bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Inhibition of Histone Demethylase JMJD1A Improves Anti-Angiogenic Therapy and Reduces Tumor-Associated Macrophages
Authors: Osawa Tsuyoshi , Tsuchida Rika , Muramatsu Masashi , Shimamura Teppei , Wang Feng , Suehiro Jun-ichi , Kanki Yasuharu , Wada Youichiro , Yuasa Yasuhito , Aburatani Hiroyuki , Miyano Satoru , Minami Takashi , Kodama Tatsuhiko , Shibuya Masabumi
Published: March 2024

Abstract
Antiangiogenic strategies can be effective for cancer therapy, but like all therapies resistance poses a major clinical challenge. Hypoxia and nutrient starvation select for aggressive qualities that may render tumors resistant to antiangiogenic attack. Here, we show that hypoxia and nutrient starvation cooperate to drive tumor aggressiveness through epigenetic regulation of the histone demethylase JMJD1A (JHDM2A; KDM3A). In cancer cells rendered resistant to long-term hypoxia and nutrient starvation, we documented a stimulation of AKT phosphorylation, cell morphologic changes, cell migration, invasion, and anchorage-independent growth in culture. These qualities associated in vivo with increased angiogenesis and infiltration of macrophages into tumor tissues. Through expression microarray analysis, we identified a cluster of functional drivers such as VEGFA, FGF18, and JMJD1A, the latter which was upregulated in vitro under conditions of hypoxia and nutrient starvation and in vivo before activation of the angiogenic switch or the prerefractory phase of antiangiogenic therapy. JMJD1A inhibition suppressed tumor growth by downregulating angiogenesis and macrophage infiltration, by suppressing expression of FGF2, HGF, and ANG2. Notably, JMJD1A inhibition enhanced the antitumor effects of the anti-VEGF compound bevacizumab and the VEGFR/KDR inhibitor sunitinib. Our results form the foundation of a strategy to attack hypoxia- and nutrient starvation–resistant cancer cells as an approach to leverage antiangiogenic treatments and limit resistance to them. Cancer Res; 73(10); 3019–28. ©2013 AACR.
Data from Cross-Species Functional Analysis of Cancer-Associated Fibroblasts Identifies a Critical Role for CLCF1 and IL-6 in Non–Small Cell Lung Cancer In Vivo
Authors: Vicent Silvestre , Sayles Leanne C. , Vaka Dedeepya , Khatri Purvesh , Gevaert Olivier , Chen Ron , Zheng Yanyan , Gillespie Anna K. , Clarke Nicole , Xu Yue , Shrager Joseph , Hoang Chuong D. , Plevritis Sylvia , Butte Atul J. , Sweet-Cordero E. Alejandro
Published: March 2024

Abstract
Cancer-associated fibroblasts (CAF) have been reported to support tumor progression by a variety of mechanisms. However, their role in the progression of non–small cell lung cancer (NSCLC) remains poorly defined. In addition, the extent to which specific proteins secreted by CAFs contribute directly to tumor growth is unclear. To study the role of CAFs in NSCLCs, a cross-species functional characterization of mouse and human lung CAFs was conducted. CAFs supported the growth of lung cancer cells in vivo by secretion of soluble factors that directly stimulate the growth of tumor cells. Gene expression analysis comparing normal mouse lung fibroblasts and mouse lung CAFs identified multiple genes that correlate with the CAF phenotype. A gene signature of secreted genes upregulated in CAFs was an independent marker of poor survival in patients with NSCLC. This secreted gene signature was upregulated in normal lung fibroblasts after long-term exposure to tumor cells, showing that lung fibroblasts are “educated” by tumor cells to acquire a CAF-like phenotype. Functional studies identified important roles for CLCF1–CNTFR and interleukin (IL)-6–IL-6R signaling in promoting growth of NSCLCs. This study identifies novel soluble factors contributing to the CAF protumorigenic phenotype in NSCLCs and suggests new avenues for the development of therapeutic strategies. Cancer Res; 72(22); 5744–56. ©2012 AACR.
Data from eIF4E/4E-BP Ratio Predicts the Efficacy of mTOR Targeted Therapies
Authors: Alain Tommy , Morita Masahiro , Fonseca Bruno D. , Yanagiya Akiko , Siddiqui Nadeem , Bhat Mamatha , Zammit Domenick , Marcus Victoria , Metrakos Peter , Voyer Lucie-Anne , Gandin Valentina , Liu Yi , Topisirovic Ivan , Sonenberg Nahum
Published: March 2024

Abstract
Active-site mTOR inhibitors (asTORi) hold great promise for targeting dysregulated mTOR signaling in cancer. Because of the multifaceted nature of mTORC1 signaling, identification of reliable biomarkers for the sensitivity of tumors to asTORi is imperative for their clinical implementation. Here, we show that cancer cells acquire resistance to asTORi by downregulating eukaryotic translation initiation factor (eIF4E)-binding proteins (4E-BPs—EIF4EBP1, EIF4EBP2). Loss of 4E-BPs or overexpression of eIF4E renders neoplastic growth and translation of tumor-promoting mRNAs refractory to mTOR inhibition. Conversely, moderate depletion of eIF4E augments the anti-neoplastic effects of asTORi. The anti-proliferative effect of asTORi in vitro and in vivo is therefore significantly influenced by perturbations in eIF4E/4E-BP stoichiometry, whereby an increase in the eIF4E/4E-BP ratio dramatically limits the sensitivity of cancer cells to asTORi. We propose that the eIF4E/4E-BP ratio, rather than their individual protein levels or solely their phosphorylation status, should be considered as a paramount predictive marker for forecasting the clinical therapeutic response to mTOR inhibitors. Cancer Res; 72(24); 6468–76. ©2012 AACR.
Data from Loss of SNAIL Regulated miR-128-2 on Chromosome 3p22.3 Targets Multiple Stem Cell Factors to Promote Transformation of Mammary Epithelial Cells
Authors: Qian PengXu , Banerjee Arindam , Wu Zheng-Sheng , Zhang Xiao , Wang Hong , Pandey Vijay , Zhang Wei-Jie , Lv Xue-Fei , Tan Sheng , Lobie Peter E. , Zhu Tao
Published: March 2024

Abstract
A discontinuous pattern of LOH at chromosome 3p has been reported in 87% of primary breast cancers. Despite the identification of several tumor suppressor genes in this region, there has yet to be a detailed analysis of noncoding RNAs including miRNAs in this region. In this study, we identified 16 aberrant miRNAs in this region and determined several that are frequently lost or amplified in breast cancer. miR-128-2 was the most commonly deleted miRNA. Embedded in the intron of the ARPP21 gene at chromosome 3p22.3, miR-128-2 was frequently downregulated along with ARPP21 in breast cancer, where it was negatively associated with clinicopathologic characteristics and survival outcome. Forced expression of miR-128 impeded several oncogenic traits of mammary carcinoma cells, whereas depleting miR-128-2 expression was sufficient for oncogenic transformation and stem cell-like behaviors in immortalized nontumorigenic mammary epithelial cells, both in vitro and in vivo. miR-128-2 silencing enabled transforming capacity partly by derepressing a cohort of direct targets (BMI1, CSF1, KLF4, LIN28A, NANOG, and SNAIL), which together acted to stimulate the PI3K/AKT and STAT3 signaling pathways. We also found that miR-128-2 was directly downregulated by SNAIL and repressed by TGF-β signaling, adding 2 additional negative feedback loops to this network. In summary, we have identified a novel TGF-β/SNAIL/miR-128 axis that provides a new avenue to understand the basis for oncogenic transformation of mammary epithelial cells. Cancer Res; 72(22); 6036–50. ©2012 AACR.
Data from TRAF4 Is a Critical Molecule for Akt Activation in Lung Cancer
Authors: Li Wei , Peng Cong , Lee Mee-Hyun , Lim DoYoung , Zhu Feng , Fu Yang , Yang Ge , Sheng Yuqiao , Xiao Lanbo , Dong Xin , Ma WeiYa , Bode Ann M. , Cao Ya , Dong Zigang
Published: March 2024

Abstract
TRAF4 is an adapter protein overexpressed in certain cancers, but its contributions to tumorigenesis are unclear. In lung cancer cells and primary lung tumors, we found that TRAF4 is overexpressed. RNA interference-mediated attenuation of TRAF4 expression blunted the malignant phenotype in this setting, exerting inhibitory effects on cell proliferation, anchorage-independent growth, and tumor development in a xenograft mouse model. Unexpectedly, we discovered that TRAF4, but not Skp2, was required for activation of the pivotal cell survival kinase Akt through ubiquitination. Furthermore, TRAF4 attenuation impaired glucose metabolism by inhibiting expression of Glut1 and HK2 mediated by the Akt pathway. Overall, our work suggests that TRAF4 offers a candidate molecular target for lung cancer prevention and therapy. Cancer Res; 73(23); 6938–50. ©2013 AACR.
Data from MUC1 Is a Potential Target for the Treatment of Acute Myeloid Leukemia Stem Cells
Authors: Stroopinsky Dina , Rosenblatt Jacalyn , Ito Keisuke , Mills Heidi , Yin Li , Rajabi Hasan , Vasir Baldev , Kufe Turner , Luptakova Katarina , Arnason Jon , Nardella Caterina , Levine James D. , Joyce Robin M. , Galinsky Ilene , Reiter Yoram , Stone Richard M. , Pandolfi Pier Paolo , Kufe Donald , Avigan David
Published: March 2024

Abstract
Acute myeloid leukemia (AML) is a malignancy of stem cells with an unlimited capacity for self-renewal. MUC1 is a secreted, oncogenic mucin that is expressed aberrantly in AML blasts, but its potential uses to target AML stem cells have not been explored. Here, we report that MUC1 is highly expressed on AML CD34+/lineage−/CD38− cells as compared with their normal stem cell counterparts. MUC1 expression was not restricted to AML CD34+ populations as similar results were obtained with leukemic cells from patients with CD34− disease. Engraftment of AML stem cell populations that highly express MUC1 (MUC1high) led to development of leukemia in NOD-SCID IL2Rgammanull (NSG) immunodeficient mice. In contrast, MUC1low cell populations established normal hematopoiesis in the NSG model. Functional blockade of the oncogenic MUC1-C subunit with the peptide inhibitor GO-203 depleted established AML in vivo, but did not affect engraftment of normal hematopoietic cells. Our results establish that MUC1 is highly expressed in AML stem cells and they define the MUC1-C subunit as a valid target for their therapeutic eradication. Cancer Res; 73(17); 5569–79. ©2013 AACR.
Data from Interleukin-6 Is Required for Pancreatic Cancer Progression by Promoting MAPK Signaling Activation and Oxidative Stress Resistance
Authors: Zhang Yaqing , Yan Wei , Collins Meredith A. , Bednar Filip , Rakshit Sabita , Zetter Bruce R. , Stanger Ben Z. , Chung Ivy , Rhim Andrew D. , di Magliano Marina Pasca
Published: March 2024

Abstract
Pancreatic cancer, one of the deadliest human malignancies, is almost invariably associated with the presence of an oncogenic form of Kras. Mice expressing oncogenic Kras in the pancreas recapitulate the stepwise progression of the human disease. The inflammatory cytokine interleukin (IL)-6 is often expressed by multiple cell types within the tumor microenvironment. Here, we show that IL-6 is required for the maintenance and progression of pancreatic cancer precursor lesions. In fact, the lack of IL-6 completely ablates cancer progression even in presence of oncogenic Kras. Mechanistically, we show that IL-6 synergizes with oncogenic Kras to activate the reactive oxygen species detoxification program downstream of the mitogen-activated protein kinase/extracellular signal—regulated kinase (MAPK/ERK) signaling cascade. In addition, IL-6 regulates the inflammatory microenvironment of pancreatic cancer throughout its progression, providing several signals that are essential for carcinogenesis. Thus, IL-6 emerges as a key player at all stages of pancreatic carcinogenesis and a potential therapeutic target. Cancer Res; 73(20); 6359–74. ©2013 AACR.
Data from Lenalidomide Inhibits Lymphangiogenesis in Preclinical Models of Mantle Cell Lymphoma
Authors: Song Kai , Herzog Brett H. , Sheng Minjia , Fu Jianxin , McDaniel J. Michael , Ruan Jia , Xia Lijun
Published: March 2024

Abstract
Lymphomas originate in and spread primarily along the lymphatic system. However, whether lymphatic vessels contribute to the growth and spreading of lymphomas is largely unclear. Mantle cell lymphoma (MCL) represents an aggressive non-Hodgkin's lymphoma. We found that MCL exhibited abundant intratumor lymphatic vessels. Our results demonstrated that the immunomodulatory drug lenalidomide potently inhibited the growth and dissemination of MCL in a xenograft MCL mouse model, at least in part, by inhibiting functional tumor lymphangiogenesis. Significant numbers of tumor-associated macrophages expressing vascular endothelial growth factor-C were found in both human MCL and mouse MCL xenograft samples. Lenalidomide treatment resulted in a significant reduction in the number of MCL-associated macrophages. In addition, in vivo depletion of monocytes/macrophages impaired functional tumor lymphangiogenesis and inhibited MCL growth and dissemination. Taken together, our results indicate that tumor lymphangiogenesis contributes to the progression of MCL and that lenalidomide is effective in decreasing MCL growth and metastasis most likely by inhibiting recruitment of MCL-associated macrophages. Cancer Res; 73(24); 7254–64. ©2013 AACR.
Data from SOX2 Expression Associates with Stem Cell State in Human Ovarian Carcinoma
Authors: Bareiss Petra M. , Paczulla Anna , Wang Hui , Schairer Rebekka , Wiehr Stefan , Kohlhofer Ursula , Rothfuss Oliver C. , Fischer Anna , Perner Sven , Staebler Annette , Wallwiener Diethelm , Fend Falko , Fehm Tanja , Pichler Bernd , Kanz Lothar , Quintanilla-Martinez Leticia , Schulze-Osthoff Klaus , Essmann Frank , Lengerke Claudia
Published: March 2024

Abstract
The SRY-related HMG-box family of transcription factors member SOX2 regulates stemness and pluripotency in embryonic stem cells and plays important roles during early embryogenesis. More recently, SOX2 expression was documented in several tumor types including ovarian carcinoma, suggesting an involvement of SOX2 in regulation of cancer stem cells (CSC). Intriguingly, however, studies exploring the predictive value of SOX2 protein expression with respect to histopathologic and clinical parameters report contradictory results in individual tumors, indicating that SOX2 may play tumor-specific roles. In this report, we analyze the functional relevance of SOX2 expression in human ovarian carcinoma. We report that in human serous ovarian carcinoma (SOC) cells, SOX2 expression increases the expression of CSC markers, the potential to form tumor spheres, and the in vivo tumor-initiating capacity, while leaving cellular proliferation unaltered. Moreover, SOX2-expressing cells display enhanced apoptosis resistance in response to conventional chemotherapies and TRAIL. Hence, our data show that SOX2 associates with stem cell state in ovarian carcinoma and induction of SOX2 imposes CSC properties on SOC cells. We propose the existence of SOX2-expressing ovarian CSCs as a mechanism of tumor aggressiveness and therapy resistance in human SOC. Cancer Res; 73(17); 5544–55. ©2013 AACR.
Data from MYC Phosphorylation at Novel Regulatory Regions Suppresses Transforming Activity
Authors: Wasylishen Amanda R. , Chan-Seng-Yue Michelle , Bros Christina , Dingar Dharmendra , Tu William B. , Kalkat Manpreet , Chan Pak-Kei , Mullen Peter J. , Huang Ling , Meyer Natalie , Raught Brian , Boutros Paul C. , Penn Linda Z.
Published: March 2024

Abstract
Despite its central role in human cancer, MYC deregulation is insufficient by itself to transform cells. Because inherent mechanisms of neoplastic control prevent precancerous lesions from becoming fully malignant, identifying transforming alleles of MYC that bypass such controls may provide fundamental insights into tumorigenesis. To date, the only activated allele of MYC known is T58A, the study of which led to identification of the tumor suppressor FBXW7 and its regulator USP28 as a novel therapeutic target. In this study, we screened a panel of MYC phosphorylation mutants for their ability to promote anchorage-independent colony growth of human MCF10A mammary epithelial cells, identifying S71A/S81A and T343A/S344A/S347A/S348A as more potent oncogenic mutants compared with wild-type (WT) MYC. The increased cell-transforming activity of these mutants was confirmed in SH-EP neuroblastoma cells and in three-dimensional MCF10A acini. Mechanistic investigations initiated by a genome-wide mRNA expression analysis of MCF10A acini identified 158 genes regulated by the mutant MYC alleles, compared with only 112 genes regulated by both WT and mutant alleles. Transcriptional gain-of-function was a common feature of the mutant alleles, with many additional genes uniquely dysregulated by individual mutant. Our work identifies novel sites of negative regulation in MYC and thus new sites for its therapeutic attack. Cancer Res; 73(21); 6504–15. ©2013 AACR.
Data from Histone Demethylase RBP2 Promotes Lung Tumorigenesis and Cancer Metastasis
Authors: Teng Yu-Ching , Lee Cheng-Feng , Li Ying-Shiuan , Chen Yi-Ren , Hsiao Pei-Wen , Chan Meng-Yu , Lin Feng-Mao , Huang Hsien-Da , Chen Yen-Ting , Jeng Yung-Ming , Hsu Chih-Hung , Yan Qin , Tsai Ming-Daw , Juan Li-Jung
Published: March 2024

Abstract
The retinoblastoma binding protein RBP2 (KDM5A) is a histone demethylase that promotes gastric cancer cell growth and is enriched in drug-resistant lung cancer cells. In tumor-prone mice lacking the tumor suppressor gene RB or MEN1, genetic ablation of RBP2 can suppress tumor initiation, but the pathogenic breadth and mechanistic aspects of this effect relative to human tumors have not been defined. Here, we approached this question in the context of lung cancer. RBP2 was overexpressed in human lung cancer tissues where its depletion impaired cell proliferation, motility, migration, invasion, and metastasis. RBP2 oncogenicity relied on its demethylase and DNA-binding activities. RBP2 upregulated expression of cyclins D1 and E1 while suppressing the expression of cyclin-dependent kinase inhibitor p27 (CDKN1B), each contributing to RBP2-mediated cell proliferation. Expression microarray analyses revealed that RBP2 promoted expression of integrin-β1 (ITGB1), which is implicated in lung cancer metastasis. Mechanistic investigations established that RBP2 bound directly to the p27, cyclin D1, and ITGB1 promoters and that exogenous expression of cyclin D1, cyclin E1, or ITGB1 was sufficient to rescue proliferation or migration/invasion, respectively. Taken together, our results establish an oncogenic role for RBP2 in lung tumorigenesis and progression and uncover novel RBP2 targets mediating this role. Cancer Res; 73(15); 4711–21. ©2013 AACR.
Data from EYA1 Phosphatase Function Is Essential to Drive Breast Cancer Cell Proliferation through Cyclin D1
Authors: Wu Kongming , Li Zhaoming , Cai Shaoxin , Tian Lifeng , Chen Ke , Wang Jing , Hu Junbo , Sun Ye , Li Xue , Ertel Adam , Pestell Richard G.
Published: March 2024

Abstract
The Drosophila Eyes Absent Homologue 1 (EYA1) is a component of the retinal determination gene network and serves as an H2AX phosphatase. The cyclin D1 gene encodes the regulatory subunits of a holoenzyme that phosphorylates and inactivates the pRb protein. Herein, comparison with normal breast showed that EYA1 is overexpressed with cyclin D1 in luminal B breast cancer subtype. EYA1 enhanced breast tumor growth in mice in vivo, requiring the phosphatase domain. EYA1 enhanced cellular proliferation, inhibited apoptosis, and induced contact-independent growth and cyclin D1 abundance. The induction of cellular proliferation and cyclin D1 abundance, but not apoptosis, was dependent upon the EYA1 phosphatase domain. The EYA1-mediated transcriptional induction of cyclin D1 occurred via the AP-1–binding site at −953 and required the EYA1 phosphatase function. The AP-1 mutation did not affect SIX1-dependent activation of cyclin D1. EYA1 was recruited in the context of local chromatin to the cyclin D1 AP-1 site. The EYA1 phosphatase function determined the recruitment of CBP, RNA polymerase II, and acetylation of H3K9 at the cyclin D1 gene AP-1 site regulatory region in the context of local chromatin. The EYA1 phosphatase regulates cell-cycle control via transcriptional complex formation at the cyclin D1 promoter. Cancer Res; 73(14); 4488–99. ©2013 AACR.
Data from APOBEC3B Upregulation and Genomic Mutation Patterns in Serous Ovarian Carcinoma
Authors: Leonard Brandon , Hart Steven N. , Burns Michael B. , Carpenter Michael A. , Temiz Nuri A. , Rathore Anurag , Vogel Rachel I. , Nikas Jason B. , Law Emily K. , Brown William L. , Li Ying , Zhang Yuji , Maurer Matthew J. , Oberg Ann L. , Cunningham Julie M. , Shridhar Viji , Bell Debra A. , April Craig , Bentley David , Bibikova Marina , Cheetham R. Keira , Fan Jian-Bing , Grocock Russell , Humphray Sean , Kingsbury Zoya , Peden John , Chien Jeremy , Swisher Elizabeth M. , Hartmann Lynn C. , Kalli Kimberly R. , Goode Ellen L. , Sicotte Hugues , Kaufmann Scott H. , Harris Reuben S.
Published: March 2024

Abstract
Ovarian cancer is a clinically and molecularly heterogeneous disease. The driving forces behind this variability are unknown. Here, we report wide variation in the expression of the DNA cytosine deaminase APOBEC3B, with elevated expression in the majority of ovarian cancer cell lines (three SDs above the mean of normal ovarian surface epithelial cells) and high-grade primary ovarian cancers. APOBEC3B is active in the nucleus of several ovarian cancer cell lines and elicits a biochemical preference for deamination of cytosines in 5′-TC dinucleotides. Importantly, examination of whole-genome sequence from 16 ovarian cancers reveals that APOBEC3B expression correlates with total mutation load as well as elevated levels of transversion mutations. In particular, high APOBEC3B expression correlates with C-to-A and C-to-G transversion mutations within 5′-TC dinucleotide motifs in early-stage high-grade serous ovarian cancer genomes, suggesting that APOBEC3B-catalyzed genomic uracil lesions are further processed by downstream DNA "repair" enzymes including error-prone translesion polymerases. These data identify a potential role for APOBEC3B in serous ovarian cancer genomic instability. Cancer Res; 73(24); 7222–31. ©2013 AACR.
Data from Disruption of Wild-Type IDH1 Suppresses D-2-Hydroxyglutarate Production in IDH1-Mutated Gliomas
Authors: Jin Genglin , Reitman Zachary J. , Duncan Christopher G. , Spasojevic Ivan , Gooden David M. , Rasheed B. Ahmed , Yang Rui , Lopez Giselle Y. , He Yiping , McLendon Roger E. , Bigner Darell D. , Yan Hai
Published: March 2024

Abstract
Point mutations at Arg132 of the cytoplasmic NADP+-dependent isocitrate dehydrogenase 1 (IDH1) occur frequently in gliomas and result in a gain of function to produce the “oncometabolite” D-2-hydroxyglutarate (D-2HG). The mutated IDH1 allele is usually associated with a wild-type IDH1 allele (heterozygous) in cancer. Here, we identify 2 gliomas that underwent loss of the wild-type IDH1 allele but retained the mutant IDH1 allele following tumor progression from World Health Organization (WHO) grade III anaplastic astrocytomas to WHO grade IV glioblastomas. Intratumoral D-2HG was 14-fold lower in the glioblastomas lacking wild-type IDH1 than in glioblastomas with heterozygous IDH1 mutations. To characterize the contribution of wild-type IDH1 to cancer cell D-2HG production, we established an IDH1-mutated astrocytoma (IMA) cell line from a WHO grade III anaplastic astrocytoma. Disruption of the wild-type IDH1 allele in IMA cells by gene targeting resulted in an 87-fold decrease in cellular D-2HG levels, showing that both wild-type and mutant IDH1 alleles are required for D-2HG production in glioma cells. Expression of wild-type IDH1 was also critical for mutant IDH1-associated D-2HG production in the colorectal cancer cell line HCT116. These insights may aid in the development of therapeutic strategies to target IDH1-mutated cancers. Cancer Res; 73(2); 496–501. ©2012 AACR.
Data from Dysregulated Expression of FOXM1 Isoforms Drives Progression of Pancreatic Cancer
Authors: Kong Xiangyu , Li Lei , Li Zhaoshen , Le Xiangdong , Huang Chen , Jia Zhiliang , Cui Jiujie , Huang Suyun , Wang Liwei , Xie Keping
Published: March 2024

Abstract
The transcription factor Forkhead box M1 (FOXM1) plays important roles in oncogenesis. However, the expression statuses of FOXM1 isoforms and their impact on and molecular basis in oncogenesis are unknown. We sought to determine the identities of FOXM1 isoforms in and the impact of their expression on pancreatic cancer development and progression using human tissues, cell lines, and animal models. Overexpression of FOXM1 mRNA and protein was pronounced in human pancreatic tumors and cancer cell lines. We identified five FOXM1 isoforms present in pancreatic cancer: FOXM1a, FOXM1b, and FOXM1c along with two isoforms tentatively designated as FOXM1b1 and FOXM1b2 because they were closely related to FOXM1b. Interestingly, FOXM1c was predominantly expressed in pancreatic tumors and cancer cell lines, whereas FOXM1a expression was generally undetectable in them. Functional analysis revealed that FOXM1b, FOXM1b1, FOXM1b2, and FOXM1c, but not FOXM1a, promoted pancreatic tumor growth and metastasis. Consistently, FOXM1b, FOXM1b1, FOXM1b2, and FOXM1c activated transcription of their typical downstream genes. Also, Sp1 mechanistically activated the FOXM1 promoter, whereas Krüppel-like factor 4 (KLF4) repressed its activity. Finally, we identified an Sp1- and KLF4-binding site in the FOXM1 promoter and showed that both Sp1 and KLF4 protein bound directly to it. Deletion mutation of this binding site significantly attenuated the transcriptional regulation of the FOXM1 promoter positively by Sp1 and negatively by KLF4. We showed that overexpression of specific FOXM1 isoforms critically regulates pancreatic cancer development and progression by enhancing tumor cell invasion and metastasis. Our findings strongly suggest that targeting specific FOXM1 isoforms effectively attenuates pancreatic cancer development and progression. Cancer Res; 73(13); 3987–96. ©2013 AACR.
Data from Targeting Truncated Retinoid X Receptor-α by CF31 Induces TNF-α–Dependent Apoptosis
Authors: Wang Guang-Hui , Jiang Fu-Quan , Duan Ying-Hui , Zeng Zhi-Ping , Chen Fan , Dai Yi , Chen Jie-Bo , Liu Jin-Xing , Liu Jie , Zhou Hu , Chen Hai-Feng , Zeng Jin-Zhang , Su Ying , Yao Xin-Sheng , Zhang Xiao-Kun
Published: March 2024

Abstract
A truncated version of retinoid X receptor-α, tRXR-α, promotes cancer cell survival by activating the phosphoinositide 3-kinase (PI3K)/AKT pathway. However, targeting the tRXR-α–mediated survival pathway for cancer treatment remains to be explored. We report here our identification of a new natural product molecule, CF31, a xanthone isolated from Cratoxylum formosum ssp. pruniflorum, and the biologic evaluation of its regulation of the tRXR-α–mediated PI3K/AKT pathway. CF31 binds RXR-α and its binding results in inhibition of RXR-α transactivation. Through RXR-α mutational analysis and computational studies, we show that Arg316 of RXR-α, known to form salt bridges with certain RXR-α ligands, such as 9-cis-retinoic acid (9-cis-RA), is not required for the antagonist effect of CF31, showing a distinct binding mode. Evaluation of several CF31 analogs suggests that the antagonist effect is mainly attributed to an interference with Leu451 of helix H12 in RXR-α. CF31 is a potent inhibitor of AKT activation in various cancer cell lines. When combined with TNF-α, it suppresses TNF-α activation of AKT by inhibiting TNF-α–induced tRXR-α interaction with the p85α regulatory subunit of PI3K. CF31 inhibition of TNF-α activation of AKT also results in TNF-α–dependent activation of caspase-8 and apoptosis. Together, our results show that CF31 is an effective converter of TNF-α signaling from survival to death by targeting tRXR-α in a unique mode and suggest that identification of a natural product that targets an RXR-mediated cell survival pathway that regulates PI3K/AKT may offer a new therapeutic strategy to kill cancer cells. Cancer Res; 73(1); 307–18. ©2012 AACR.
Data from Stress-Response Protein RBM3 Attenuates the Stem-like Properties of Prostate Cancer Cells by Interfering with CD44 Variant Splicing
Authors: Zeng Yu , Wodzenski Dana , Gao Dong , Shiraishi Takumi , Terada Naoki , Li Youqiang , Vander Griend Donald J. , Luo Jun , Kong Chuize , Getzenberg Robert H. , Kulkarni Prakash
Published: March 2024

Abstract
Stress-response pathways play an important role in cancer. The cold-inducible RNA-binding protein RBM3 is upregulated in several types of cancer, including prostate cancer, but its pathogenic contributions are undetermined. RBM3 is expressed at low basal levels in human fetal prostate or in CD133+ prostate epithelial cells (PrEC), compared with the adult prostate or CD133-PrEC, and RBM3 is downregulated in cells cultured in soft agar or exposed to stress. Notably, RBM3 overexpression in prostate cancer cells attenuated their stem cell-like properties in vitro as well as their tumorigenic potential in vivo. Interestingly, either overexpressing RBM3 or culturing cells at 32°C suppressed RNA splicing of the CD44 variant v8-v10 and increased expression of the standard CD44 (CD44s) isoform. Conversely, silencing RBM3 or culturing cells in soft agar (under conditions that enrich for stem cell-like cells) increased the ratio of CD44v8-v10 to CD44s mRNA. Mechanistic investigations showed that elevating CD44v8-v10 interfered with MMP9-mediated cleavage of CD44s and suppressed expression of cyclin D1, whereas siRNA-mediated silencing of CD44v8-v10 impaired the ability of prostate cancer cells to form colonies in soft agar. Together, these findings suggested that RBM3 contributed to stem cell-like character in prostate cancer by inhibiting CD44v8-v10 splicing. Our work uncovers a hitherto unappreciated role of RBM3 in linking stress-regulated RNA splicing to tumorigenesis, with potential prognostic and therapeutic implications in prostate cancer. Cancer Res; 73(13); 4123–33. ©2013 AACR.
Data from Neuropilin-2 Promotes Extravasation and Metastasis by Interacting with Endothelial α5 Integrin
Authors: Cao Ying , Hoeppner Luke H. , Bach Steven , E Guangqi , Guo Yan , Wang Enfeng , Wu Jianmin , Cowley Mark J. , Chang David K. , Waddell Nicola , Grimmond Sean M. , Biankin Andrew V. , Daly Roger J. , Zhang Xiaohui , Mukhopadhyay Debabrata
Published: March 2024

Abstract
Metastasis, the leading cause of cancer death, requires tumor cell intravasation, migration through the bloodstream, arrest within capillaries, and extravasation to invade distant tissues. Few mechanistic details have been reported thus far regarding the extravasation process or re-entry of circulating tumor cells at metastatic sites. Here, we show that neuropilin-2 (NRP-2), a multifunctional nonkinase receptor for semaphorins, vascular endothelial growth factor (VEGF), and other growth factors, expressed on cancer cells interacts with α5 integrin on endothelial cells to mediate vascular extravasation and metastasis in zebrafish and murine xenograft models of clear cell renal cell carcinoma (RCC) and pancreatic adenocarcinoma. In tissue from patients with RCC, NRP-2 expression is positively correlated with tumor grade and is highest in metastatic tumors. In a prospectively acquired cohort of patients with pancreatic cancer, high NRP-2 expression cosegregated with poor prognosis. Through biochemical approaches as well as Atomic Force Microscopy (AFM), we describe a unique mechanism through which NRP-2 expressed on cancer cells interacts with α5 integrin on endothelial cells to mediate vascular adhesion and extravasation. Taken together, our studies reveal a clinically significant role of NRP-2 in cancer cell extravasation and promotion of metastasis. Cancer Res; 73(14); 4579–90. ©2013 AACR.
Data from Evidence for a Role of the PD-1:PD-L1 Pathway in Immune Resistance of HPV-Associated Head and Neck Squamous Cell Carcinoma
Authors: Lyford-Pike Sofia , Peng Shiwen , Young Geoffrey D. , Taube Janis M. , Westra William H. , Akpeng Belinda , Bruno Tullia C. , Richmon Jeremy D. , Wang Hao , Bishop Justin A. , Chen Lieping , Drake Charles G. , Topalian Suzanne L. , Pardoll Drew M. , Pai Sara I.
Published: March 2024

Abstract
Human papillomavirus-associated head and neck squamous cell carcinomas (HPV-HNSCC) originate in the tonsils, the major lymphoid organ that orchestrates immunity to oral infections. Despite its location, the virus escapes immune elimination during malignant transformation and progression. Here, we provide evidence for the role of the PD-1:PD-L1 pathway in HPV-HNSCC immune resistance. We show membranous expression of PD-L1 in the tonsillar crypts, the site of initial HPV infection. In HPV-HNSCCs that are highly infiltrated with lymphocytes, PD-L1 expression on both tumor cells and CD68+ tumor-associated macrophages is geographically localized to sites of lymphocyte fronts, whereas the majority of CD8+ tumor-infiltrating lymphocytes express high levels of PD-1, the inhibitory PD-L1 receptor. Significant levels of mRNA for IFN-γ, a major cytokine inducer of PD-L1 expression, were found in HPV+ PD-L1(+) tumors. Our findings support the role of the PD-1:PD-L1 interaction in creating an “immune-privileged” site for initial viral infection and subsequent adaptive immune resistance once tumors are established and suggest a rationale for therapeutic blockade of this pathway in patients with HPV-HNSCC. Cancer Res; 73(6); 1733–41. ©2012 AACR.
Data from DNA Methylation-Mediated Repression of miR-886-3p Predicts Poor Outcome of Human Small Cell Lung Cancer
Authors: Cao Jianzhong , Song Yongmei , Bi Nan , Shen Jie , Liu Wenyang , Fan Jing , Sun Guogui , Tong Tong , He Jie , Shi Yuankai , Zhang Xun , Lu Ning , He Yinghua , Zhang Hongyu , Ma Kelong , Luo Xiaoying , Lv Lei , Deng Hui , Cheng Jing , Zhu Jingde , Wang Luhua , Zhan Qimin
Published: March 2024

Abstract
Small cell lung cancer (SCLC) is one of the most aggressive types of cancer, yet the pathologic mechanisms underlying its devastating clinical outcome remain elusive. In this report, we surveyed 924 miRNA (miR) for their expressions in the formalin-fixed paraffin-embedded specimens from 42 patients with SCLC, and found that the downregulated miR-886-3p is closely correlated with the shorter survival of SCLC. This correlation was validated with another 40 cases. It was further discovered that loss of miR-886-3p expression was mediated by DNA hypermethylation of its promoter in both cultured SCLC cells and tumor samples. Moreover, miR-886-3p potently repressed cell proliferation, migration, and invasion of NCI-H446 cell in cell culture via suppression of the expression of its target genes: PLK1 and TGF-β1 at posttranscription levels. Forced upregulation of miR-886-3p greatly inhibited in vivo tumor growth, bone/muscle invasion, and lung metastasis of NCI-H446 cells. This newly identified miR-886-3p-PLK1/TGF-β1 nexus that modulates SCLC aggression suggests that both loss of miR-886-3p expression and hypermethylation of the miR-886 promoter are the promising indicators for poor outcome of as well as new therapeutic targets for SCLC. Cancer Res; 73(11); 3326–35. ©2013 AACR.
Data from PPARδ Induces Estrogen Receptor-Positive Mammary Neoplasia through an Inflammatory and Metabolic Phenotype Linked to mTOR Activation
Authors: Yuan Hongyan , Lu Jin , Xiao Junfeng , Upadhyay Geeta , Umans Rachel , Kallakury Bhaskar , Yin Yuhzi , Fant Michael E. , Kopelovich Levy , Glazer Robert I.
Published: March 2024

Abstract
The peroxisome proliferator-activated receptor-δ (PPARδ) regulates a multitude of physiological processes associated with glucose and lipid metabolism, inflammation, and proliferation. One or more of these processes are potential risk factors for the ability of PPARδ agonists to promote tumorigenesis in the mammary gland. In this study, we describe a new transgenic mouse model in which activation of PPARδ in the mammary epithelium by endogenous or synthetic ligands resulted in progressive histopathologic changes that culminated in the appearance of estrogen receptor- and progesterone receptor-positive and ErbB2-negative infiltrating ductal carcinomas. Multiparous mice presented with mammary carcinomas after a latency of 12 months, and administration of the PPARδ ligand GW501516 reduced tumor latency to 5 months. Histopathologic changes occurred concurrently with an increase in an inflammatory, invasive, metabolic, and proliferative gene signature, including expression of the trophoblast gene, Plac1, beginning 1 week after GW501516 treatment, and remained elevated throughout tumorigenesis. The appearance of malignant changes correlated with a pronounced increase in phosphatidylcholine and lysophosphatidic acid metabolites, which coincided with activation of Akt and mTOR signaling that were attenuated by treatment with the mTOR inhibitor everolimus. Our findings are the first to show a direct role of PPARδ in the pathogenesis of mammary tumorigenesis, and suggest a rationale for therapeutic approaches to prevent and treat this disease. Cancer Res; 73(14); 4349–61. ©2013 AACR.
Data from Intestinal Bacteria Modify Lymphoma Incidence and Latency by Affecting Systemic Inflammatory State, Oxidative Stress, and Leukocyte Genotoxicity
Authors: Yamamoto Mitsuko L. , Maier Irene , Dang Angeline Tilly , Berry David , Liu Jared , Ruegger Paul M. , Yang Jiue-in , Soto Phillip A. , Presley Laura L. , Reliene Ramune , Westbrook Aya M. , Wei Bo , Loy Alexander , Chang Christopher , Braun Jonathan , Borneman James , Schiestl Robert H.
Published: March 2024

Abstract
Ataxia-telangiectasia is a genetic disorder associated with high incidence of B-cell lymphoma. Using an ataxia-telangiectasia mouse model, we compared lymphoma incidence in several isogenic mouse colonies harboring different bacterial communities, finding that intestinal microbiota are a major contributor to disease penetrance and latency, lifespan, molecular oxidative stress, and systemic leukocyte genotoxicity. High-throughput sequence analysis of rRNA genes identified mucosa-associated bacterial phylotypes that were colony-specific. Lactobacillus johnsonii, which was deficient in the more cancer-prone mouse colony, was causally tested for its capacity to confer reduced genotoxicity when restored by short-term oral transfer. This intervention decreased systemic genotoxicity, a response associated with reduced basal leukocytes and the cytokine-mediated inflammatory state, and mechanistically linked to the host cell biology of systemic genotoxicity. Our results suggest that intestinal microbiota are a potentially modifiable trait for translational intervention in individuals at risk for B-cell lymphoma, or for other diseases that are driven by genotoxicity or the molecular response to oxidative stress. Cancer Res; 73(14); 4222–32. ©2013 AACR.
Data from FGFR1 Is Essential for Prostate Cancer Progression and Metastasis
Authors: Yang Feng , Zhang Yongyou , Ressler Steven J. , Ittmann Michael M. , Ayala Gustavo E. , Dang Truong D. , Wang Fen , Rowley David R.
Published: March 2024

Abstract
The fibroblast growth factor receptor 1 (FGFR1) is ectopically expressed in prostate carcinoma cells, but its functional contributions are undefined. In this study, we report the evaluation of a tissue-specific conditional deletion mutant generated in an ARR2PBi(Pbsn)-Cre/TRAMP/fgfr1loxP/loxP transgenic mouse model of prostate cancer. Mice lacking fgfr1, in prostate cells developed smaller tumors that also included distinct cancer foci still expressing fgfr1 indicating focal escape from gene excision. Tumors with confirmed fgfr1 deletion exhibited increased foci of early, well-differentiated cancer and phyllodes-type tumors, and tumors that escaped fgfr1 deletion primarily exhibited a poorly differentiated phenotype. Consistent with these phenotypes, mice carrying the fgfr1 null allele survived significantly longer than those without fgfr1 deletion. Most interestingly, all metastases were primarily negative for the fgfr1 null allele, exhibited high FGFR1 expression, and a neuroendocrine phenotype regardless of fgfr1 status in the primary tumors. Together, these results suggest a critical and permissive role of ectopic FGFR1 signaling in prostate tumorigenesis and particularly in mechanisms of metastasis. Cancer Res; 73(12); 3716–24. ©2013 AACR.
Data from Novel Recombinant Human B7-H4 Antibodies Overcome Tumoral Immune Escape to Potentiate T-Cell Antitumor Responses
Authors: Dangaj Denarda , Lanitis Evripidis , Zhao Aizhi , Joshi Shree , Cheng Yi , Sandaltzopoulos Raphael , Ra Hyun-Jeong , Danet-Desnoyers Gwenn , Powell Daniel J. , Scholler Nathalie
Published: March 2024

Abstract
B7-H4 (VTCN1, B7x, B7s) is a ligand for inhibitory coreceptors on T cells implicated in antigenic tolerization. B7-H4 is expressed by tumor cells and tumor-associated macrophages (TAM), but its potential contributions to tumoral immune escape and therapeutic targeting have been less studied. To interrogate B7-H4 expression on tumor cells, we analyzed fresh primary ovarian cancer cells collected from patient ascites and solid tumors, and established cell lines before and after in vivo passaging. B7-H4 expression was detected on the surface of all fresh primary human tumors and tumor xenotransplants, but not on most established cell lines, and B7-H4 was lost rapidly by tumor xenograft cells after short-term in vitro culture. These results indicated an in vivo requirement for B7-H4 induction and defined conditions for targeting studies. To generate anti-B7-H4–targeting reagents, we isolated antibodies by differential cell screening of a yeast-display single-chain fragments variable (scFv) library derived from patients with ovarian cancer. We identified anti-B7-H4 scFv that reversed in vitro inhibition of CD3-stimulated T cells by B7-H4 protein. Notably, these reagents rescued tumor antigen-specific T-cell activation, which was otherwise inhibited by coculture with antigen-loaded B7-H4+ APCs, B7-H4+ tumor cells, or B7-H4- tumor cells mixed with B7-H4+ TAMs; peritoneal administration of anti-B7-H4 scFv delayed the growth of established tumors. Together, our findings showed that cell surface expression of B7-H4 occurs only in tumors in vivo and that antibody binding of B7-H4 could restore antitumor T-cell responses. We suggest that blocking of B7-H4/B7-H4 ligand interactions may represent a feasible therapeutic strategy for ovarian cancer. Cancer Res; 73(15); 4820–9. ©2013 AACR.
Data from Kinetic Modeling–Based Detection of Genetic Signatures That Provide Chemoresistance via the E2F1-p73/DNp73-miR-205 Network
Authors: Vera Julio , Schmitz Ulf , Lai Xin , Engelmann David , Khan Faiz M. , Wolkenhauer Olaf , Pützer Brigitte M.
Published: March 2024

Abstract
Drug resistance is a major cause of deaths from cancer. E2F1 is a transcription factor involved in cell proliferation, apoptosis. and metastasis through an intricate regulatory network, which includes other transcription factors like p73 and cancer-related microRNAs like miR-205. To investigate the emergence of drug resistance, we developed a methodology that integrates experimental data with a network biology and kinetic modeling. Using a regulatory map developed to summarize knowledge on E2F1 and its interplay with p73/DNp73 and miR-205 in cancer drug responses, we derived a kinetic model that represents the network response to certain genotoxic and cytostatic anticancer drugs. By perturbing the model parameters, we simulated heterogeneous cell configurations referred to as in silico cell lines. These were used to detect genetic signatures characteristic for single or double drug resistance. We identified a signature composed of high E2F1 and low miR-205 expression that promotes resistance to genotoxic drugs. In this signature, downregulation of miR-205, can be mediated by an imbalance in the p73/DNp73 ratio or by dysregulation of other cancer-related regulators of miR-205 expression such as TGFβ-1 or TWIST1. In addition, we found that a genetic signature composed of high E2F1, low miR-205, and high ERBB3 can render tumor cells insensitive to both cytostatic and genotoxic drugs. Our model simulations also suggested that conventional genotoxic drug treatment favors selection of chemoresistant cells in genetically heterogeneous tumors, in a manner requiring dysregulation of incoherent feedforward loops that involve E2F1, p73/DNp73, and miR-205. Cancer Res; 73(12); 3511–24. ©2013 AACR.
Data from Identification of Two Distinct Carcinoma-Associated Fibroblast Subtypes with Differential Tumor-Promoting Abilities in Oral Squamous Cell Carcinoma
Authors: Costea Daniela Elena , Hills Allison , Osman Amani H. , Thurlow Johanna , Kalna Gabriela , Huang Xiaohong , Pena Murillo Claudia , Parajuli Himalaya , Suliman Salwa , Kulasekara Keerthi K. , Johannessen Anne Chr. , Partridge Max
Published: March 2024

Abstract
Heterogeneity of carcinoma-associated fibroblasts (CAF) has long been recognized, but the functional significance remains poorly understood. Here, we report the distinction of two CAF subtypes in oral squamous cell carcinoma (OSCC) that have differential tumor-promoting capability, one with a transcriptome and secretome closer to normal fibroblasts (CAF-N) and the other with a more divergent expression pattern (CAF-D). Both subtypes supported higher tumor incidence in nonobese diabetic/severe combined immunodeficient (NOD/SCID) Ilγ2(null) mice and deeper invasion of malignant keratinocytes than normal or dysplasia-associated fibroblasts, but CAF-N was more efficient than CAF-D in enhancing tumor incidence. CAF-N included more intrinsically motile fibroblasts maintained by high autocrine production of hyaluronan. Inhibiting CAF-N migration by blocking hyaluronan synthesis or chain elongation impaired invasion of adjacent OSCC cells, pinpointing fibroblast motility as an essential mechanism in this process. In contrast, CAF-D harbored fewer motile fibroblasts but synthesized higher TGF-β1 levels. TGF-β1 did not stimulate CAF-D migration but enhanced invasion and expression of epithelial–mesenchymal transition (EMT) markers in malignant keratinocytes. Inhibiting TGF-β1 in three-dimensional cultures containing CAF-D impaired keratinocyte invasion, suggesting TGF-β1–induced EMT mediates CAF-D–induced carcinoma cell invasion. TGF-β1–pretreated normal fibroblasts also induced invasive properties in transformed oral keratinocytes, indicating that TGF-β1–synthesizing fibroblasts, as well as hyaluronan-synthesizing fibroblasts, are critical for carcinoma invasion. Taken together, these results discern two subtypes of CAF that promote OSCC cell invasion via different mechanisms. Cancer Res; 73(13); 3888–901. ©2013 AACR.
Data from Trop-2 Promotes Prostate Cancer Metastasis By Modulating β1 Integrin Functions
Authors: Trerotola Marco , Jernigan Danielle L. , Liu Qin , Siddiqui Javed , Fatatis Alessandro , Languino Lucia R.
Published: March 2024

Abstract
The molecular mechanisms underlying metastatic dissemination are still not completely understood. We have recently shown that β1 integrin-dependent cell adhesion to fibronectin and signaling is affected by a transmembrane molecule, Trop-2, which is frequently upregulated in human carcinomas. Here, we report that Trop-2 promotes metastatic dissemination of prostate cancer cells in vivo and is abundantly expressed in metastasis from human prostate cancer. We also show here that Trop-2 promotes prostate cancer cell migration on fibronectin, a phenomenon dependent on β1 integrins. Mechanistically, we demonstrate that Trop-2 and the α5β1 integrin associate through their extracellular domains, causing relocalization of α5β1 and the β1-associated molecule talin from focal adhesions to the leading edges. Trop-2 effect is specific as this molecule does not modulate migration on vitronectin, does not associate with the major vitronectin receptor, αvβ3 integrin, and does not affect localization of αvβ3 integrin as well as vinculin in focal adhesions. We show that Trop-2 enhances directional prostate cancer cell migration, through modulation of Rac1 GTPase activity. Finally, we show that Trop-2 induces activation of PAK4, a kinase that has been reported to mediate cancer cell migration. In conclusion, we provide the first evidence that β1 integrin-dependent migratory and metastatic competence of prostate cancer cells is enhanced by Trop-2. Cancer Res; 73(10); 3155–67. ©2013 AACR.