bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting Src Family Kinases Inhibits Growth and Lymph Node Metastases of Prostate Cancer in an Orthotopic Nude Mouse Model
Authors: Park Serk In , Zhang Jing , Phillips Kacy A. , Araujo John C. , Najjar Amer M. , Volgin Andrei Y. , Gelovani Juri G. , Kim Sun-Jin , Wang Zhengxin , Gallick Gary E. 
Published: May 2008

Abstract
Aberrant expression and/or activity of members of the Src family of nonreceptor protein tyrosine kinases (SFK) are commonly observed in progressive stages of human tumors. In prostate cancer, two SFKs (Src and Lyn) have been specifically implicated in tumor growth and progression. However, there are no data in preclinical models demonstrating potential efficacy of Src inhibitors against prostate cancer growth and/or metastasis. In this study, we used the small molecule SFK/Abl kinase inhibitor dasatinib, currently in clinical trials for solid tumors, to examine in vitro and in vivo effects of inhibiting SFKs in prostate tumor cells. In vitro, dasatinib inhibits both Src and Lyn activity, resulting in decreased cellular proliferation, migration, and invasion. In orthotopic nude mouse models, dasatinib treatment effectively inhibits expression of activated SFKs, resulting in inhibition of both tumor growth and development of lymph node metastases in both androgen-sensitive and androgen-resistant tumors. In primary tumors, SFK inhibition leads to decreased cellular proliferation (determined by immunohistochemistry for proliferating cell nuclear antigen). In vitro, small interfering RNA (siRNA)–mediated inhibition of Lyn affects cellular proliferation; siRNA inhibition of Src affects primarily cellular migration. Therefore, we conclude that SFKs are promising therapeutic targets for treatment of human prostate cancer and that Src and Lyn activities affect different cellular functions required for prostate tumor growth and progression. [Cancer Res 2008;68(9):3323–33]
Quantitative Spatiotemporal Analysis of Antibody Fragment Diffusion and Endocytic Consumption in Tumor Spheroids
Authors: Thurber Greg M. , Wittrup K. Dane 
Published: May 2008

Abstract
Antibody-based cancer treatment depends upon distribution of the targeting macromolecule throughout tumor tissue, and spatial heterogeneity could significantly limit efficacy in many cases. Antibody distribution in tumor tissue is a function of drug dosage, antigen concentration, binding affinity, antigen internalization, drug extravasation from blood vessels, diffusion in the tumor extracellular matrix, and systemic clearance rates. We have isolated the effects of a subset of these variables by live-cell microscopic imaging of single-chain antibody fragments against carcinoembryonic antigen in LS174T tumor spheroids. The measured rates of scFv penetration and retention were compared with theoretical predictions based on simple scaling criteria. The theory predicts that antibody dose must be large enough to drive a sufficient diffusive flux of antibody to overcome cellular internalization, and exposure time must be long enough to allow penetration to the spheroid center. The experimental results in spheroids are quantitatively consistent with these predictions. Therefore, simple scaling criteria can be applied to accurately predict antibody and antibody fragment penetration distance in tumor tissue. [Cancer Res 2008;68(9):3334–41]
Pituitary Tumor-Transforming 1 Increases Cell Motility and Promotes Lymph Node Metastasis in Esophageal Squamous Cell Carcinoma
Authors: Ito Tetsuo , Shimada Yutaka , Kan Takatsugu , David Stefan , Cheng Yulan , Mori Yuriko , Agarwal Rachana , Paun Bogdan , Jin Zhe , Olaru Alexandru , Hamilton James P. , Yang Jian , Abraham John M. , Meltzer Stephen J. , Sato Fumiaki 
Published: May 2008

Abstract
Human pituitary tumor-transforming 1 (PTTG1)/securin is a putative oncoprotein that is overexpressed in various tumor types. However, the involvement of PTTG1 in gastrointestinal cancer development and progression remains unclear. In this study, we investigated the clinical significance and biological effects of PTTG1 in esophageal squamous cell carcinoma (ESCC). Immunohistochemical studies performed on 113 primary ESCC specimens revealed a high prevalence of PTTG1 overexpression (60.2%), which was significantly associated with lymph node metastasis (regional, P = 0.042; distant, P = 0.005), advanced tumor stage (P = 0.028), and poorer overall survival (P = 0.017, log-rank test; P = 0.044, Cox proportional hazard model). Eleven ESCC cell lines expressed PTTG1 protein at levels 2.4 to 6.6 times higher than those in normal esophageal epithelial cells (HEEpiC). PTTG1 protein expression was confined to the nucleus in HEEpiC cells but present in both the cytoplasm and nucleus in ESCC cells. Two small interfering RNAs (siRNA) inhibited PTTG1 mRNA and protein expression in three ESCC cell lines by 77% to 97%. In addition, PTTG1 down-regulation by these siRNAs significantly reduced cell motility in all three ESCC cell lines (P &lt; 0.01) in vitro, as well as popliteal lymph node metastases of ESCC cells in nude mice (P = 0.020). Global gene expression profiling suggested that several members of the Ras and Rho gene families, including RRAS, RHOG, ARHGAP1, and ARHGADIA, represented potential downstream genes in the PTTG1 pathway. Taken together, these findings suggest that PTTG1 overexpression promotes cell motility and lymph node metastasis in ESCC patients, leading to poorer survival. Thus, PTTG1 constitutes a potential biomarker and therapeutic target in ESCCs with lymph node metastases. [Cancer Res 2008;68(9):3214–24]
The Estrogen Receptor Pathway in Rhabdomyosarcoma: A Role for Estrogen Receptor-β in Proliferation and Response to the Antiestrogen 4′OH-Tamoxifen
Authors: Greenberg Joshua A. , Somme Stig , Russnes Hege E. , Durbin Adam D. , Malkin David 
Published: May 2008

Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Highly malignant, RMS frequently fails to respond to conventional aggressive multimodal radiation, surgery, and chemotherapy treatment protocols that also cause significant sequelae in the growing child. Other tumors of mesenchymal origin, such as locally aggressive fibromatoses and desmoid tumors, have been successfully treated with a selective estrogen receptor (ER) modulator, tamoxifen. In an effort to identify new targets for RMS therapy, our group investigated the previously uncharacterized ER pathway in RMS cell culture and primary tumors. We detected ER isoform β (ERβ), but not isoform α, RNA, and protein in five RMS cell lines. Immunohistochemical staining of primary RMS tumor sections confirmed high levels of ERβ but not ERα protein. RMS cell growth was dramatically inhibited in steroid-free conditions, and this growth inhibition was rescued with 17-β-estradiol (E2) supplementation. Exposure of RMS cells to 4′OH-tamoxifen (4OHT) decreased cell viability and inhibited colony formation as detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony-forming assays. 4OHT also induced apoptotic signaling in RMS cells as detected by cleavage of caspase-3 and poly(ADP)ribose polymerase. This effect increased 3- to 8-fold in steroid-deprived conditions but was rescued by supplementation with E2. Immunofluorescence studies detected a change in the subcellular localization of ERβ in response to 4OHT. Together, these data suggest an active ERβ-mediated signal transduction pathway in RMS. The ability of 4OHT to induce apoptotic signaling and disrupt estradiol-mediated proliferation provides a rationale to explore a role for selective ER modulators in the treatment of RMS. [Cancer Res 2008;68(9):3476–85]
Targeted Deletion of Hepatic Igf1 in TRAMP Mice Leads to Dramatic Alterations in the Circulating Insulin-Like Growth Factor Axis but Does Not Reduce Tumor Progression
Authors: Anzo Makoto , Cobb Laura J. , Hwang David L. , Mehta Hemal , Said Jonathan W. , Yakar Shoshana , LeRoith Derek , Cohen Pinchas 
Published: May 2008

Abstract
The role of systemic and local insulin-like growth factor I (IGF-I) in the development of prostate cancer is still controversial. Transgenic adenocarcinoma mouse prostate (TRAMP) mice express the SV40 T-antigen under the control of the probasin promoter, and spontaneously develop prostate cancer. We crossed TRAMP mice with liver IGF–deficient (LID) mice to produce LID-TRAMP mice, a mouse model of prostate cancer with low serum IGF-I, to allow us to study the effect of circulatory IGF-I levels on the development of prostate cancer. LID mice have a targeted deletion of the hepatic Igf1 gene but retain normal expression of Igf1 in extrahepatic tissues. Serum IGF-I and IGFBP-3 levels in LID and LID-TRAMP mice were measured using novel assays, which showed that they are ∼10% and 60% of control L/L− mice, respectively. Serum growth hormone (GH) levels of LID-TRAMP mice were 3.5-fold elevated relative to L/L-TRAMP mice (P &lt; 0.001), but IGFBP-2 levels were not different. Surprisingly, rates of survival, metastasis, and the ratio of genitourinary tissue weight to body weight were not significantly different between LID-TRAMP and L/L-TRAMP mice. There was also no difference in the pathologic stage of the prostate cancer between the two groups at 9 to 19 weeks of age. LID-TRAMP tumors displayed increased levels of GH receptors and increased Akt phosphorylation. These results are in striking contrast with the published model of the GH-deficient lit/lit-TRAMP, which has smaller tumors and improved survival, and indicate that the reduction in systemic IGF-I is not sufficient to inhibit prostate cancer tumor progression in the TRAMP model, which may require a reduction of GH levels as well. [Cancer Res 2008;68(9):3342–9]
Frzb, a Secreted Wnt Antagonist, Decreases Growth and Invasiveness of Fibrosarcoma Cells Associated with Inhibition of Met Signaling
Authors: Guo Yi , Xie Jun , Rubin Elyssa , Tang Ya-Xiong , Lin Fritz , Zi Xiaolin , Hoang Bang H. 
Published: May 2008

Abstract
Soft tissue sarcomas (STS) have a strong propensity for aggressive growth and metastasis. We showed that the secreted Wnt antagonist Frzb exhibited potent antitumor activity against prostate cancer, an epithelial type of malignancy. In this study, we further showed the antitumor efficacy of Frzb in STS, a mesenchymal group of cancer. Frzb transfection of HT1080 (fibrosarcoma) and SW872 (liposarcoma) cell lines and their conditioned media resulted in a significant reduction in cellular invasion, motility, and colony formation in soft agar compared with vector control–transfected cells. In a xenograft mouse model, Frzb dramatically suppressed tumor growth of HT1080 cells in nude mice. In a tail-vein injection metastatic model, Frzb-transfected HT1080 cells formed fewer and smaller lung nodules than vector control cells. In addition, we identified new mechanisms for Frzb antitumor activities. Frzb reduced c-Met expression and inhibited Met-mediated signaling, associated with up-regulation of epithelial markers (i.e., keratins 8 and 18) and down-regulation of mesenchymal markers (i.e., vimentin, N-cadherin, fibronectin, Slug, and Twist). Similar to Frzb, silencing of c-Met by short hairpin RNA or using a dominant-negative LRP5 receptor also suppressed Met signaling, leading to reduced cellular motility, invasion, and in vivo tumor growth. Given recent studies indicating an important role of c-Met in sarcoma development and progression, our data showed that Frzb expression was significantly inversely correlated with Met expression in both STS cell lines and tissues. These results suggested the usefulness of Frzb in modulating Met signaling as a new treatment strategy for STS. [Cancer Res 2008;68(9):3350–60]
Oncogene Addiction
Authors: Weinstein I. Bernard , Joe Andrew 
Published: May 2008

Abstract
Cancer cells contain multiple genetic and epigenetic abnormalities. Despite this complexity, their growth and survival can often be impaired by the inactivation of a single oncogene. This phenomenon, called “oncogene addiction,” provides a rationale for molecular targeted therapy. The efficacy of this strategy requires novel methods, including integrative genomics and systems biology, to identify the state of oncogene addiction (i.e., the “Achilles heel”) in specific cancers. Combination therapy may also be required to prevent the escape of cancers from a given state of oncogene addiction. [Cancer Res 2008;68(9):3077–80]
Exuberated Numbers of Tumor-Specific T Cells Result in Tumor Escape
Authors: Goldberger Ofir , Volovitz Ilan , Machlenkin Arthur , Vadai Ezra , Tzehoval Esther , Eisenbach Lea 
Published: May 2008

AbstractCytotoxic T cells (CTL) play a major role in tumor rejection. Expansion of CTLs, either by immunization or adoptive transfer, is a prominent goal in current immunotherapy. The antigen-specific nature of these expansion processes inevitably initiates a clonotypic attack on the tumor. By injecting an Ovalbumin-expressing melanoma into OT-I mice, in which &gt;90% of CTLs recognize an Ovalbumin peptide, we show that an increased number of tumor-specific CTLs causes emergence of escape variants. We show that these escape variants are a result of antigen silencing via a yet undetermined epigenetic mechanism, which occurs frequently and is spontaneously reversible. We further show that an increase in the time of tumor onset in OT-I compared with C57BL/6J is a result of immune selection. [Cancer Res 2008;68(9):3450–7]
Androgens Transduce the Gαs-Mediated Activation of Protein Kinase A in Prostate Cells
Authors: Bagchi Gargi , Wu Juanjuan , French John , Kim Jae , Moniri Nader H. , Daaka Yehia 
Published: May 2008

Abstract
Androgens regulate the development and function of male reproductive organs and play a crucial role in the onset and progression of prostate cancer. Androgen action is primarily mediated through the nuclear androgen receptor (AR) which acts as a ligand-dependent transcription factor. This mode of androgen action takes hours to manifest and is called the genomic pathway. The androgen-mediated genomic responses require activity of cyclic AMP (cAMP)-dependent protein kinase (PKA). Androgens also act through nongenomic pathways in certain cell types to evoke rapid responses (manifested in minutes) that are mediated through changes in ion currents and second messengers. Here, we show that androgen causes the rapid and cAMP-dependent activation of PKA in prostate cells. The androgen-induced PKA activation is not inhibited by nuclear AR antagonist bicalutamide and can be observed in cells that do not express nuclear AR gene. Reduction of Gαs expression with siRNA attenuates the androgen-mediated activation of PKA, which is required for the androgen-induced prostate cell proliferation. We conclude that androgen actively evokes a nongenomic signaling pathway to activate PKA that is needed for the genomic functioning of nuclear AR. The inhibition of PKA activation, together with standard AR-targeted therapies, may be more efficacious for treatment of patients with prostate cancer. [Cancer Res 2008;68(9):3225–31]
Restoration of Tumor Immunosurveillance via Targeting of Interleukin-13 Receptor-α2
Authors: Fichtner-Feigl Stefan , Terabe Masaki , Kitani Atsushi , Young Cheryl A. , Fuss Ivan , Geissler Edward K. , Schlitt Hans-Jürgen , Berzofsky Jay A. , Strober Warren 
Published: May 2008

AbstractIn previous studies, we described a “counter-immunosurveillance” mechanism initiated by tumor-activated, interleukin-13 (IL-13)–producing natural killer T cells that signal Gr-1+ cells to produce transforming growth factor-β1 (TGF-β1), a cytokine that suppresses the activity of tumor-inhibiting cytolytic CD8+ T cells. Here, we show that in two tumor models (the CT-26 metastatic colon cancer and the 15-12RM fibrosarcoma regressor models), this counter-surveillance mechanism requires the expression of a novel IL-13 receptor, IL-13Rα2, on Gr-1intermediate cells, because down-regulation of IL-13Rα2 expression or the activator protein-1 signal generated by the receptor via in vivo administration of specific small interfering RNA or decoy oligonucleotides leads to loss of TGF-β1 production. Furthermore, acting on prior studies showing that IL-13Rα2 expression is induced (in part) by tumor necrosis factor-α (TNF-α), we show that receptor expression and TGF-β1 production is inhibited by administration of a TNF-α–neutralizing substance, TNF-αR-Fc (etanercept). Taking advantage of this latter fact, we then show in the CT-26 model that counter-immunosurveillance can be inhibited, anti-CT-26–specific CD8+ cytolytic activity can be restored, and CT-26 metastatic tumor nodules can be greatly decreased by administration of TNF-αR-Fc. Corroborative data were obtained using the 15-12RM fibrosarcoma model. These studies point to the prevention of metastatic cancer with an available agent with already known clinically acceptable adverse effects and toxicity. [Cancer Res 2008;68(9):3467–75]
Transforming Growth Factor β Induces Apoptosis through Repressing the Phosphoinositide 3-Kinase/AKT/Survivin Pathway in Colon Cancer Cells
Authors: Wang Jing , Yang Limin , Yang Junhua , Kuropatwinski Karen , Wang Wang , Liu Xiao-Qiong , Hauser Jennie , Brattain Michael G. 
Published: May 2008

Abstract
FET cells, derived from an early-stage colon carcinoma, are nontumorigenic in athymic mice. Stable transfection of a dominant-negative transforming growth factor β (TGFβ) type II receptor (DNRII) into FET cells that express autocrine TGFβ shows loss of TGFβ signaling and increased tumorigenicity in vivo indicating tumor suppressor activity of TGFβ signaling in this model. The ability of tumorigenic cells to withstand growth factor and nutrient deprivation stress (GFDS) is widely regarded as a key attribute for tumor formation and progression. We hypothesized that increased tumorigenicity of FET/DNRII cells was due to loss of participation of autocrine TGFβ in a “fail-safe” mechanism to generate cell death in response to this stress. Here, we document that loss of autocrine TGFβ in FET/DNRII cells resulted in greater endogenous cell survival in response to GFDS due to activation of the phosphoinositide 3-kinase (PI3K)/Akt/survivin pathway. Treatment of FET DNRII cells with a PI3K inhibitor (LY294002) inhibited Akt phosphorylation and reduced survivin expression resulting in increased apoptosis in FET/DNRII cells. We also show that exogenous TGFβ increased apoptosis in FET cells through repression of the PI3K/Akt/survivin pathway during GFDS. These results indicate that the PI3K/Akt/survivin pathway is blocked by TGFβ signaling and that loss of autocrine TGFβ leads to increased cell survival during GFDS through the novel linkage of TGFβ-mediated repression of survivin expression. Inhibition of survivin function by dominant-negative approaches showed that this inhibitor of apoptosis family member is critical to cell survival in the FET/DNRII cells, thus indicating the importance of this target for TGFβ-mediated apoptosis. [Cancer Res 2008;68(9):3152–60]
Cancer Stem Cells Contribute to Cisplatin Resistance in Brca1/p53–Mediated Mouse Mammary Tumors
Authors: Shafee Norazizah , Smith Christopher R. , Wei Shuanzeng , Kim Yoon , Mills Gordon B. , Hortobagyi Gabriel N. , Stanbridge Eric J. , Lee Eva Y-H. P. 
Published: May 2008

Abstract
The majority of BRCA1-associated breast cancers are basal cell–like, which is associated with a poor outcome. Using a spontaneous mouse mammary tumor model, we show that platinum compounds, which generate DNA breaks during the repair process, are more effective than doxorubicin in Brca1/p53–mutated tumors. At 0.5 mg/kg of daily cisplatin treatment, 80% primary tumors (n = 8) show complete pathologic response. At greater dosages, 100% show complete response (n = 19). However, after 2 to 3 months of complete remission following platinum treatment, tumors relapse and become refractory to successive rounds of treatment. Approximately 3.8% to 8.0% (mean, 5.9%) of tumor cells express the normal mammary stem cell markers, CD29hi24med, and these cells are tumorigenic, whereas CD29med24−/lo and CD29med24hi cells have diminished tumorigenicity or are nontumorigenic, respectively. In partially platinum-responsive primary transplants, 6.6% to 11.0% (mean, 8.8%) tumor cells are CD29hi24med; these populations significantly increase to 16.5% to 29.2% (mean, 22.8%; P &lt; 0.05) in platinum-refractory secondary tumor transplants. Further, refractory tumor cells have greater colony-forming ability than the primary transplant–derived cells in the presence of cisplatin. Expression of a normal stem cell marker, Nanog, is decreased in the CD29hi24med populations in the secondary transplants. Top2A expression is also down-regulated in secondary drug-resistant tumor populations and, in one case, was accompanied by genomic deletion of Top2A. These studies identify distinct cancer cell populations for therapeutic targeting in breast cancer and implicate clonal evolution and expansion of cancer stem-like cells as a potential cause of chemoresistance. [Cancer Res 2008;68(9):3243–50]
Subtypes of Breast Cancer Show Preferential Site of Relapse
Authors: Smid Marcel , Wang Yixin , Zhang Yi , Sieuwerts Anieta M. , Yu Jack , Klijn Jan G.M. , Foekens John A. , Martens John W.M. 
Published: May 2008

Abstract
We explored whether the five previously reported molecular subtypes in breast cancer show a preference for organ-specific relapse and searched for molecular pathways involved. The “intrinsic” gene list describing the subtypes was used to classify 344 primary breast tumors of lymph node–negative patients. Fisher exact tests were used to determine the association between a tumor subtype and a particular site of distant relapse in these patients who only received local treatment. Modulated genes and pathways were identified in the various groups using Significance Analysis of Microarrays and Global Testing. Bone relapse patients were most abundant in the luminal subtypes but were found less than expected in the basal subtype. The reverse was true for lung and brain relapse patients with the remark that absence of lung relapse was luminal A specific. Finally, a pleura relapse, although rare, was found almost exclusively in both luminal subtypes. Many differentially expressed genes were identified, of which several were in common in a subtype and the site to which the subtype preferentially relapsed. WNT signaling was up-regulated in the basal subtype and in brain-specific relapse, and down-modulated in the luminal B subtype and in bone-specific relapse. Focal adhesion was found up-regulated in the luminal A subtype but down-regulated in lung relapse. The five major molecular subtypes in breast cancer are evidently different with regard to their ability to metastasize to distant organ(s), and share biological features and pathways with their preferred distant metastatic site. [Cancer Res 2008;68(9):3108–14]
MS4A12 Is a Colon-Selective Store-Operated Calcium Channel Promoting Malignant Cell Processes
Authors: Koslowski Michael , Sahin Ugur , Dhaene Karl , Huber Christoph , Türeci Özlem 
Published: May 2008

AbstractUsing a data mining approach for the discovery of new targets for antibody therapy of colon cancer, we identified MS4A12, a sequence homologue of CD20. We show that MS4A12 is a cell surface protein. Expression analysis and immunohistochemistry revealed MS4A12 to be a colonic epithelial cell lineage gene confined to the apical membrane of colonocytes with strict transcriptional repression in all other normal tissue types. Expression is maintained upon malignant transformation in 63% of colon cancers. Ca2+ flux analyses disclosed that MS4A12 is a novel component of store-operated Ca2+ entry in intestinal cells. Using RNAi-mediated gene silencing, we show that loss of MS4A12 in LoVo colon cancer cells attenuates epidermal growth factor receptor–mediated effects. In particular, proliferation, cell motility, and chemotactic invasion of cells are significantly impaired. Cancer cells expressing MS4A12, in contrast, are sensitized and respond to lower concentrations of epidermal growth factor. In summary, these findings have implications for both the physiology of colonic epithelium as well as for the biology and treatment of colon cancer. [Cancer Res 2008;68(9):3458–66]