bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Macrophage Expression of Hypoxia-Inducible Factor-1α Suppresses T-Cell Function and Promotes Tumor Progression
Authors: Doedens Andrew L. , Stockmann Christian , Rubinstein Mark P. , Liao Debbie , Zhang Na , DeNardo David G. , Coussens Lisa M. , Karin Michael , Goldrath Ananda W. , Johnson Randall S.
Published: March 2023

Abstract
T cells can inhibit tumor growth, but their function in the tumor microenvironment is often suppressed. Many solid tumors exhibit abundant macrophage infiltration and low oxygen tension, yet how hypoxic conditions may affect innate immune cells and their role in tumor progression is poorly understood. Targeted deletion of the hypoxia-responsive transcription factor hypoxia-inducible factor-1α (HIF-1α) in macrophages in a progressive murine model of breast cancer resulted in reduced tumor growth, although vascular endothelial growth factor-A levels and vascularization were unchanged. Tumor-associated macrophages can suppress tumor-infiltrating T cells by several mechanisms, and we found that hypoxia powerfully augmented macrophage-mediated T-cell suppression in vitro in a manner dependent on macrophage expression of HIF-1α. Our findings link the innate immune hypoxic response to tumor progression through induction of T-cell suppression in the tumor microenvironment. Cancer Res; 70(19); 7465–75. ©2010 AACR.
Data from Characterization of Phosphoglycerate Kinase-1 Expression of Stromal Cells Derived from Tumor Microenvironment in Prostate Cancer Progression
Authors: Wang Jianhua , Ying Gigi , Wang Jingchen , Jung Younghun , Lu Jian , Zhu Jiang , Pienta Kenneth J. , Taichman Russell S.
Published: March 2023

Abstract
Tumor and stromal interactions in the tumor microenvironment are critical for oncogenesis and cancer progression. Our understanding of the molecular events by which reactive stromal fibroblasts—myofibroblast or cancer-associated fibroblasts (CAF)—affect the growth and invasion of prostate cancer remains unclear. Laser capture microdissection and cDNA microarray analysis of CAFs in prostate tumors revealed strong upregulation of phosphoglycerate kinase-1 (PGK1), an ATP-generating glycolytic enzyme that forms part of the glycolytic pathway and is directly involved in CXCL12-CXCR4 signaling. Normal fibroblasts overexpressing PGK1 resembled myofibroblasts in their expression of smooth muscle α-actin, vimentin, and high levels of CXCL12. These cells also displayed a higher proliferative index and the capability to contribute to prostate tumor cell invasion in vitro, possibly through expression of MMP-2 and MMP-3 and activation of the AKT and ERK pathways. Coimplantation of PGK1-overexpressing fibroblasts with prostate tumor cells promoted tumor cell growth in vivo. Collectively, these observations suggest that PGK1 helps support the interactions between cancer and its microenvironment. Cancer Res; 70(2); 471–80
Data from Aldehyde Dehydrogenase Activity Selects for Lung Adenocarcinoma Stem Cells Dependent on Notch Signaling
Authors: Sullivan James P. , Spinola Monica , Dodge Michael , Raso Maria G. , Behrens Carmen , Gao Boning , Schuster Katja , Shao Chunli , Larsen Jill E. , Sullivan Laura A. , Honorio Sofia , Xie Yang , Scaglioni Pier P. , DiMaio J. Michael , Gazdar Adi F. , Shay Jerry W. , Wistuba Ignacio I. , Minna John D.
Published: March 2023

Abstract
Aldehyde dehydrogenase (ALDH) is a candidate marker for lung cancer cells with stem cell-like properties. Immunohistochemical staining of a large panel of primary non–small cell lung cancer (NSCLC) samples for ALDH1A1, ALDH3A1, and CD133 revealed a significant correlation between ALDH1A1 (but not ALDH3A1 or CD133) expression and poor prognosis in patients including those with stage I and N0 disease. Flow cytometric analysis of a panel of lung cancer cell lines and patient tumors revealed that most NSCLCs contain a subpopulation of cells with elevated ALDH activity, and that this activity is associated with ALDH1A1 expression. Isolated ALDH+ lung cancer cells were observed to be highly tumorigenic and clonogenic as well as capable of self-renewal compared with their ALDH− counterparts. Expression analysis of sorted cells revealed elevated Notch pathway transcript expression in ALDH+ cells. Suppression of the Notch pathway by treatment with either a γ-secretase inhibitor or stable expression of shRNA against NOTCH3 resulted in a significant decrease in ALDH+ lung cancer cells, commensurate with a reduction in tumor cell proliferation and clonogenicity. Taken together, these findings indicate that ALDH selects for a subpopulation of self-renewing NSCLC stem-like cells with increased tumorigenic potential, that NSCLCs harboring tumor cells with ALDH1A1 expression have inferior prognosis, and that ALDH1A1 and CD133 identify different tumor subpopulations. Therapeutic targeting of the Notch pathway reduces this ALDH+ component, implicating Notch signaling in lung cancer stem cell maintenance. Cancer Res; 70(23); 9937–48. ©2010 AACR.
Data from Dual Functional Monoclonal Antibody PF-04605412 Targets Integrin α5β1 and Elicits Potent Antibody-Dependent Cellular Cytotoxicity
Authors: Li Gang , Zhang Lianglin , Chen Enhong , Wang Jianying , Jiang Xin , Chen Jeffrey H. , Wickman Grant , Amundson Karin , Bergqvist Simon , Zobel James , Buckman Dana , Baxi Sangita M. , Bender Steven L. , Casperson Gerald F. , Hu-Lowe Dana D.
Published: March 2023

Abstract
Integrin α5β1 is overexpressed in tumor-associated stroma and cancer cells, and has been implicated in angiogenesis, tumor survival, and metastasis. Antibody-dependent cellular cytotoxicity (ADCC) by immune effector cells has been shown to contribute to clinical efficacy for several IgG1 monoclonal antibody (mAb) therapeutics. Taking advantage of these two mechanisms, we generated a fully human, fragment crystalizable (Fc)-engineered IgG1 mAb, PF-04605412 (PF-5412), which specifically neutralizes α5 and binds the Fcγ receptors (FcγR) with enhanced affinity. In vitro, PF-5412 potently inhibited α5β1-mediated intracellular signaling, cell adhesion, migration, and endothelial cell (EC) tubulogenesis. PF-5412 induced significantly greater ADCC in α5-expressing tumor cells and ECs compared with a wild-type IgG1 (IgG1/wt) or IgG2 of identical antigen specificity. The degree of ADCC correlated with the abundance of natural killer (NK) cells in the peripheral blood mononuclear cells but was independent of donor FcγRIIIa polymorphism. In animal studies, PF-5412 displayed robust and dose-dependent antitumor efficacy superior to that observed with IgG1/wt, IgG2, or IgG4 of identical antigen specificity. The degree of efficacy correlated with α5 expression, macrophage and NK cell infiltration, and NK activity in the tumor. Depletion of host macrophages abrogated antitumor activity, suggesting a critical contribution of macrophage-mediated antitumor activity of PF-5412. Combination of PF-5412 with sunitinib significantly improved antitumor efficacy compared with either agent alone. The dual mechanism of action and robust antitumor efficacy of PF-5412 support its clinical development for the treatment of a broad spectrum of human malignancies. Cancer Res; 70(24); 10243–54. ©2010 AACR.
Data from Definition of a Functional Single Nucleotide Polymorphism in the Cell Migration Inhibitory Gene MIIP That Affects the Risk of Breast Cancer
Authors: Song Fangfang , Ji Ping , Zheng Hong , Song Fengju , Wang Yingmei , Hao Xishan , Wei Qingyi , Zhang Wei , Chen Kexin
Published: March 2023

Abstract
The migration and invasion inhibitory protein MIIP is an inhibitor of cancer cell migration and invasion that inhibits breast tumorigenesis. In this case-control study, we evaluated the MIIP single nucleotide polymorphism (SNP) rs2295283 (codon 167, A>G, K>E) from 1,524 breast cancer patients and 1,592 age-matched controls for its association with breast cancer risk. SNP analysis included a validation set of 736 cases and 760 controls. Colony formation and cell migration assays were then conducted to functionally interrogate the genotype difference. When compared with the AA genotype, the combined AG + GG genotypes (167E) were associated with a significantly lower risk of breast cancer. In the test set, the protective effects of the AG + GG genotypes were more evident among participants with a family history of cancer. Further case series analysis revealed that the GG genotype was associated with reduced breast cancer susceptibility in cases of tumor size >2 cm and late clinical stage (II + III + IV). Colony formation assays showed that MIIP 167E (the G variant) was a more potent inhibitor of colony formation but not cell migration. These results suggest MIIP K167E as a functional genetic marker of breast cancer development and prognosis. Cancer Res; 70(3); 1024–32
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 2023

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 Antiangiogenesis Enhances Intratumoral Drug Retention
Authors: Ma Jie , Chen Chong-Sheng , Blute Todd , Waxman David J.
Published: March 2023

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 Cancer Immunotherapy Using a Bispecific NK Receptor Fusion Protein that Engages both T Cells and Tumor Cells
Authors: Zhang Tong , Sentman Charles L.
Published: March 2023

Abstract
T-cell immunotherapy is a promising strategy to treat cancer, but its efficacy, complexity, and costs may pose challenges. In this study, we report the results of an investigation of a new approach to selectively activate a T-cell attack against tumor cells. The immunotherapeutic approach we developed utilizes a bifunctional fusion protein that binds tumor cells through NK (natural killer)–activating receptor NKG2D and that recruits and stimulates T cells through an anti-CD3 single-chain variable fragment (scFv-NKG2D). In vitro, this scFv-NKG2D fusion protein engaged both T cells and tumor cells, stimulating T cells to produce IFN-γ, and cytotoxicity against NKG2D ligand–positive tumor cells. In vivo, expression of scFv-NKG2D by NKG2D ligand–positive tumor cells reduced tumor burden and, in some cases, led to tumor-free survival. Administration of scFv-NKG2D in vivo also promoted survival in a murine lymphoma model. Tumor-free mice were resistant to rechallenge with cognate tumor cells, suggesting that a host-specific immunologic memory response had been generated. Host adaptive immunity including γδ T cells was required for scFv-NKG2D–mediated therapeutic efficacy. ScFv-NKG2D also inhibited the growth of NKG2D ligand–negative B16F10 tumors, reduced the percentage of myeloid-derived suppressor cells and regulatory T cells, and increased the infiltration of T cells, suggesting that scFv-NKG2D may target these immune suppressive cells. Together, these results establish scFv-NKG2D as a promising biological fusion protein to induce effective antitumor immunity. Cancer Res; 71(6); 2066–76. ©2011 AACR.
Data from Detection of Circulating Tumor Cells in Human Peripheral Blood Using Surface-Enhanced Raman Scattering Nanoparticles
Authors: Wang Xu , Qian Ximei , Beitler Jonathan J. , Chen Zhuo Georgia , Khuri Fadlo R. , Lewis Melinda M. , Shin Hyung Ju C. , Nie Shuming , Shin Dong M.
Published: March 2023

Abstract
The detection and characterization of circulating tumor cells (CTC) holds great promise for personalizing medicine and optimizing systemic therapy. However, low specificity, low sensitivity, and the time consuming nature of current approaches have impeded clinical adoption. Here we report a new method using surface-enhanced Raman spectroscopy (SERS) to directly measure targeted CTCs in the presence of white blood cells. SERS nanoparticles with epidermal growth factor peptide as a targeting ligand have successfully identified CTCs in the peripheral blood of 19 patients with squamous cell carcinoma of the head and neck (SCCHN), with a range of 1 to 720 CTCs per milliliter of whole blood. Our technique may provide an important new clinical tool for management of patients with SCCHN and other cancers. Cancer Res; 71(5); 1526–32. ©2011 AACR.
Data from MicroRNA-301 Mediates Proliferation and Invasion in Human Breast Cancer
Authors: Shi Wei , Gerster Kate , Alajez Nehad M. , Tsang Jasmine , Waldron Levi , Pintilie Melania , Hui Angela B. , Sykes Jenna , P'ng Christine , Miller Naomi , McCready David , Fyles Anthony , Liu Fei-Fei
Published: March 2023

Abstract
Several microRNAs have been implicated in human breast cancer but none to date have been validated or utilized consistently in clinical management. MicroRNA-301 (miR-301) overexpression has been implicated as a negative prognostic indicator in lymph node negative (LNN) invasive ductal breast cancer, but its potential functional impact has not been determined. Here we report that in breast cancer cells, miR-301 attenuation decreased cell proliferation, clonogenicity, migration, invasion, tamoxifen resistance, tumor growth, and microvessel density, establishing an important oncogenic role for this gene. Algorithm-based and experimental strategies identified FOXF2, BBC3, PTEN, and COL2A1 as candidate miR-301 targets, all of which were verified as direct targets through luciferase reporter assays. We noted that miR-301 is located in an intron of the SKA2 gene which is responsible for kinetochore assembly, and both genes were found to be coexpressed in primary breast cancer samples. In summary, our findings define miR-301 as a crucial oncogene in human breast cancer that acts through multiple pathways and mechanisms to promote nodal or distant relapses. Cancer Res; 71(8); 2926–37. ©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 2023

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 HSulf-1 Modulates FGF2- and Hypoxia-Mediated Migration and Invasion of Breast Cancer Cells
Authors: Khurana Ashwani , Liu Peng , Mellone Pasquale , Lorenzon Laura , Vincenzi Bruno , Datta Kaustubh , Yang Bo , Linhardt Robert J. , Lingle Wilma , Chien Jeremy , Baldi Alfonso , Shridhar Viji
Published: March 2023

Abstract
HSulf-1 modulates the sulfation states of heparan sulfate proteoglycans critical for heparin binding growth factor signaling. In the present study, we show that HSulf-1 is transcriptionally deregulated under hypoxia in breast cancer cell lines. Knockdown of HIF-1α rescued HSulf-1 downregulation imposed by hypoxia, both at the RNA and protein levels. Chromatin immunoprecipitation with HIF-1α and HIF-2α antibodies confirmed recruitment of HIF-α proteins to the two functional hypoxia-responsive elements on the native HSulf-1 promoter. HSulf-1 depletion in breast cancer cells resulted in an increased and sustained bFGF2 (basic fibroblast growth factor) signaling and promoted cell migration and invasion under hypoxic conditions. In addition, FGFR2 (fibroblast growth factor receptor 2) depletion in HSulf-1–silenced breast cancer cells attenuated hypoxia-mediated cell invasion. Immunohistochemical analysis of 53 invasive ductal carcinomas and their autologous metastatic lesions revealed an inverse correlation for the expression of HSulf-1 to CAIX in both the primary tumors (P ≥ 0.0198) and metastatic lesions (P ≥ 0.0067), respectively, by χ2 test. Finally, HSulf-1 expression levels in breast tumors by RNA in situ hybridization showed that high HSulf-1 expression is associated with increased disease-free and overall survival (P ≥ 0.03 and P ≥ 0.0001, respectively). Collectively, these results reveal an important link between loss of HSulf-1 under hypoxic microenvironment and increased growth factor signaling, cell migration, and invasion. Cancer Res; 71(6); 2152–61. ©2011 AACR.
Data from Serglycin Is a Theranostic Target in Nasopharyngeal Carcinoma that Promotes Metastasis
Authors: Li Xin-Jian , Ong Choon Kiat , Cao Yun , Xiang Yan-Qun , Shao Jian-Yong , Ooi Aikseng , Peng Li-Xia , Lu Wen-Hua , Zhang Zhongfa , Petillo David , Qin Li , Bao Ying-Na , Zheng Fang-Jing , Chia Claramae Shulyn , Iyer N. Gopalakrishna , Kang Tie-Bang , Zeng Yi-Xin , Soo Khee Chee , Trent Jeffrey M. , Teh Bin Tean , Qian Chao-Nan
Published: March 2023

Abstract
Nasopharyngeal carcinoma (NPC) is known for its high-metastatic potential. Here we report the identification of the proteoglycan serglycin as a functionally significant regulator of metastasis in this setting. Comparative genomic expression profiling of NPC cell line clones with high- and low-metastatic potential revealed the serglycin gene (SRGN) as one of the most upregulated genes in highly metastatic cells. RNAi-mediated inhibition of serglycin expression blocked serglycin secretion and the invasive motility of highly metastatic cells, reducing metastatic capacity in vivo. Conversely, serglycin overexpression in poorly metastatic cells increased their motile behavior and metastatic capacity in vivo. Growth rate was not influenced by serglycin in either highly or poorly metastatic cells. Secreted but not bacterial recombinant serglycin promoted motile behavior, suggesting a critical role for glycosylation in serglycin activity. Serglycin inhibition was associated with reduced expression of vimentin but not other epithelial–mesenchymal transition proteins. In clinical specimens, serglycin expression was elevated significantly in liver metastases from NPC relative to primary NPC tumors. We evaluated the prognostic value of serglycin by immunohistochemical staining of tissue microarrays from 263 NPC patients followed by multivariate analyses. High serglycin expression in primary NPC was found to be an unfavorable independent indicator of distant metastasis-free and disease-free survival. Our findings establish that glycosylated serglycin regulates NPC metastasis via autocrine and paracrine routes, and that it serves as an independent prognostic indicator of metastasis-free survival and disease-free survival in NPC patients. Cancer Res; 71(8); 3162–72. ©2011 AACR.
Data from Progression of Human Bronchioloalveolar Carcinoma to Invasive Adenocarcinoma Is Modeled in a Transgenic Mouse Model of K-ras–Induced Lung Cancer by Loss of the TGF-β Type II Receptor
Authors: Borczuk Alain C. , Sole Marieta , Lu Ping , Chen Jinli , Wilgus May-Lin , Friedman Richard A. , Albelda Steven M. , Powell Charles A.
Published: March 2023

Abstract
Clinical investigations have suggested that repression of the TGF-β type II receptor (TβRII) may be an important step in progression of lung adenocarcinoma from an indolent in situ state to a frank invasive carcinoma. To test this hypothesis, we compared the effects of deleting the murine homolog of this receptor (Tgfbr2) in a mouse model of mutant K-ras–induced lung carcinoma, which normally induces the formation of multifocal tumors of low invasive potential. In this model, loss of Tgfbr2 induced a highly invasive phenotype associated with lymph node metastasis and reduced survival. Tumor-associated stromal cells displayed an immunosuppressive profile marked by increased numbers of B and T cells. Moreover, tumor stromal cell profiling revealed a developmental TGF-β response profile that associated with a collagenized extracellular matrix and increased invasion of TGF-β nonresponsive tumor cells. Together, these results suggest that our KrasTgfbr2−/− mouse model of invasive lung carcinoma mirrors the genomic response and clinical progression of human lung adenocarcinoma, recapitulating changes in lung stromal pathways that occur in the tumor microenvironment during malignant progression in this disease. Cancer Res; 71(21); 6665–75. ©2011 AACR.
Data from Tissue Factor–Activated Coagulation Cascade in the Tumor Microenvironment Is Critical for Tumor Progression and an Effective Target for Therapy
Authors: Liu Yuan , Jiang Pengfei , Capkova Katerina , Xue Dong , Ye Longwu , Sinha Subhash C. , Mackman Nigel , Janda Kim D. , Liu Cheng
Published: March 2023

Abstract
Tissue factor (TF), a rate-limiting enzyme cofactor in activating coagulation, is highly expressed in a wide spectrum of human tumor and tumor stromal cells. Using TF-deficient cancer cells and a conditional TF-knockout mouse model, we show that TF expressed by cancer cells, but not by the host stromal cells, plays a critical role in tumor growth. In the tumor microenvironment, serum coagulation factors are readily extravasated and therefore lead to continuous TF-mediated activation of coagulation proteases. To target this highly specific cascade of serine proteases, we used both a TF:VIIa inhibitor and doxorubicin-based prodrugs that are selectively activated by TF:FVIIa, FXa, and thrombin. Treatment with the TF:FVIIa inhibitor led to growth retardation in breast tumor models. In contrast, treatment with the prodrug eliminated primary tumor cells and lung metastases without apparent toxicity. Our findings offer preclinical proof of principle that targeting the coagulation cascade that is activated in the tumor microenvironment can be a highly effective approach for cancer therapy. Cancer Res; 71(20); 6492–502. ©2011 AACR.
Data from Pivotal Role of Reduced let-7g Expression in Breast Cancer Invasion and Metastasis
Authors: Qian Pengxu , Zuo Zehua , Wu Zhengsheng , Meng Xianyi , Li Gaopeng , Wu Zhengzhou , Zhang Weijie , Tan Sheng , Pandey Vijay , Yao Yandan , Wang Puyue , Zhao Liqing , Wang Jun , Wu Qiang , Song Erwei , Lobie Peter E. , Yin Zhinan , Zhu Tao
Published: March 2023

Abstract
Screening of the entire let-7 family of microRNAs (miRNA) by in situ hybridization identified let-7g as the only member, the diminished expression of which was significantly associated with lymph node metastasis and poor survival in breast cancer patients. Abrogation of let-7g expression in otherwise nonmetastatic mammary carcinoma cells elicited rapid metastasis from the orthotopic location, through preferential targets, Grb2-associated binding protein 2 (GAB2) and fibronectin 1 (FN1), and consequent activation of p44/42 mitogen-activated protein kinase (MAPK) and specific matrix metalloproteinases. Treatment with estrogen or epidermal growth factor specifically reduced the expression of mature let-7g through activation of p44/42 MAPK and subsequently stimulated expression of GAB2 and FN1, which, in turn, promoted tumor invasion. We thus identify let-7g as a unique member of the let-7 miRNA family that can serve as a prognostic biomarker in breast cancer and also propose a paradigm used by specific signaling molecules via let-7g to cooperatively promote breast cancer invasion and metastasis. Thus, let-7 family members neither possess equivalent clinicopathologic correlation nor function in breast cancer. Cancer Res; 71(20); 6463–74. ©2011 AACR.
Data from CARMA3 is Crucial for EGFR-Induced Activation of NF-κB and Tumor Progression
Authors: Jiang Tang , Grabiner Brian , Zhu Yifan , Jiang Changying , Li Hongxiu , You Yun , Lang Jingyu , Hung Mien-Chie , Lin Xin
Published: March 2023

Abstract
EGF activates NF-κB, and constitutively activated NF-κB contributes to EGFR mutation-associated tumorigenesis, but it remains unclear precisely how EGFR signaling leads to NF-κB activation. Here we report that CARMA3, a caspase recruitment domain (CARD)-containing scaffold molecule, is required for EGF-induced NF-κB activation. CARMA3 deficiency impaired the activation of the IKK complex following EGF stimulation, resulting in a defect of EGF-induced IκBα phosphorylation and NF-κB activation. We found that CARMA3 and Bcl10 contributed to several characteristics of EGFR-associated malignancy, including proliferation, survival, migration, and invasion. Most importantly, CARMA3 contributed to tumor growth in vivo. Our findings elucidate a crucial link between EGFR-proximal signaling components and the downstream IKK complex, and they suggest a new therapeutic target for treatment of EGFR-driven cancers. Cancer Res; 71(6); 2183–92. ©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 2023

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 Dynamic Mast Cell–Stromal Cell Interactions Promote Growth of Pancreatic Cancer
Authors: Ma Ying , Hwang Rosa F. , Logsdon Craig D. , Ullrich Stephen E.
Published: March 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) exists in a complex desmoplastic microenvironment, which includes cancer-associated fibroblasts [also known as pancreatic stellate cells (PSC)] and immune cells that provide a fibrotic niche that impedes successful cancer therapy. We have found that mast cells are essential for PDAC tumorigenesis. Whether mast cells contribute to the growth of PDAC and/or PSCs is unknown. Here, we tested the hypothesis that mast cells contribute to the growth of PSCs and tumor cells, thus contributing to PDAC development. Tumor cells promoted mast cell migration. Both tumor cells and PSCs stimulated mast cell activation. Conversely, mast cell–derived interleukin (IL)-13 and tryptase stimulated PSC proliferation. Treating tumor-bearing mice with agents that block mast cell migration and function depressed PDAC growth. Our findings suggest that mast cells exacerbate the cellular and extracellular dynamics of the tumor microenvironment found in PDAC. Therefore, targeting mast cells may inhibit stromal formation and improve therapy. Cancer Res; 73(13); 3927–37. ©2013 AACR.
Data from AC1MMYR2, an Inhibitor of Dicer-Mediated Biogenesis of Oncomir miR-21, Reverses Epithelial–Mesenchymal Transition and Suppresses Tumor Growth and Progression
Authors: Shi Zhendong , Zhang Junxia , Qian Xiaomin , Han Lei , Zhang Kailiang , Chen Luyue , Liu Jilong , Ren Yu , Yang Ming , Zhang Anling , Pu Peiyu , Kang Chunsheng
Published: March 2023

Abstract
The extensive involvement of miRNAs in cancer pathobiology has opened avenues for drug development based on oncomir inhibition. Dicer is the core enzyme in miRNA processing that cleaves the terminal loop of precursor microRNAs (pre-miRNAs) to generate mature miRNA duplexes. Using the three-dimensional structure of the Dicer binding site on the pre-miR-21 oncomir, we conducted an in silico high-throughput screen for small molecules that block miR-21 maturation. By this method, we identified a specific small-molecule inhibitor of miR-21, termed AC1MMYR2, which blocked the ability of Dicer to process pre-miR-21 to mature miR-21. AC1MMYR2 upregulated expression of PTEN, PDCD4, and RECK and reversed epithelial–mesenchymal transition via the induction of E-cadherin expression and the downregulation of mesenchymal markers, thereby suppressing proliferation, survival, and invasion in glioblastoma, breast cancer, and gastric cancer cells. As a single agent in vivo, AC1MMYR2 repressed tumor growth, invasiveness, and metastasis, increasing overall host survival with no observable tissue cytotoxicity in orthotopic models. Our results offer a novel, high-throughput method to screen for small-molecule inhibitors of miRNA maturation, presenting AC1MMYR2 as a broadly useful candidate antitumor drug. Cancer Res; 73(17); 5519–31. ©2013 AACR.
Data from Notch1-Induced Brain Tumor Models the Sonic Hedgehog Subgroup of Human Medulloblastoma
Authors: Natarajan Sivaraman , Li Yaochen , Miller Emily E. , Shih David J. , Taylor Michael D. , Stearns Timothy M. , Bronson Roderick T. , Ackerman Susan L. , Yoon Jeong K. , Yun Kyuson
Published: March 2023

Abstract
While activation of the Notch pathway is observed in many human cancers, it is unknown whether elevated Notch1 expression is sufficient to initiate tumorigenesis in most tissues. To test the oncogenic potential of Notch1 in solid tumors, we expressed an activated form of Notch1 (N1ICD) in the developing mouse brain. N1ICD;hGFAP-cre mice were viable but developed severe ataxia and seizures, and died by weaning age. Analysis of transgenic embryo brains revealed that N1ICD expression induced p53-dependent apoptosis. When apoptosis was blocked by genetic deletion of p53, 30% to 40% of N1ICD;GFAP-cre;p53+/− and N1ICD;GFAP-cre;p53−/− mice developed spontaneous medulloblastomas. Interestingly, N1ICD-induced medulloblastomas most closely resembled the sonic hedgehog subgroup of human medulloblastoma at the molecular level. Surprisingly, N1ICD-induced tumors do not maintain high levels of the Notch pathway gene expression, except for Notch2, showing that initiating oncogenic events may not be decipherable by analyzing growing tumors in some cases. In summary, this study shows that Notch1 has an oncogenic potential in the brain when combined with other oncogenic hits, such as p53 loss, and provides a novel mouse model of medulloblastoma. Cancer Res; 73(17); 5381–90. ©2013 AACR.
Data from Specific Elimination of CD133+ Tumor Cells with Targeted Oncolytic Measles Virus
Authors: Bach Patricia , Abel Tobias , Hoffmann Christopher , Gal Zoltan , Braun Gundula , Voelker Iris , Ball Claudia R. , Johnston Ian C.D. , Lauer Ulrich M. , Herold-Mende Christel , Mühlebach Michael D. , Glimm Hanno , Buchholz Christian J.
Published: March 2023

Abstract
Tumor-initiating cells (TIC) are critical yet evasive targets for the development of more effective antitumoral strategies. The cell surface marker CD133 is frequently used to identify TICs of various tumor entities, including hepatocellular cancer and glioblastoma. Here, we describe oncolytic measles viruses (MV) retargeted to CD133. The viruses, termed MV-141.7 and MV-AC133, infected and selectively lysed CD133+ tumor cells. Both viruses exerted strong antitumoral effects on human hepatocellular carcinoma growing subcutaneously or multifocally in the peritoneal cavity of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Notably, the CD133-targeted viruses were more effective in prolonging survival than the parental MV-NSe, which is currently assessed as oncolytic agent in clinical trials. Interestingly, target receptor overexpression or increased spreading kinetics through tumor cells were excluded as being causative for the enhanced oncolytic activity of CD133-targeted viruses. MV-141.7 was also effective in mouse models of orthotopic glioma tumor spheres and primary colon cancer. Our results indicate that CD133-targeted measles viruses selectively eliminate CD133+ cells from tumor tissue, offering a key tool for research in tumor biology and cancer therapy. Cancer Res; 73(2); 865–74. ©2013 AACR.
Data from Activation of HIF2α in Kidney Proximal Tubule Cells Causes Abnormal Glycogen Deposition but not Tumorigenesis
Authors: Fu Leiping , Wang Gang , Shevchuk Maria M. , Nanus David M. , Gudas Lorraine J.
Published: March 2023

Abstract
Renal cell carcinoma (RCC) is the most common primary cancer arising from the kidney in adults, with clear cell renal cell carcinoma (ccRCC) representing approximately 75% of all RCCs. Increased expression of the hypoxia-induced factors-1α (HIF1α) and HIF2α has been suggested as a pivotal step in ccRCC carcinogenesis, but this has not been thoroughly tested. Here, we report that expression of a constitutively activated form of HIF2α (P405A, P530A, and N851A, named as HIF2αM3) in the proximal tubules of mice is not sufficient to promote ccRCC by itself, nor does it enhance HIF1αM3 oncogenesis when coexpressed with constitutively active HIF1αM3. Neoplastic transformation in kidneys was not detected at up to 33 months of age, nor was increased expression of Ki67 (MKI67), γH2AX (H2AFX), or CD70 observed. Furthermore, the genome-wide transcriptome of the transgenic kidneys does not resemble human ccRCC. We conclude that a constitutively active HIF2α is not sufficient to cause neoplastic transformation of proximal tubules, arguing against the idea that HIF2α activation is critical for ccRCC tumorigenesis. Cancer Res; 73(9); 2916–25. ©2013 AACR.
Data from Neutralizing Murine TGFβR2 Promotes a Differentiated Tumor Cell Phenotype and Inhibits Pancreatic Cancer Metastasis
Authors: Ostapoff Katherine T. , Cenik Bercin Kutluk , Wang Miao , Ye Risheng , Xu Xiaohong , Nugent Desiree , Hagopian Moriah M. , Topalovski Mary , Rivera Lee B. , Carroll Kyla D. , Brekken Rolf A.
Published: March 2023

Abstract
Elevated levels of TGFβ are a negative prognostic indicator for patients diagnosed with pancreatic cancer; as a result, the TGFβ pathway is an attractive target for therapy. However, clinical application of pharmacologic inhibition of TGFβ remains challenging because TGFβ has tumor suppressor functions in many epithelial malignancies, including pancreatic cancer. In fact, direct neutralization of TGFβ promotes tumor progression of genetic murine models of pancreatic cancer. Here, we report that neutralizing the activity of murine TGFβ receptor 2 using a monoclonal antibody (2G8) has potent antimetastatic activity in orthotopic human tumor xenografts, syngeneic tumors, and a genetic model of pancreatic cancer. 2G8 reduced activated fibroblasts, collagen deposition, microvessel density, and vascular function. These stromal-specific changes resulted in tumor cell epithelial differentiation and a potent reduction in metastases. We conclude that TGFβ signaling within stromal cells participates directly in tumor cell phenotype and pancreatic cancer progression. Thus, strategies that inhibit TGFβ-dependent effector functions of stromal cells could be efficacious for the therapy of pancreatic tumors. Cancer Res; 74(18); 4996–5007. ©2014 AACR.
Data from Adiponectin Receptor Signaling on Dendritic Cells Blunts Antitumor Immunity
Authors: Tan Peng H. , Tyrrell Helen E.J. , Gao Liquan , Xu Danmei , Quan Jianchao , Gill Dipender , Rai Lena , Ding Yunchuan , Plant Gareth , Chen Yuan , Xue John Z. , Handa Ashok I. , Greenall Michael J. , Walsh Kenneth , Xue Shao-An
Published: March 2023

Abstract
Immune escape is a fundamental trait of cancer. Dendritic cells (DC) that interact with T cells represent a crucial site for the development of tolerance to tumor antigens, but there remains incomplete knowledge about how DC-tolerizing signals evolve during tumorigenesis. In this study, we show that DCs isolated from patients with metastatic or locally advanced breast cancer express high levels of the adiponectin receptors AdipoR1 and AdipoR2, which are sufficient to blunt antitumor immunity. Mechanistic investigations of ligand–receptor interactions on DCs revealed novel signaling pathways for each receptor. AdipoR1 stimulated IL10 production by activating the AMPK and MAPKp38 pathways, whereas AdipoR2 modified inflammatory processes by activating the COX-2 and PPARγ pathways. Stimulation of these pathways was sufficient to block activation of NF-κB in DC, thereby attenuating their ability to stimulate antigen-specific T-cell responses. Together, our findings reveal novel insights into how DC-tolerizing signals evolve in cancer to promote immune escape. Furthermore, by defining a critical role for adiponectin signaling in this process, our work suggests new and broadly applicable strategies for immunometabolic therapy in patients with cancer. Cancer Res; 74(20); 5711–22. ©2014 AACR.
Data from CCL2/CCR2-Dependent Recruitment of Functional Antigen-Presenting Cells into Tumors upon Chemotherapy
Authors: Ma Yuting , Mattarollo Stephen R. , Adjemian Sandy , Yang Heng , Aymeric Laetitia , Hannani Dalil , Portela Catani João Paulo , Duret Helene , Teng Michele W.L. , Kepp Oliver , Wang Yidan , Sistigu Antonella , Schultze Joachim L. , Stoll Gautier , Galluzzi Lorenzo , Zitvogel Laurence , Smyth Mark J. , Kroemer Guido
Published: March 2023

Abstract
The therapeutic efficacy of anthracyclines relies, at least partially, on the induction of a dendritic cell– and T-lymphocyte–dependent anticancer immune response. Here, we show that anthracycline-based chemotherapy promotes the recruitment of functional CD11b+CD11c+Ly6ChighLy6G−MHCII+ dendritic cell–like antigen-presenting cells (APC) into the tumor bed, but not into lymphoid organs. Accordingly, draining lymph nodes turned out to be dispensable for the proliferation of tumor antigen–specific T cells within neoplastic lesions as induced by anthracyclines. In addition, we found that tumors treated with anthracyclines manifest increased expression levels of the chemokine Ccl2. Such a response is important as neoplasms growing in Ccl2−/− mice failed to accumulate dendritic cell–like APCs in response to chemotherapy. Moreover, cancers developing in mice lacking Ccl2 or its receptor (Ccr2) exhibited suboptimal therapeutic responses to anthracycline-based chemotherapy. Altogether, our results underscore the importance of the CCL2/CCR2 signaling axis for therapeutic anticancer immune responses as elicited by immunogenic chemotherapy. Cancer Res; 74(2); 436–45. ©2013 AACR.
Data from Activation of the NOTCH Pathway in Head and Neck Cancer
Authors: Sun Wenyue , Gaykalova Daria A. , Ochs Michael F. , Mambo Elizabeth , Arnaoutakis Demetri , Liu Yan , Loyo Myriam , Agrawal Nishant , Howard Jason , Li Ryan , Ahn Sun , Fertig Elana , Sidransky David , Houghton Jeffery , Buddavarapu Kalyan , Sanford Tiffany , Choudhary Ashish , Darden Will , Adai Alex , Latham Gary , Bishop Justin , Sharma Rajni , Westra William H. , Hennessey Patrick , Chung Christine H. , Califano Joseph A.
Published: March 2023

Abstract
NOTCH1 mutations have been reported to occur in 10% to 15% of head and neck squamous cell carcinomas (HNSCC). To determine the significance of these mutations, we embarked upon a comprehensive study of NOTCH signaling in a cohort of 44 HNSCC tumors and 25 normal mucosal samples through a set of expression, copy number, methylation, and mutation analyses. Copy number increases were identified in NOTCH pathway genes, including the NOTCH ligand JAG1. Gene set analysis defined a differential expression of the NOTCH signaling pathway in HNSCC relative to normal tissues. Analysis of individual pathway-related genes revealed overexpression of ligands JAG1 and JAG2 and receptor NOTCH3. In 32% of the HNSCC examined, activation of the downstream NOTCH effectors HES1/HEY1 was documented. Notably, exomic sequencing identified 5 novel inactivating NOTCH1 mutations in 4 of the 37 tumors analyzed, with none of these tumors exhibiting HES1/HEY1 overexpression. Our results revealed a bimodal pattern of NOTCH pathway alterations in HNSCC, with a smaller subset exhibiting inactivating NOTCH1 receptor mutations but a larger subset exhibiting other NOTCH1 pathway alterations, including increases in expression or gene copy number of the receptor or ligands as well as downstream pathway activation. Our results imply that therapies that target the NOTCH pathway may be more widely suitable for HNSCC treatment than appreciated currently. Cancer Res; 74(4); 1091–104. ©2013 AACR.
Data from Histone H1.3 Suppresses H19 Noncoding RNA Expression and Cell Growth of Ovarian Cancer Cells
Authors: Medrzycki Magdalena , Zhang Yunzhe , Zhang Weijia , Cao Kaixiang , Pan Chenyi , Lailler Nathalie , McDonald John F. , Bouhassira Eric E. , Fan Yuhong
Published: March 2023

Abstract
Ovarian cancer is a deadly gynecologic malignancy for which novel biomarkers and therapeutic targets are imperative for improving survival. Previous studies have suggested the expression pattern of linker histone variants as potential biomarkers for ovarian cancer. To investigate the role of histone H1 in ovarian cancer cells, we characterize individual H1 variants and overexpress one of the major somatic H1 variants, H1.3, in the OVCAR-3 epithelial ovarian cancer cell line. We find that overexpression of H1.3 decreases the growth rate and colony formation of OVCAR-3 cells. We identify histone H1.3 as a specific repressor for the noncoding oncogene H19. Overexpression of H1.3 suppresses H19 expression, and knockdown of H1.3 increases its expression in multiple ovarian epithelial cancer cell lines. Furthermore, we demonstrate that histone H1.3 overexpression leads to increased occupancy of H1.3 at the H19 regulator region encompassing the imprinting control region (ICR), concomitant with increased DNA methylation and reduced occupancy of the insulator protein CTCF at the ICR. Finally, we demonstrate that H1.3 overexpression and H19 knockdown synergistically decrease the growth rate of ovarian cancer cells. Our findings suggest that H1.3 dramatically inhibits H19 expression, which contributes to the suppression of epithelial ovarian carcinogenesis. Cancer Res; 74(22); 6463–73. ©2014 AACR.
Data from Activin Upregulation by NF-κB Is Required to Maintain Mesenchymal Features of Cancer Stem–like Cells in Non–Small Cell Lung Cancer
Authors: Wamsley J. Jacob , Kumar Manish , Allison David F. , Clift Sheena H. , Holzknecht Caitlyn M. , Szymura Szymon J. , Hoang Stephen A. , Xu Xiaojiang , Moskaluk Christopher A. , Jones David R. , Bekiranov Stefan , Mayo Marty W.
Published: March 2023

Abstract
Soluble growth factors and cytokines within the tumor microenvironment aid in the induction of the epithelial-to-mesenchymal transition (EMT). Although EMT promotes the development of cancer-initiating cells (CIC), cellular mechanisms by which cancer cells maintain mesenchymal phenotypes remain poorly understood. Work presented here indicates that induction of EMT stimulates non–small cell lung cancer (NSCLC) to secrete soluble factors that function in an autocrine fashion. Using gene expression profiling of all annotated and predicted secreted gene products, we find that NF-κB activity is required to upregulate INHBA/Activin, a morphogen in the TGFβ superfamily. INHBA is capable of inducing and maintaining mesenchymal phenotypes, including the expression of EMT master-switch regulators and self-renewal factors that sustain CIC phenotypes and promote lung metastasis. Our work demonstrates that INHBA mRNA and protein expression are commonly elevated in primary human NSCLC and provide evidence that INHBA is a critical autocrine factor that maintains mesenchymal properties of CICs to promote metastasis in NSCLC. Cancer Res; 75(2); 426–35. ©2014 AACR.