bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD44 on LS174T Colon Carcinoma Cells Possesses E-Selectin Ligand Activity
Authors: Hanley William D. , Burdick Monica M. , Konstantopoulos Konstantinos , Sackstein Robert 
Published: September 2005

AbstractMetastasis of circulating tumor cells requires a multistep cascade of events initiated by adhesion of tumor cells to the vascular endothelium of involved tissues. This process occurs under the forces of blood flow and is promoted by adhesion molecules specialized to interact under shear conditions. The endothelial molecule E-selectin is a major mediator of these adhesive events, and there is strong evidence that E-selectin receptor-ligand interactions contribute to the formation of metastasis. However, little is known about the identity of E-selectin ligand(s) expressed on cancer cells. To address this issue, we did SDS-PAGE analysis of membrane proteins, metabolic inhibition studies, and blot rolling assays of LS174T, a colon carcinoma cell line known to interact with E-selectin under physiologic flow conditions. Our studies show that LS174T cells express the hematopoietic cell E/L-selectin (HCELL) glycoform of CD44, which functions as a high-affinity E-selectin glycoprotein ligand on these cells. However, in contrast to the HCELL glycoform on human hematopoietic progenitor cells, which expresses carbohydrate-binding determinant(s) for E-selectin primarily on N-glycans of standard CD44, the relevant determinant(s) on LS174T cells is expressed on O-glycans and is predominantly found on variant isoforms of CD44 (CD44v). Our finding that tumor-associated CD44 splice variant(s) express E-selectin ligand activity provides novel perspectives on the biology of CD44 in cancer metastasis.
ZD6474 Suppresses Oncogenic RET Isoforms in a Drosophila Model for Type 2 Multiple Endocrine Neoplasia Syndromes and Papillary Thyroid Carcinoma
Authors: Vidal Marcos , Wells Samuel , Ryan Anderson , Cagan Ross 
Published: September 2005

Abstract
Patients with hereditary medullary thyroid carcinoma (MTC) associated with multiple endocrine neoplasia (MEN) types 2A and 2B and familial MTC (FMTC) have mutations in the RET proto-oncogene. Approximately 40 percent of patients with papillary thyroid carcinoma (PTC) typically have either intrachromosomal or extrachromosomal rearrangements that join the promoter and NH2-terminal domains of unrelated genes to the COOH-terminal fragment of RET. The RET point mutations associated with MEN2A, MEN2B, or FMTC, or the chromosomal breakpoints and translocations associated with PTC, typically activate the RET receptor tyrosine kinase (RTK). RET kinase inhibitors are likely to be beneficial for patients with hereditary MTC, where currently there is no effective chemotherapy or radiation therapy. Recently, the low molecular weight tyrosine kinase inhibitor ZD6474 was found to block the enzymatic activity of RET-derived oncoproteins in cultured cell lines. We have developed a Drosophila model for MEN2A and MEN2B diseases by targeting oncogenic forms of RET to the developing Drosophila eye. Here we show that, when fed orally, ZD6474 suppressed RET-mediated phenotypes within the context of this in vivo model. Importantly, ZD6474 showed high efficacy and very low toxicity. This compound failed to significantly suppress an activated form of another RTK, the Drosophila epidermal growth factor receptor, nor did it suppress the activity of downstream components of the RET/Ras pathway. Our results support the view that targeting chemical kinase inhibitors such as ZD6474 to tissues with oncogenic forms of RET is a useful treatment strategy for RET-dependent carcinomas.
Vascular Endothelial Cell Growth Factor Receptor 3–Mediated Activation of Lymphatic Endothelium Is Crucial for Tumor Cell Entry and Spread via Lymphatic Vessels
Authors: He Yulong , Rajantie Iiro , Pajusola Katri , Jeltsch Michael , Holopainen Tanja , Yla-Herttuala Seppo , Harding Thomas , Jooss Karin , Takahashi Takashi , Alitalo Kari 
Published: September 2005

Abstract
Lymphangiogenic growth factors vascular endothelial growth factor (VEGF)-C and VEGF-D have been shown to promote lymphatic metastasis by inducing tumor-associated lymphangiogenesis. In this study, we have investigated how tumor cells gain access into lymphatic vessels and at what stage tumor cells initiate metastasis. We show that VEGF-C produced by tumor cells induced extensive lymphatic sprouting towards the tumor cells as well as dilation of the draining lymphatic vessels, suggesting an active role of lymphatic endothelial cells in lymphatic metastasis. A significant increase in lymphatic vessel growth occurred between 2 and 3 weeks after tumor xenotransplantation, and lymph node metastasis occurred at the same stage. These processes were blocked dose-dependently by inhibition of VEGF receptor 3 (VEGFR-3) signaling by systemic delivery of a soluble VEGFR-3-immunoglobulin (Ig) fusion protein via adenoviral or adeno-associated viral vectors. However, VEGFR-3-Ig did not suppress lymph node metastasis when the treatment was started at a later stage after the tumor cells had already spread out, suggesting that tumor cell entry into lymphatic vessels is a key step during tumor dissemination via the lymphatics. Whereas lymphangiogenesis and lymph node metastasis were significantly inhibited by VEGFR-3-Ig, some tumor cells were still detected in the lymph nodes in some of the treated mice. This indicates that complete blockade of lymphatic metastasis may require the targeting of both tumor lymphangiogenesis and tumor cell invasion.
Transforming Growth Factor-β Suppresses Nonmetastatic Colon Cancer through Smad4 and Adaptor Protein ELF at an Early Stage of Tumorigenesis
Authors: Tang Yi , Katuri Varalakshmi , Srinivasan Radhika , Fogt Franz , Redman Robert , Anand Girish , Said Anan , Fishbein Thomas , Zasloff Michael , Reddy E. Premkumar , Mishra Bibhuti , Mishra Lopa 
Published: September 2005

Abstract
Although transforming growth factor-β (TGF-β) is both a suppressor and promoter of tumorigenesis, its contribution to early tumor suppression and staging remains largely unknown. In search of the mechanism of early tumor suppression, we identified the adaptor protein ELF, a β-spectrin from stem/progenitor cells committed to foregut lineage. ELF activates and modulates Smad4 activation of TGF-β to confer cell polarity, to maintain cell architecture, and to inhibit epithelial-to-mesenchymal transition. Analysis of development of colon cancer in (adult) elf+/−/Smad4+/−, elf+/−, Smad4+/−, and gut epithelial cells from elf−/− mutant mouse embryos pinpoints the defect to hyperplasia/adenoma transition. Further analysis of the role of ELF in human colorectal cancer confirms reduced expression of ELF in Dukes' B1 stage tissues (P &lt; 0.05) and of Smad4 in advanced colon cancers (P &lt; 0.05). This study indicates that by modulating Smad 4, ELF has a key role in TGF-β signaling in the suppression of early colon cancer.
Antitumor Activity of Rapamycin in a Transgenic Mouse Model of ErbB2-Dependent Human Breast Cancer
Authors: Liu Mei , Howes Amy , Lesperance Jacqueline , Stallcup William B. , Hauser Craig A. , Kadoya Kuniko , Oshima Robert G. , Abraham Robert T. 
Published: September 2005

Abstract
The ErbB2 (Neu) receptor tyrosine kinase is frequently overexpressed in human breast cancers, and this phenotype correlates with a poor clinical prognosis. We examined the effects of the mammalian target of rapamycin inhibitor, rapamycin, on mammary tumorigenesis in transgenic mice bearing an activated ErbB2 (NeuYD) transgene in the absence or presence of a second transgene encoding vascular endothelial growth factor (VEGF). Treatment of NeuYD or NeuYD × VEGF mice with rapamycin dramatically inhibited tumor growth accompanied by a marked decrease in tumor vascularization. Two key events that may underlie the antitumor activity of rapamycin were decreased expression of ErbB3 and inhibition of hypoxia-inducible factor-1–dependent responses to hypoxic stress. Rapamycin exposure caused only a modest inhibition of the proliferation of tumor-derived cell lines in standard monolayer cultures, but dramatically inhibited the growth of the same cells in three-dimensional cultures, due in part to the induction of apoptotic cell death. These studies underscore the therapeutic potential of mammalian target of rapamycin inhibitors in ErbB2-positive breast cancers and indicate that, relative to monolayer cultures, three-dimensional cell cultures are more predictive in vitro models for studies of the antitumor mechanisms of rapamycin and related compounds.
Inactivation of Nuclear Factor κB by Soy Isoflavone Genistein Contributes to Increased Apoptosis Induced by Chemotherapeutic Agents in Human Cancer Cells
Authors: Li Yiwei , Ahmed Fakhara , Ali Shadan , Philip Philip A. , Kucuk Omer , Sarkar Fazlul H. 
Published: September 2005

Abstract
Cancer chemotherapeutic strategies commonly require multiple agents. However, use of multiple agents contributes to added toxicity resulting in poor treatment outcome. Thus, combination chemotherapy must be optimized to increase tumor response and at the same time lower its toxicity. Chemotherapeutic agents are known to induce nuclear factor κB (NF-κB) activity in tumor cells, resulting in lower cell killing and drug resistance. In contrast, genistein has been shown to inhibit the activity of NF-κB and the growth of various cancer cells without causing systemic toxicity. We therefore investigated whether the inactivation of NF-κB by genistein before treatment of various cancer cells with chemotherapeutic agents could lead to better tumor cell killing as tested by in vitro studies using gene transfections and also by animal studies. PC-3 (prostate), MDA-MB-231 (breast), H460 (lung), and BxPC-3 (pancreas) cancer cells were pretreated with 15 to 30 μmol/L genistein for 24 hours and then exposed to low doses of chemotherapeutic agents for an additional 48 to 72 hours. We found that 15 to 30 μmol/L genistein combined with 100 to 500 nmol/L cisplatin, 0.5 to 2 nmol/L docetaxel, or 50 ng/mL doxorubicin resulted in significantly greater inhibition of cell growth and induction of apoptosis compared with either agent alone. Moreover, we found that the NF-κB activity was significantly increased within 2 hours of cisplatin and docetaxel treatment and that the NF-κB inducing activity of these agents was completely abrogated in cells pretreated with genistein. These results were also supported, for the first time, by animal experiments, p65 cDNA transfection and p65 small interfering RNA studies, which clearly showed that a specific target (NF-κB) was affected in vivo. Collectively, our results clearly suggest that genistein pretreatment inactivates NF-κB and may contribute to increased growth inhibition and apoptosis induced by cisplatin, docetaxel, and doxorubicin in prostate, breast, lung, and pancreatic cancer cells. Theses results warrant carefully designed clinical studies investigating the combination of soy isoflavones and commonly used chemotherapeutic agents for the treatment of human cancers.
Serum Antibodies to Huntingtin Interacting Protein-1: A New Blood Test for Prostate Cancer
Authors: Bradley Sarah V. , Oravecz-Wilson Katherine I. , Bougeard Gaelle , Mizukami Ikuko , Li Lina , Munaco Anthony J. , Sreekumar Arun , Corradetti Michael N. , Chinnaiyan Arul M. , Sanda Martin G. , Ross Theodora S. 
Published: September 2005

Abstract
Huntingtin-interacting protein 1 (HIP1) is frequently overexpressed in prostate cancer. HIP1 is a clathrin-binding protein involved in growth factor receptor trafficking that transforms fibroblasts by prolonging the half-life of growth factor receptors. In addition to human cancers, HIP1 is also overexpressed in prostate tumors from the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model. Here we provide evidence that HIP1 plays an important role in mouse tumor development, as tumor formation in the TRAMP mice was impaired in the Hip1null/null background. In addition, we report that autoantibodies to HIP1 developed in the sera of TRAMP mice with prostate cancer as well as in the sera from human prostate cancer patients. This led to the development of an anti-HIP1 serum test in humans that had a similar sensitivity and specificity to the anti–α-methylacyl CoA racemase (AMACR) and prostate-specific antigen tests for prostate cancer and when combined with the anti-AMACR test yielded a specificity of 97%. These data suggest that HIP1 plays a functional role in tumorigenesis and that a positive HIP1 autoantibody test may be an important serum marker of prostate cancer.
Milk Thistle and Prostate Cancer: Differential Effects of Pure Flavonolignans from Silybum marianum on Antiproliferative End Points in Human Prostate Carcinoma Cells
Authors: Davis-Searles Paula R. , Nakanishi Yuka , Kim Nam-Cheol , Graf Tyler N. , Oberlies Nicholas H. , Wani Mansukh C. , Wall Monroe E. , Agarwal Rajesh , Kroll David J. 
Published: September 2005

Abstract
Extracts from the seeds of milk thistle, Silybum marianum, are known commonly as silibinin and silymarin and possess anticancer actions on human prostate carcinoma in vitro and in vivo. Seven distinct flavonolignan compounds and a flavonoid have been isolated from commercial silymarin extracts. Most notably, two pairs of diastereomers, silybin A and silybin B and isosilybin A and isosilybin B, are among these compounds. In contrast, silibinin is composed only of a 1:1 mixture of silybin A and silybin B. With these isomers now isolated in quantities sufficient for biological studies, each pure compound was assessed for antiproliferative activities against LNCaP, DU145, and PC3 human prostate carcinoma cell lines. Isosilybin B was the most consistently potent suppressor of cell growth relative to either the other pure constituents or the commercial extracts. Isosilybin A and isosilybin B were also the most effective suppressors of prostate-specific antigen secretion by androgen-dependent LNCaP cells. Silymarin and silibinin were shown for the first time to suppress the activity of the DNA topoisomerase IIα gene promoter in DU145 cells and, among the pure compounds, isosilybin B was again the most effective. These findings are significant in that isosilybin B composes no more than 5% of silymarin and is absent from silibinin. Whereas several other more abundant flavonolignans do ultimately influence the same end points at higher exposure concentrations, these findings are suggestive that extracts enriched for isosilybin B, or isosilybin B alone, might possess improved potency in prostate cancer prevention and treatment.
Proline-, Glutamic Acid-, and Leucine-Rich Protein-1 Is Essential in Growth Factor Regulation of Signal Transducers and Activators of Transcription 3 Activation
Authors: Manavathi Bramanandam , Nair Sujit S. , Wang Rui-An , Kumar Rakesh , Vadlamudi Ratna K. 
Published: September 2005

Abstract
Proline-, glutamic acid-, and leucine-rich protein-1 (PELP1) is a novel estrogen receptor coactivator that plays an important role in the genomic and nongenomic actions of estrogen receptor by interacting with histones and src-mitogen-activated protein kinase pathway, respectively. A great deal of information has emerged in recent years about the possible role of PELP1 in estrogen receptor signaling. However, the participation and significance of PELP1 in other cellular signaling pathways remains unknown. Using a yeast two-hybrid screen, we identified PELP1 as a novel interacting protein of signal transducers and activators of transcription 3 (STAT3) and found evidence of physiologic interaction between PELP1 and STAT3. We also found that these interactions played a mechanistic role in the positive regulation of STAT3 transcription from synthetic promoters and endogenous target genes such as cyclin D1, c-myc, and c-fos. Overexpression of PELP1 enhanced phosphorylation of STAT3 at Ser727 in a src-mitogen-activated protein kinase–sensitive manner and, conversely, down-regulation of PELP1 compromised growth factor–mediated induction of STAT3 target genes. We also discovered that PELP1 interacts with STAT3 in the nuclear compartment and down-regulation of PELP1 interfered with the recruitment of STAT3 to its target gene promoters. In summary, our results highlight a novel role for PELP1 in growth factor signaling and indicate that PELP1-mediated genomic and nongenomic functions play a role in the growth factor–mediated STAT3 transactivation functions. Such regulatory interactions of PELP1 may have important functional implications in the cross-talk of estrogen receptor and growth factor signaling.
In vivo Assessment of RAS-Dependent Maintenance of Tumor Angiogenesis by Real-time Magnetic Resonance Imaging
Authors: Tang Yi , Kim Minjung , Carrasco Daniel , Kung Andrew L. , Chin Lynda , Weissleder Ralph 
Published: September 2005

Abstract
New blood vessel formation is a prominent feature of human cancers and tumor progression and is frequently accompanied by the acquisition of an angiogenic phenotype associated with a switch in the balance of proangiogenic and antiangiogenic molecules. This study was designed to investigate the role of activated H-RAS on the angiogenic phenotype of melanoma that arises in the inducible Tyr/Tet-RAS Ink4a/Arf−/− model using in vivo imaging with histopathologic correlation. We show that loss of RAS activity in fully established melanomas led to a reduction in tumor volume, which was preceded by impairment of vascular function as determined by in vivo magnetic resonance imaging. This correlated with activation of apoptosis in host-derived endothelial cells as well as in tumor cells. Thus, real-time in vivo imaging provided evidence that maintenance of tumor angiogenesis requires activated RAS in this model system, and that loss of vascular integrity upon inactivation of RAS is an active process rather than a consequence of loss of tumor cell viability.
Targeted Expression of BRAFV600E in Thyroid Cells of Transgenic Mice Results in Papillary Thyroid Cancers that Undergo Dedifferentiation
Authors: Knauf Jeffrey A. , Ma Xiaolan , Smith Eric P. , Zhang Lei , Mitsutake Norisato , Liao Xiao-Hui , Refetoff Samuel , Nikiforov Yuri E. , Fagin James A. 
Published: September 2005

Abstract
The BRAFT1799A mutation is the most common genetic alteration in papillary thyroid carcinomas (PTC). It is also found in a subset of papillary microcarcinomas, consistent with a role in tumor initiation. PTCs with BRAFT1799A are often invasive and present at a more advanced stage. BRAFT1799A is found with high prevalence in tall-cell variant PTCs and in poorly differentiated and undifferentiated carcinomas arising from PTCs. To explore the role of BRAFV600E in thyroid cancer pathogenesis, we targeted its expression to thyroid cells of transgenic FVB/N mice with a bovine thyroglobulin promoter. Two Tg-BRAFV600E lines (Tg-BRAF2 and Tg-BRAF3) were propagated for detailed analysis. Tg-BRAF2 and Tg-BRAF3 mice had increased thyroid-stimulating hormone levels (&gt;7- and ∼2-fold, respectively). This likely resulted from decreased expression of thyroid peroxidase, sodium iodine symporter, and thyroglobulin. All lines seemed to successfully compensate for thyroid dysfunction, as serum thyroxine/triiodothyronine and somatic growth were normal. Thyroid glands of transgenic mice were markedly enlarged by 5 weeks of age. In Tg-BRAF2 mice, PTCs were present at 12 and 22 weeks in 14 of 15 and 13 of 14 animals, respectively, with 83% exhibiting tall-cell features, 83% areas of invasion, and 48% foci of poorly differentiated carcinoma. Tg-BRAF3 mice also developed PTCs, albeit with lower prevalence (3 of 12 and 4 of 9 at 12 and 22 weeks, respectively). Tg-BRAF2 mice had a 30% decrease in survival at 5 months. In summary, thyroid-specific expression of BRAFV600E induces goiter and invasive PTC, which transitions to poorly differentiated carcinomas. This closely recapitulates the phenotype of BRAF-positive PTCs in humans and supports a key role for this oncogene in its pathogenesis.
Requirement of Epidermal Growth Factor Receptor for Hyperplasia Induced by E5, a High-Risk Human Papillomavirus Oncogene
Authors: Genther Williams Sybil M. , Disbrow Gary L. , Schlegel Richard , Lee Daekee , Threadgill David W. , Lambert Paul F. 
Published: September 2005

Abstract
Multicellular organisms rely on complex networks of signaling cascades for development, homeostasis, and responses to the environment. These networks involve diffusible signaling molecules, their receptors, and a variety of downstream effectors. Alterations in the expression or function of any one of these factors can contribute to disease, including cancer. Many viruses have been implicated in cancer, and some of these modulate cellular signal transduction cascades to carry out their life cycles. High-risk human papillomaviruses (HPVs), the causative agents of most cervical and anogenital cancers, encode three oncogenes. One of these, E5, has been postulated to transform cells in tissue culture by modulating growth factor receptors. In this study, we generate and characterize transgenic mice in which the E5 gene of the most common high-risk HPV, HPV16, is targeted to the basal layer of the stratified squamous epithelium. In these mice, E5 alters the growth and differentiation of stratified epithelia and induces epithelial tumors at a high frequency. Through the analysis of these mice, we show a requirement of the epidermal growth factor receptor for the hyperplastic properties of E5.
Inhibition of the Phosphatidylinositol 3-Kinase/Akt Pathway by Inositol Pentakisphosphate Results in Antiangiogenic and Antitumor Effects
Authors: Maffucci Tania , Piccolo Enza , Cumashi Albana , Iezzi Manuela , Riley Andrew M. , Saiardi Adolfo , Godage H. Yasmin , Rossi Cosmo , Broggini Massimo , Iacobelli Stefano , Potter Barry V.L. , Innocenti Paolo , Falasca Marco 
Published: September 2005

Abstract
The purpose of this study was to investigate the antiangiogenic and in vivo properties of the recently identified phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor Inositol(1,3,4,5,6) pentakisphosphate [Ins(1,3,4,5,6)P5]. Because activation of the PI3K/Akt pathway is a crucial step in some of the events leading to angiogenesis, the effect of Ins(1,3,4,5,6)P5 on basic fibroblast growth factor (FGF-2)–induced Akt phosphorylation, cell survival, motility, and tubulogenesis in vitro was tested in human umbilical vein endothelial cells (HUVEC). The effect of Ins(1,3,4,5,6)P5 on FGF-2-induced angiogenesis in vivo was evaluated using s.c. implanted Matrigel in mice. In addition, the effect of Ins(1,3,4,5,6)P5 on growth of ovarian carcinoma SKOV-3 xenograft was tested. Here, we show that FGF-2 induces Akt phosphorylation in HUVEC resulting in antiapoptotic effect in serum-deprived cells and increase in cellular motility. Ins(1,3,4,5,6)P5 blocks FGF-2-mediated Akt phosphorylation and inhibits both survival and migration in HUVEC. Moreover, Ins(1,3,4,5,6)P5 inhibits the FGF-2-mediated capillary tube formation of HUVEC plated on Matrigel and the FGF-2-induced angiogenic reaction in BALB/c mice. Finally, Ins(1,3,4,5,6)P5 blocks the s.c. growth of SKOV-3 xenografted in nude mice to the same extent than cisplatin and it completely inhibits Akt phosphorylation in vivo. These data definitively identify the Akt inhibitor Ins(1,3,4,5,6)P5 as a specific antiangiogenic and antitumor factor. Inappropriate activation of the PI3K/Akt pathway has been linked to the development of several diseases, including cancer, making this pathway an attractive target for therapeutic strategies. In this respect, Ins(1,3,4,5,6)P5, a water-soluble, natural compound with specific proapoptotic and antiangiogenic properties, might result in successful anticancer therapeutic strategies.