bluuebunny/crossref_metadata_2025_split huggingface dataset:
2-Methoxyestradiol Suppresses Osteolytic Breast Cancer Tumor Progression In vivo
Authors: Cicek Muzaffer , Iwaniec Urszula T. , Goblirsch Michael J. , Vrabel Anne , Ruan Ming , Clohisy Denis R. , Turner Russell R. , Oursler Merry Jo 
Published: November 2007

Abstract
2-Methoxyestradiol (2ME2), a physiologic metabolite of 17β-estradiol (estrogen), has emerged as a promising cancer therapy because of its potent growth-inhibitory and proapoptotic effects on both endothelial and tumor cells. 2ME2 also suppresses osteoclast differentiation and induces apoptosis of mature osteoclasts, and has been shown to effectively repress bone loss in an animal model of postmenopausal osteoporosis. Given these observations, we have examined whether 2ME2 could effectively target metastasis to bone, osteolytic tumors, and soft tissue tumors. A 4T1 murine metastatic breast cancer cell line was generated that stably expressed Far Red fluorescence protein (4T1/Red) to visualize tumor development and metastasis to bone. In an intervention study, 4T1/Red cells were injected into bone marrow of the left femur and the mammary pad. In the latter study, 2ME2 (10, 25, and 50 mg/kg/d) treatment began on the same day as surgery and was continued for the 16-day duration of study. Tumor cell growth and metastasis to bone were monitored and bone volume was determined by micro-computed tomography. 2ME2 inhibited tumor growth in soft tissue, metastasis to bone, osteolysis, and tumor growth in bone, with maximum effects at 50 mg/kg/d. Furthermore, tumor-induced osteolysis was significantly reduced in mice receiving 2ME2. In vitro, 2ME2 repressed osteoclast number by inducing apoptosis of osteoclast precursors as well as mature osteoclasts. Our data support the conclusion that 2ME2 could be an important new therapy in the arsenal to fight metastatic breast cancer. [Cancer Res 2007;67(21):10106–11]
Differing Src Signaling Levels Have Distinct Outcomes in Drosophila
Authors: Vidal Marcos , Warner Stephen , Read Renee , Cagan Ross L. 
Published: November 2007

Abstract
High levels of Src activity are found in a broad spectrum of cancers. The roles of Src and its negative regulator Csk have been extensively studied, although results have often proved contradictory or the relevance to whole organisms is unclear. In Drosophila, overexpression of either Src orthologue resulted in apoptotic cell death, but paradoxically, reducing dCsk activity led to over-proliferation and tissue overgrowth. Here, we show that in Drosophila epithelia in situ, the levels of Src signaling determine the cellular outcome of Src activation. Apoptotic cell death was triggered specifically at high Src signaling levels; lower levels directed antiapoptotic signals while promoting proliferation. Furthermore, our data indicate that expression of kinase-dead Src isoforms do not necessarily act as dominant-negative factors, but can instead increase Src pathway activity, most likely by titrating Csk activity away from endogenous Src. The importance of Src activity levels was emphasized when we examined oncogenic cooperation between Src and Ras: malignant overgrowth was observed specifically when high Src signaling levels were achieved. We propose a model in which low levels of Src signaling promote survival and proliferation during early stages of tumorigenesis, whereas strong Src signaling, coupled with antiapoptotic signals, directs invasive migration and metastasis during advanced tumor stages. [Cancer Res 2007;67(21):10278–85]
Aurora-A, a Negative Prognostic Marker, Increases Migration and Decreases Radiosensitivity in Cancer Cells
Authors: Guan Zhong , Wang Xian-ren , Zhu Xiao-feng , Huang Xue-fei , Xu Jie , Wang Li-hui , Wan Xiang-bo , Long Zi-jie , Liu Jian-nan , Feng Gong-kan , Huang Wenlin , Zeng Yi-xin , Chen Fu-jin , Liu Quentin 
Published: November 2007

Abstract
Centrosomal Aurora-A (Aur-A) kinase ensures proper spindle assembly and accurate chromosome segregation in mitosis. Overexpression of Aur-A leads to centrosome amplification, aberrant spindle, and consequent genetic instability. In the present study, Aur-A was found to be overexpressed in laryngeal squamous cell carcinoma (LSCC). Moreover, Aur-A expression was adversely correlated with median survival, and further identified as a potential independent factor for disease prognosis. Suppression of Aurora kinase activity chemically or genetically led to LSCC Hep2 cell cycle arrest and apoptotic cell death. Importantly, we found that Aur-A increases cell migration and this novel function was correlated with Akt1 activation. The enhanced cell migration induced by Aur-A overexpression could be abrogated by either small-molecule Akt1 inhibitor or short interfering RNA. VX-680, a selective Aurora kinase inhibitor, decreased Akt1 phosphorylation at Ser473 and inhibited cell migration, but failed to do so in constitutive active Akt1 (myr-Akt1)–overexpressed cells. Moreover, our data suggested that overexpression of Aur-A kinase might also contribute to radioresistance of LSCC. Inhibiting Aur-A by VX-680 induced expression of p53 and potently sensitized cells to radiotherapy, leading to significant cell death. Ectopic overexpression of Aur-A, however, reduced p53 level and rendered cells more resistant to irradiation. Taken together, we showed that Aur-A kinase, a negative prognostic marker, promotes migration and reduces radiosensitivity in laryngeal cancer cells. [Cancer Res 2007;67(21):10436–44]
The HiNF-P/p220NPAT Cell Cycle Signaling Pathway Controls Nonhistone Target Genes
Authors: Medina Ricardo , van der Deen Margaretha , Miele-Chamberland Angela , Xie Rong-Lin , van Wijnen Andre J. , Stein Janet L. , Stein Gary S. 
Published: November 2007

Abstract
HiNF-P and its cofactor p220NPAT are principal factors regulating histone gene expression at the G1-S phase cell cycle transition. Here, we have investigated whether HiNF-P controls other cell cycle– and cancer-related genes. We used cDNA microarrays to monitor responsiveness of gene expression to small interfering RNA–mediated depletion of HiNF-P. Candidate HiNF-P target genes were examined for the presence of HiNF-P recognition motifs, in vitro HiNF-P binding to DNA, and in vivo association by chromatin immunoprecipitations and functional reporter gene assays. Of 177 proliferation-related genes we tested, 20 are modulated in HiNF-P–depleted cells and contain putative HiNF-P binding motifs. We validated that at least three genes (i.e., ATM, PRKDC, and CKS2) are HiNF-P dependent and provide data indicating that the DNA damage response is altered in HiNF-P–depleted cells. We conclude that, in addition to histone genes, HiNF-P also regulates expression of nonhistone targets that influence competency for cell cycle progression. [Cancer Res 2007;67(21):10334–42]
Bmi-1 Cooperates with H-Ras to Transform Human Mammary Epithelial Cells via Dysregulation of Multiple Growth-Regulatory Pathways
Authors: Datta Sonal , Hoenerhoff Mark J. , Bommi Prashant , Sainger Rachana , Guo Wei-Jian , Dimri Manjari , Band Hamid , Band Vimla , Green Jeffrey E. , Dimri Goberdhan P. 
Published: November 2007

Abstract
Elevated expression of Bmi-1 is associated with many cancers, including breast cancer. Here, we examined the oncogenic potential of Bmi-1 in MCF10A cells, a spontaneously immortalized, nontransformed strain of human mammary epithelial cells (HMEC). Bmi-1 overexpression alone in MCF10A cells did not result in oncogenic transformation. However, Bmi-1 co-overexpression with activated H-Ras (RasG12V) resulted in efficient transformation of MCF10A cells in vitro. Although early-passage H-Ras–expressing MCF10A cells were not transformed, late-passage H-Ras–expressing cells exhibited features of transformation in vitro. Early- and late-passage H-Ras–expressing cells also differed in levels of expression of H-Ras and Ki-67, a marker of proliferation. Subsets of early-passage H-Ras–expressing cells exhibited high Ras expression and were negative for Ki-67, whereas most late-passage H-Ras–expressing cells expressed low levels of Ras and were Ki-67 positive. Injection of late-passage H-Ras–expressing cells in severe combined immunodeficient mice formed carcinomas with leiomatous, hemangiomatous, and mast cell components; these tumors were quite distinct from those induced by late-passage cells co-overexpressing Bmi-1 and H-Ras, which formed poorly differentiated carcinomas with spindle cell features. Bmi-1 and H-Ras co-overexpression in MCF10A cells also induced features of epithelial-to-mesenchymal transition. Importantly, Bmi-1 inhibited senescence and permitted proliferation of cells expressing high levels of Ras. Examination of various growth-regulatory pathways suggested that Bmi-1 overexpression together with H-Ras promotes HMEC transformation and breast oncogenesis by deregulation of multiple growth-regulatory pathways by p16INK4a-independent mechanisms. [Cancer Res 2007;67(21):10286–95]
Estrogen Insensitivity in a Model of Estrogen Receptor–Positive Breast Cancer Lymph Node Metastasis
Authors: Harrell Joshua Chuck , Dye Wendy W. , Harvell Djuana M.E. , Pinto Mauricio , Jedlicka Paul , Sartorius Carol A. , Horwitz Kathryn B. 
Published: November 2007

Abstract
The lymphatic system is a common avenue for the spread of breast cancer cells and dissemination through it occurs at least as frequently as hematogenous metastasis. Approximately 75% of primary breast cancers are estrogen receptor (ER) positive and the majority of these maintain receptor expression as lymph node (LN) metastases. However, it is unknown if ER function is equivalent in cancer cells growing in the breast and in the LNs. We have developed a model to assess estrogen responsiveness in ER+ breast tumors and LN metastases. Fluorescent ER+ MCF-7 tumors were grown in ovariectomized nude mice supplemented with estradiol. Once axillary LN metastasis arose, estradiol was withdrawn (EWD), for 1 or 4 weeks, or continued, to assess estradiol responsiveness. On EWD, proliferation rates fell similarly in tumors and LN metastases. However, estradiol-dependent ER down-regulation and progesterone receptor induction were deficient in LN metastases, indicating that ER-dependent transcriptional function was altered in the LN. Cancer cells from estradiol-treated and EWD primary tumors and matched LN metastases were isolated by laser capture microdissection. Global gene expression profiling identified transcripts that were regulated by the tissue microenvironment, by hormones, or by both. Interestingly, numerous genes that were estradiol regulated in tumors lost estradiol sensitivity or were regulated in the opposite direction by estradiol in LN metastases. We propose that the LN microenvironment alters estradiol signaling and may contribute to local antiestrogen resistance. [Cancer Res 2007;67(21):10582–91]
Photodynamic Therapy Enhancement of Antitumor Immunity Is Regulated by Neutrophils
Authors: Kousis Philaretos C. , Henderson Barbara W. , Maier Patricia G. , Gollnick Sandra O. 
Published: November 2007

AbstractPhotodynamic therapy (PDT) is a Food and Drug Administration–approved local cancer treatment that can be curative of early disease and palliative in advanced disease. PDT of murine tumors results in regimen-dependent induction of an acute local inflammatory reaction, characterized in part by rapid neutrophil infiltration into the treated tumor bed. In this study, we show that a PDT regimen that induced a high level of neutrophilic infiltrate generated tumor-specific primary and memory CD8+ T-cell responses. In contrast, immune cells isolated from mice treated with a PDT regimen that induced little or no neutrophilic infiltrate exhibited minimal antitumor immunity. Mice defective in neutrophil homing to peripheral tissues (CXCR2−/− mice) or mice depleted of neutrophils were unable to mount strong antitumor CD8+ T-cell responses following PDT. Neutrophils seemed to be directly affecting T-cell proliferation and/or survival rather than dendritic cell maturation or T-cell migration. These novel findings indicate that by augmenting T-cell proliferation and/or survival, tumor-infiltrating neutrophils play an essential role in establishment of antitumor immunity following PDT. Furthermore, our results may suggest a mechanism by which neutrophils might affect antitumor immunity following other inflammation-inducing cancer therapies. Our findings lay the foundation for the rational design of PDT regimens that lead to optimal enhancement of antitumor immunity in a clinical setting. Immune-enhancing PDT regimens may then be combined with treatments that result in optimal ablation of primary tumors, thus inhibiting growth of primary tumor and controlling disseminated disease. [Cancer Res 2007;67(21):10501–10]
The Opioid Growth Factor (OGF)–OGF Receptor Axis Uses the p16 Pathway to Inhibit Head and Neck Cancer
Authors: Cheng Fan , Zagon Ian S. , Verderame Michael F. , McLaughlin Patricia J. 
Published: November 2007

Abstract
Head and neck squamous cell carcinoma (HNSCC) represents 5.5% of malignancies worldwide, with ∼30,000 new cases and ∼11,000 deaths reported in the United States annually. The opioid growth factor (OGF; [Met5]-enkephalin) and the OGF receptor (OGFr) form an endogenous growth regulating system; the OGF-OGFr axis influences the G0-G1 phase of the cell cycle in HNSCC. Cells treated with small interfering RNA (siRNA) for OGFr no longer responded to the growth inhibitory effects of OGF or the growth stimulatory effects of naltrexone, indicating that these activities are entirely mediated by OGFr. In this investigation, we examined the precise target of OGF in the cell cycle. Using SCC-1 cells, OGF decreased the phosphorylation of retinoblastoma protein. This change was correlated with reduced Cdk4, but not Cdk2, kinase activity. OGF treatment increased cyclin-dependent kinase inhibitor p16 protein expression. Importantly, p16 complexed with Cdk4 was increased by OGF treatment at all time points, consistent with the hypothesis that OGF mediated growth inhibition through p16. Blockade of OGF-OGFr interactions with naloxone abolished the increased expression of p16 protein by OGF. Inhibition of p16 (INK4a) activation by p16-specific siRNA blocked OGF's repressive action on proliferation of SCC-1, CAL-27, and SCC-4 HNSCC cells. These data are the first to reveal that the target of cell proliferative inhibitory action of OGF in human HNSCC is a cyclin-dependent kinase inhibitory pathway, and this may be useful in the diagnosis and treatment of HNSCC. [Cancer Res 2007;67(21):10511–8]
Chemotherapeutic Agents Up-regulate the Cytomegalovirus Promoter: Implications for Bioluminescence Imaging of Tumor Response to Therapy
Authors: Svensson Robert U. , Barnes J. Matthew , Rokhlin Oskar W. , Cohen Michael B. , Henry Michael D. 
Published: November 2007

AbstractBioluminescence imaging is widely used to evaluate tumor growth and response to therapy in living animals. In cells expressing luciferase under the control of a constitutive promoter, light output in part depends on viable cell number, so that changes in bioluminescence intensity may be correlated with changes in viable tumor mass over time. We have found that treatment of cancer cell lines expressing luciferase under control of the cytomegalovirus (CMV) promoter with staurosporine, doxorubicin, and paclitaxel results in a transient increase in bioluminescence, which is positively correlated with apoptosis and inversely correlated with cell viability. In contrast, similar treatment of cell lines expressing luciferase under control of the SV40 promoter did not exhibit this result. We found that low doses of staurosporine induced bioluminescence in CMV- but not SV40-driven luciferase cell lines, whereas high doses elicited induction in both, indicating promoter-dependent and promoter-independent mechanisms of bioluminescence induction. The promoter-dependent increase in bioluminescence intensity from CMV-driven luciferase is a result of induction of luciferase mRNA and protein expression. We extended these findings in vivo; doxorubicin treatment resulted in a transient induction in bioluminescence when normalized to tumor volume in CMV- but not SV40-driven luciferase-expressing xenografts. We found that inhibition of the p38 mitogen-activated protein kinase pathway blocked bioluminescence induction by doxorubicin, paclitaxel, and staurosporine in CMV-driven luciferase-expressing cells. These findings have important implications when using bioluminescence to monitor the efficacy of anticancer therapy and underscore the complex regulation of the CMV promoter, which is widely used for high-level protein expression in mammalian cells. [Cancer Res 2007;67(21):10445–54]
Keeping Out the Bad Guys: Gateway to Cellular Target Therapy
Authors: Kitamura Takanori , Taketo Makoto M. 
Published: November 2007

Abstract
Tumor-stromal interaction is implicated in many stages of tumor development, although it remains unclear how genetic lesions in tumor cells affect stromal cells. We have recently shown that inactivation of transforming growth factor-β family signaling within colon cancer epithelium increases chemokine CC chemokine ligand 9 (CCL9) and promotes recruitment of the matrix metalloproteinase (MMP)-expressing stromal cells that carry CC chemokine receptor 1 (CCR1), the cognate receptor for CCL9. We have further shown that lack of CCR1 prevents the accumulation of MMP-expressing cells at the invasion front and suppresses tumor invasion. These results provide the possibility of a novel therapeutic strategy for advanced cancer—prevention of the recruitment of MMP-expressing cells by chemokine receptor antagonist. [Cancer Res 2007;67(21):10099–102]
Integrative Microarray Analysis of Pathways Dysregulated in Metastatic Prostate Cancer
Authors: Setlur Sunita R. , Royce Thomas E. , Sboner Andrea , Mosquera Juan-Miguel , Demichelis Francesca , Hofer Matthias D. , Mertz Kirsten D. , Gerstein Mark , Rubin Mark A. 
Published: November 2007

Abstract
Microarrays have been used to identify genes involved in cancer progression. We have now developed an algorithm that identifies dysregulated pathways from multiple expression array data sets without a priori definition of gene expression thresholds. Integrative microarray analysis of pathways (IMAP) was done using existing expression array data from localized and metastatic prostate cancer. Comparison of metastatic cancer and localized disease in multiple expression array profiling studies using the IMAP approach yielded a list of about 100 pathways that were significantly dysregulated (P &lt; 0.05) in prostate cancer metastasis. The pathway that showed the most significant dysregulation, HIV-I NEF, was validated at both the transcript level and the protein level by quantitative PCR and immunohistochemical analysis, respectively. Validation by unsupervised analysis on an independent data set using the gene expression signature from the HIV-I NEF pathway verified the accuracy of our method. Our results indicate that this pathway is especially dysregulated in hormone-refractory prostate cancer. [Cancer Res 2007;67(21):10296–303]
Local Radiotherapy Induces Homing of Hematopoietic Stem Cells to the Irradiated Bone Marrow
Authors: Bastianutto Carlo , Mian Asim , Symes Julie , Mocanu Joseph , Alajez Nehad , Sleep Gillian , Shi Wei , Keating Armand , Crump Michael , Gospodarowicz Mary , Medin Jeff , Minden Mark , Liu Fei-Fei 
Published: November 2007

Abstract
Local breast radiation therapy (RT) is associated with a 3-fold increased risk of secondary acute myeloid leukemia. As a first step in determining the mechanism(s) underlying this observation, we investigated the role of RT in mediating the active recruitment of hematopoietic stem cells (HSC) to the site of RT. Our results show in a mouse model that local RT delivered to the left leg causes preferential accumulation of bone marrow mononuclear cells to the irradiated site, with maximum signal intensity observed at 7 days post-RT. This is associated with a 4-fold higher number of donor-derived HSC present in the left leg, demonstrating recruitment of HSC to the site of RT. SDF-1, matrix metalloproteinase 2 (MMP-2), and MMP-9 expression is significantly increased in the irradiated bone marrow, and their inhibition significantly reduced HSC recruitment to the irradiated bone marrow. Our data show that local RT has significant systemic effects by recruiting HSC to the irradiated bone marrow site, a process mediated by SDF-1, MMP-2, and MMP-9. These results raise the possibility that the exposure of increased numbers of HSC at a local site to fractionated irradiation may increase the risk of leukemogenesis. Our data also suggest some opportunities for leukemia prevention in breast cancer patients undergoing RT. [Cancer Res 2007;67(21):10112–6]
Aneuploidy: Instigator and Inhibitor of Tumorigenesis
Authors: Weaver Beth A.A. , Cleveland Don W. 
Published: November 2007

Abstract
Aneuploidy, an aberrant chromosome number, has been recognized as a common characteristic of cancer cells for more than 100 years and has been suggested as a cause of tumorigenesis for nearly as long. However, this proposal had remained untested due to the difficulty of selectively generating aneuploidy without causing other damage. Using Cenp-E heterozygous animals, which develop whole chromosome aneuploidy in the absence of other defects, we have found that aneuploidy promotes tumorigenesis in some contexts and inhibits it in others. These findings confirm that aneuploidy can act oncogenically and reveal a previously unsuspected role for aneuploidy as a tumor suppressor. [Cancer Res 2007;67(21):10103–5]
Inhibition of Cyclooxygenase-2 Suppresses Lymph Node Metastasis via Reduction of Lymphangiogenesis
Authors: Iwata Caname , Kano Mitsunobu R. , Komuro Akiyoshi , Oka Masako , Kiyono Kunihiko , Johansson Erik , Morishita Yasuyuki , Yashiro Masakazu , Hirakawa Kosei , Kaminishi Michio , Miyazono Kohei 
Published: November 2007

Abstract
Cyclooxygenase-2 (COX-2) inhibitor has been reported to suppress tumor progression. However, it is unclear whether this inhibitor can also prevent lymphatic metastasis. To determine the effects of COX-2 inhibitor on lymphatic metastasis, etodolac, a COX-2 inhibitor, was given p.o. to mice bearing orthotopic xenografts or with carcinomatous peritonitis induced with a highly metastatic human diffuse-type gastric carcinoma cell line, OCUM-2MLN. Tumor lymphangiogenesis was significantly decreased in etodolac-treated mice compared with control mice. Consistent with this decrease in lymphangiogenesis, the total weight of metastatic lymph nodes was less in etodolac-treated mice than in control mice. Immunohistochemical analysis revealed that the major source of vascular endothelial growth factor-C (VEGF-C) and VEGF-D was F4/80-positive macrophages in our models. The mRNA levels of VEGF-C in mouse macrophage-like RAW264.7 cells, as well as those in tumor tissues, were suppressed by etodolac. The growth of human dermal lymphatic microvascular endothelial cells was also suppressed by etodolac. Supporting these findings, etodolac also inhibited lymphangiogenesis in a model of chronic aseptic peritonitis, suggesting that COX-2 can enhance lymphangiogenesis in the absence of cancer cells. Our findings suggest that COX-2 inhibitor may be useful for prophylaxis of lymph node metastasis by reducing macrophage-mediated tumor lymphangiogenesis. [Cancer Res 2007;67(21):10181–9]