VEGF-A, thereby inhibiting angiogenesis. It has received FDA approval for patients with recurrent glioblastoma (GBM); however, greater than 30% of patients are non-responsive and the underlying mechanism for the lack of response is not known. It has been assumed that Bevacizumab solely targets circulating VEGF-A; however, VEGF-A found in the tumor could also be an important target for Bevacizumab that impacts the response of patients. We hypothesized that Bevacizumab is transcytosed across brain endothelial cells (ECs), gains access to the perivascular niche containing glioma stem cells (GSCs), and that differences in GSC endocytosis of Bevacizumab and either recycling or degradation determine a patients response. We found that Bevacizumab is internalized by normal and tumor-isolated brain ECs in a time-dependent manner that is partially inhibited by amiloride and stimulated by EGF, suggesting Bevacizumab enters the cells by an endocytic pathway such as macropinocytosis. In a standard transcytosis assay, we showed that brain ECs transcytose 62% of Bevacizumab from the upper chamber to the lower chamber over two-hours. We also found that GSCs internalize Bevacizumab in a manner resembling macropinocytosis and that it is partially co-localized with LAMP1, suggesting Bevacizumab is partly targeted for degradation. Furthermore, in an orthotopic xenograft model of GBM administered Bevacizumab, we found that Bevacizumab was localized to the perivascular space, found within perivascular GBM tumor cells, and that a gradient of Bevacizumab was detected with less observed at further distances from vessels. Ongoing experiments will determine the endocytic compartment(s) containing Bevacizumab in GSCs and its trafficking. Understanding the mechanism of internalization and trafficking of Bevacizumab in GBM tumors and in isolated GSCs from different molecular subtypes will likely help us understand who will be responsive to Bevacizumab, and perhaps who will be responsive to therapy with other mAbs.
Citation Format: Gaelle M. Muller-Greven, Cathleen Carlin, Jeremy Rich, Petra Hamerlik, Candece L. Gladson. Bevacizumab fate in glioblastoma: Mechanism of internalization by endothelial cells and glioma stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-65. doi:10.1158/1538-7445.AM2014-LB-65