bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aromatase Localization in Human Breast Cancer Tissues: Possible Interactions between Intratumoral Stromal and Parenchymal Cells
Authors: Miki Yasuhiro , Suzuki Takashi , Tazawa Chika , Yamaguchi Yuri , Kitada Kunio , Honma Seijiro , Moriya Takuya , Hirakawa Hisashi , Evans Dean B. , Hayashi Shin-ichi , Ohuchi Noriaki , Sasano Hironobu 
Published: April 2007

Abstract
Aromatase is a key enzyme in intratumoral estrogen production required for the production of estrogens through the conversion of serum androgens in postmenopausal breast cancer patients. There have been, however, controversies regarding the intratumoral localization of aromatase in human breast carcinoma tissues. Therefore, we have first examined the intratumoral localization of aromatase mRNA/protein in 19 breast carcinomas using laser capture microdissection/quantitative reverse transcription-PCR (RT-PCR) and immunohistochemistry. Aromatase mRNA and protein were detected in both intratumoral stromal and parenchymal cells in breast carcinoma tissues. Subsequent microarray expression profiling and clustering analyses, in addition to quantitative RT-PCR studies, showed a significant positive correlation between aromatase and estrogen-related receptor α mRNA expression in isolated carcinoma cells. We further examined an interaction between stromal cells isolated from human breast carcinoma tissues and breast carcinoma cell lines using a coculture system to study the biological characteristic of aromatase expression in carcinoma cells. Aromatase mRNA and enzyme activity and 17β-hydroxysteroid dehydrogenase type 1 mRNA in breast carcinoma cell lines, including MCF-7 and SK-BR-3 cells, were up-regulated in the presence of patient-derived 32N or 74T intratumoral stromal cells. The results from steroid conversion assays were also consistent with the findings above. The results of our study also showed that aromatase inhibitors were more effective in inhibiting aromatization induced by coculture in MCF-7 than that in stromal 32N. The examination of the localization of aromatase and its regulation, including the interactions existing between different cell types in human breast carcinoma tissues, may provide important information as to achieving better clinical response to aromatase inhibitors in breast cancer patients. [Cancer Res 2007;67(8):3945–54]
Interleukin-12 Deficiency Is Permissive for Angiogenesis in UV Radiation-Induced Skin Tumors
Authors: Meeran Syed M. , Katiyar Suchitra , Elmets Craig A. , Katiyar Santosh K. 
Published: April 2007

AbstractWe have shown previously that endogenous deficiency of interleukin (IL)-12 promotes photocarcinogenesis in mice. To characterize the role of IL-12 deficiency in tumor angiogenesis, we developed IL-12p35 knockout (IL-12 KO) mice on a C3H/HeN background. IL-12 KO mice and their wild-type (WT) counterparts were subjected to a photocarcinogenesis protocol. When tumor yield was stabilized, samples of tumor and tumor-uninvolved UVB-exposed skin were collected and subjected to immunohistochemistry, gelatinolytic zymography, real-time PCR, and Western blot analysis of angiogenic factors. We found that the protein, mRNA expression and/or activity of the matrix metalloproteinases (MMP)-2, MMP-3, MMP-7, and MMP-9, and basic fibroblast growth factor, which play crucial roles in tumor growth, were significantly higher in UVB-exposed skin and tumors of IL-12 KO mice compared with WT mice. With respect to the tumor vasculature, the expression of CD31-positive cells and the expression of vascular endothelial growth factor were higher in the tumors of IL-12 KO mice than WTs. The proliferative capacity of tumor cells of the IL-12 KO mice was significantly higher than their WT counterparts when determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and by analyzing the expression of cyclin D1. The level of the proinflammatory cytokine IL-6 and the expression of IL-23 in tumors of IL-12 KO mice were markedly higher than in the tumors of WT mice. IL-23 has been shown to promote tumor growth. Together, these data indicate for the first time that IL-12 deficiency promotes proangiogenic stimuli in UVB-induced skin tumors and suggest that endogenous enhancement of IL-12 levels may be effective in the prevention and treatment of UV-induced skin cancers. [Cancer Res 2007;67(8):3785–93]
Sulfasalazine Suppresses Drug Resistance and Invasiveness of Lung Adenocarcinoma Cells Expressing AXL
Authors: Lay Jong-Ding , Hong Chih-Chen , Huang Jhy-Shrian , Yang Ya-Yu , Pao Chung-Yi , Liu Ching-Hang , Lai Yi-Pin , Lai Gi-Ming , Cheng Ann-Lii , Su Ih-Jen , Chuang Shuang-En 
Published: April 2007

Abstract
Metastasis and drug resistance are the major causes of mortality in patients with non–small cell lung cancer (NSCLC). Several receptor tyrosine kinases (RTKs), including AXL, are involved in the progression of NSCLC. The AXL/MER/SKY subfamily is involved in cell adhesion, motility, angiogenesis, and signal transduction and may play a significant role in the invasiveness of cancer cells. Notably, no specific inhibitors of AXL have been described. A series of CL1 sublines with progressive invasiveness established from a patient with NSCLC has been identified that positively correlates with AXL expression and resistance to chemotherapeutic drugs. The ectopic overexpression of AXL results in elevated cell invasiveness and drug resistance. Nuclear factor-κB (NF-κB) signaling activity is associated with AXL expression and may play an important role in the enhancement of invasiveness and doxorubicin resistance, as shown by using the NF-κB inhibitor, sulfasalazine, and IκB dominant-negative transfectants. In the current study, sulfasalazine exerted a synergistic anticancer effect with doxorubicin and suppressed cancer cell invasiveness in parallel in CL1 sublines and various AXL-expressing cancer cell lines. Phosphorylation of AXL and other RTKs (ErbB2 and epidermal growth factor receptor) was abolished by sulfasalazine within 15 min, suggesting that the inhibition of NF-κB and the kinase activity of RTKs are involved in the pharmacologic effects of sulfasalazine. Our study suggests that AXL is involved in NSCLC metastasis and drug resistance and may therefore provide a molecular basis for RTK-targeted therapy using sulfasalazine to enhance the efficacy of chemotherapy in NSCLC. [Cancer Res 2007;67(8):3878–87]
Transforming Growth Factor β Signaling via Ras in Mesenchymal Cells Requires p21-Activated Kinase 2 for Extracellular Signal-Regulated Kinase-Dependent Transcriptional Responses
Authors: Suzuki Kaori , Wilkes Mark C. , Garamszegi Nandor , Edens Maryanne , Leof Edward B. 
Published: April 2007

Abstract
Transforming growth factor β (TGF-β) signaling via Smad proteins occurs in various cell types. However, whereas the biological response to TGF-β can be as distinct as growth promoting (i.e., mesenchymal cells) versus growth inhibiting (i.e., epithelial cells), few discernible differences in TGF-β signaling have been reported. In the current study, we examined the role of Ras in the proliferative response to TGF-β and how it might interface with Smad-dependent and Smad-independent TGF-β signaling targets. TGF-β stimulated Ras activity in a subset of mesenchymal, but not epithelial, cultures and was required for extracellular signal-regulated kinase (ERK)–dependent transcriptional responses. Although dominant negative Ras had no effect on TGF-β internalization or Smad-dependent signaling (i.e., phosphorylation, nuclear translocation, or SBE-luciferase activity), it did prevent the hyperphosphorylation of the Smad transcriptional corepressor TG-interacting factor (TGIF). This was not sufficient, however, to overcome the mitogenic response stimulated by TGF-β, which was dependent on signals downstream of p21-activated kinase 2 (PAK2). Moreover, although the initial activation of Ras and PAK2 are distinctly regulated, TGF-β–stimulated PAK2 activity is required for Ras-dependent ERK phosphorylation and Elk-1 transcription. These findings show the requirement for crosstalk between two Smad-independent pathways in regulating TGF-β proliferation and indicate that the mechanism(s) by which TGF-β stimulates growth is not simply the opposite of its growth inhibitory actions. [Cancer Res 2007;67(8):3673–82]
Estrogen Receptor β2 Negatively Regulates the Transactivation of Estrogen Receptor α in Human Breast Cancer Cells
Authors: Zhao Chunyan , Matthews Jason , Tujague Michel , Wan Jinghong , Ström Anders , Toresson Gudrun , Lam Eric W-F. , Cheng Guojun , Gustafsson Jan-Åke , Dahlman-Wright Karin 
Published: April 2007

Abstract
Estrogens, by binding to and activating two estrogen receptors (ERα and ERβ), are critically involved in the development of the mammary gland and breast cancer. An isoform of ERβ, ERβ2 (also called ERβcx), with an altered COOH-terminal region, is coexpressed with ERα in many human breast cancers. In this study, we generated a stable cell line from MCF7 breast cancer cells expressing an inducible version of ERβ2, along with endogenous ERα, and examined the effects of ERβ2 on the ERα protein levels and function. We showed that ERβ2 inhibited ERα-mediated transactivation via estrogen response element and activator protein-1 sites of reporter constructs as well as the endogenous genes pS2 and MMP-1. Chromatin immunoprecipitation assays revealed that ERβ2 expression caused a significant reduction in the recruitment of ERα to both the pS2 and MMP-1 promoters. Furthermore, ERβ2 expression induced proteasome-dependent degradation of ERα. The inhibitory effects of ERβ2 on ERα activity were further confirmed in HEK293 cells that lack functional endogenous ERs. We also showed that ERβ2 can interact with ERα both in vitro and in mammalian cells, which is compatible with a model where ERβ2/ERα heterodimers are targeted to the proteasome. Finally, in human breast cancer samples, we observed that expression of ERβ2 significantly correlated with ERα-negative phenotype. Our data suggest that ERβ2 could influence ERα-mediated effects relevant for breast cancer development, including hormone responsiveness. [Cancer Res 2007;67(8):3955–62]
Celecoxib Toxicity Is Cell Cycle Phase Specific
Authors: Bock Jonathan M. , Menon Sarita G. , Sinclair Lori L. , Bedford Nichole S. , Goswami Prabhat C. , Domann Frederick E. , Trask Douglas K. 
Published: April 2007

Abstract
Celecoxib inhibits proliferation and induces apoptosis in human tumors, but the molecular mechanisms for these processes are poorly understood. In this study, we evaluated the ability of celecoxib to induce toxicity in head and neck squamous cell carcinomas (HNSCC) and explored the relationships between celecoxib-induced cell cycle inhibition and toxicity in HNSCC. Celecoxib inhibited the proliferation of UM-SCC-1 and UM-SCC-17B cells both in vitro and in vivo, accompanied by G1 phase cell cycle arrest and apoptosis. Celecoxib induced p21waf1/cip1 at the transcriptional level independent of wild-type p53 function, leading to decreased expression of cyclin D1 and hypophosphorylation of Rb, with subsequent marked downstream decreases in nuclear E2F-1 protein expression and E2F transactivating activity by luciferase reporter assay. Cell cycle phase–specific cytometric sorting showed that celecoxib induced clonogenic toxicity preferentially to cells within the S phase greater than G1 and G2 phases. Levels of p21waf1/cip1 and cyclin D1 protein were reduced in the S phase compared with the G1 and G2 phases, suggesting a possible protective role for p21waf1/cip1 expression in celecoxib toxicity. In conclusion, we show that celecoxib has marked antiproliferative activity against head and neck cancer cells through transcriptional induction of p21waf1/cip1 and G1 phase accumulation leading to S phase–specific clonogenic toxicity. We additionally show that a profound inhibition of nuclear E2F function provides a possible mechanism for this S phase–specific toxicity. [Cancer Res 2007;67(8):3801–8]
Specific Growth Rate versus Doubling Time for Quantitative Characterization of Tumor Growth Rate
Authors: Mehrara Esmaeil , Forssell-Aronsson Eva , Ahlman Håkan , Bernhardt Peter 
Published: April 2007

Abstract
Doubling time (DT) is widely used for quantification of tumor growth rate. DT is usually determined from two volume estimations with measurement time intervals comparable with or shorter than DT. Clinical data show that the frequency distribution of DT in patients is positively skewed, with some very long DT values compared with the average DT. Growth rate can also be quantified using specific growth rate (SGR; %/d), equal to ln2/DT. The aim of this work was to compare DT and SGR as growth rate variables. Growth rate calculations were computer simulated for a tumor with DT of 100 days, measurement time interval of 1 to 200 days, and volume estimation uncertainty of 5% to 20%. Growth rate variables were determined and compared for previously published clinical data. The study showed that DT is not a suitable variable for tumor growth rate because (a) for short measurement time intervals, or high volume uncertainties, mean DT can either overestimate or underestimate the average growth rate; (b) DT is not defined if the consecutively estimated volumes are equal; and (c) the asymmetrical frequency distribution of DT makes it unsuitable for common statistical testing. In contrast, mean SGR and its equivalent DT give the correct values for average growth rate, SGR is defined for all tumor volume changes, and it has a symmetrical frequency distribution. SGR is also more accurate to use when discussing, for example, growth fraction, cell loss rate, and growth rate heterogeneities within the tumor. SGR should thus be used, instead of DT, to quantify tumor growth rate. [Cancer Res 2007;67(8):3970–5]
Most C6 Cells Are Cancer Stem Cells: Evidence from Clonal and Population Analyses
Authors: Zheng Xuesheng , Shen Gang , Yang Xiaofeng , Liu Weiguo 
Published: April 2007

Abstract
Cancer stem cells have been isolated from human gliomas and many other parenchymal tumors. It was previously assumed that many established malignant cell lines also contain a rare subpopulation of stem cells. This study was designed to investigate the fraction of cancer stem cells in the C6 glioma cell line using clonal and population analyses, rather than isolating methods, which are based on specific markers. Interestingly, in the serum-containing medium, each of the 67 single C6 cells plated per miniwell was able to generate a clone and subclones, which subsequently gave rise to a xenograft glioma in the BALB/C-nude mouse. The CD133− C6 cells also possessed clonogenic, self-renewal, and tumorigenic capacities. Moreover, our findings indicated that brief exposure to Hoechst 33342 was harmful to the clonogenicity and proliferation of individual C6 cells. Therefore, the non–side-population cells may be deprived of their stem cell features in the process of Hoechst 33342 staining as a step in isolating a Hoechst-negative side population with flow cytometry. Thus, we concluded that the C6 line was mainly composed of cancer stem cells, although many of them were neither CD133+ nor side population. [Cancer Res 2007;67(8):3691–7]
Novel Action of Paclitaxel against Cancer Cells: Bystander Effect Mediated by Reactive Oxygen Species
Authors: Alexandre Jérôme , Hu Yumin , Lu Weiqin , Pelicano Helene , Huang Peng 
Published: April 2007

Abstract
Generation of reactive oxygen species (ROS) has been observed in cancer cells treated with paclitaxel, but the underlying mechanisms and therapeutic implications remain unclear. In the present study, we showed that paclitaxel promoted ROS generation through enhancing the activity of NADPH oxidase (NOX) associated with plasma membranes. Treatment of breast cancer cells caused an increased translocation of Rac1, a positive regulatory protein of NOX, to the membrane fraction. The paclitaxel-induced ROS generation occurred rapidly within several hours of drug exposure, with O2− and H2O2 accumulation mainly outside the cells while the intracellular ROS remained unchanged. Importantly, the increase in extracellular ROS caused lethal damage to the bystander cancer cells not exposed to paclitaxel, as shown by two different methods using coculture systems where the bystander cells were differentiated from the paclitaxel-treated cells by fluorescent or radioactive labeling. This cytotoxic bystander effect was also observed with other microtubule-targeted agents vincristine and taxotere but not with 5-fluorouracil or doxorubicin. This toxic bystander effect was enhanced by CuZnSOD that converts O2− to H2O2 and was abolished by a catalase that eliminates H2O2. Furthermore, paclitaxel was able to induce an almost complete inhibition of proliferation of the bystander cells in the coculture system. Our study revealed a novel mechanism by which paclitaxel induces toxic bystander effect through generation of extracellular H2O2 from the membrane-associated NOX. This may contribute to the potent anticancer activity of paclitaxel and provide a novel basis to improve the clinical use of this important drug. [Cancer Res 2007;67(8):3512–7]
Synergistic Effect of Cyclin D1 and c-Myc Leads to More Aggressive and Invasive Mammary Tumors in Severe Combined Immunodeficient Mice
Authors: Wang Yong , Thakur Archana , Sun Yuan , Wu Jack , Biliran Hector , Bollig Aliccia , Liao D. Joshua 
Published: April 2007

Abstract
Cyclin D1 is one of the most commonly overexpressed oncogenes in breast cancer; yet, it is not clear whether cyclin D1 alone is capable of causing malignant transformation of mammary epithelial cells. Here, we show that ectopic expression of cyclin D1 in benign mouse mammary epithelial cells promotes cell proliferation, anchorage-independent growth in soft agar, and tumorigenesis in severe combined immunodeficient mice. To address the possible interaction of cyclin D1 and c-myc in malignant transformation, we used cyclin D1/c-myc dual-expressing clones, which displayed more aggressive and invasive phenotype than cyclin D1–expressing clones. These data provide evidence that overexpression of cyclin D1 or coexpression with c-myc could cause invasive malignant transformation of benign mouse mammary epithelial cells. Furthermore, microarray analysis of cyclin D1 and cyclin D1/c-myc clones showed that these two tumor-producing clones might use distinct invasive pathways. In summary, overexpression of cyclin D1 may commit mammary epithelia to a tumor-prone phenotype in which cooperation with other genes, such as synergy with c-myc, may lead to a more aggressive phenotype. [Cancer Res 2007;67(8):3698–707]
Systemic Overexpression of Angiopoietin-2 Promotes Tumor Microvessel Regression and Inhibits Angiogenesis and Tumor Growth
Authors: Cao Yiting , Sonveaux Pierre , Liu Shanling , Zhao Yulin , Mi Jing , Clary Bryan M. , Li Chuan-Yuan , Kontos Christopher D. , Dewhirst Mark W. 
Published: April 2007

Abstract
Angiopoietin-2 (Ang-2) is a conditional antagonist and agonist for the endothelium-specific Tie-2 receptor. Although endogenous Ang-2 cooperates with vascular endothelial growth factor (VEGF) to protect tumor endothelial cells, the effect on tumor vasculature of high levels of exogenous Ang-2 with different levels of VEGF has not been studied in detail. Here, we report that systemic overexpression of Ang-2 leads to unexpected massive tumor vessel regression within 24 h, even without concomitant inhibition of VEGF. By impairing pericyte coverage of the tumor vasculature, Ang-2 destabilizes the tumor vascular bed while improving perfusion in surviving tumor vessels. Ang-2 overexpression transiently exacerbates tumor hypoxia without affecting ATP levels. Although sustained systemic Ang-2 overexpression does not affect tumor hypoxia and proliferation, it significantly inhibits tumor angiogenesis, promotes tumor apoptosis, and suppresses tumor growth. The similar antitumoral, antiangiogenic efficacy of systemic overexpression of Ang-2, soluble VEGF receptor-1, and the combination of both suggests that concomitant VEGF inhibition is not required for Ang-2–induced tumor vessel regression and growth delay. This study shows the important roles of Ang-2–induced pericyte dropout during tumor vessel regression. It also reveals that elevated Ang-2 levels have profound pleiotropic effects on tumor vessel structure, perfusion, oxygenation, and apoptosis. [Cancer Res 2007;67(8):3835–44]
Mutagen Sensitivity: A Genetic Predisposition Factor for Cancer
Authors: Wu Xifeng , Gu Jian , Spitz Margaret R. 
Published: April 2007

Abstract
Mutagen sensitivity, measured by quantifying the chromatid breaks induced by mutagens in short-term cultures of peripheral blood lymphocytes, has been used as an indirect measure of DNA repair capacity. Numerous epidemiologic studies have suggested that mutagen sensitivity is a cancer susceptibility factor for a variety of epithelial cancers. A recent classic twin study examined systematically the role of genetic and environmental factors on the mutagen sensitivity phenotype and provided compelling evidence that mutagen sensitivity is highly heritable. A new prospective analysis provides further support to the notion that mutagen sensitivity increases the risk of cancer. In this review, we briefly summarize nearly two decades of epidemiologic and genetic studies linking mutagen sensitivity and cancer risk. The evidence is becoming increasingly convincing that mutagen sensitivity is a risk factor for cancer development. [Cancer Res 2007;67(8):3493–5]
Syndecan-2 Affects the Basal and Chemotherapy-Induced Apoptosis in Osteosarcoma
Authors: Orosco Armelle , Fromigué Olivia , Bazille Céline , Entz-Werle Natacha , Levillain Pierre , Marie Pierre J. , Modrowski Dominique 
Published: April 2007

Abstract
Syndecans are transmembrane heparan sulfate proteoglycans controlling cell adhesion, migration, and proliferation. We previously showed that syndecan-2 is involved in the control of apoptosis in cultured osteosarcoma cells. These data led us to the hypothesis that syndecan-2 may play a role in the apoptotic signaling in bone tumors. We immunohistochemically analyzed tissue sections from biopsies from 21 patients with well-characterized osteosarcoma. These tissues expressed low levels of syndecan-2 compared with osteoblasts and osteocytes in normal bone. Cultured human osteosarcoma cells also produced lower mRNA levels of syndecan-2 than normal osteoblastic cells. Moreover, the presence of syndecan-2 correlated with spontaneous apoptosis in osteosarcoma tissues as assessed by detection of DNA fragmentation in situ. Overexpression of syndecan-2 resulted in decreased number of migrating and invading U2OS osteosarcoma cells in Matrigel. In addition, overexpression of syndecan-2 sensitized human osteosarcoma cells to chemotherapy-induced apoptosis, increasing the response to methotrexate, doxorubicin, and cisplatin. Consistently, knockdown of the proteoglycan using stable transfection with a plasmid coding small interfering RNA resulted in inhibition of chemotherapy-induced apoptosis. Analysis of syndecan-2 expression both in biopsies and in corresponding postchemotherapy-resected tumors, as well as in cells treated with methotrexate or doxorubicin, showed that the cytotoxic action of chemotherapy can be associated with an increase in syndecan-2. These results provide support for a tumor-suppressor function for syndecan-2 and suggest that dysregulation of apoptosis may be related to abnormal syndecan-2 expression or induction in osteosarcoma. Moreover, our data identify syndecan-2 as a new factor mediating the antioncogenic effect of chemotherapeutic drugs. [Cancer Res 2007;67(8):3708–14]