bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Kaposi's Sarcoma–Associated Herpesvirus G Protein–Coupled Receptor as a Therapeutic Target for the Treatment of Kaposi's Sarcoma
Authors: Montaner Silvia , Sodhi Akrit , Ramsdell Amanda K. , Martin Daniel , Hu Jiadi , Sawai Earl T. , Gutkind J. Silvio 
Published: January 2006

Abstract
The Kaposi's sarcoma–associated herpesvirus (KSHV) encodes a G protein–coupled receptor (vGPCR) that has been implicated in the initiation of Kaposi's sarcoma, identifying vGPCR as an attractive target for preventing Kaposi's sarcoma. However, as only a fraction of cells in advanced Kaposi's sarcoma lesions express vGPCR, it is unclear whether this unique viral oncogene contributes to Kaposi's sarcoma progression. We therefore set out to determine whether the few cells that express vGPCR in established tumors represent an appropriate therapeutic target for the treatment of patients with preexisting Kaposi's sarcoma. To this end, we generated endothelial cell lines stably expressing vGPCR or key KSHV latently expressed proteins (vCyclin, vFlip, and LANA1). The endothelial cell line expressing vGPCR was rendered sensitive to treatment with the nucleoside analogue ganciclovir by using a bicistronic construct coexpressing the herpes simplex virus 1 thymidine kinase. S.c. injection into nude mice with mixed-cell populations formed tumors that approximate the ratio of vGPCR-expressing and KSHV latent gene-expressing cells. These mice were then treated with ganciclovir to specifically target only the vGPCR-expressing cells. Surprisingly, despite the expression of KSHV latent genes in the vast majority of tumor cells, specifically targeting only the few vGPCR-expressing cells in established tumors resulted in tumor regression. Moreover, we observed an increase in apoptosis of latent gene-expressing cells after the pharmacologic deletion of the vGPCR-expressing cells. These findings indicate that vGPCR may play a key role in Kaposi's sarcoma progression and provide experimental justification for developing molecular-based therapies specifically targeting vGPCR and its effectors for the treatment of Kaposi's sarcoma patients. (Cancer Res 2006; 66(1): 168-74)
Epidermal Growth Factor Receptor Overexpression Results in Increased Tumor Cell Motility In vivo Coordinately with Enhanced Intravasation and Metastasis
Authors: Xue Chengsen , Wyckoff Jeffrey , Liang Fubo , Sidani Mazen , Violini Stefania , Tsai Kun-Lin , Zhang Zhong-Yin , Sahai Erik , Condeelis John , Segall Jeffrey E. 
Published: January 2006

Abstract
Although overexpression of the epidermal growth factor receptor (EGFR; ErbB1) has been correlated with poor prognosis in breast and other cancers, clinical trials of ErbB1 inhibitors have shown limited efficacy in inhibiting tumor proliferation. To evaluate other possible roles of ErbB1 in tumor malignancy besides proliferation, we have developed a series of tools for analysis of intravasation. Overexpression of ErbB1 in MTLn3 mammary adenocarcinoma cells results in increased intravasation and lung metastasis from tumors formed by injection of cells in the mammary fat pad. However, increased ErbB1 expression has no effect on primary tumor growth and lung seeding efficiency of cells injected i.v. Chemotactic responses to low concentrations of EGF in vitro and cell motility in vivo in the primary tumor measured using intravital imaging are significantly increased by ErbB1 overexpression. The increased cell motility is restricted to ErbB1-overexpressing cells in tumors containing mixtures of cells expressing different ErbB1 levels, arguing for a cell-autonomous effect of increased ErbB1 expression rather than alteration of the tumor microenvironment. In summary, we propose that ErbB1 overexpression makes more significant contributions to intravasation than growth in some tumors and present a novel model for studying ErbB1 contributions to tumor metastasis via chemotaxis and intravasation. (Cancer Res 2006; 66(1): 192-7)
Noninvasive Magnetic Resonance Spectroscopic Pharmacodynamic Markers of the Choline Kinase Inhibitor MN58b in Human Carcinoma Models
Authors: Al-Saffar Nada M.S. , Troy Helen , de Molina Ana Ramírez , Jackson Laura E. , Madhu Basetti , Griffiths John R. , Leach Martin O. , Workman Paul , Lacal Juan C. , Judson Ian R. , Chung Yuen-Li 
Published: January 2006

Abstract
MN58b is a novel anticancer drug that inhibits choline kinase, resulting in inhibition of phosphocholine synthesis. The aim of this work was to develop a noninvasive and robust pharmacodynamic biomarker for target inhibition and, potentially, tumor response following MN58b treatment. Human HT29 (colon) and MDA-MB-231 (breast) carcinoma cells were examined by proton (1H) and phosphorus (31P) magnetic resonance spectroscopy (MRS) before and after treatment with MN58b both in culture and in xenografts. An in vitro time course study of MN58b treatment was also carried out in MDA-MB-231 cells. In addition, enzymatic assays of choline kinase activity in cells were done. A decrease in phosphocholine and total choline levels (P &lt; 0.05) was observed in vitro in both cell lines after MN58b treatment, whereas the inactive analogue ACG20b had no effect. In MDA-MB-231 cells, phosphocholine fell significantly as early as 4 hours following MN58b treatment, whereas a drop in cell number was observed at 48 hours. Significant correlation was also found between phosphocholine levels (measured by MRS) and choline kinase activities (r2 = 0.95, P = 0.0008) following MN58b treatment. Phosphomonoesters also decreased significantly (P &lt; 0.05) in both HT29 and MDA-MB-231 xenografts with no significant changes in controls. 31P-MRS and 1H-MRS of tumor extracts showed a significant decrease in phosphocholine (P ≤ 0.05). Inhibition of choline kinase by MN58b resulted in altered phospholipid metabolism both in cultured tumor cells and in vivo. Phosphocholine levels were found to correlate with choline kinase activities. The decrease in phosphocholine, total choline, and phosphomonoesters may have potential as noninvasive pharmacodynamic biomarkers for determining tumor response following treatment with choline kinase inhibitors. (Cancer Res 2006; 66(1): 427-34)
Germ-Line Mutation of NKX3.1 Cosegregates with Hereditary Prostate Cancer and Alters the Homeodomain Structure and Function
Authors: Zheng S. Lilly , Ju Jeong-ho , Chang Bao-li , Ortner Elizabeth , Sun Jielin , Isaacs Sarah D. , Sun Jishang , Wiley Kathy E. , Liu Wennuan , Zemedkun Micheas , Walsh Patrick C. , Ferretti James , Gruschus James , Isaacs William B. , Gelmann Edward P. , Xu Jianfeng 
Published: January 2006

Abstract
NKX3.1, a gene mapped to 8p21, is a member of the NK class of homeodomain proteins and is expressed primarily in the prostate. NKX3.1 exerts a growth-suppressive and differentiating effect on prostate epithelial cells. Because of its known functions and its location within a chromosomal region where evidence for prostate cancer linkage and somatic loss of heterozygosity is found, we hypothesize that sequence variants in the NKX3.1 gene increase prostate cancer risk. To address this, we first resequenced the NKX3.1 gene in 159 probands of hereditary prostate cancer families recruited at Johns Hopkins Hospital; each family has at least three first-degree relatives affected with prostate cancer. Twenty-one germ-line variants were identified in this analysis, including one previously described common nonsynonymous change (R52C), two novel rare nonsynonymous changes (A17T and T164A), and a novel common 18-bp deletion in the promoter. Overall, the germ-line variants were significantly linked to prostate cancer, with a peak heterogeneity logarithm of odds of 2.04 (P = 0.002) at the NKX3.1 gene. The rare nonsynonymous change, T164A, located in the homeobox domain of the gene, segregated with prostate cancer in a family with three affected brothers and one unaffected brother. Importantly, nuclear magnetic resonance solution structure analysis and circular dichroism studies showed this specific mutation to affect the stability of the homeodomain of the NKX3.1 protein and decreased binding to its cognate DNA recognition sequence. These results suggest that germ-line sequence variants in NKX3.1 may play a role in susceptibility to hereditary prostate cancer and underscore a role for NKX3.1 as a prostate cancer gatekeeper. (Cancer Res 2006; 66(1): 69-77)
Molecular Fingerprinting and Autocrine Growth Regulation of Endothelial Cells in a Murine Model of Hepatocellular Carcinoma
Authors: Ryschich Eduard , Lizdenis Paulius , Ittrich Carina , Benner Axel , Stahl Simone , Hamann Alf , Schmidt Jan , Knolle Percy , Arnold Bernd , Hämmerling Günter J. , Ganss Ruth 
Published: January 2006

AbstractIn a mouse model of hepatocellular carcinogenesis, highly vascularized tumors develop through two distinct morphologic phases of neovascularization. We show that increased vascular caliber occurs first, followed by extensive vessel sprouting in late-stage carcinomas. To define molecular pathways in tumor neovascularization, endothelial cells were directly purified from normal liver and advanced tumors. Gene expression profiling experiments were then designed to identify genes enriched in the vascular compartment. We report that Cathepsin S is the major protease specifically overexpressed during vessel sprouting. We also show that the CC chemokines CCL2 and CCL3 are secreted by neovessels and stimulate proliferation through their cognate receptors in an autocrine fashion. This suggests that chemokine signaling represents the most prominent signaling pathway in tumor-associated endothelial cells and directly regulates vessel remodeling. Furthermore, high angiogenic activity is associated with attenuated lymphocyte extravasation and correlates with expression of the immunomodulatory cytokine interleukin 10. This is the first comprehensive study addressing liver-specific vascular changes in a murine autochthonous tumor model. These novel insights into liver angiogenesis infer an environmental control of neovascularization and have important implications for the design of antiangiogenic therapies. (Cancer Res 2006; 66(1): 198-211)
Increased Susceptibility to UV-Induced Skin Carcinogenesis in Polymerase η–deficient Mice
Authors: Lin Qingcong , Clark Alan B. , McCulloch Scott D. , Yuan Tao , Bronson Roderick T. , Kunkel Thomas A. , Kucherlapati Raju 
Published: January 2006

Abstract
Xeroderma pigmentosum variant (XPV) patients with mutations in the DNA polymerase η (pol η) gene are hypersensitive to sunlight and have greatly increased susceptibility to sunlight-induced skin cancer. Consistent with the ability of Pol η to efficiently bypass UV light–induced cyclobutane pyrimidine dimers, XPV cells lacking Pol η have diminished capacity to replicate UV-damaged DNA and are sensitive to UV light–induced killing and mutagenesis. To better understand these and other Pol η functions, we generated Pol η–deficient mice. Mice homozygous for a null mutation in pol η are viable, fertile, and do not show any obvious spontaneous defects during the first year of life. However, fibroblasts derived from these mutant mice are sensitive to killing by exposure to UV light, and all Pol η–deficient mice develop skin tumors after UV irradiation, in contrast to the wild-type littermate controls that did not develop such tumors. These results and biochemical studies of translesion synthesis by mouse Pol η indicate that Pol η–dependent bypass of cyclobutane pyrimidine dimers suppresses UV light–induced skin cancer in mice. Moreover, 37.5% of pol η heterozygous mice also developed skin cancer during 5 months after a 5-month exposure to UV light, suggesting that humans who are heterozygous for mutations in pol η may also have an increased risk of skin cancer. (Cancer Res 2006; 66(1): 87-94)
Potent Antiandrogen and Androgen Receptor Activities of anAngelica gigas–Containing Herbal Formulation: Identification of Decursin as a Novel and Active Compound with Implications for Prevention and Treatment of Prostate Cancer
Authors: Jiang Cheng , Lee Hyo-Jeong , Li Guang-xun , Guo Junming , Malewicz Barbara , Zhao Yan , Lee Eun-Ok , Lee Hyo-Jung , Lee Jae-Ho , Kim Min-Seok , Kim Sung-Hoon , Lu Junxuan 
Published: January 2006

AbstractAndrogen and androgen receptor (AR)–mediated signaling are crucial for the development of prostate cancer. Identification of novel and naturally occurring phytochemicals that target androgen and AR signaling from Oriental medicinal herbs holds exciting promises for the chemoprevention of this disease. In this article, we report the discovery of strong and long-lasting antiandrogen and AR activities of the ethanol extract of a herbal formula (termed KMKKT) containing Korean Angelica gigas Nakai (AGN) root and nine other Oriental herbs in the androgen-dependent LNCaP human prostate cancer cell model. The functional biomarkers evaluated included a suppression of the expression of prostate-specific antigen (PSA) mRNA and protein (IC50, ∼7 μg/mL, 48-hour exposure) and an inhibition of androgen-induced cell proliferation through G1 arrest and of the ability of androgen to suppress neuroendocrine differentiation at exposure concentrations that did not cause apoptosis. Through activity-guided fractionation, we identified decursin from AGN as a novel antiandrogen and AR compound with an IC50 of ∼0.4 μg/mL (1.3 μmol/L, 48-hour exposure) for suppressing PSA expression. Decursin also recapitulated the neuroendocrine differentiation induction and G1 arrest actions of the AGN and KMKKT extracts. Mechanistically, decursin in its neat form or as a component of AGN or KMKKT extracts inhibited androgen-stimulated AR translocation to the nucleus and down-regulated AR protein abundance without affecting the AR mRNA level. The novel antiandrogen and AR activities of decursin and decursin-containing herbal extracts have significant implications for the chemoprevention and treatment of prostate cancer and other androgen-dependent diseases. (Cancer Res 2006; 66(1): 453-63)
Antagonism of Sphingosine-1-Phosphate Receptors by FTY720 Inhibits Angiogenesis and Tumor Vascularization
Authors: LaMontagne Kenneth , Littlewood-Evans Amanda , Schnell Christian , O'Reilly Terence , Wyder Lorenza , Sanchez Teresa , Probst Beatrice , Butler Jeannene , Wood Alexander , Liau Gene , Billy Eric , Theuer Andreas , Hla Timothy , Wood Jeanette 
Published: January 2006

Abstract
FTY720, a potent immunomodulator, becomes phosphorylated in vivo (FTY-P) and interacts with sphingosine-1-phosphate (S1P) receptors. Recent studies showed that FTY-P affects vascular endothelial growth factor (VEGF)–induced vascular permeability, an important aspect of angiogenesis. We show here that FTY720 has antiangiogenic activity, potently abrogating VEGF- and S1P-induced angiogenesis in vivo in growth factor implant and corneal models. FTY720 administration tended to inhibit primary and significantly inhibited metastatic tumor growth in a mouse model of melanoma growth. In combination with a VEGFR tyrosine kinase inhibitor PTK787/ZK222584, FTY720 showed some additional benefit. FTY720 markedly inhibited tumor-associated angiogenesis, and this was accompanied by decreased tumor cell proliferation and increased apoptosis. In transfected HEK293 cells, FTY-P internalized S1P1 receptors, inhibited their recycling to the cell surface, and desensitized S1P receptor function. Both FTY720 and FTY-P apparently failed to impede VEGF-produced increases in mitogen-activated protein kinase activity in human umbilical vascular endothelial cells (HUVEC), and unlike its activity in causing S1PR internalization, FTY-P did not result in a decrease of surface VEGFR2 levels in HUVEC cells. Pretreatment with FTY720 or FTY-P prevented S1P-induced Ca2+ mobilization and migration in vascular endothelial cells. These data show that functional antagonism of vascular S1P receptors by FTY720 potently inhibits angiogenesis; therefore, this may provide a novel therapeutic approach for pathologic conditions with dysregulated angiogenesis. (Cancer Res 2006; 66(1): 221-31)
Activation of RhoB by Hypoxia Controls Hypoxia-Inducible Factor-1α Stabilization through Glycogen Synthase Kinase-3 in U87 Glioblastoma Cells
Authors: Skuli Nicolas , Monferran Sylvie , Delmas Caroline , Lajoie-Mazenc Isabelle , Favre Gilles , Toulas Christine , Cohen-Jonathan-Moyal Elizabeth 
Published: January 2006

Abstract
Hypoxia is a crucial factor in tumor aggressiveness and resistance to treatment, particularly in glioma. Our previous results have shown that inhibiting the small GTPase RhoB increased oxygenation of U87 human glioblastoma xenografts, in part, by regulating angiogenesis. We investigated here whether RhoB might also control a signaling pathway that would permit glioma cells to adapt to hypoxia. We first showed that silencing RhoB with siRNA induced degradation and inhibition of the transcriptional activity of the hypoxia-inducible factor by the proteasome in U87 hypoxic cells. This RhoB-dependent degradation of hypoxia-inducible factor-1α in hypoxic conditions was mediated by the Akt/glycogen synthase kinase-3β pathway. While investigating how hypoxia could activate this signaling pathway, using the GST-Rhotekin RBD pulldown assay, we showed the early activation of RhoB by reactive oxygen species under hypoxic conditions and, subsequently, its participation in the ensuing cellular adaptation to hypoxia. Overall, therefore, our results have not only highlighted a new signaling pathway for hypoxia controlled by the small GTPase RhoB, but they also strongly implicate RhoB as a potentially important therapeutic target for decreasing tumor hypoxia. (Cancer Res 2006; 66(1): 482-9)
Preferential Dependence of Breast Cancer Cells versus Normal Cells on Integrin-Linked Kinase for Protein Kinase B/Akt Activation and Cell Survival
Authors: Troussard Armelle A. , McDonald Paul C. , Wederell Elizabeth D. , Mawji Nasrin M. , Filipenko Nolan R. , Gelmon Karen A. , Kucab Jill E. , Dunn Sandra E. , Emerman Joanne T. , Bally Marcel B. , Dedhar Shoukat 
Published: January 2006

AbstractThe emerging paradigm of “oncogene addiction” has been called an Achilles' heel of cancer that can be exploited therapeutically. Here, we show that integrin-linked kinase (ILK), which is either activated or overexpressed in many types of cancers, is a critical regulator of breast cancer cell survival through the protein kinase B (PKB)/Akt pathway but is largely dispensable for the survival of normal breast epithelial cells and mesenchymal cells. We show that inhibition of ILK activity with a pharmacologic ILK inhibitor, QLT-0267, results in the inhibition of PKB/Akt Ser473 phosphorylation, stimulation of apoptosis, and a decrease in mammalian target of rapamycin (mTOR) expression in human breast cancer cells. In contrast, QLT-0267 treatment has no effect on PKB/Akt Ser473 phosphorylation or apoptosis in normal human breast epithelial, mouse fibroblast, or vascular smooth muscle cells. The inhibition of PKB/Akt Ser473 phosphorylation by QLT-0267 in breast cancer cells was rescued by a kinase-active ILK mutant but not by a kinase-dead ILK mutant. Furthermore, a dominant-negative ILK mutant increased apoptosis in the MDA-MB-231 breast cancer cell line but not in normal human breast epithelial cells. The inhibitor was active against ILK isolated from all cell types but did not have any effect on cell attachment and spreading. Our data point to an “ILK addiction” of breast cancer cells whereby they become dependent on ILK for cell survival through the mTOR-PKB/Akt signaling pathway and show that ILK is a promising target for the treatment of breast cancer. (Cancer Res 2006; 66(1): 393-403)
Natural Killer Cells Produce T Cell–Recruiting Chemokines in Response to Antibody-Coated Tumor Cells
Authors: Roda Julie M. , Parihar Robin , Magro Cynthia , Nuovo Gerard J. , Tridandapani Susheela , Carson William E. 
Published: January 2006

AbstractIn the current report, we have examined the ability of natural killer (NK) cells to produce T cell–recruiting chemokines following dual stimulation with interleukin (IL)-2 or IL-12 and human breast cancer cells coated with an antitumor antibody (trastuzumab). NK cells stimulated in this manner secreted an array of T cell–recruiting chemotactic factors, including IL-8, macrophage-derived chemokine, macrophage inflammatory protein 1α (MIP-1α), monocyte chemoattractant protein 1, and regulated on activation, normal T-cell expressed and secreted (RANTES), whereas stimulation of NK cells with either agent alone had minimal effect. Furthermore, these factors were functional for T-cell chemotaxis as culture supernatants derived from costimulated NK cells induced migration of both naïve and activated T cells in an in vitro chemotaxis assay. T-cell migration was significantly reduced when neutralizing antibodies to IL-8, MIP-1α, or RANTES were added to culture supernatants before their use in the chemotaxis assay. In addition, coadministration of trastuzumab-coated tumor cells and IL-12 to mice led to enhanced serum MIP-1α. As a clinical correlate, we examined the chemokine content of serum samples from breast cancer patients enrolled on a phase I trial of trastuzumab and IL-12, and found elevated levels of IL-8, RANTES, IFN-γ inducible protein 10, monokine induced by IFN-γ, and MIP-1α, specifically in those patients that experienced a clinical benefit. Sera from these patients exhibited the ability to direct T-cell migration in a chemotaxis assay, and neutralization of chemokines abrogated this effect. These data are the first to show chemokine production by NK cells, specifically in response to stimulation with antibody-coated tumor cells, and suggest a potential role for NK cell–derived chemokines in patients receiving therapeutic monoclonal antibodies. (Cancer Res 2006; 66(1): 517-26)
Matrix Metalloproteinase-9 from Bone Marrow–Derived Cells Contributes to Survival but not Growth of Tumor Cells in the Lung Microenvironment
Authors: Acuff Heath B. , Carter Kathy J. , Fingleton Barbara , Gorden D. Lee , Matrisian Lynn M. 
Published: January 2006

AbstractThe role of specific stromal-derived matrix metalloproteinases (MMPs) was analyzed in experimental metastasis assays in wild-type and either MMP-9, MMP-7, or MMP-2 null mice. MMP-9 null mice showed an 81% reduction in Lewis lung carcinoma tumor number, whereas MMP-7 null mice showed a 42% increase in tumor number, and there was no difference in tumor number in MMP-2 null mice compared with wild-type controls. Similarly, in an orthotopic model of lung cancer, 50% fewer MMP-9 null mice were able to establish tumors in the lung compared with control mice, although the size of the tumors was not different. The effect of MMP-9 on lung tumor colonization was dependent on the expression of MMP-9 from bone marrow–derived cells and is most likely contributed by neutrophils. To examine temporal effects of stromal MMP-9, bioluminescence imaging from luciferase-expressing human lung cancer–derived A549 cells revealed that there were fewer tumor cells in the lungs of MMP-9 null mice as early as 19 hours after injection compared with control mice, with no difference in subsequent growth rates. Six hours after injection of tumor cells, MMP-9 null mice showed a 4-fold increase in the percent of tumor cells undergoing apoptosis compared with control mice. We conclude that MMP-9 from the bone marrow contributes to the early survival and establishment of tumors in the lung and has no effect on subsequent growth. These results provide insights into the failure of MMP inhibitors in clinical trials in patients with late-stage lung cancer. (Cancer Res 2006; 66(1): 259-66)