bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Novel Histone Demethylase LSD1 Inhibitors Selectively Target Cancer Cells with Pluripotent Stem Cell Properties
Authors: Wang Jing , Lu Fei , Ren Qi , Sun Hong , Xu Zhengshuang , Lan Rongfeng , Liu Yuqing , Ward David , Quan Junmin , Ye Tao , Zhang Hui
Published: March 2024

Abstract
Histone modification determines epigenetic patterns of gene expression with methylation of histone H3 at lysine 4 (H3K4) often associated with active promoters. LSD1/KDM1 is a histone demethylase that suppresses gene expression by converting dimethylated H3K4 to mono- and unmethylated H3K4. LSD1 is essential for metazoan development, but its pathophysiologic functions in cancer remain mainly uncharacterized. In this study, we developed specific bioactive small inhibitors of LSD1 that enhance H3K4 methylation and derepress epigenetically suppressed genes in vivo. Strikingly, these compounds inhibited the proliferation of pluripotent cancer cells including teratocarcinoma, embryonic carcinoma, and seminoma or embryonic stem cells that express the stem cell markers Oct4 and Sox2 while displaying minimum growth-inhibitory effects on non-pluripotent cancer or normal somatic cells. RNA interference–mediated knockdown of LSD1 expression phenocopied these effects, confirming the specificity of small molecules and further establishing the high degree of sensitivity and selectivity of pluripotent cancer cells to LSD1 ablation. In support of these results, we found that LSD1 protein level is highly elevated in pluripotent cancer cells and in human testicular seminoma tissues that express Oct4. Using these novel chemical inhibitors as probes, our findings establish LSD1 and histone H3K4 methylation as essential cancer-selective epigenetic targets in cancer cells that have pluripotent stem cell properties. Cancer Res; 71(23); 7238–49. ©2011 AACR.
Data from Anti-DLL4 Inhibits Growth and Reduces Tumor-Initiating Cell Frequency in Colorectal Tumors with Oncogenic KRAS Mutations
Authors: Fischer Marcus , Yen Wan-Ching , Kapoun Ann M. , Wang Min , O'Young Gilbert , Lewicki John , Gurney Austin , Hoey Timothy
Published: March 2024

Abstract
KRAS mutations are frequent in colorectal cancer (CRC) and are associated with clinical resistance to treatment with the epidermal growth factor receptor (EGFR)–targeted monoclonal antibodies. Delta-like 4 ligand (DLL4) is an important component of the Notch signaling pathway and mediates stem cell self-renewal and vascular development. DLL4 inhibition in colon tumor cells reduces tumor growth and stem cell frequency. Considering the need for new drugs to treat colon cancers with oncogenic KRAS mutations, we examined in this study the efficacy of anti-DLL4 antibodies in KRAS mutant tumors in a panel of early passage colon tumor xenograft models derived from patients. Consistent with clinical findings, mutant KRAS colorectal xenograft tumors were insensitive to the EGFR therapeutic antibody cetuximab, whereas KRAS wild-type tumors responded to cetuximab. In contrast, anti-DLL4 was efficacious against both wild-type and mutant KRAS colon tumors as a single agent and in combination with irinotecan. Further analysis of mutant KRAS tumors indicated that the anti-DLL4/irinotecan combination produced a significant decrease in colon cancer stem cell frequency while promoting apoptosis in tumor cells. Our findings provide a rationale for targeting DLL4-Notch signaling for improved treatment of CRC patients with activating KRAS mutations. Cancer Res; 71(5); 1520–5. ©2010 AACR.
Data from Mitochondrial Bcl-2 Family Dynamics Define Therapy Response and Resistance in Neuroblastoma
Authors: Goldsmith Kelly C. , Gross Michelle , Peirce Susan , Luyindula Dema , Liu Xueyuan , Vu Annette , Sliozberg Michael , Guo Rong , Zhao Huaqing , Reynolds C. Patrick , Hogarty Michael D.
Published: March 2024

Abstract
Neuroblastoma is a childhood tumor in which transient therapeutic responses are typically followed by recurrence with lethal chemoresistant disease. In this study, we characterized the apoptotic responses in diverse neuroblastomas using an unbiased mitochondrial functional assay. We defined the apoptotic set point of neuroblastomas using responses to distinct BH3 death domains providing a BH3 response profile and directly confirmed survival dependencies. We found that viable neuroblastoma cells and primary tumors are primed for death with tonic sequestration of Bim, a direct activator of apoptosis, by either Bcl-2 or Mcl-1, providing a survival dependency that predicts the activity of Bcl-2 antagonists. The Bcl-2/Bcl-xL/Bcl-w inhibitor ABT-737 showed single-agent activity against only Bim:Bcl-2 primed tumor xenografts. Durable complete regressions were achieved in combination with noncurative chemotherapy even for highest risk molecular subtypes with MYCN amplification and activating ALK mutations. Furthermore, the use of unique isogenic cell lines from patients at diagnosis and at the time of relapse showed that therapy resistance was not mediated by upregulation of Bcl-2 homologues or loss of Bim priming, but by repressed Bak/Bax activation. Together, our findings provide a classification system that identifies tumors with clinical responses to Bcl-2 antagonists, defines Mcl-1 as the principal mediator of Bcl-2 antagonist resistance at diagnosis, and isolates the therapy resistant phenotype to the mitochondria. Cancer Res; 72(10); 2565–77. ©2012 AACR.
Data from miR-221 Silencing Blocks Hepatocellular Carcinoma and Promotes Survival
Authors: Park Jong-Kook , Kogure Takayuki , Nuovo Gerard J. , Jiang Jinmai , He Lei , Kim Ji Hye , Phelps Mitch A. , Papenfuss Tracey L. , Croce Carlo M. , Patel Tushar , Schmittgen Thomas D.
Published: March 2024

Abstract
Patients with advanced hepatocellular carcinoma (HCC) face a dismal prognosis because of a lack of any effective therapies. To address this situation, we conducted a preclinical investigation of the therapeutic efficacy of oligonucleotides directed against the oncogenic microRNA miR-221, which has been implicated in HCC. Of 9 chemistries evaluated, we determined that a 2′-O-methyl phosphorothioate-modified anti-miR-221 oligonucleotide was most effective at reducing proliferation in vitro. A cholesterol-modified isoform of anti-miR-221 (chol-anti-miR-221) exhibited improved pharmacokinetics and liver tissue distribution compared with unmodified oligonucleotide. Chol-anti-miR-221 significantly reduced miR-221 levels in liver within a week of intravenous administration and in situ hybridization studies confirmed accumulation of the oligonucleotide in tumor cells in vivo. Within the same period, chol-anti-miR-221 reduced tumor cell proliferation and increased markers of apoptosis and cell-cycle arrest, elevating the tumor doubling time and increasing mouse survival. Taken together, our findings offer a preclinical proof of efficacy for chol-anti-miR-221 in a valid orthotopic mouse model of HCC, suggesting that this targeted agent could benefit treatment for patients with advanced HCC. Cancer Res; 71(24); 7608–16. ©2011 AACR.
Data from Identification of a Tumor Suppressor Relay between the FOXP3 and the Hippo Pathways in Breast and Prostate Cancers
Authors: Li Weiquan , Wang Lizhong , Katoh Hiroto , Liu Runhua , Zheng Pan , Liu Yang
Published: March 2024

Abstract
Defective expression of LATS2, a negative regulator of YAP oncoprotein, has been reported in cancer of prostate, breast, liver, brain, and blood origins. However, no transcriptional regulators for the LATS2 gene have been identified. Here we report that spontaneous mutation of the transcription factor FOXP3 reduces expression of the LATS2 gene in mammary epithelial cells. shRNA-mediated silencing of FOXP3 in normal or malignant mammary epithelial cells of mouse and human origin repressed LATS2 expression and increased YAP protein levels. LATS2 induction required binding of FOXP3 to a specific sequence in the LATS2 promoter, and this interaction contributed to FOXP3-mediated growth inhibition of tumor cells. In support of these results, reduced expression and somatic mutations of FOXP3 correlated strongly with defective LATS2 expression in microdissected prostate cancer tissues. Thus, defective expression of LATS2 is attributable to FOXP3 defects and may be a major independent determinant of YAP protein elevation in cancer. Our findings identify a novel mechanism of LATS2 downregulation in cancer and reveal an important tumor suppressor relay between the FOXP3 and HIPPO pathways which are widely implicated in human cancer. Cancer Res; 71(6); 2162–71. ©2011 AACR.
Data from Antiangiogenesis Enhances Intratumoral Drug Retention
Authors: Ma Jie , Chen Chong-Sheng , Blute Todd , Waxman David J.
Published: March 2024

Abstract
The tumor vasculature delivers nutrients, oxygen, and therapeutic agents to tumor cells. Unfortunately, the delivery of anticancer drugs through tumor blood vessels is often inefficient and can constitute an important barrier for cancer treatment. This barrier can sometimes be circumvented by antiangiogenesis-induced normalization of tumor vasculature. However, such normalizing effects are transient; moreover, they are not always achieved, as shown here, when 9L gliosarcoma xenografts were treated over a range of doses with the VEGF receptor-selective tyrosine kinase inhibitors axitinib and AG-028262. The suppression of tumor blood perfusion by antiangiogenesis agents can be turned to therapeutic advantage, however, through their effects on tumor drug retention. In 9L tumors expressing the cyclophosphamide-activating enzyme P450 2B11, neoadjuvant axitinib treatment combined with intratumoral cyclophosphamide administration significantly increased tumor retention of cyclophosphamide and its active metabolite, 4-hydroxycyclophosphamide. Similar increases were achieved using other angiogenesis inhibitors, indicating that increased drug retention is a general response to antiangiogenesis. This approach can be extended to include systemic delivery of an anticancer prodrug that is activated intratumorally, where antiangiogenesis-enhanced retention of the therapeutic metabolite counterbalances the decrease in drug uptake from systemic circulation, as exemplified for cyclophosphamide. Importantly, the increase in intratumoral drug retention induced by neoadjuvant antiangiogenic drug treatment is shown to increase tumor cell killing and substantially enhance therapeutic activity in vivo. Thus, antiangiogenic agents can be used to increase tumor drug exposure and improve therapeutic activity following intratumoral drug administration, or following systemic drug administration in the case of a therapeutic agent that is activated intratumorally. Cancer Res; 71(7); 2675–85. ©2011 AACR.
Data from Altered TGF-β Signaling in a Subpopulation of Human Stromal Cells Promotes Prostatic Carcinogenesis
Authors: Franco Omar E. , Jiang Ming , Strand Douglas W. , Peacock James , Fernandez Suzanne , Jackson Roger S. , Revelo Monica P. , Bhowmick Neil A. , Hayward Simon W.
Published: March 2024

Abstract
Carcinoma-associated fibroblasts (CAF) play a critical role in malignant progression. Loss of TGF-β receptor II (TGFβR2) in the prostate stroma is correlated with prostatic tumorigenesis. To determine the mechanisms by which stromal heterogeneity because of loss of TGFβR2 might contribute to cancer progression, we attenuated transforming growth factor beta (TGF-β) signaling in a subpopulation of immortalized human prostate fibroblasts in a model of tumor progression. In a tissue recombination model, loss of TGFβR2 function in 50% of the stromal cell population resulted in malignant transformation of the nontumorigenic human prostate epithelial cell line BPH1. Mixing fibroblasts expressing the empty vector and dominant negative TGFβR2 increased the expression of markers of myofibroblast differentiation [coexpression of vimentin and alpha smooth muscle actin (αSMA)] through elevation of TGF-β1 and activation of the Akt pathway. In combination, these two populations of stromal cells recapitulated the tumor inductive activity of CAFs. TGFβR2 activity in mixed stromal cell populations cultured in vitro caused secretion of factors that are known to promote tumor progression, including TGF-β1, SDF1/CXCL12, and members of the fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) families. In vivo, tissue recombination of fibroblasts overexpressing TGF-β1 and SDF1/CXCL12 not only induced transformation of BPH1 cells, but also promoted a robust growth of highly invasive cells, similar to effects produced by CAFs. While the precise nature and/or origin of the particular stromal cell populations in vivo remain unknown, these findings strongly link heterogeneity in TGF-β signaling to tumor promotion by tumor stromal cells. Cancer Res; 71(4); 1272–81. ©2011 AACR.
Data from Lung Cancer Diagnosis from Proteomic Analysis of Preinvasive Lesions
Authors: Rahman S.M. Jamshedur , Gonzalez Adriana L. , Li Ming , Seeley Erin H. , Zimmerman Lisa J. , Zhang Xueqiong J. , Manier M. Lisa , Olson Sandra J. , Shah Ronak N. , Miller Alison N. , Putnam Joe B. , Miller York E. , Franklin Wilbur A. , Blot William J. , Carbone David P. , Shyr Yu , Caprioli Richard M. , Massion Pierre P.
Published: March 2024

Abstract
Early detection may help improve survival from lung cancer. In this study, our goal was to derive and validate a signature from the proteomic analysis of bronchial lesions that could predict the diagnosis of lung cancer. Using previously published studies of bronchial tissues, we selected a signature of nine matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) mass-to-charge ratio features to build a prediction model diagnostic of lung cancer. The model was based on MALDI MS signal intensity (MALDI score) from bronchial tissue specimens from our 2005 published cohort of 51 patients. The performance of the prediction model in identifying lung cancer was tested in an independent cohort of bronchial specimens from 60 patients. The probability of having lung cancer based on the proteomic analysis of the bronchial specimens was characterized by an area under the receiver operating characteristic curve of 0.77 (95% CI 0.66–0.88) in this validation cohort. Eight of the nine features were identified and validated by Western blotting and immunohistochemistry. These results show that proteomic analysis of endobronchial lesions may facilitate the diagnosis of lung cancer and the monitoring of high-risk individuals for lung cancer in surveillance and chemoprevention trials. Cancer Res; 71(8); 3009–17. ©2011 AACR.
Data from Definition of a FoxA1 Cistrome That Is Crucial for G1 to S-Phase Cell-Cycle Transit in Castration-Resistant Prostate Cancer
Authors: Zhang Chunpeng , Wang Liguo , Wu Dayong , Chen Hongyan , Chen Zhong , Thomas-Ahner Jennifer M. , Zynger Debra L. , Eeckhoute Jérôme , Yu Jindan , Luo Jun , Brown Myles , Clinton Steven K. , Nephew Kenneth P. , Huang Tim H.-M. , Li Wei , Wang Qianben
Published: March 2024

Abstract
The enhancer pioneer transcription factor FoxA1 is a global mediator of steroid receptor (SR) action in hormone-dependent cancers. In castration-resistant prostate cancer (CRPC), FoxA1 acts as an androgen receptor cofactor to drive G2 to M-phase cell-cycle transit. Here, we describe a mechanistically distinct SR-independent role for FoxA1 in driving G1 to S-phase cell-cycle transit in CRPC. By comparing FoxA1 binding sites in prostate cancer cell genomes, we defined a codependent set of FoxA1-MYBL2 and FoxA1-CREB1 binding sites within the regulatory regions of the Cyclin E2 and E2F1 genes that are critical for CRPC growth. Binding at these sites upregulate the Cyclin E2 and Cyclin A2 genes in CRPC but not in earlier stage androgen-dependent prostate cancer, establishing a stage-specific role for this pathway in CRPC growth. Mechanistic investigations indicated that FoxA1, MYBL2, or CREB1 induction of histone H3 acetylation facilitated nucleosome disruption as the basis for codependent transcriptional activation and G1 to S-phase cell-cycle transit. Our findings establish FoxA1 as a pivotal driver of the cell-cycle in CRPC which promotes G1 to S-phase transit as well as G2 to M-phase transit through two distinct mechanisms. Cancer Res; 71(21); 6738–48. ©2011 AACR.
Data from Novel Cryo-Imaging of the Glioma Tumor Microenvironment Reveals Migration and Dispersal Pathways in Vivid Three-Dimensional Detail
Authors: Burden-Gulley Susan M. , Qutaish Mohammed Q. , Sullivant Kristin E. , Lu Hong , Wang Jing , Craig Sonya E.L. , Basilion James P. , Wilson David L. , Brady-Kalnay Susann M.
Published: March 2024

Abstract
Traditional methods of imaging cell migration in the tumor microenvironment include serial sections of xenografts and standard histologic stains. Current molecular imaging techniques suffer from low resolution and difficulty in imaging through the skull. Here we show how computer algorithms can be used to reconstruct images from tissue sections obtained from mouse xenograft models of human glioma and can be rendered into three-dimensional images offering exquisite anatomic detail of tumor cell dispersal. Our findings identify human LN-229 and rodent CNS-1 glioma cells as valid systems to study the highly dispersive nature of glioma tumor cells along blood vessels and white matter tracts in vivo. This novel cryo-imaging technique provides a valuable tool to evaluate therapeutic interventions targeted at limiting tumor cell invasion and dispersal. Cancer Res; 71(17); 5932–40. ©2011 AACR.
Data from Human CD59 Inhibitor Sensitizes Rituximab-Resistant Lymphoma Cells to Complement-Mediated Cytolysis
Authors: Hu Weiguo , Ge Xiaowen , You Tao , Xu Ting , Zhang Jinyan , Wu Gongxiong , Peng Zhihai , Chorev Michael , Aktas Bertal H. , Halperin Jose A. , Brown Jennifer R. , Qin Xuebin
Published: March 2024

Abstract
Rituximab efficacy in cancer therapy depends in part on induction of complement-dependent cytotoxicity (CDC). Human CD59 (hCD59) is a key complement regulatory protein that restricts the formation of the membrane attack complex, thereby inhibiting induction of CDC. hCD59 is highly expressed in B-cell non–Hodgkin's lymphoma (NHL), and upregulation of hCD59 is an important determinant of the sensitivity of NHL cells to rituximab treatment. Here, we report that the potent hCD59 inhibitor rILYd4 enhances CDC in vitro and in vivo, thereby sensitizing rituximab-resistant lymphoma cells and primary chronic lymphocytic leukemia cells (CLL) to rituximab treatment. By defining pharmcokinetic/pharmacodynamic profiles of rILYd4 in mice, we showed that by itself rILYd4 does not adversely mediate in vivo hemolysis of hCD59-expressing erythrocytes. Increasing expression levels of the complement regulators CD59 and CD55 in rituximab-resistant cells occur due to selection of preexisting clones rather than de novo induction of these proteins. Moreover, lymphoma cells overexpressing CD59 were directly responsible for the resistance to rituximab-mediated CDC therapy. Our results rationalize the use of rILYd4 as a therapeutic adjuvant for rituximab treatment of rituximab-resistant lymphoma and CLL. Furthermore, they suggest that preemptive elimination of CD59-overexpressing subpopulations along with rituximab treatment may be a useful approach to ablate or conquer rituximab resistance. Cancer Res; 71(6); 2298–307. ©2011 AACR.
Data from STAT3 Is Necessary for Proliferation and Survival in Colon Cancer–Initiating Cells
Authors: Lin Li , Liu Aiguo , Peng Zhengang , Lin Huey-Jen , Li Pui-Kai , Li Chenglong , Lin Jiayuh
Published: March 2024

Abstract
STAT3 is constitutively activated in colon cancer but its contributions in cancer-initiating cells have not been explored. In this study, we characterized STAT3 in aldehyde dehydrogenase (ALDH)-positive (ALDH+) and CD133-positive (CD133+) subpopulations of human colon tumor cells that exhibited more potent tumor-initiating ability than ALDH−/CD133− cells in tumor xenograft assays in mice. We found that ALDH+/CD133+ cells expressed higher levels of the active phosphorylated form of STAT3 than either ALDH−/CD133− or unfractionated colon cancer cells. STAT3 inhibition by RNA interference–mediated knockdown or small-molecule inhibitors LLL12 or Stattic blocked downstream target gene expression, cell viability, and tumorsphere-forming capacity in cancer-initiating cells. Similarly, treatment of mouse tumor xenografts with STAT3 short hairpin RNA (shRNA), interleukin 6 shRNA, or LLL12 inhibited tumor growth. Our results establish that STAT3 is constitutively activated in colon cancer–initiating cells and that these cells are sensitive to STAT3 inhibition. These findings establish a powerful rationale to develop STAT3 inhibitory strategies for treating advanced colorectal cancers. Cancer Res; 71(23); 7226–37. ©2011 AACR.
Data from HMGA2 Overexpression-Induced Ovarian Surface Epithelial Transformation Is Mediated Through Regulation of EMT Genes
Authors: Wu Jingjing , Liu Zhaojian , Shao Changshun , Gong Yaoqin , Hernando Eva , Lee Peng , Narita Masashi , Muller William , Liu Jinsong , Wei Jian-Jun
Published: March 2024

Abstract
The AT-hook transcription factor HMGA2 is an oncogene involved in the tumorigenesis of many malignant neoplasms. HMGA2 overexpression is common in both early and late-stage high-grade ovarian serous papillary carcinoma. To test whether HMGA2 participates in the initiation of ovarian cancer and promotion of aggressive tumor growth, we examined the oncogenic properties of HMGA2 in ovarian surface epithelial (OSE) cell lines. We found that introduction of HMGA2 overexpression was sufficient to induce OSE transformation in vitro. HMGA2-mediated OSE transformation resulted in tumor formation in the xenografts of nude mice. By silencing HMGA2 in HMGA2-overexpressing OSE and ovarian cancer cell lines, the aggressiveness of tumor cell growth behaviors was partially suppressed. Global gene profiling analyses revealed that HMGA2-mediated tumorigenesis was associated with expression changes of target genes and microRNAs that are involved in epithelial-to-mesenchymal transition (EMT). Lumican, a tumor suppressor that inhibits EMT, was found to be transcriptionally repressed by HMGA2 and was frequently lost in human high-grade serous papillary carcinoma. Our findings show that HMGA2 overexpression confers a powerful oncogenic signal in ovarian cancers through the modulation of EMT genes. Cancer Res; 71(2); 349–59. ©2011 AACR.
Data from GLIPR1 Suppresses Prostate Cancer Development through Targeted Oncoprotein Destruction
Authors: Li Likun , Ren Chengzhen , Yang Guang , Fattah Elmoataz Abdel , Goltsov Alexei A. , Kim Soo Mi , Lee Ju-Seog , Park Sanghee , Demayo Francesco J. , Ittmann Michael M. , Troncoso Patricia , Thompson Timothy C.
Published: March 2024

Abstract
Downregulation of the proapoptotic p53 target gene glioma pathogenesis-related protein 1 (GLIPR1) occurs frequently in prostate cancer, but the functional meaning of this event is obscure. Here, we report the discovery of functional relationship between GLIPR1 and c-Myc in prostate cancer where c-Myc is often upregulated. We found that the expression of GLIPR1 and c-Myc were inversely correlated in human prostate cancer. Restoration of GLIPR1 expression in prostate cancer cells downregulated c-myc levels, inhibiting cell-cycle progression. Downregulation was linked to a reduction in β-catenin/TCF4-mediated transcription of the c-myc gene, which was caused by GLIPR1-mediated redistribution of casein kinase 1α (CK1α) from the Golgi apparatus to the cytoplasm where CK1α could phosphorylate β-catenin and mediate its destruction. In parallel, GLIPR1 also promoted c-Myc protein ubiquitination and degradation by glycogen synthase kinase-3α- and/or CK1α-mediated c-Myc phosphorylation. Notably, genetic ablation of the mouse homolog of Glipr1 cooperated with c-myc overexpression to induce prostatic intraepithelial neoplasia and prostate cancer. Together, our findings provide evidence for CK1α-mediated destruction of c-Myc and identify c-Myc S252 as a crucial CK1α phosphorylation site for c-Myc degradation. Furthermore, they reveal parallel mechanisms of c-myc downregulation by GLIPR1 that when ablated in the prostate are sufficient to drive c-Myc expression and malignant development. Cancer Res; 71(24); 7694–704. ©2011 AACR.
Data from Gastrointestinal Adenocarcinomas of the Esophagus, Stomach, and Colon Exhibit Distinct Patterns of Genome Instability and Oncogenesis
Authors: Dulak Austin M. , Schumacher Steven E. , van Lieshout Jasper , Imamura Yu , Fox Cameron , Shim Byoungyong , Ramos Alex H. , Saksena Gordon , Baca Sylvan C. , Baselga Jose , Tabernero Josep , Barretina Jordi , Enzinger Peter C. , Corso Giovanni , Roviello Franco , Lin Lin , Bandla Santhoshi , Luketich James D. , Pennathur Arjun , Meyerson Matthew , Ogino Shuji , Shivdasani Ramesh A. , Beer David G. , Godfrey Tony E. , Beroukhim Rameen , Bass Adam J.
Published: March 2024

Abstract
A more detailed understanding of the somatic genetic events that drive gastrointestinal adenocarcinomas is necessary to improve diagnosis and therapy. Using data from high-density genomic profiling arrays, we conducted an analysis of somatic copy-number aberrations in 486 gastrointestinal adenocarcinomas including 296 esophageal and gastric cancers. Focal amplifications were substantially more prevalent in gastric/esophageal adenocarcinomas than colorectal tumors. We identified 64 regions of significant recurrent amplification and deletion, some shared and others unique to the adenocarcinoma types examined. Amplified genes were noted in 37% of gastric/esophageal tumors, including in therapeutically targetable kinases such as ERBB2, FGFR1, FGFR2, EGFR, and MET, suggesting the potential use of genomic amplifications as biomarkers to guide therapy of gastric and esophageal cancers where targeted therapeutics have been less developed compared with colorectal cancers. Amplified loci implicated genes with known involvement in carcinogenesis but also pointed to regions harboring potentially novel cancer genes, including a recurrent deletion found in 15% of esophageal tumors where the Runt transcription factor subunit RUNX1 was implicated, including by functional experiments in tissue culture. Together, our results defined genomic features that were common and distinct to various gut-derived adenocarcinomas, potentially informing novel opportunities for targeted therapeutic interventions. Cancer Res; 72(17); 4383–93. ©2012 AACR.
Data from MLK3 Regulates Paxillin Phosphorylation in Chemokine-Mediated Breast Cancer Cell Migration and Invasion to Drive Metastasis
Authors: Chen Jian , Gallo Kathleen A.
Published: March 2024

Abstract
MLK3 kinase activates multiple mitogen-activated protein kinases and plays a critical role in cancer cell migration and invasion. In the tumor microenvironment, prometastatic factors drive breast cancer invasion and metastasis, but their associated signaling pathways are not well-known. Here, we provide evidence that MLK3 is required for chemokine (CXCL12)-induced invasion of basal breast cancer cells. We found that MLK3 induced robust phosphorylation of the focal adhesion scaffold paxillin on Ser 178 and Tyr 118, which was blocked by silencing or inhibition of MLK3-JNK. Silencing or inhibition of MLK3, inhibition of JNK, or expression of paxillin S178A all led to enhanced Rho activity, indicating that the MLK3–JNK–paxillin axis limits Rho activity to promote focal adhesion turnover and migration. Consistent with this, MLK3 silencing increased focal adhesions and stress fibers in breast cancer cells. MLK3 silencing also decreased the formation of breast cancer lung metastases in vivo, and breast cancer cells derived from mouse lung metastases showed enhanced Ser 178 paxillin phosphorylation. Taken together, our findings suggest that the MLK3–JNK–paxillin signaling axis may represent a potential therapeutic target and/or prognostic marker in breast cancer metastasis. Cancer Res; 72(16); 4130–40. ©2012 AACR.
Data from Urinary Estrogens and Estrogen Metabolites and Subsequent Risk of Breast Cancer among Premenopausal Women
Authors: Eliassen A. Heather , Spiegelman Donna , Xu Xia , Keefer Larry K. , Veenstra Timothy D. , Barbieri Robert L. , Willett Walter C. , Hankinson Susan E. , Ziegler Regina G.
Published: March 2024

Abstract
Endogenous estrogens and estrogen metabolism are hypothesized to be associated with premenopausal breast cancer risk but evidence is limited. We examined 15 urinary estrogens/estrogen metabolites and breast cancer risk among premenopausal women in a case–control study nested within the Nurses' Health Study II (NHSII). From 1996 to 1999, urine was collected from 18,521 women during the mid-luteal menstrual phase. Breast cancer cases (N = 247) diagnosed between collection and June 2005 were matched to two controls each (N = 485). Urinary estrogen metabolites were measured by liquid chromatography-tandem mass spectrometry and adjusted for creatinine level. Relative risks (RR) and 95% confidence intervals (CI) were estimated by multivariate conditional logistic regression. Higher urinary estrone and estradiol levels were strongly significantly associated with lower risk (top vs. bottom quartile RR: estrone = 0.52; 95% CI, 0.30–0.88; estradiol = 0.51; 95% CI, 0.30–0.86). Generally inverse, although nonsignificant, patterns also were observed with 2- and 4-hydroxylation pathway estrogen metabolites. Inverse associations generally were not observed with 16-pathway estrogen metabolites and a significant positive association was observed with 17-epiestriol (top vs. bottom quartile RR = 1.74; 95% CI, 1.08–2.81; Ptrend = 0.01). In addition, there was a significant increased risk with higher 16-pathway/parent estrogen metabolite ratio (comparable RR = 1.61; 95% CI, 0.99–2.62; Ptrend = 0.04). Other pathway ratios were not significantly associated with risk except parent estrogen metabolites/non–parent estrogen metabolites (comparable RR = 0.58; 95% CI, 0.35–0.96; Ptrend = 0.03). These data suggest that most mid-luteal urinary estrogen metabolite concentrations are not positively associated with breast cancer risk among premenopausal women. The inverse associations with parent estrogen metabolites and the parent estrogen metabolite/non–parent estrogen metabolite ratio suggest that women with higher urinary excretion of parent estrogens are at lower risk. Cancer Res; 72(3); 696–706. ©2011 AACR.
Data from Stat3 Inhibition Augments the Immunogenicity of B-cell Lymphoma Cells, Leading to Effective Antitumor Immunity
Authors: Cheng Fengdong , Wang Hongwei , Horna Pedro , Wang Zi , Shah Bijal , Sahakian Eva , Woan Karrune V. , Villagra Alejandro , Pinilla-Ibarz Javier , Sebti Said , Smith Mitchell , Tao Jianguo , Sotomayor Eduardo M.
Published: March 2024

Abstract
Mantle cell lymphoma (MCL) is an aggressive and incurable subtype of B-cell non–Hodgkin lymphomas. Although patients often respond initially to first-line treatment with chemotherapy plus monoclonal antibodies, relapse and decreased response to further lines of treatment eventually occurs. Harnessing the immune system to elicit its exquisite specificity and long-lasting protection might provide sustained MCL immunity that could potentially eradicate residual malignant cells responsible for disease relapse. Here, we show that genetic or pharmacologic disruption of Stat3 in malignant B cells augments their immunogenicity leading to better activation of antigen-specific CD4+ T cells and restoration of responsiveness of tolerized T cells. In addition, treatment of MCL-bearing mice with a specific Stat3 inhibitor resulted in decreased Stat3 phosphorylation in malignant B cells and anti-lymphoma immunity in vivo. Our findings therefore indicate that Stat3 inhibition may represent a therapeutic strategy to overcome tolerance to tumor antigens and elicit a strong immunity against MCL and other B-cell malignancies. Cancer Res; 72(17); 4440–8. ©2012 AACR.
Data from Endothelial Expression of TNF Receptor-1 Generates a Proapoptotic Signal Inhibited by Integrin α6β1 in Glioblastoma
Authors: Huang Ping , Rani M.R. Sandhya , Ahluwalia Manmeet S. , Bae Eunnyung , Prayson Richard A. , Weil Robert J. , Nowacki Amy S. , Hedayat Hirad , Sloan Andrew E. , Lathia Justin D. , Rich Jeremy N. , Tipps Russell , Gladson Candece L.
Published: March 2024

Abstract
Activation of TNF receptor 1 (TNF-R1) can generate signals that promote either apoptosis or survival. In this study, we show that these signals can be determined by the character of the extracellular matrix in the tumor microenvironment. Specifically, through studies of glioblastoma, we showed that TNFα stimulation induced apoptosis of primary brain endothelial cells (EC) attached to collagen or fibronectin (which engage integrins α2β1/α3β1 and α5β1, respectively), but did not induce apoptosis of ECs attached to laminin (which engages integrins α6β1 and α3β1). TNF-R1 expression was significantly higher in ECs in glioblastoma (GBM) tumors compared with ECs in normal brain specimens. TNFα was also expressed in GBM tumor-associated ECs, which was associated with longer patient survival. ECs plated on anti-integrin α2 or α3 antibody were susceptible to TNFα-induced apoptosis, whereas those plated on anti-integrin α6 antibody were not. Moreover, the ECs plated on laminin, but not collagen, expressed cellular FLICE inhibitory protein (cFLIP) and TNFα stimulation of laminin-attached cells in which cFLIP had been downregulated resulted in the induction of apoptosis. In contrast, attachment to laminin did not induce cFLIP expression in GBM tumor stem cells. Together, our findings indicate that the laminin receptor integrin α6β1 promotes the survival of brain ECs by inhibiting prodeath signaling by TNF-R1, in part by inducing cFLIP expression. Cancer Res; 72(6); 1428–37. ©2012 AACR.
Data from Combined EGFR/MET or EGFR/HSP90 Inhibition Is Effective in the Treatment of Lung Cancers Codriven by Mutant EGFR Containing T790M and MET
Authors: Xu Lu , Kikuchi Eiki , Xu Chunxiao , Ebi Hiromichi , Ercan Dalia , Cheng Katherine A. , Padera Robert , Engelman Jeffrey A. , Jänne Pasi A. , Shapiro Geoffrey I. , Shimamura Takeshi , Wong Kwok-Kin
Published: March 2024

Abstract
Tyrosine kinase inhibitors (TKI) that target the EGF receptor (EGFR) are effective in most non–small cell lung carcinoma (NSCLC) patients whose tumors harbor activating EGFR kinase domain mutations. Unfortunately, acquired resistance eventually emerges in these chronically treated cancers. Two of the most common mechanisms of acquired resistance to TKIs seen clinically are the acquisition of a secondary “gatekeeper” T790M EGFR mutation that increases the affinity of mutant EGFR for ATP and activation of MET to offset the loss of EGFR signaling. Although up to one-third of patient tumors resistant to reversible EGFR TKIs harbor concurrent T790M mutation and MET amplification, potential therapies for these tumors have not been modeled in vivo. In this study, we developed a preclinical platform to evaluate potential therapies by generating transgenic mouse lung cancer models expressing EGFR-mutant Del19-T790M or L858R-T790M, each with concurrent MET overexpression. We found that monotherapy targeting EGFR or MET alone did not produce significant tumor regression. In contrast, combination therapies targeting EGFR and MET simultaneously were highly efficacious against EGFR TKI–resistant tumors codriven by Del19-T790M or L858R-T790M and MET. Our findings therefore provide an in vivo model of intrinsic resistance to reversible TKIs and offer preclinical proof-of-principle that combination targeting of EGFR and MET may benefit patients with NSCLC. Cancer Res; 72(13); 3302–11. ©2012 AACR.
Data from Hyaluronan Synthase HAS2 Promotes Tumor Progression in Bone by Stimulating the Interaction of Breast Cancer Stem–Like Cells with Macrophages and Stromal Cells
Authors: Okuda Hiroshi , Kobayashi Aya , Xia Bo , Watabe Misako , Pai Sudha K. , Hirota Shigeru , Xing Fei , Liu Wen , Pandey Puspa R. , Fukuda Koji , Modur Vishnu , Ghosh Arnab , Wilber Andrew , Watabe Kounosuke
Published: March 2024

Abstract
The molecular mechanisms that operate within the organ microenvironment to support metastatic progression remain unclear. Here, we report that upregulation of hyaluronan synthase 2 (HAS2) occurs in highly metastatic breast cancer stem–like cells (CSC) defined by CD44+/CD24−/ESA+ phenotype, where it plays a critical role in the generation of a prometastatic microenvironment in breast cancer. HAS2 was critical for the interaction of CSCs with tumor-associated macrophages (TAM), leading to enhanced secretion of platelet-derived growth factor-BB from TAMs, which then activated stromal cells and enhanced CSC self-renewal. Loss of HAS2 in CSCs or treatment with 4-methylumbelliferone, an inhibitor of HAS, which blocks hyaluronan production, drastically reduced the incidence and growth of metastatic lesions in vitro or in vivo, respectively. Taken together, our findings show a critical role of HAS2 in the development of a prometastatic microenvironment and suggest that HAS2 inhibitors can act as antimetastatic agents that disrupt a paracrine growth factor loop within this microenvironment. Cancer Res; 72(2); 537–47. ©2011 AACR.
Data from TMEM16A Induces MAPK and Contributes Directly to Tumorigenesis and Cancer Progression
Authors: Duvvuri Umamaheswar , Shiwarski Daniel J. , Xiao Dong , Bertrand Carol , Huang Xin , Edinger Robert S. , Rock Jason R. , Harfe Brian D. , Henson Brian J. , Kunzelmann Karl , Schreiber Rainer , Seethala Raja S. , Egloff Ann Marie , Chen Xing , Lui Vivian W. , Grandis Jennifer R. , Gollin Susanne M.
Published: March 2024

Abstract
Frequent gene amplification of the receptor-activated calcium-dependent chloride channel TMEM16A (TAOS2 or ANO1) has been reported in several malignancies. However, its involvement in human tumorigenesis has not been previously studied. Here, we show a functional role for TMEM16A in tumor growth. We found TMEM16A overexpression in 80% of head and neck squamous cell carcinoma (SCCHN), which correlated with decreased overall survival in patients with SCCHN. TMEM16A overexpression significantly promoted anchorage-independent growth in vitro, and loss of TMEM16A resulted in inhibition of tumor growth both in vitro and in vivo. Mechanistically, TMEM16A-induced cancer cell proliferation and tumor growth were accompanied by an increase in extracellular signal–regulated kinase (ERK)1/2 activation and cyclin D1 induction. Pharmacologic inhibition of MEK/ERK and genetic inactivation of ERK1/2 (using siRNA and dominant-negative constructs) abrogated the growth effect of TMEM16A, indicating a role for mitogen-activated protein kinase (MAPK) activation in TMEM16A-mediated proliferation. In addition, a developmental small-molecule inhibitor of TMEM16A, T16A-inh01 (A01), abrogated tumor cell proliferation in vitro. Together, our findings provide a mechanistic analysis of the tumorigenic properties of TMEM16A, which represents a potentially novel therapeutic target. The development of small-molecule inhibitors against TMEM16A may be clinically relevant for treatment of human cancers, including SCCHN. Cancer Res; 72(13); 3270–81. ©2012 AACR.
Data from Jab1/CSN5 Negatively Regulates p27 and Plays a Role in the Pathogenesis of Nasopharyngeal Carcinoma
Authors: Pan Yunbao , Zhang Qingxiu , Tian Ling , Wang Xin , Fan Xiaohang , Zhang Huizhong , Claret Francois X. , Yang Huiling
Published: March 2024

Abstract
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus–associated malignancy most common in East Asia and Africa. Aberrant expression of Jab1/CSN5, a negative regulator of the cell-cycle inhibitor p27, is correlated with reduced p27 expression and associated with advanced tumor stage and poor prognosis in several human cancers. In this study, we examined the functional relationship between Jab1 and p27 protein expression in NPC. Immunohistochemical analysis showed an inverse association between Jab1 and p27 in NPC tissue samples, and overexpression of Jab1 correlated with poor survival in patients with NPC. Mechanistically, Jab1 and p27 were found to interact directly in NPC cells, with Jab1 mediating p27 degradation in a proteasome-dependent manner. Knockdown of Jab1 resulted in a remarkable increase in p27 levels and inhibition of cell proliferation, indicating that Jab1 targets p27 for degradation, thereby controlling its stability. Jab1 depletion also enhanced the antitumor effects of cisplatin in NPC cells. Together, our findings suggest that Jab1 overexpression plays an important role in the pathogenesis of NPC through Jab1-mediated p27 degradation. Jab1 therefore represents a novel diagnostic marker and therapeutic target in patients with NPC. Cancer Res; 72(7); 1890–900. ©2012 AACR.
Data from Stromal Progenitor Cells from Endogenous Adipose Tissue Contribute to Pericytes and Adipocytes That Populate the Tumor Microenvironment
Authors: Zhang Yan , Daquinag Alexes C. , Amaya-Manzanares Felipe , Sirin Olga , Tseng Chieh , Kolonin Mikhail G.
Published: March 2024

Abstract
Epidemiologic studies associate cancer with obesity, but the pathophysiologic connections remain obscure. In this study, we show that obesity facilitates tumor growth in mice irrespective of concurrent diet, suggesting a direct effect of excess white adipose tissue (WAT). When transplanted into mice, adipose stromal cells (ASC) can serve as perivascular adipocyte progenitors that promote tumor growth, perhaps helping explain the obesity–cancer link. In developing this hypothesis, we showed that ASCs are expanded in obesity and that they traffic from endogenous WAT to tumors in several mouse models of cancer. Strikingly, a comparison of circulating and tumor-infiltrating cell populations in lean, and obese mice revealed that cancer induces a six-fold increase of ASC frequency in the systemic circulation. We obtained evidence that ASCs mobilized in this way can be recruited into tumors, where they can be incorporated into blood vessels as pericytes and they can differentiate into adipocytes in an obesity-dependent manner. Extending this evidence, we found that increased tumor vascularization (reflected by changes in tumor vascular morphology and a two-fold increase in vascular density) was associated with intratumoral adipocytes and elevated proliferation of neighboring malignant cells. Taken together, our results suggest that ASCs recruited from endogenous adipose tissue can be recruited by tumors to potentiate the supportive properties of the tumor microenvironment. Cancer Res; 72(20); 5198–208. ©2012 AACR.
Data from A Developmental Taxonomy of Glioblastoma Defined and Maintained by MicroRNAs
Authors: Kim Tae-Min , Huang Wei , Park Richard , Park Peter J. , Johnson Mark D.
Published: March 2024

Abstract
mRNA expression profiling has suggested the existence of multiple glioblastoma subclasses, but their number and characteristics vary among studies and the etiology underlying their development is unclear. In this study, we analyzed 261 microRNA expression profiles from The Cancer Genome Atlas (TCGA), identifying five clinically and genetically distinct subclasses of glioblastoma that each related to a different neural precursor cell type. These microRNA-based glioblastoma subclasses displayed microRNA and mRNA expression signatures resembling those of radial glia, oligoneuronal precursors, neuronal precursors, neuroepithelial/neural crest precursors, or astrocyte precursors. Each subclass was determined to be genetically distinct, based on the significant differences they displayed in terms of patient race, age, treatment response, and survival. We also identified several microRNAs as potent regulators of subclass-specific gene expression networks in glioblastoma. Foremost among these is miR-9, which suppresses mesenchymal differentiation in glioblastoma by downregulating expression of JAK kinases and inhibiting activation of STAT3. Our findings suggest that microRNAs are important determinants of glioblastoma subclasses through their ability to regulate developmental growth and differentiation programs in several transformed neural precursor cell types. Taken together, our results define developmental microRNA expression signatures that both characterize and contribute to the phenotypic diversity of glioblastoma subclasses, thereby providing an expanded framework for understanding the pathogenesis of glioblastoma in a human neurodevelopmental context. Cancer Res; 71(9); 3387–99. ©2011 AACR.
Data from Cathepsin B Inhibition Limits Bone Metastasis in Breast Cancer
Authors: Withana Nimali P. , Blum Galia , Sameni Mansoureh , Slaney Clare , Anbalagan Arulselvi , Olive Mary B. , Bidwell Bradley N. , Edgington Laura , Wang Ling , Moin Kamiar , Sloane Bonnie F. , Anderson Robin L. , Bogyo Matthew S. , Parker Belinda S.
Published: March 2024

Abstract
Metastasis to bone is a major cause of morbidity in breast cancer patients, emphasizing the importance of identifying molecular drivers of bone metastasis for new therapeutic targets. The endogenous cysteine cathepsin inhibitor stefin A is a suppressor of breast cancer metastasis to bone that is coexpressed with cathepsin B in bone metastases. In this study, we used the immunocompetent 4T1.2 model of breast cancer which exhibits spontaneous bone metastasis to evaluate the function and therapeutic targeting potential of cathepsin B in this setting of advanced disease. Cathepsin B abundancy in the model mimicked human disease, both at the level of primary tumors and matched spinal metastases. RNA interference–mediated knockdown of cathepsin B in tumor cells reduced collagen I degradation in vitro and bone metastasis in vivo. Similarly, intraperitoneal administration of the highly selective cathepsin B inhibitor CA-074 reduced metastasis in tumor-bearing animals, a reduction that was not reproduced by the broad spectrum cysteine cathepsin inhibitor JPM-OEt. Notably, metastasis suppression by CA-074 was maintained in a late treatment setting, pointing to a role in metastatic outgrowth. Together, our findings established a prometastatic role for cathepsin B in distant metastasis and illustrated the therapeutic benefits of its selective inhibition in vivo. Cancer Res; 72(5); 1199–209. ©2012 AACR.
Data from An Insertion/Deletion Polymorphism within RERT-lncRNA Modulates Hepatocellular Carcinoma Risk
Authors: Zhu Zhansheng , Gao Xueren , He Yan , Zhao Hua , Yu Qiang , Jiang Deke , Zhang Pingzhao , Ma Xiaopin , Huang Huixing , Dong Dong , Wan Jiao , Gu Zhenyong , Jiang Xinghong , Yu Long , Gao Yuzhen
Published: March 2024

Abstract
The Prolyl hydroxylase 1 (EGLN2) is known to affect tumorigenesis by regulating the degradation of hypoxia-inducible factor. Polymorphisms in EGLN2 may facilitate cancer cell survival under hypoxic conditions and directly associate with cancer susceptibility. Here, we examined the contribution of a 4-bp insertion/deletion polymorphism (rs10680577) within the distal promoter of EGLN2 to the risk of hepatocelluar carcinoma (HCC) in Chinese populations. The contribution of rs10680577 to HCC risk was investigated in 623 HCC cases and 1,242 controls and replicated in an independent case–control study consisting of 444 HCC cases and 450 controls. Logistic regression analysis showed that the deletion allele of rs10680577 was significantly associated with increased risk for HCC occurrence in both case–control studies [OR = 1.40; 95% confidence interval (CI) = 1.18–1.66, P < 0.0001; OR = 1.49; 95% CI = 1.18–1.88, P = 0.0007]. Such positive association was more pronounced in current smokers (OR = 3.49, 95% CI = 2.24–5.45) than nonsmokers (OR = 1.24, 95% CI = 1.03–1.50; heterogeneity P = 0.0002). Genotype–phenotype correlation studies showed that the deletion allele was significantly correlated with higher expression of both EGLN2 and RERT-lncRNA [a long noncoding RNA whose sequence overlaps with Ras-related GTP-binding protein 4b (RAB4B) and EGLN2)] in vivo and in vitro. Furthermore, RERT-lncRNA expression was also significantly correlated with EGLN2 expression in vivo, consistent with in vitro gain-of-function study that showed overexpressing RERT-lncRNA upregulated EGLN2. Finally, in silico prediction suggested that the insertion allele could disrupt the structure of RERT-lncRNA. Taken together, our findings provided strong evidence for the hypothesis that rs10680577 contributes to hepatocarcinogenesis, possibly by affecting RERT-lncRNA structure and subsequently EGLN2 expression, making it a promising biomarker for early diagnosis of HCC. Cancer Res; 72(23); 6163–72. ©2012 AACR.