bluuebunny/crossref_metadata_2025_split huggingface dataset:
Invasion of Human Breast Cancer Cells In vivo Requires Both Paracrine and Autocrine Loops Involving the Colony-Stimulating Factor-1 Receptor
Authors: Patsialou Antonia , Wyckoff Jeffrey , Wang Yarong , Goswami Sumanta , Stanley E. Richard , Condeelis John S. 
Published: November 2009

Abstract
Colony-stimulating factor-1 (CSF-1) and its receptor (CSF-1R) have been implicated in the pathogenesis and progression of various types of cancer, including breast cancer. This is based on high levels of circulating CSF-1 in patient sera with aggressive disease and increased CSF-1R staining in the tumor tissues. However, there have been no direct in vivo studies to determine whether a CSF-1 autocrine signaling loop functions in human breast cancer cells in vivo and whether it contributes to invasion. Recently, in mouse and rat models, it has been shown that invasion and metastasis are driven by an epidermal growth factor (EGF)/CSF-1 paracrine loop between tumor cells and host macrophages. In this macrophage-dependent invasion, tumor cells secrete CSF-1 and sense EGF, whereas the macrophages secrete EGF and sense CSF-1. Here, we test the hypothesis that in human breast tumors, the expression of both the CSF-1 ligand and its receptor in tumor cells leads to a CSF-1/CSF-1R autocrine loop which contributes to the aggressive phenotype of human breast tumors. Using MDA-MB-231 cell–derived mammary tumors in severe combined immunodeficiency mice, we show here for the first time in vivo that invasion in a human mammary tumor model is dependent on both paracrine signaling with host macrophages as well as autocrine signaling involving the tumor cells themselves. In particular, we show that the autocrine contribution to invasion is specifically amplified in vivo through a tumor microenvironment–induced upregulation of CSF-1R expression via the transforming growth factor-β1. [Cancer Res 2009;69(24):9498–506]
Activating Peroxisome Proliferator-Activated Receptor γ Mutant Promotes Tumor Growth In vivo by Enhancing Angiogenesis
Authors: Tian Lifeng , Zhou Jie , Casimiro Mathew C. , Liang Bing , Ojeifo John O. , Wang Min , Hyslop Terry , Wang Chenguang , Pestell Richard G. 
Published: November 2009

Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is expressed in a variety of cancer cells. The addition of ligand activates the receptor by inducing a conformational change in the receptor, which can be recapitulated by mutation. To investigate the role of activated PPARγ signaling in breast cancer, we compared the function of a constitutively active PPARγ (PγCA) mutant with the wild-type PPARγ in ErbB2-induced mammary tumorigenesis in vivo. Tumor cells transduced with either PPARγ or PγCA were implanted into immunocompetent FVB mice. Enhanced tumor growth was observed in PγCA-transduced cells, which was associated with increased angiogenesis and endothelial stem cells as evidenced by increased number of cells stained with von Willebrand factor, c-Kit, CD133, and CD31. Genome-wide expression profiling identified a group of genes within the angiogenesis pathway, including Angptl4, as targets of activated PPARγ; PγCA also induced Angptl4 protein secretion in ErbB2-transformed mammary epithelial cells. Angptl4 promoted vascular endothelial cell migration; conversely, immunodepletion of Angptl4 reduced PγCA-mediated cellular migration. Collectively, these studies suggest that activated PPARγ induces Angptl4 to promote tumor growth through enhanced angiogenesis in vivo. [Cancer Res 2009;69(24):9236–44]
Disruption of Sphingosine 1-Phosphate Lyase Confers Resistance to Chemotherapy and Promotes Oncogenesis through Bcl-2/Bcl-xL Upregulation
Authors: Colié Sandra , Van Veldhoven Paul P. , Kedjouar Blandine , Bedia Carmen , Albinet Virginie , Sorli Sonia-Caroline , Garcia Virginie , Djavaheri-Mergny Mojgan , Bauvy Chantal , Codogno Patrice , Levade Thierry , Andrieu-Abadie Nathalie 
Published: November 2009

Abstract
Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in cancer development through stimulation of cell survival, proliferation, migration, and angiogenesis. Irreversible degradation of S1P is catalyzed by S1P lyase (SPL). The human SGPL1 gene that encodes SPL maps to a region often mutated in cancers. To investigate the effect of SPL deficiency on cell survival and transformation, the susceptibility to anticancer drugs of fibroblasts generated from SPL-deficient mouse embryos (Sgpl1−/−) was compared with that of cells from heterozygous (Sgpl1+/−) or wild-type (Sgpl1+/+) embryos. First, loss of SPL caused resistance to the toxic effects of etoposide and doxorubicin. Interestingly, heterozygosity for the Sgpl1 gene resulted in partial resistance to apoptosis. Secondly, doxorubicin-induced apoptotic signaling was strongly inhibited in Sgpl1−/− cells (phosphatidylserine externalization, caspase activation, and cytochrome c release). This was accompanied by a strong increase in Bcl-2 and Bcl-xL protein content. Whereas correction of SPL deficiency in Sgpl1−/− cells led to downregulation of antiapoptotic proteins, Bcl-2 and Bcl-xL small interfering RNA–mediated knockdown in SPL-deficient cells resulted in increased sensitivity to doxorubicin, suggesting that Bcl-2 upregulation mediates SPL protective effects. Moreover, SPL deficiency led to increased cell proliferation, anchorage-independent cell growth, and formation of tumors in nude mice. Finally, transcriptomic studies showed that SPL expression is downregulated in human melanoma cell lines. Thus, by affecting S1P metabolism and the expression of Bcl-2 members, the loss of SPL enhances cell resistance to anticancer regimens and results in an increased ability of cells to acquire a transformed phenotype and become malignant. [Cancer Res 2009;69(24):9346–53]
Natural Sphingadienes Inhibit Akt-Dependent Signaling and Prevent Intestinal Tumorigenesis
Authors: Fyrst Henrik , Oskouian Babak , Bandhuvula Padmavathi , Gong Yaqiong , Byun Hoe Sup , Bittman Robert , Lee Andrew R. , Saba Julie D. 
Published: November 2009

Abstract
Sphingolipid metabolites regulate cell proliferation, migration, and stress responses. Alterations in sphingolipid metabolism have been proposed to contribute to carcinogenesis, cancer progression, and drug resistance. We identified a family of natural sphingolipids called sphingadienes and investigated their effects in colon cancer. We find that sphingadienes induce colon cancer cell death in vitro and prevent intestinal tumorigenesis in vivo. Sphingadienes exert their influence by blocking Akt translocation from the cytosol to the membrane, thereby inhibiting protein translation and promoting apoptosis and autophagy. Sphingadienes are orally available, are slowly metabolized through the sphingolipid degradative pathway, and show limited short-term toxicity. Thus, sphingadienes represent a new class of therapeutic and/or chemopreventive agents that blocks Akt signaling in neoplastic and preneoplastic cells. [Cancer Res 2009;69(24):9457–64]
Targeting the Fanconi Anemia/BRCA Pathway Circumvents Drug Resistance in Multiple Myeloma
Authors: Yarde Danielle N. , Oliveira Vasco , Mathews Linda , Wang Xingyu , Villagra Alejandro , Boulware David , Shain Kenneth H. , Hazlehurst Lori A. , Alsina Melissa , Chen Dung-Tsa , Beg Amer A. , Dalton William S. 
Published: November 2009

Abstract
The Fanconi anemia/BRCA (FA/BRCA) DNA damage repair pathway plays a pivotal role in the cellular response to replicative stress induced by DNA alkylating agents and greatly influences drug response in cancer treatment. We recently reported that FA/BRCA genes are overexpressed and causative for drug resistance in human melphalan-resistant multiple myeloma cell lines. However, the transcriptional regulation of the FA/BRCA pathway is not understood. In this report, we describe for the first time a novel function of the NF-κB subunits, RelB/p50, as transcriptional activators of the FA/BRCA pathway. Specifically, our findings point to constitutive phosphorylation of IκB kinase α and subsequent alterations in FANCD2 expression and function as underlying events leading to melphalan resistance in repeatedly exposed multiple myeloma cells. Inhibiting NF-κB by small interfering RNA, blocking the IκB kinase complex with BMS-345541, or using the proteasome inhibitor bortezomib drastically reduced FA/BRCA gene expression and FANCD2 protein expression in myeloma cells, resulting in diminished DNA damage repair and enhanced melphalan sensitivity. Importantly, we also found that bortezomib decreases FA/BRCA gene expression in multiple myeloma patients. These results show for the first time that NF-κB transcriptionally regulates the FA/BRCA pathway and provide evidence for targeting Fanconi anemia–mediated DNA repair to enhance chemotherapeutic response and circumvent drug resistance in myeloma patients. [Cancer Res 2009;69(24):9367–75]
Confounding Effects in “A Six-Gene Signature Predicting Breast Cancer Lung Metastasis”: Reply
Authors: Driouch Keltouma , Bonin Florian , Sin Soraya , Clairac Géraldine , Lidereau Rosette 
Published: November 2009

Abstract
Molecular signatures have begun to elucidate the biological and molecular mechanisms underlying the phenotypic diversity of breast tumors. Breast tumors are characterized by five different molecular subtypes that are associated with distinct clinical outcomes in terms of prognosis, treatment response, and site of relapse. In particular, the basal-like and luminal B subtypes of tumors are more aggressive and have a higher tendency to metastasize to the lung than do the other subtypes. Given this difference in metastatic profiles of breast tumors, the six-gene signature (6GS) that we showed to be predictive of lung relapse was reexamined in the context of the tumor subtypes. This first analysis suggested that the 6GS is a surrogate for molecular subtype, discriminating basal-like tumors rather than tumors that metastasize to the lung. Here, we show that the 6GS discriminates the two overlapping features, the basal-like subtype and the tendency to metastasize to the lung. Nevertheless, the 6GS predicts lung metastases of breast tumors independent of the molecular subtypes. [Cancer Res 2009;69(24):9507–11]
Construction and Characterization of Novel, Recombinant Immunotoxins Targeting the Her2/neu Oncogene Product: In vitro and In vivo Studies
Authors: Cao Yu , Marks James D. , Marks John W. , Cheung Lawrence H. , Kim Sehoon , Rosenblum Michael G. 
Published: November 2009

Abstract
The goal of this study was to characterize a series of anti-Her2/neu immunotoxin constructs to identify how different antibodies and linker choices affect the specificity and cytotoxicity of these proteins. We constructed a series of immunotoxins containing either the human single-chain antibody (scFv) C6.5 or the murine scFv e23 fused to the highly toxic recombinant gelonin (rGel) molecule. Based on the flexible GGGGS linker (L), the fusion construct C6.5-L-rGel was compared with e23-L-rGel to evaluate the specific cytotoxic effects against Her2/neu-positive and Her2/neu-negative tumor cells. Both constructs retained the specificity of the original antibody as well as the biological activity of rGel toxin. The two constructs displayed similar cytotoxicity against different carcinoma cells. We additionally introduced the modified linkers TRHRQPRGWEQL (Fpe) and AGNRVRRSVG (Fdt), which contained furin cleavage sites, to determine the effect of these design changes on stability and cell killing efficiency. The introduction of furin cleavage linkers (Fpe or Fdt) into the molecules resulted in dissimilar sensitivity to protease cleavage compared with the constructs containing the L linker, but very similar intracellular rGel release, cytotoxic kinetics, and induction of autophagic cell death in vitro. Xenograft studies with SKOV3 ovarian tumors were done using various C6.5/rGel constructs. C6.5-L-rGel was more efficient in tumor inhibition than constructs containing furin linkers, attributing to a higher stability in vivo of the L version. Therefore, our studies suggest that human C6.5-L-rGel may be an effective novel clinical agent for therapy of patients with Her2/neu-overexpressing malignancies. [Cancer Res 2009;69(23):8987–95]
Prevention of Mammary Carcinogenesis in MMTV-neuMice by Cruciferous Vegetable Constituent Benzyl Isothiocyanate
Authors: Warin Renaud , Chambers William H. , Potter Douglas M. , Singh Shivendra V. 
Published: November 2009

AbstractBenzyl isothiocyanate (BITC), a constituent of edible cruciferous vegetables, inhibits growth of human breast cancer cells in culture. The present study provides in vivo evidence for efficacy of BITC for prevention of mammary cancer in MMTV-neu mice. Administration of BITC at 1 and 3 mmol/kg diet for 25 weeks markedly suppressed the incidence and/or burden of mammary hyperplasia and carcinoma in female MMTV-neu mice without causing weight loss or affecting neu protein level. For example, cumulative incidence of hyperplasia/carcinoma was significantly lower in mice fed BITC-supplemented diets compared with control mice (P = 0.01 by Fisher's test). The BITC-mediated prevention of mammary carcinogenesis correlated with suppression of cell proliferation and increased apoptosis. The average number of Ki-67–positive cells in the carcinoma lesions of 3 mmol BITC group was lower by ∼21% (P &lt; 0.05) compared with tumors from control mice. Apoptotic bodies in the mammary tumor were higher by about 2- to 2.5-fold in the 1 and 3 mmol BITC treatment groups (P &lt; 0.05) compared with control group. The BITC administration also resulted in overexpression of E-cadherin and infiltration of CD3+ T-cells in the tumor. Although BITC treatment increased cytotoxicity of natural killer (NK) cells in vitro, dietary feeding of BITC failed to augment NK cell lytic activity in an ex vivo assay. The present study demonstrating efficacy of BITC against mammary cancer in an animal model provides impetus to determine its activity in a clinical setting. [Cancer Res 2009;69(24):9473–80]
MBP-1 Inhibits Breast Cancer Growth and Metastasis in Immunocompetent Mice
Authors: Kanda Tatsuo , Raychoudhuri Amit , Steele Robert , Sagartz John E. , West Cheri , Ray Ratna B. 
Published: November 2009

Abstract
Breast cancer is the leading cause of cancer death among women. We have shown previously an antiproliferative effect of MBP-1 on several human cancer cells. In this study, we have examined the potential of MBP-1 as a gene therapeutic candidate in regression of breast cancer growth and metastasis in an immunocompetent mouse model. For this, we have used a mouse breast cancer cell line (EO771) and syngeneic C57BL/6 mice. EO771 cells were implanted into the mammary fat pad of C57BL/6 mice. Replication-deficient recombinant adenovirus expressing MBP-1 was administered intratumorally to determine gene therapeutic potential. The results showed a significant regression of primary and distant (lung) tumor growth. Animals exhibited prolonged survival on treatment with MBP-1 compared with the control group (dl312). Subsequent studies suggested that MBP-1 inhibits matrix metalloproteinase expression in human breast cancer cells. Cells transduced with MBP-1 displayed inhibition of migration in a wound-healing assay. The conditioned medium from MBP-1–transduced cells blocked in vitro tube formation assay and inhibited expression of several angiogenic molecules. Taken together, our study shows that MBP-1 acts as a double-edged sword by inhibiting primary and metastatic tumor growth and modulating matrix metalloproteinase expression with a therapeutic potential against breast cancer progression. [Cancer Res 2009;69(24):9354–9]
Srcasm Inhibits Fyn-Induced Cutaneous Carcinogenesis with Modulation of Notch1 and p53
Authors: Zhao Liang , Li Weijie , Marshall Christine , Griffin Thomas , Hanson Matthew , Hick Ryan , Dentchev Tzvete , Williams Erik , Werth Adrienne , Miller Christopher , Bashir Hasan , Pear Warren , Seykora John T. 
Published: November 2009

Abstract
Src family tyrosine kinases (SFK) regulate cell proliferation, and increased SFK activity is common in human carcinomas, including cutaneous squamous cell carcinomas (SCC) and its precursors. The elevated SFK activity in cutaneous SCCs was modeled using K14-Fyn Y528F transgenic mice, which spontaneously form punctate keratotic lesions, scaly plaques, and large tumors resembling actinic keratoses, SCC in situ, and SCCs, respectively. Lesional tissue showed increased levels of activated SFKs, PDK1, STAT3, and ERK1/2, whereas Notch1/NICD protein and transcript levels were decreased. p53 levels also were decreased in SCC in situ and SCCs. Increasing Srcasm levels using a K14-Fyn Y528F/K14-Srcasm double transgenic model markedly inhibited cutaneous neoplasia. In contrast, increased expression of a nonphosphorylatable Srcasm mutant maintained the neoplastic phenotype. Increasing Srcasm levels decreased levels of Fyn, activated SFKs, ERK1/2, PDK1, and phospho-STAT3, and increased Notch1/NICD and p53 levels. Analysis of human specimens revealed that levels of Fyn and activated SFKs were elevated in SCCs compared with adjacent nonlesional epidermis. In addition, Notch1 and Srcasm protein and transcript levels were decreased in human SCCs compared with nonlesional epidermis. Therefore, the SCCs produced by the Fyn Y528F mice resemble their human counterparts at the molecular level. K14-Fyn Y528F mice represent a robust model of cutaneous carcinogenesis that manifests precancerous lesions and SCCs resembling human disease. The Fyn/Srcasm signaling nexus modulates activity of STAT3, PDK1, ERK1/2, Notch1, and p53. Further study of Fyn and Srcasm should provide insights into the mechanisms regulating keratinocyte proliferation and skin carcinogenesis. [Cancer Res 2009;69(24):9439–47]
Genetic Factors on Mouse Chromosome 18 Affecting Susceptibility to Testicular Germ Cell Tumors and Permissiveness to Embryonic Stem Cell Derivation
Authors: Anderson Philip D. , Nelson Vicki R. , Tesar Paul J. , Nadeau Joseph H. 
Published: November 2009

Abstract
Despite strong heritability, little is known about the genetic control of susceptibility to testicular germ cell tumors (TGCT) in humans or mice. Although the mouse model of spontaneous TGCTs has been extensively studied, conventional linkage analysis has failed to locate the factors that control teratocarcinogenesis in the susceptible 129 family of inbred strains. As an alternative approach, we used both chromosome substitution strains (CSS) to identify individual chromosomes that harbor susceptibility genes and a panel of congenic strains derived from a selected CSS to determine the number and location of susceptibility variants on the substituted chromosome. We showed that 129-Chr 18MOLF males are resistant to spontaneous TGCTs and that at least four genetic variants control susceptibility in males with this substituted chromosome. In addition, early embryonic cells from this strain fail to establish embryonic stem cell lines as efficiently as those from the parental 129/Sv strain. For the first time, 129-derived genetic variants that control TGCT susceptibility and fundamental aspects of embryonic stem cell biology have been localized in a genetic context in which the genes can be identified and functionally characterized. [Cancer Res 2009;69(23):9112–7]
Targeting the RET Pathway in Thyroid Cancer
Authors: Wells Samuel A. , Santoro Massimo 
Published: November 2009

Abstract
The RET (rearranged during transfection) protooncogene encodes a single pass transmembrane receptor that is expressed in cells derived from the neural crest and the urogenital tract. As part of a cell-surface complex, RET binds glial derived neurotrophic factor (GDNF) ligands in conjunction with GDNF-family α co-receptors (GFRα). Ligand-induced activation induces dimerization and tyrosine phosphorylation of the RET receptor with downstream activation of several signal transduction pathways. Activating germline RET mutations play a central role in the development of the multiple endocrine neoplasia (MEN) syndromes MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC) and also in the development of the congenital abnormality Hirschsprung's disease. Approximately 50% of patients with sporadic MTC have somatic RET mutations, and a significant portion of papillary thyroid carcinomas result from chromosomal inversions or translocations, which activate RET (RET/PTC oncogenes). The RET protooncogene has a significant place in cancer prevention and treatment. Timely thyroidectomy in kindred members who have inherited a mutated RET allele, characteristic of MEN2A, MEN2B, or FMTC, can prevent MTC, the most common cause of death in these syndromes. Also, recently developed molecular therapeutics that target the RET pathway have shown activity in clinical trials of patients with advanced MTC, a disease for which there has been no effective therapy. (Clin Cancer Res 2009;15(23):7119–23)
A Prospective Study of Telomere Length Measured by Monochrome Multiplex Quantitative PCR and Risk of Non-Hodgkin Lymphoma
Authors: Lan Qing , Cawthon Richard , Shen Min , Weinstein Stephanie J. , Virtamo Jarmo , Lim Unhee , Hosgood H. Dean , Albanes Demetrius , Rothman Nathaniel 
Published: November 2009

Abstract
Purpose: Telomere length plays an important role in the maintenance of chromosomal stability and in tumorigenesis. We hypothesized that telomere length in peripheral WBC DNA obtained from healthy individuals would be a predictor of future risk of developing non-Hodgkin lymphoma.
Experimental Design: Using a new assay to measure relative telomere length, monochrome multiplex quantitative PCR, which strongly correlates with telomere length measured by Southern blot (Spearman r = 0.91, P &lt; 0.0001) and has high precision (coefficient of variation = 7%), we compared telomere length in peripheral WBC DNA in 107 incident male non-Hodgkin lymphoma cases and 107 matched controls within the prospective Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort.
Results: Median (10th, 90th percentile) telomere length was 1.10 (0.79, 1.43) in cases and 1.02 (0.78, 1.26) in controls (P = 0.0017, Wilcoxon sign test). There was a strong dose-response relationship between quartiles of telomere length and risk of non-Hodgkin lymphoma overall [odds ratios (95% confidence intervals) by quartile: 1.0; 1.1 (0.4-2.7); 1.8 (0.7-4.9); and 3.6 (1.4-8.9); P trend = 0.003], and this association was similar across the most common non-Hodgkin lymphoma subtypes present in this study.
Conclusion: These results suggest that longer telomere length may be a potential predictor for future risk of non-Hodgkin lymphoma. (Clin Cancer Res 2009;15(23):7429–33)