bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1375: Contrasting effects of VEGF pathway inhibitors in primary and metastatic disease using perioperative neoadjuvant mouse models
Authors: Ebos John M.L. , Lee Christina R. , Cruz-Munoz William , Jedeszko Christopher , Kerbel Robert S. 
Published: August 2012

Abstract
Recent clinical trial failures with antiangiogenic therapy in patients with early-stage disease have raised the possibility that drug efficacy in preclinical studies, typically involving models of localized primary grown tumors, may not always predict for efficacy in treating metastatic disease, which is the most common cause of mortality in patients. Moreover, depending on disease stage and treatment circumstances, the efficacy of VEGF-pathway inhibitors administered as monotherapies may be offset in certain settings by increased aggressive invasiveness and augmented metastatic potential. Thus, with hundreds of trials underway in neoadjuvant and adjuvant settings to evaluate the efficacy of antiangiogenic therapy in blocking or slowing micrometastatic disease and eventual tumor recurrence, there is an urgent need clarify the utility of such drugs in all stages of tumor progression. Herein we describe a novel preclinical neoadjuvant therapeutic methodology used to compare the effects of short-term VEGF pathway inhibition in highly metastatic human breast, melanoma, and kidney tumor cells grown orthotopically in SCID mice before and after surgical resection. While cytotoxic chemotherapy administered in the maximum tolerated dose could slow tumor growth and lead to a prolongation of survival after resection, similar significant benefits by various VEGF inhibitors in primary tumor inhibition did not consistently translate into significant prevention of recurrent local and distant metastasis after treatment cessation. Furthermore, reductions in primary tumor growth by neutralizing antibodies to VEGF or VEGFR-2 were more predictive of modest survival benefits after tumor resection, compared to the VEGFR tyrosine kinase inhibitor (TKI) sunitinib, which had either no effect or decreased survival compared to control - despite significant reductions in primary tumor growth after neoadjuvant treatment. Potential tumor-independent ‘host’ drug responses could account for this difference as short-term treatment of immunocompromised nu/nu mice prior to intravenous tumor inoculation lead to modest or negligible benefits with VEGF or VEGFR2 antibodies compared to worse outcomes in VEGFR TKI pre-treated animals. Taken together, preclinical neoadjuvant therapy allows for the distinction of ‘anti-primary’ and ‘anti-metastatic’ effects and may serve as a predictive tool to model ongoing clinical trials as well as indicate potential drug combinations which may be used to overcome limitations when such drugs are used as a monotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1375. doi:1538-7445.AM2012-1375
Abstract 1379: The role of PERK and the unfolded protein response in the development of resistance to antiangiogenic agents in renal cell carcinoma
Authors: Zhu Shudong , Panka David J. , Mier James W. , Cho Daniel C. 
Published: August 2012

Abstract
Introduction: Intrinsic and delayed resistance of renal cell carcinoma (RCC) towards agents targeting VEGF-signaling remains a major therapeutic problem. The initial regression of RCC metastases observed in many patients treated with VEGFR2 antagonists is due to the hypoxia and diminished supply of nutrients resulting from the involution of tumor microvasculature. However, hypoxia also elicits a series of adaptive responses in tumor cells that enhance their survival, including activation of the unfolded protein response. To investigate the role of the unfolded protein response in the resistance of RCC to antiangiogenic agents, we assessed the effects of suppressing PERK in RCC cell lines. Experimental Design: A 786-O cell line was generated which was transfected with tetracycline-regulable shRNA targeting PERK. The 786-0 PERK shRNA cell line was exposed to hypoxia (0.5% O2) and glucose deprivation both in the presence and absence of doxycycline. Cells thus treated were lysed after 24 hours for western blot analysis for PERK, LC3, phospho-ACC, BIP, and phopsho-eIF2α. Similarly treated cells were also analyzed after 48 hours for viability by propidium iodide staining. Xenografts were generated from 786-O PERK snRNA cells in nude beige mice and grown to 10mm in size. Mice were then treated with saline, doxycycline (2mg/ml in drinking water), sunitinib (50mg/kg) once daily by gavage, or the combination of both doxycline and sunitinib. Results: Treatment of 786-O PERK shRNA cells with doxycycline suppressed expression level of PERK by approximately 80%. Knockdown of PERK significantly increased cell death resulting from exposure of cell lines to hypoxia and nutrient deprivation in vitro associated with diminished expression of LC3. Treatment of mice bearing 786-0 PERK snRNA xenografts with doxycycline or sunitnib alone had little effect on tumor growth compared with saline treated mice. However, the combination of both sorafenib and doxycline resulted in a sustained tumor growth arrest. Conclusions: These data suggested that PERK and the unfolded protein response have a critical role in the ability of tumor cells to survive the insult of hypoxia and nutrient deprivation caused by the diminished vasculature induced by antiangiogenic therapy. Therapeutic strategies to oppose to unfolded protein response may be promising adjuncts to antiangiogenc agents in RCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1379. doi:1538-7445.AM2012-1379
Abstract 138: The effects of microRNA transfections on global patterns of gene expression are functionally coordinated
Authors: McDonald John F. , Shahab Shubin , Mezencev Roman , Matyunina Lilya , Wang LiJuan 
Published: August 2012

Abstract
A current challenge in the application of miRNAs in cancer therapeutics is the inability to accurately predict the functional consequences of exogenous perturbations in the levels of potentially therapeutic miRNAs. To systematically address this issue, two miRNAs (miR-7 and miR-128) were separately transfected into a well characterized ovarian cancer cell line (HEY) and global changes in levels of gene expression were monitored. While ∼20% of the changes in expression patterns of hundreds to thousands of genes could be attributed to direct miRNA-mRNA interactions, the majority of the changes were indirect, involving the downstream consequences of miRNA-mediated changes in regulatory gene expression. The pathways most significantly affected by miR-7 transfection are involved with cell adhesion and other developmental networks previously associated with epithelial-mesenchymal transitions (EMT) and other processes linked with metastasis. In contrast, the pathways most significantly affected by miR-128 transfection are more focused on cell cycle control and other processes commonly linked with cellular replication. These computational predictions were experimentally verified. Our results indicate that changes in patterns of gene expression induced by exogenous expression of miRNAs are not random but functionally coordinated and that different families of miRNAs may regulate distinct cellular functions related to cancer. Our findings suggest that miRNAs may be of unique therapeutic value by providing clinicians with a strategy to treat cancer from a systems rather than a single gene perspective.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 138. doi:1538-7445.AM2012-138
Abstract 1380: Mechanisms of resistance to antiangiogenic therapy in preclinical models of head and neck squamous cell carcinoma (HNSCC)
Authors: Gyanchandani Rekha , Grandis Jennifer R. , Kim Seungwon 
Published: August 2012

Abstract
Purpose: The Vascular Endothelial Growth Factor (VEGF) is ubiquitously expressed and targeted with FDA-approved agent bevacizumab in many types of cancer including colon, lung and renal carcinoma. In head and neck cancer, bevacizumab is under active clinical investigation. However, its efficacy in most cases is limited, with only modest response rates observed in the clinical trials. These incomplete drug responses suggest the presence of alternative signaling mechanisms that compensate for VEGF blockade. The proinflammatory cytokine, Interleukin 8 (IL-8) is known to promote tumor angiogenesis, and is coexpressed with VEGF in HNSCC. Hence, IL-8 signaling may be a possible mechanism of resistance to anti-VEGF therapy. Experimental Design: In this study, we assessed the efficacy of bevacizumab in preclinical HNSCC models to identify tumors that were sensitive or resistant to the treatment. In order to identify potential mediators of bevacizumab resistance, we evaluated the angiogenic profile of HNSCC cells from the non-isogenic pair of sensitive and resistant cell lines by performing angiogenesis antibody array. We further examined the potential contribution of IL-8 signaling to the in vivo growth of bevacizumab-resistant xenografts, using shRNA-mediated knockdown of the IL-8 gene. Results: HNSCC cell lines showed a range of response to bevacizumab in vivo. Interestingly, the resistant cell lines expressed high levels of proangiogenic factors including IL-8, IL-1a and VEGF compared to the sensitive cell lines. Further, combined inhibition of VEGF and IL-8 in the resistant xenografts resulted in a significant reduction in tumor volume and microvessel density compared to targeting VEGF alone. Conclusions: Our results indicate that HNSCC xenografts display a differential response to anti-VEGF therapy. IL-8 was the most differentially expressed protein in the angiogenic signature of the bevacizumab-resistant and sensitive cells. Finally, abrogation of IL-8 signaling sensitized the resistant xenografts to anti-VEGF therapy. These findings suggest that IL-8 may be associated with anti-VEGF resistance in HNSCC. Hence, co-targeting of VEGF and IL-8 may improve antiangiogenic therapeutic efficacy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1380. doi:1538-7445.AM2012-1380
Abstract 1382: Increased expression of placental growth factor is linked with shortened survival of patients with advanced ovarian cancer
Authors: Block Matthew S. , Maurer Matthew J. , Ramar Priya , Behrens Marshall D. , Erskine Courtney L. , Kalli Kimberly R. , Hartmann Lynn C. , Knutson Keith L. 
Published: August 2012

Abstract
Background: Ovarian cancer (OC) is the leading cause of gynecologic cancer death in the United States. Survival in advanced OC is highly variable; some patients are cured of their disease with a combination of surgery and systemic chemotherapy, while the majority of patients develop recurrence and ultimately die of metastatic OC. While markers of poor prognosis within advanced OC exist, they have not translated to changes in therapy or outcomes. Vascular growth factors are important soluble mediators of tumor growth, vasculogenesis and angiogenesis that may be targeted therapeutically. We therefore explored the association between plasma levels of vascular growth factors and clinical outcomes in advanced OC. Methods: We enrolled 200 patients with OC or benign surgical conditions from the Mayo Ovarian SPORE Biospecimens Core. Presurgical plasma samples from patients with advanced OC (AJCC Stage III and IV, n = 100), early stage OC (Stage I and II, n = 50), and benign surgical conditions (n = 50) were assayed for vascular growth factors via multiplex electrochemiluminescence and by ELISA. Differences in plasma levels between benign, early, and advanced OC patient groups were assessed using plate-adjusted linear models. Associations between plasma levels of vascular growth factors and overall survival in advanced OC patients were assessed by Cox proportional hazards models. Results: Both vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) levels were increased in patients with advanced OC (mean ng/mL = 130.8, p = 0.004; mean ng/mL = 20.1, p = 0.025, respectively) compared to patients with early stage (mean ng/mL = 75.1 and 19.0 respectively) and benign conditions (mean ng/mL = 86.8 and 15.0, respectively). An increase in PlGF levels was associated with poor overall survival in patients with advanced OC (HR = 2.52, p = 0.005), while increase in VEGF levels were of borderline significance (HR = 1.21, p = 0.061) Conclusions: Soluble PlGF and VEGF are increased in the setting of advanced OC. Increased plasma PlGF is strongly linked to poor prognosis, while VEGF levels have a borderline association with prognosis. These data provide a rationale for therapeutic targeting of both VEGF and PlGF.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1382. doi:1538-7445.AM2012-1382
Abstract 1383: High levels of CD109+ circulating endothelial cells and progenitors as marker of response to bevacizumab and irinotecan in high grade gliomas
Authors: Cuppini Lucia , Pellegatta Serena , Calleri Angelica , Bruzzone Maria Grazia , Prodi Elena , Anghileri Elena , Mancuso Patrizia , Bertolini Francesco , Finocchiaro Gaetano , Eoli Marica 
Published: August 2012

Abstract
Purpose: Bevacizumab, an anti-VEGF antibody, has shown significant activity in high grade gliomas (HGG). Previous studies emphasized the need for predictive markers of response. Experimental Design: We treated 63 recurrent HGG patients with poor prognostic factors with bevacizumab (10 mg/kg) and irinotecan (125 or 340 mg/m2) every 2 weeks, and investigated the predictive potential of circulating endothelial cells (CECs) and their progenitors (CEPs). Results: After a median follow-up of 27 weeks, median OS and PFS were 33 and 18 weeks, respectively. PFS at 6 and 12 months were 32% and 12%. OS at 6 months was 60%. No complete response but fourteen partial responses according to RANO criteria were observed. Toxicity and side effects were mild. Patients with distant intracerebral disease or leptomeningeal dissemination at baseline MRI had shorter PFS (p=0.002; p=0.01) and OS (p=0.005; p=0.03). Baseline CEP over 32.8 cells/ml (1st quartile) or CD45dimCD34+CD133+ hematopoietic committed progenitors over 27 cells/ml (1st quartile) were associated with an increased PFS (p=0.01; p=0.001, respectively). Baseline CD109+ CECs over 47.5 cells/ml (2nd quartile) were associated with longer PFS and OS (p= 0.001; p=0.02). Patients who progressed after 18 weeks of therapy or more (n=22) had baseline levels of CD109+ CECs and CD45dimCD34+VEGFR2+ cells significantly higher than others (p=0.008; p=0.04, respectively). At progression no significant change in CEC and CEP was detected. Conclusions: The data point to baseline CD109+ CECs, CEP and CD45dimCD34+CD133+ hematopoietic committed progenitors as promising markers for the selection of patients who could benefit from bevacizumab in the treatment of HGG.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1383. doi:1538-7445.AM2012-1383
Abstract 1384: Axl and VE-cadherin expression as markers of angiogenesis in human breast cancers
Authors: Veien Kristi Anne , Krüger Kristi , Stefansson Ingunn , Arnes Jarle B. , Collett Karin , Akslen Lars A. 
Published: August 2012

Abstract
Background: The aim of our study was to investigate vascular expression of Axl and VE-cadherin as potential markers of angiogenesis in human breast carcinoma. Materials and methods: Immunohistochemical staining was performed using antibodies against Axl and VE-cadherin. Expression was examined in a population-based series of breast cancers collected in Hordaland County (Norway) during 1996-2001. The series is a nested case-control study as part of the Norwegian Breast Cancer Screening Program, and consists of 95 invasive interval cancers and 95 invasive screen detected cancers matched by tumor diameter. Positive microvessels were counted in 10 consecutive high power fields within hot-spot areas according to previously established criteria and expressed as microvessel density (MVD) by mean number of microvessels per mm2. Results: The MVD for Axl was associated with progesterone receptor status (p=0.026), HER-2 status (p=0.030) and basal-like phenotypes: CK5/6+ P-cadherin+ (p=0.009), ER- HER2-CK5/6+ (p=0.014) and ER- HER2- CK5/6+ and/or EGFR+ (p=0.027). In contrast, MVD by VE-cadherin expression (n=127) indicated negative associations with basal-like phenotypes: CK5/6+ or P-cadherin+ or EGFR+ (p=0.034), and ER- HER2- P-cadherin+ (p=0.003). VE-cadherin expression also tended to be associated with better patient survival (p=0.067). Conclusion: High MVD by vascular expression of Axl was associated with aggressive features in our breast cancer series, especially the basal-like phenotype, whereas MVD by VE-cadherin expression appeared to be related to less aggressive tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1384. doi:1538-7445.AM2012-1384
Abstract 1390: In vivo tracking of cancer-cell-derived exosomes
Authors: Homma Kimi , Suetsugu Atsushi , Ochiya Takahiro , Hoffman Robert M. 
Published: August 2012

Abstract
The goal of the present study was to determine if exosomes play a role in cell-to-cell communication to promote tumor metastasis. Green fluorescence protein (GFP) was linked to CD63, which is a general marker of exosomes, in order to track breast-cancer-cell-derived exosomes cancer in nude mice. Breast cancer cells transferred their own exosomes to other cancer cells and normal lung tissue cells in culture. In the nude mouse, breast cancer cells secreted GFP exosomes into the tumor micro environments as well as the circulation. Numerous GFP in exosomes were visualized in breast cancer metastases in nude mice. The results of this study suggest that tumor-derived exosomes may contribute to formation of a niche to promote metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1390. doi:1538-7445.AM2012-1390
Abstract 1391: Breast cancer cells and the bone: A tale of treachery
Authors: Das Shamik , Tucker J. Allan , Khullar Shikha , Samant Rajeev S. , Shevde Lalita A. 
Published: August 2012

Abstract
Under normal physiological conditions there is a dynamic equilibrium in the bone maintained by the bone forming osteoblasts and bone resorbing osteoclasts. The bone stroma provides hospitable sites for disseminating, colonization-competent breast cancer cells. The Hedgehog (Hh) pathway plays an important role in skeletogenesis. Our studies have determined that breast tumor cells have an activated Hh pathway characterized by upregulation of Hh ligands and the transcription factor GLI1. Our findings show that breast cancer cells activate Hh signaling in pre-osteoclasts and thereby upregulate osteoclastogenesis. Paracrine Hh signaling induced in osteoclasts by breast cancer cells mediates a series of events by the up-regulation of osteopontin (OPN), which in turn enhances osteoclastic activity by up-regulating the essential proteases cathepsin K and MMP9. Surprisingly, we found that breast cancer cells also activate osteoblast differentiation as an early event, by activating Hh signaling in pre-osteoblasts. This leads to the expression of RANKL and PTHrP by the osteoblasts. RANKL and PTHrP promote osteoclastogenesis while the osteoblasts are eliminated by apoptosis. Pharmacological inhibition of Hh signaling results in an overall decrease in osteoblast differentiation and osteoclastogenesis/resorptive activity. Thus our studies suggest that the breast cancer cells orchestrate a chain of events in which they directly foster osteoclastogenesis and deceptively induce osteoblasts to differentiate which in turn produce factors that promote osteoclast differentiation. A vicious cycle ensues and in the presence of increased number of metastasing breast cancer cells the balance now shifts in favor of the osteoclasts resulting in osteolysis, the final painful outcome of a majority of breast cancer patients. Thus in the light of our findings, any therapeutic approach utilizing inhibitors for the Hh pathway need to take into consideration the dual role of the pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1391. doi:1538-7445.AM2012-1391