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PDF file - 4313K, Results of immunostaining of ovarian tumor sections obtained from mice

PDF file - 2007K, Results of Biacore studies of FGFR4mut:Fc FGF-binding affinity

PDF file - 2539K, Detailed protocol used for immunolocalization of FGFR4 in ovarian tumor sections

PDF file - 2929K, FGFR4 silencing in ovarian cancer cells by siRNA transfection

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Purpose: To evaluate the prognostic value of fibroblast growth factor receptor 4 (FGFR4) protein expression in patients with advanced-stage, high-grade serous ovarian cancer, delineate the functional role of FGFR4 in ovarian cancer progression, and evaluate the feasibility of targeting FGFR4 in serous ovarian cancer treatment.Experimental Design: Immunolocalization of FGFR4 was conducted on 183 ovarian tumor samples. The collected FGFR4 expression data were correlated with overall survival using Kaplan–Meier and Cox regression analyses. The effects of FGFR4 silencing on ovarian cancer cell growth, survival, invasiveness, apoptosis, and FGF1-mediated signaling pathway activation were evaluated by transfecting cells with FGFR4-specific siRNAs. An orthotopic mouse model was used to evaluate the effect of injection of FGFR4-specific siRNAs and FGFR4 trap protein encapsulated in nanoliposomes on ovarian tumor growth in vivo.Results: Overexpression of FGFR4 protein was significantly associated with decreased overall survival durations. FGFR4 silencing significantly decreased the proliferation, survival, and invasiveness and increased apoptosis of ovarian cancer cells. Also, downregulation of FGFR4 significantly abrogated the mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), and WNT signaling pathways, which are activated by FGF1. Targeting FGFR4 with the FGFR4-specific siRNAs and FGFR4 trap protein significantly decreased ovarian tumor growth in vivo.Conclusions: FGFR4 is a prognostic marker for advanced-stage, high-grade serous ovarian carcinoma. Silencing FGFR4 and inhibiting ligand-receptor binding significantly decrease ovarian tumor growth both in vitro and in vivo, suggesting that targeting ovarian cancer cells with high levels of FGFR4 protein expression is a new therapeutic modality for this disease and will improve survival of it. Clin Cancer Res; 19(4); 809–20. ©2012 AACR.

PDF file - 2689K, Common differentially expressed genes in both OVCA432 and SKOV3 cells transfected with the FGFR4-specific siRNAs Hs_FGFR4_5 and Hs_FGFR4_6

PDF file - 3119K, Effect of FGFR4 overexpression and exogenous FGF1 and on ovarian cancer cell proliferation

PDF file, 2794K, The proposed model of TGF-B-modulated cross-talk between ovarian cancer cells and CAFs in the ovarian tumor microenvironment.

PDF file, 282K, Microdissection of normal ovarian tissue and high-grade serous ovarian tumor samples.

PDF file, 254K, Complete list of VCAN-regulated genes identified in OVCA433 cells treated with VCAN.

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PDF file, 193K, Immunostaining of ovarian tissue sections for TGF-B receptor type 1 and 2.

PDF file, 4737K, Expression of EMT markers in ovarian cancer cells co-cultured with fibroblasts.

PDF file, 1213K, A primary CAF line treated with TGF-B in the presence or absence of TGF-B pathway inhibitor.

PDF file, 130K, TGF-B concentrations in conditioned media of the co-culture system.

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PDF file, 152K, Complete list of CAF-specific, TGF-B-regulated genes identified in NOF151-hTERT fibroblasts treated with TGF-B.

TGF-β has limited effects on ovarian cancer cells, but its contributions to ovarian tumor growth might be mediated through elements of the tumor microenvironment. In the present study, we tested the hypothesis that TGF modulates ovarian cancer progression by modulating the contribution of cancer-associated fibroblasts (CAF) that are present in the microenvironment. Transcriptome profiling of microdissected stromal and epithelial components of high-grade serous ovarian tumors and TGF-β–treated normal ovarian fibroblasts identified versican (VCAN) as a key upregulated target gene in CAFs. Functional evaluations in coculture experiments showed that TGF-β enhanced the aggressiveness of ovarian cancer cells by upregulating VCAN in CAFs. VCAN expression was regulated in CAFs through TGF-β receptor type II and SMAD signaling. Upregulated VCAN promoted the motility and invasion of ovarian cancer cells by activating the NF-κB signaling pathway and by upregulating expression of CD44, matrix metalloproteinase-9, and the hyaluronan-mediated motility receptor. Our work identified a TGF-β–inducible gene signature specific to CAFs in advanced high-grade serous ovarian tumors, and showed how TGF-β stimulates ovarian cancer cell motility and invasion by upregulating the CAF-specific gene VCAN. These findings suggest insights to develop or refine strategies for TGF-β–targeted therapy of ovarian cancer. Cancer Res; 73(16); 5016–28. ©2013 AACR.

Increased number of tumor-infiltrating CD8+ lymphocytes is associated with improved survival in patients with advanced stage high grade serous ovarian cancer (HGSOC) but the underlying molecular mechanism has not been thoroughly explored. Using transcriptome profiling of microdissected HGSOC tissue with high and low CD8+ lymphocyte count and subsequent validation studies, we demonstrated that significantly increased ISG15 (Interferon-stimulated gene 15) expression in HGSOC was associated with high CD8+ lymphocyte count and with the improvement in median overall survival in both univariate and multivariate analyses. Further functional studies showed that endogenous and exogenous ISG15 suppressed ovarian cancer progression through ISGylation of ERK in HGSOC, and activation of NK cells and CD8+ T lymphocytes. These data suggest that the development of treatment strategies based on up-regulating ISG15 in ovarian cancer cells or increased circulating ISG15 in ovarian cancer patients is warranted.

TGF-β has limited effects on ovarian cancer cells, but its contributions to ovarian tumor growth might be mediated through elements of the tumor microenvironment. In the present study, we tested the hypothesis that TGF modulates ovarian cancer progression by modulating the contribution of cancer-associated fibroblasts (CAF) that are present in the microenvironment. Transcriptome profiling of microdissected stromal and epithelial components of high-grade serous ovarian tumors and TGF-β–treated normal ovarian fibroblasts identified versican (VCAN) as a key upregulated target gene in CAFs. Functional evaluations in coculture experiments showed that TGF-β enhanced the aggressiveness of ovarian cancer cells by upregulating VCAN in CAFs. VCAN expression was regulated in CAFs through TGF-β receptor type II and SMAD signaling. Upregulated VCAN promoted the motility and invasion of ovarian cancer cells by activating the NF-κB signaling pathway and by upregulating expression of CD44, matrix metalloproteinase-9, and the hyaluronan-mediated motility receptor. Our work identified a TGF-β–inducible gene signature specific to CAFs in advanced high-grade serous ovarian tumors, and showed how TGF-β stimulates ovarian cancer cell motility and invasion by upregulating the CAF-specific gene VCAN. These findings suggest insights to develop or refine strategies for TGF-β–targeted therapy of ovarian cancer. Cancer Res; 73(16); 5016–28. ©2013 AACR.

Purpose: To evaluate the prognostic value of fibroblast growth factor receptor 4 (FGFR4) protein expression in patients with advanced-stage, high-grade serous ovarian cancer, delineate the functional role of FGFR4 in ovarian cancer progression, and evaluate the feasibility of targeting FGFR4 in serous ovarian cancer treatment. Experimental Design: Immunolocalization of FGFR4 was conducted on 183 ovarian tumor samples. The collected FGFR4 expression data were correlated with overall survival using Kaplan–Meier and Cox regression analyses. The effects of FGFR4 silencing on ovarian cancer cell growth, survival, invasiveness, apoptosis, and FGF1-mediated signaling pathway activation were evaluated by transfecting cells with FGFR4-specific siRNAs. An orthotopic mouse model was used to evaluate the effect of injection of FGFR4-specific siRNAs and FGFR4 trap protein encapsulated in nanoliposomes on ovarian tumor growth in vivo. Results: Overexpression of FGFR4 protein was significantly associated with decreased overall survival durations. FGFR4 silencing significantly decreased the proliferation, survival, and invasiveness and increased apoptosis of ovarian cancer cells. Also, downregulation of FGFR4 significantly abrogated the mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), and WNT signaling pathways, which are activated by FGF1. Targeting FGFR4 with the FGFR4-specific siRNAs and FGFR4 trap protein significantly decreased ovarian tumor growth in vivo. Conclusions: FGFR4 is a prognostic marker for advanced-stage, high-grade serous ovarian carcinoma. Silencing FGFR4 and inhibiting ligand-receptor binding significantly decrease ovarian tumor growth both in vitro and in vivo, suggesting that targeting ovarian cancer cells with high levels of FGFR4 protein expression is a new therapeutic modality for this disease and will improve survival of it. Clin Cancer Res; 19(4); 809–20. ©2012 AACR.

Key processes in normal and diseased cells depend directly or indirectly on the viscoelastic properties of the cytoplasm. Particle-tracking microrheology is a highly versatile method that measures the viscoelastic properties of cytoplasm directly by tracking fluorescent nanoparticles embedded in the cytoskeleton with high spatial and temporal resolutions. Here we present a new method that combines cell transfection, ballistic injection, and particle-tracking microrheology to monitor changes in cytoplasmic micromechanics following controlled changes in protein expression. We demonstrate that cells transfected with GFP (green fluorescent protein) display viscoelastic properties identical to untransfected fibroblasts, that low levels of expression of GFP-alpha-actinin do not affect cell microrheology, and that the transient transfection with GFP-C3 transferase reduces the elasticity of the cytoplasm of fibroblasts to a similar extent as C3 transferase toxin, which de-activates the GTPase Rho. Combining cell transfection with particle-tracking microrheology opens the way to quantitative, single live-cell mechanical studies where stable cell lines cannot be easily established, but where commonly used transfections can be exploited to manipulate cytoskeletal organization.

Key processes in normal and diseased cells depend directly or indirectly on the viscoelastic properties of the cytoplasm. Particle‐tracking microrheology is a highly versatile method that measures the viscoelastic properties of cytoplasm directly by tracking fluorescent nanoparticles embedded in the cytoskeleton with high spatial and temporal resolutions. Here we present a new method that combines cell transfection, ballistic injection, and particle‐tracking microrheology to monitor changes in cytoplasmic micromechanics following controlled changes in protein expression. We demonstrate that cells transfected with GFP (green fluorescent protein) display viscoelastic properties identical to untransfected fibroblasts, that low levels of expression of GFP‐α‐actinin do not affect cell microrheology, and that the transient transfection with GFP‐C3 transferase reduces the elasticity of the cytoplasm of fibroblasts to a similar extent as C3 transferase toxin, which de‐activates the GTPase Rho. Combining cell transfection with particle‐tracking microrheology opens the way to quantitative, single live‐cell mechanical studies where stable cell lines cannot be easily established, but where commonly used transfections can be exploited to manipulate cytoskeletal organization.

Cadherins are ubiquitous cell surface molecules that are expressed in virtually all solid tissues and localize at sites of cell-cell contact. Cadherins form a large and diverse family of adhesion molecules, which play a crucial role in a multitude of cellular processes, including cell-cell adhesion, motility, and cell sorting in maturing organs and tissues, presumably because of their different binding capacity and specificity. Here, we develop a method that probes the biochemical and biophysical properties of the binding interactions between cadherins expressed on the surface of living cells, at the single-molecule level. Single-molecule force spectroscopy reveals that classical cadherins, N-cadherin and E-cadherin, form bonds that display adhesion specificity, and a pronounced difference in adhesion force and reactive compliance, but not in bond lifetime. Moreover, their potentials of interaction, derived from force-spectroscopy measurements, are qualitatively different when comparing the single-barrier energy potential for the dissociation of an N-cadherin-N-cadherin bond with the double-barrier energy potential for an E-cadherin-E-cadherin bond. Together these results suggest that N-cadherin and E-cadherin molecules form homophilic bonds between juxtaposed cells that have significantly different kinetic and micromechanical properties.

Objectives: Adipose tissue contains a population of multipotent adipose stem cells (ASCs) that form tumor stroma and can promote tumor progression. Given the high rate of ovarian cancer metastasis to the omental adipose, we hypothesized that omental-derived ASC may contribute to ovarian cancer growth and dissemination. Materials and Methods: We isolated ASCs from the omentum of three patients with ovarian cancer, with (O-ASC4, O-ASC5) and without (O-ASC1) omental metastasis. BM-MSCs, SQ-ASCs, O-ASCs were characterized with gene expression arrays and metabolic analysis. Stromal cells effects on ovarian cancer cells proliferation, chemoresistance and radiation resistance was evaluated using co-culture assays with luciferase-labeled human ovarian cancer cell lines. Transwell migration assays were performed with conditioned media from O-ASCs and control cell lines. SKOV3 cells were intraperitionally injected with or without O-ASC1 to track in-vivo engraftment. Results: O-ASCs significantly promoted in vitro proliferation, migration chemotherapy and radiation response of ovarian cancer cell lines. O-ASC4 had more marked effects on migration and chemotherapy response on OVCA 429 and OVCA 433 cells than O-ASC1. Analysis of microarray data revealed that O-ASC4 and O-ASC5 have similar gene expression profiles, in contrast to O-ASC1, which was more similar to BM-MSCs and subcutaneous ASCs in hierarchical clustering. Human O-ASCs were detected in the stroma of human ovarian cancer murine xenografts but not uninvolved ovaries. Conclusions: ASCs derived from the human omentum can promote ovarian cancer proliferation, migration, chemoresistance and radiation resistance in-vitro. Furthermore, clinical O-ASCs isolates demonstrate heterogenous effects on ovarian cancer in-vitro.

The tumor microenvironment has been definitively shown to be a key player in tumor progression and metastasis in a variety of cancers, including ovarian cancer and provides a plethora of potentially significant therapeutic targets. As ovarian cancer is the deadliest gynecological disease due to a lack of reliable diagnostic testing and efficacious treatments, our objective was to determine how the ovarian cancer-associated fibroblasts (CAFs) are contributing to the propagation of ovarian cancer. Our lab has identified a distinct gene signature for the ovarian stromal component of high-grade late-stage (HGLS) serous ovarian cancer as compared to normal stroma, human ovarian surface epithelium, and ovarian tumor, and many of these genes are secreted proteins suggesting a paracrine role for the tumor microenvironment. Secreted frizzled related protein 2 (SFRP2), a protein integral to stemness and proliferation, is overexpressed in ovarian CAFs by over 10-fold. Quantitative RT-PCR and immunohistochemical staining validated the overexpression of SFRP2 in ovarian CAFs and also showed a clinical correlation for stromal SFRP2 overexpression with poorer overall survival and chemoresistance in patients with HGLS serous ovarian cancer. Furthermore, increased SFRP2 expression correlated with significantly higher microvessel density suggesting an angiogenic effect. In vitro functional studies illustrated increased ovarian cancer cell proliferation in response to recombinant SFRP2 that was dose and time dependent. Ovarian cancer cells overexpressing SFRP2 (autocrine signaling) also illustrated increased cell proliferation. Additionally, ovarian cancer cell co-cultured with ovarian CAFs induced increased SFRP2 expression in the CAFs. Using an allogenic mouse model, we determined that silencing stromal SFRP2 using a SFRP2 knockout mouse significantly decreased ovarian cancer cell growth, suggesting that eliminating tumor stromal signaling cues may mitigate ovarian cancer progression. Together, these results illustrate a direct and specific signaling linkage between ovarian tumor cells and their associated microenvironment, specifically CAFs, suggesting that elimination of this signaling linkage may slow ovarian cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C234.

5049 Background: Poor survival associated with the amplicon 5q31-35(previously reported) in HGSC may be due to subsequent overexpression of FGFR4. This work aims to correlate FGFR4 with survival in...

Objective: Transcriptome profiling performed on RNA isolated from microdissected epithelial and stromal fibroblastic components of advanced stage high-grade serous ovarian cancer (HGSC) and normal ovarian epithelial tissue identified a set of genes coding for secretory proteins that were significantly up-regulated in ovarian cancer associated fibroblasts (CAFs). One of the most significant differentially expressed genes is matrilin-3 (MATN3), which has been shown to play an important role in cartilage morphogenesis. The purpose of this study is to validate the differential expression patterns of MATN3 and its role in ovarian cancer progression. Methods: Validation studies on MATN3 expression were carried out using quantitative RT-PCR analysis on RNA samples isolated from the microdissected stromal and epithelial components of 44 HGSC samples and 10 normal ovaries. In addition, immunohistochemistry (IHC) was performed to determine over-expression of MATN3 in the stromal component of HGSCs. To assess the functional role of matrilin-3 in ovarian cancer pathogenesis, multiple ovarian cancer cells including SKOV3 ipluc, OVCA 432, OVCA 433, and ALST were treated with exogenous recombinant MATN3. Its effect on cell proliferation was evaluated by the WST-1 assay. Furthermore, the effect of MATN3 on invasion potential was determined by counting the number of cells migrating through a transwell membrane coated with a 0.1% type I collagen matrix containing 7.5 nM MATN3. Results: Quantitative RT-PCR analysis showed significantly over-expression of MATN3 in the stromal component of HGSC compared to the epithelial component and the normal ovaries (P=0.003). Immunohistochemistry (IHC) confirmed overexpression of MATN3 in a majority of ovarian cancer stromal specimens. When treated with recombinant exogenous matrilin-3, ALST and SKOV3 ip luc ovarian cancer cells showed a dose-dependent inhibition of proliferation by MATN3. Treatment of ovarian cancer cells SKOV3 and OVCA 432 with exogenous MATN3 significantly decreased the number of cells migrating through the transwell membrane (P Conclusions: Over-expression of MATN3 in ovarian cancer stroma inhibits cell proliferation and invasion potential. Further evaluating the underlying molecular mechanism of MATN3 in ovarian cancer progression is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1506. doi:10.1158/1538-7445.AM2011-1506

Objectives: Utilizing the transcriptome profiling approach to identify genes that are differentially expressed in normal ovaries, and serous borderline ovarian tumors of low-malignant potential (LMP), and low-grade ovarian serous carcinomas compared with high-grade ovarian serous carcinomas (HGSC), we identified ISG15, an ubiquitin-like molecule that is strongly up regulated by type I interferon, to be highly up-regulated in advanced stage HGSCs. We seek to validate the expression patterns of ISG15 and correlated them with clinical outcomes. Methods: Over-expression of ISG15 was confirmed in ovarian cancer cell lines and tissue by real time PCR and immunohistochemistry, respectively. Immunolocalizaation of ISG15 was performed on 155 HGSCs, 10 serous LMPs, 10 normal ovaries, and 10 fallopian tubes. Expression levels of ISG15 were quantified by Image-Pro plus software. The correlation between overall survival and progression free survival and ISG15 expression levels was performed on 155 and 130 HGSC, respectively, using both Kaplan Meier and Cox Regression analyses. Results: ISG15 expression was not detected in normal ovaries, fallopian tubes and LMPs. Over-expressed of ISG15 was confirmed in a majority of HGSC cell lines and tumor tissue. To further evaluate the clinical significance of nuclear ISG15 expression, both Cox and Kaplan-Meier analyses were performed on patients with HGSC. Multivariate Cox analysis showed that ISG15 expression levels were associated with improved overall survival (HR:0.9, P=0.011). In addition, using median ISF15 staining intensity as a cut-off, Kaplan-Meier analysis and log rank test demonstrated that strong ISG15 expression was associated with improved overall and progression free survival (P Conclusion: Over-expression of ISG15 is common in high-grade serous ovarian adenocarcinoma. The expression levels in tumor cells are strongly correlated with overall survivals, suggesting ISG15 may be a powerful prognostic marker for patients with HGSC. Further functional studies on the functional role of ISG15 in ovarian cancer progression are warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 408. doi:10.1158/1538-7445.AM2011-408

Objectives: To identify the effect of FGF1 on cell proliferation in ovarian cancer and endothelial cells, its relation to FGFR4 over expression and signaling pathways involved Methods: Amplification of FGFR4 on 5q31-35, which was previously shown to be associated with poor survival in patients with advanced stage high-grade serous ovarian cancer (HGSC), was validated by quantitative PCR in 52 HGSC. Association between DNA copy numbers of FGFR4 and FGF1 located on the same segment was performed by Spearman correlation analysis. Over expression of FGFR4 protein was confirmed in ovarian cancer cell lines and tissue by western blot analysis and immunohistochemistry, respectively. Endogenous FGF1 production by several ovarian cancer cell lines in conditioned medium was quantified using ELISA. Effect of exogenous FGF1 on cell proliferation of high and low-FGFR4 expressing ovarian cancer cell lines and an immortalized microvascular endothelial cell line was determined by WST-1 assay. Signaling pathways activation was screened by treating ovarian cancer cell lines and endothelial cells transduced with six different transcription response elements using the Cignal-Lenti reporter system with exogenous FGF1. Results: FGFR4 was amplified and over-expressed in a majority of ovarian cancer cell lines and tumor tissue and FGFR4 DNA copy number was significantly correlated with that of FGF1 (r=0.4, p=0.04). Endogenous FGF1 production was detected by ELISA in 2 of 5 screened ovarian cell lines. FGF1 significantly induced cell proliferation in high FGFR4 expressing ovarian cancer cells (20%, p Conclusions: Our report provides preliminary evidence that poor survival associated with FGF1 amplification and over expression appears to be mediated through FGFR4, which is also amplified and over-expressed in ovarian cancer cell. In addition, FGF1 produced by ovarian cancer cells may exert both autocrine and paracrine effect on cancer cells and endothelial cells through the activation of MAPK/ERK pathway. These data suggests that new regimens targeting FGF1, FGFR4 and downstream signaling pathways may improve ovarian cancer patient survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3132.

Ovarian cancer the deadliest gynecologic disease and despite the significant role of the tumor-associated stroma in cancer progression, little research has been done on the specific role of the tumor-associated stromal microenvironment on ovarian cancer progression. Our objective was to identify genes that are differentially regulated in the stromal component of high-grade late-stage serous ovarian cancer and illustrate direct and specific effects of their differential expression on ovarian cancer progression. Microarray analysis performed on RNA isolated from 10 microdissected normal ovarian fibroblasts, and the epithelial and stromal component of 16 high-grade late stage serous ovarian cancers revealed more than 40 secreted proteins that are overexpressed more than 5 fold by cancer-associated fibroblasts (CAFs) exclusively. Quantitative RT-PCR validated the overexpression of several genes, including sFRP2, by the CAFs. Clinical data correlated stromal sFRP2 overexpression with poorer overall survival and chemoresistance in patients with high-grade late stage serous ovarian cancer, suggesting that sFRP2 promotes ovarian cancer progression. In vitro functional studies illustrate increased ovarian cancer cell proliferation rates in response to recombinant sFRP2 as well as CAF-conditioned medium and pathway analysis via transcription-reporter assays revealed that recombinant sFRP2 signals through the NFκB and Wnt pathways in ovarian cancer cells, both of which affect cell growth. While not affecting cell proliferation, recombinant sFRP2 increased endothelial signaling to the NFAT pathway, which affects endothelial tubal branching. These results were corroborated in vivo such that microenvironments expressing higher levels of sFRP2 exhibited significantly higher microvessel density compared with microenvironments with lower sFRP2 expression. Our results illustrate a direct and specific signaling linkage from the tumor microenvironment to tumor cells and endothelial cells that contributes to tumor progression. In this case, sFRP2 exhibited significant influence on characteristics of tumor progression (i.e. tumor proliferation, microvessel morphology) suggesting that other differentially expressed genes identified by the microarray in CAFs may also play significant roles in this process. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1426.