bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Diagnosis of Prostate Cancer Using Differentially Expressed Genes in Stroma
Authors: Jia Zhenyu , Wang Yipeng , Sawyers Anne , Yao Huazhen , Rahmatpanah Farahnaz , Xia Xiao-Qin , Xu Qiang , Pio Rebecca , Turan Tolga , Koziol James A. , Goodison Steve , Carpenter Philip , Wang-Rodriguez Jessica , Simoneau Anne , Meyskens Frank , Sutton Manuel , Lernhardt Waldemar , Beach Thomas , Monforte Joseph , McClelland Michael , Mercola Dan
Published: March 2024

Abstract
More than one million prostate biopsies are performed in the United States every year. A failure to find cancer is not definitive in a significant percentage of patients due to the presence of equivocal structures or continuing clinical suspicion. We have identified gene expression changes in stroma that can detect tumor nearby. We compared gene expression profiles of 13 biopsies containing stroma near tumor and 15 biopsies from volunteers without prostate cancer. About 3,800 significant expression changes were found and thereafter filtered using independent expression profiles to eliminate possible age-related genes and genes expressed at detectable levels in tumor cells. A stroma-specific classifier for nearby tumor was constructed on the basis of 114 candidate genes and tested on 364 independent samples including 243 tumor-bearing samples and 121 nontumor samples (normal biopsies, normal autopsies, remote stroma, as well as stroma within a few millimeters of tumor). The classifier predicted the tumor status of patients using tumor-free samples with an average accuracy of 97% (sensitivity = 98% and specificity = 88%) whereas classifiers trained with sets of 100 randomly generated genes had no diagnostic value. These results indicate that the prostate cancer microenvironment exhibits reproducible changes useful for categorizing the presence of tumor in patients when a prostate sample is derived from near the tumor but does not contain any recognizable tumor. Cancer Res; 71(7); 2476–87. ©2011 AACR.
Data from Adjuvant Combination and Antigen Targeting as a Strategy to Induce Polyfunctional and High-Avidity T-Cell Responses against Poorly Immunogenic Tumors
Authors: Aranda Fernando , Llopiz Diana , Díaz-Valdés Nancy , Riezu-Boj José Ignacio , Bezunartea Jaione , Ruiz Marta , Martínez Marta , Durantez Maika , Mansilla Cristina , Prieto Jesús , Lasarte Juan José , Borrás-Cuesta Francisco , Sarobe Pablo
Published: March 2024

Abstract
Low antigen expression and an absence of coimmunostimulatory signals may be partly responsible for the low immunogenicity of many tumors. It may be possible to overcome this situation by defining a combination of adjuvants and antigens that can activate a high-avidity antitumor response. Using the poorly immunogenic B16-OVA melanoma cells as tumor model, we tested different combinations of adjuvants and antigens to treat established tumors. In the absence of exogenous antigens, repeated administration of the TLR7 ligand Imiquimod together with anti-CD40 agonistic antibodies activated only innate immunity, which was insufficient to reject intradermal tumors. Administering this adjuvant combination together with OVA as a tumor antigen induced T-cell responses that delayed tumor growth. However, administering a combination of anti-CD40 plus TLR3 and TLR7 ligands, together with antigen targeting to dendritic cells through TLR4, was sufficient to induce tumor rejection in 50% of mice. This response was associated with a greater activation of innate immunity and induction of high-avidity polyfunctional CD8+ T-cell responses, which each contributed to tumor rejection. This therapy activated T-cell responses not only against OVA, which conferred protection against a rechallenge with B16-OVA cells, but also activated T-cell responses against other melanoma-associated antigens. Our findings support the concept that multiple adjuvant combination and antigen targeting may be a useful immunotherapeutic strategy against poorly immunogenic tumors. Cancer Res; 71(9); 3214–24. ©2011 AACR.
Data from High Basal Nuclear Levels of Nrf2 in Acute Myeloid Leukemia Reduces Sensitivity to Proteasome Inhibitors
Authors: Rushworth Stuart A. , Bowles Kristian M. , MacEwan David J.
Published: March 2024

Abstract
Proteasome inhibitors such as bortezomib exhibit clinical efficacy in multiple myeloma, but studies in acute myeloid leukemia (AML) have been disappointing to date. The apparent failure in AML likely reflects a lack of biological understanding that might clarify applications of proteosome inhibitors in this disease. Here we show that AML cells are considerably less sensitive than control noncancerous cells to bortezomib-induced cytotoxicity, permitting most bortezomib-treated AML cells to survive treatment. We traced reduced bortezomib sensitivity to increased basal levels of nuclear Nrf2, a transcription factor that stimulates protective antioxidant enzymes. Bortezomib stimulates cytotoxicity through accumulation of reactive oxygen species (ROS) but elevated basal levels of nuclear Nrf2 present in AML cells reduced ROS levels, permitting AML cells to survive drug treatment. We further found that the Nrf2 transcriptional repressor Bach1 is rapidly inactivated by bortezomib, allowing rapid induction of Nrf2-regulated cytoprotective and detoxification genes that protect AML cells from bortezomib-induced apoptosis. By contrast, nonmalignant control cells lacked constitutive activation of Nrf2, such that bortezomib-mediated inactivation of Bach1 led to a delay in induction of Nrf2-regulated genes, effectively preventing the manifestation of apoptotic protection that is seen in AML cells. Together, our findings argue that AML might be rendered sensitive to proteasome inhibitors by cotreatment with either an Nrf2-inhibitory or Bach1-inhibitory treatment, rationalizing a targeted therapy against AML. Cancer Res; 71(5); 1999–2009. ©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 2024

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 Anti-IL-23 Monoclonal Antibody Synergizes in Combination with Targeted Therapies or IL-2 to Suppress Tumor Growth and Metastases
Authors: Teng Michele W.L. , von Scheidt Bianca , Duret Helene , Towne Jennifer E. , Smyth Mark J.
Published: March 2024

Abstract
Immunosuppressive barricades erected by tumors during the evolution of immune escape represent a major obstacle to many potentially effective cancer therapies and vaccines. We have shown that host interleukin (IL)-23 suppresses the innate immune response during carcinogenesis and metastasis, independently of effects on the proinflammatory cytokine IL-17A. Based on these findings, we envisioned that IL-23 neutralization might offer a promising strategy to modulate immunosuppression, particularly in combination with immunostimulatory agents. Here we show that by itself a neutralizing monoclonal antibody (mAb) to IL-23 suppressed early experimental lung metastases in the B16F10 mouse model of melanoma and also modestly inhibited the subcutaneous growth of primary tumors. These antitumor effects were respectively mediated by natural killer cells or CD8+ T cells. More notably, combinatorial treatments of anti-IL-23 mAb with IL-2 or anti-erbB2 mAb significantly inhibited subcutaneous growth of established mammary carcinomas and suppressed established experimental and spontaneous lung metastases. Overall, our results suggest the potential of anti-human IL-23 mAbs to improve the immunostimulatory effects of IL-2 and trastuzumab in the current management of some advanced human cancers. Cancer Res; 71(6); 2077–86. ©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 2024

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 Targeting PI3K/mTOR Signaling in Cancer
Authors: Emerling Brooke M. , Akcakanat Argun
Published: March 2024

Abstract
The American Association for Cancer Research (AACR) Special Conference on Targeting PI3K/mTOR Signaling in Cancer was held in San Francisco, California from February 24 to 27, 2011. The meeting was cochaired by Drs. Lewis C. Cantley, David M. Sabatini, and Funda Meric-Bernstam. The main focus of this event was the therapeutic potential of drugs targeting the PI3K/mTOR signaling pathway for the treatment of cancer. This article summarizes the recent discoveries in the field, with particular emphasis on the major themes of the conference. Cancer Res; 71(24); 7351–9. ©2011 AACR.
Data from Dual IGF-I/II–Neutralizing Antibody MEDI-573 Potently Inhibits IGF Signaling and Tumor Growth
Authors: Gao Jin , Chesebrough Jon W. , Cartlidge Susan A. , Ricketts Sally-Ann , Incognito Leonard , Veldman-Jones Margaret , Blakey David C. , Tabrizi Mohammad , Jallal Bahija , Trail Pamela A. , Coats Steven , Bosslet Klaus , Chang Yong S.
Published: March 2024

Abstract
Insulin-like growth factors (IGF), IGF-I and IGF-II, are small polypeptides involved in regulating cell proliferation, survival, differentiation, and transformation. IGF activities are mediated through binding and activation of IGF-1R or insulin receptor isoform A (IR-A). The role of the IGF-1R pathway in promoting tumor growth and survival is well documented. Overexpression of IGF-II and IR-A is reported in multiple types of cancer and is proposed as a potential mechanism for cancer cells to develop resistance to IGF-1R–targeting therapy. MEDI-573 is a fully human antibody that neutralizes both IGF-I and IGF-II and inhibits IGF signaling through both the IGF-1R and IR-A pathways. Here, we show that MEDI-573 blocks the binding of IGF-I and IGF-II to IGF-1R or IR-A, leading to the inhibition of IGF-induced signaling pathways and cell proliferation. MEDI-573 significantly inhibited the in vivo growth of IGF-I– or IGF-II–driven tumors. Pharmacodynamic analysis demonstrated inhibition of IGF-1R phosphorylation in tumors in mice dosed with MEDI-573, indicating that the antitumor activity is mediated via inhibition of IGF-1R signaling pathways. Finally, MEDI-573 significantly decreased 18F-fluorodeoxyglucose (18F-FDG) uptake in IGF-driven tumor models, highlighting the potential utility of 18F-FDG-PET as a noninvasive pharmacodynamic readout for evaluating the use of MEDI-573 in the clinic. Taken together, these results demonstrate that the inhibition of IGF-I and IGF-II ligands by MEDI-573 results in potent antitumor activity and offers an effective approach to selectively target both the IGF-1R and IR-A signaling pathways. Cancer Res; 71(3); 1029–40. ©2011 AACR.
Data from STAT3 Inhibition Is a Therapeutic Strategy for ABC-like Diffuse Large B-Cell Lymphoma
Authors: Scuto Anna , Kujawski Maciej , Kowolik Claudia , Krymskaya Ludmila , Wang Lin , Weiss Lawrence M. , DiGiusto David , Yu Hua , Forman Stephen , Jove Richard
Published: March 2024

Abstract
Persistent STAT3 signaling contributes to malignant progression in many diverse types of human cancer. STAT3 is constitutively active in activated B-cell (ABC)–like diffuse large B-cell lymphomas (DLBCL), a class of nongerminal center derived DLBCL cells for which existing therapy is weakly effective. In this report, we provide a preclinical proof of concept that STAT3 is an effective molecular target for ABC-like DLBCL therapy. Direct inhibition of STAT3 with short hairpin RNA suppressed the growth of human ABC-like DLBCL in mouse models in a manner associated with apoptosis, repression of STAT3 target genes, and inhibition of a tumor-promoting microenvironment. Together, these results suggest that STAT3 is essential to maintain the pathophysiology of ABC-like DLBCL and therefore that STAT3 inhibition may offer a promising approach in its therapy. Cancer Res; 71(9); 3182–8. ©2011 AACR.
Data from Cell-Permeable NM23 Blocks the Maintenance and Progression of Established Pulmonary Metastasis
Authors: Lim Junghee , Jang Giyong , Kang Seeun , Lee Guewha , Nga Do Thi Thuy , Phuong Do Thi Lan , Kim Hyuncheol , El-Rifai Wael , Ruley H. Earl , Jo Daewoong
Published: March 2024

Abstract
Occult metastases are a major cause of cancer mortality, even among patients undergoing curative resection. Therefore, practical strategies to target the growth and persistence of already established metastases would provide an important advance in cancer treatment. Here, we assessed the potential of protein therapy using a cell permeable NM23-H1 metastasis suppressor protein. Hydrophobic transduction domains developed from a screen of 1,500 signaling peptide sequences enhanced the uptake of the NM23 protein by cultured cells and systemic delivery to animal tissues. The cell-permeable (CP)-NM23 inhibited metastasis-associated phenotypes in tumor cell lines, blocked the establishment of lung metastases, and cleared already established pulmonary metastases, significantly prolonging the survival of tumor-bearing animals. Therefore, these results establish the potential use of cell-permeable metastasis suppressors as adjuvant therapy against disseminated cancers. Cancer Res; 71(23); 7216–25. ©2011 AACR.
Data from Human Breast Tumor Cells Induce Self-Tolerance Mechanisms to Avoid NKG2D-Mediated and DNAM-Mediated NK Cell Recognition
Authors: Mamessier Emilie , Sylvain Aude , Bertucci François , Castellano Rémy , Finetti Pascal , Houvenaeghel Gilles , Charaffe-Jaufret Emmanuelle , Birnbaum Daniel , Moretta Alessandro , Olive Daniel
Published: March 2024

Abstract
Breast cancer is the leading cause of death for women between the ages of 35 to 65. This is mostly due to intertumor heterogeneity and the lack of specific therapies for all subtypes. However, some breast cancers with an unexpected good prognosis are associated with enhanced antitumor immunity in situ. We studied whether breast cancer subtypes might have different susceptibilities to natural killer (NK) cells' antitumor immunity. We collected a large public set of microarray data for primary breast tumors and determined NK cell ligand expression. We found that despite heterogeneous levels of inhibitory HLA members, NKG2D ligands and DNAM ligands are expressed in virtually all breast tumor subtypes. Functional experiments in breast cancer subtypes expressing various levels of NK cell ligands showed that NK-mediated cytotoxicity is mainly HLA, NKG2D, and DNAM dependent. In parallel, we showed that cell lines and primary breast tumor cells secrete soluble inhibitory factors that alter NK cell functions. Finally, we showed that these mechanisms of escape occur in vivo in the MMTV-Neu model of spontaneous murine breast cancer. Our study shows that breast cancer cells, independent of the subtype, have developed different mechanisms to escape from NK cells' antitumor immunity. These results emphasize the role of NK cells in breast tumor clearance and underlie the importance of devising future therapy aiming at enhancing NK cell–mediated recognition in parallel with the prevention of the tumor-editing process. Cancer Res; 71(21); 6621–32. ©2011 AACR.
Data from Cancer-Induced Immunosuppression: IL-18–Elicited Immunoablative NK Cells
Authors: Terme Magali , Ullrich Evelyn , Aymeric Laetitia , Meinhardt Kathrin , Coudert Jérôme D. , Desbois Mélanie , Ghiringhelli François , Viaud Sophie , Ryffel Bernard , Yagita Hideo , Chen Lieping , Mécheri Salaheddine , Kaplanski Gilles , Prévost-Blondel Armelle , Kato Masashi , Schultze Joachim L. , Tartour Eric , Kroemer Guido , Degli-Esposti Mariapia , Chaput Nathalie , Zitvogel Laurence
Published: March 2024

Abstract
During cancer development, a number of regulatory cell subsets and immunosuppressive cytokines subvert adaptive immune responses. Although it has been shown that tumor-derived interleukin (IL)-18 participates in the PD-1–dependent tumor progression in NK cell–controlled cancers, the mechanistic cues underlying this immunosuppression remain unknown. Here, we show that IL-18 converts a subset of Kit− (CD11b−) into Kit+ natural killer (NK) cells, which accumulate in all lymphoid organs of tumor bearers and mediate immunoablative functions. Kit+ NK cells overexpressed B7-H1/PD-L1, a ligand for PD-1. The adoptive transfer of Kit+ NK cells promoted tumor growth in two pulmonary metastases tumor models and significantly reduced the dendritic and NK cell pools residing in lymphoid organs in a B7-H1–dependent manner. Neutralization of IL-18 by RNA interference in tumors or systemically by IL-18–binding protein dramatically reduced the accumulation of Kit+CD11b− NK cells in tumor bearers. Together, our findings show that IL-18 produced by tumor cells elicits Kit+CD11b− NK cells endowed with B7-H1–dependent immunoablative functions in mice. Cancer Res; 72(11); 2757–67. ©2012 AACR.
Data from Classification of Epstein–Barr Virus–Positive Gastric Cancers by Definition of DNA Methylation Epigenotypes
Authors: Matsusaka Keisuke , Kaneda Atsushi , Nagae Genta , Ushiku Tetsuo , Kikuchi Yasuko , Hino Rumi , Uozaki Hiroshi , Seto Yasuyuki , Takada Kenzo , Aburatani Hiroyuki , Fukayama Masashi
Published: March 2024

Abstract
Epstein–Barr virus (EBV) is associated with Burkitt lymphoma, nasopharyngeal carcinoma, opportunistic lymphomas in immunocompromised hosts, and a fraction of gastric cancers. Aberrant promoter methylation accompanies human gastric carcinogenesis, though the contribution of EBV to such somatic methylation changes has not been fully clarified. We analyzed promoter methylation in gastric cancer cases with Illumina's Infinium BeadArray and used hierarchical clustering analysis to classify gastric cancers into 3 subgroups: EBV−/low methylation, EBV−/high methylation, and EBV+/high methylation. The 3 epigenotypes were characterized by 3 groups of genes: genes methylated specifically in the EBV+ tumors (e.g., CXXC4, TIMP2, and PLXND1), genes methylated both in EBV+ and EBV−/high tumors (e.g., COL9A2, EYA1, and ZNF365), and genes methylated in all of the gastric cancers (e.g., AMPH, SORCS3, and AJAP1). Polycomb repressive complex (PRC) target genes in embryonic stem cells were significantly enriched among EBV−/high-methylation genes and commonly methylated gastric cancer genes (P = 2 × 10−15 and 2 × 10−34, respectively), but not among EBV+ tumor-specific methylation genes (P = 0.2), suggesting a different cause for EBV+-associated de novo methylation. When recombinant EBV was introduced into the EBV−/low-methylation epigenotype gastric cancer cell, MKN7, 3 independently established subclones displayed increases in DNA methylation. The promoters targeted by methylation were mostly shared among the 3 subclones, and the new methylation changes caused gene repression. In summary, DNA methylation profiling classified gastric cancer into 3 epigenotypes, and EBV+ gastric cancers showed distinct methylation patterns likely attributable to EBV infection. Cancer Res; 71(23); 7187–97. ©2011 AACR.
Data from FLT3 Ligand Enhances the Cancer Therapeutic Potency of Naked RNA Vaccines
Authors: Kreiter Sebastian , Diken Mustafa , Selmi Abderraouf , Diekmann Jan , Attig Sebastian , Hüsemann Yves , Koslowski Michael , Huber Christoph , Türeci Özlem , Sahin Ugur
Published: March 2024

Abstract
Intranodal immunization with antigen-encoding naked RNA may offer a simple and safe approach to induce antitumor immunity. RNA taken up by nodal dendritic cells (DC) coactivates toll-like receptor (TLR) signaling that will prime and expand antigen-specific T cells. In this study, we show that RNA vaccination can be optimized by coadministration of the DC-activating Fms-like tyrosine kinase 3 (FLT3) ligand as an effective adjuvant. Systemic administration of FLT3 ligand prior to immunization enhanced priming and expansion of antigen-specific CD8+ T cells in lymphoid organs, T-cell homing into melanoma tumors, and therapeutic activity of the intranodal RNA. Unexpectedly, plasmacytoid DCs (pDC) were found to be essential for the adjuvant effect of FLT3 ligand and they were systemically expanded together with conventional DCs after treatment. In response to FLT3 ligand, pDCs maintained an immature phenotype, internalized RNA, and presented the RNA-encoded antigen for efficient induction of antigen-specific CD8+ T-cell responses. Coadministration of FLT3 ligand with RNA vaccination achieved remarkable cure rates and survival of mice with advanced melanoma. Our findings show how to improve the simple and safe strategy offered by RNA vaccines for cancer immunotherapy. Cancer Res; 71(19); 6132–42. ©2011 AACR.
Data from Adipokines Linking Obesity with Colorectal Cancer Risk in Postmenopausal Women
Authors: Ho Gloria Y.F. , Wang Tao , Gunter Marc J. , Strickler Howard D. , Cushman Mary , Kaplan Robert C. , Wassertheil-Smoller Sylvia , Xue Xiaonan , Rajpathak Swapnil N. , Chlebowski Rowan T. , Vitolins Mara Z. , Scherer Philipp E. , Rohan Thomas E.
Published: March 2024

Abstract
Mechanistic associations between obesity and colorectal cancer remain unclear. In this study, we investigated whether adipokines are risk factors for colorectal cancer and whether they may mediate its association with obesity. In a case–cohort study nested within the Women's Health Initiative cohort of postmenopausal women, baseline plasma samples from 457 colorectal cancer cases and 841 subcohort subjects were assayed for seven adipokines—adiponectin, leptin, plasminogen activator inhibitor-1 (PAI-1), resistin, hepatocyte growth factor, interleukin-6 (IL-6), and TNF-α. Serum insulin and estradiol values measured previously were also available for data analysis. After adjusting for age, race, smoking, colonoscopy history, and estrogen level, a low level of anti-inflammatory adiponectin and high levels of proinflammatory leptin, PAI-1, and IL-6 were associated with increased colorectal cancer risk, though only leptin remained significant after further adjustment for insulin [HRs comparing extreme quartiles (HRQ4–Q1), 1.84; 95% CI, 1.17–2.90]. Mediation analyses showed that leptin and insulin partially explained the association between waist circumference and colorectal cancer and attenuated it by 25% and 37%, respectively, with insulin being a significant mediator (P = 0.041). Our findings support the conclusion that adipokines involved in inflammation are associated with colorectal cancer risk, but that their effects may be mediated mostly by insulin, with leptin exerting an independent effect. Hyperinsulinemia and hyperleptinemia may therefore partially explain the adiposity association with colorectal cancer in postmenopausal women. Cancer Res; 72(12); 3029–37. ©2012 AACR.
Data from Host Response to Short-term, Single-Agent Chemotherapy Induces Matrix Metalloproteinase-9 Expression and Accelerates Metastasis in Mice
Authors: Gingis-Velitski Svetlana , Loven David , Benayoun Liat , Munster Michal , Bril Rotem , Voloshin Tali , Alishekevitz Dror , Bertolini Francesco , Shaked Yuval
Published: March 2024

Abstract
Mounting evidence suggests that bone marrow–derived cells (BMDC) contribute to tumor growth, angiogenesis, and metastasis. In acute reactions to cancer therapy, several types of BMDCs are rapidly mobilized to home tumors. Although this host reaction to therapy can promote tumor regrowth, its contribution to metastasis has not been explored. To focus only on the effects of chemotherapy on the host, we studied non–tumor-bearing mice. Plasma from animals treated with the chemotherapy paclitaxel induced angiogenesis, migration, and invasion of tumor cells along with host cell colonization. Lesser effects were seen with the chemotherapy gemcitabine. Conditioned medium from BMDCs and plasma from chemotherapy-treated mice each promoted metastatic properties in tumor cells by inducing matrix metalloproteinase-9 (MMP9) and epithelial-to-mesenchymal transition. In mice in which Lewis lung carcinoma cells were injected intravenously, treatment with paclitaxel, but not gemcitabine or vehicle, accelerated metastases in a manner that could be blocked by an MMP9 inhibitor. Moreover, chimeric mice reconstituted with BMDC where MMP9 activity was attenuated did not support accelerated metastasis by carcinoma cells that were pretreated with chemotherapy before their introduction to host animals. Taken together, our findings illustrate how some chemotherapies can exert prometastatic effects that may confound treatment outcomes. Cancer Res; 71(22); 6986–96. ©2011 AACR.
Data from Insulin Increases De Novo Steroidogenesis in Prostate Cancer Cells
Authors: Lubik Amy A. , Gunter Jennifer H. , Hendy Stephen C. , Locke Jennifer A. , Adomat Hans H. , Thompson Vanessa , Herington Adrian , Gleave Martin E. , Pollak Michael , Nelson Colleen C.
Published: March 2024

Abstract
Androgen-dependent pathways regulate maintenance and growth of normal and malignant prostate tissues. Androgen deprivation therapy (ADT) exploits this dependence and is used to treat metastatic prostate cancer; however, regression initially seen with ADT gives way to development of incurable castration-resistant prostate cancer (CRPC). Although ADT generates a therapeutic response, it is also associated with a pattern of metabolic alterations consistent with metabolic syndrome including elevated circulating insulin. Because CRPC cells are capable of synthesizing androgens de novo, we hypothesized that insulin may also influence steroidogenesis in CRPC. In this study, we examined this hypothesis by evaluating the effect of insulin on steroid synthesis in prostate cancer cell lines. Treatment with 10 nmol/L insulin increased mRNA and protein expression of steroidogenesis enzymes and upregulated the insulin receptor substrate insulin receptor substrate 2 (IRS-2). Similarly, insulin treatment upregulated intracellular testosterone levels and secreted androgens, with the concentrations of steroids observed similar to the levels reported in prostate cancer patients. With similar potency to dihydrotestosterone, insulin treatment resulted in increased mRNA expression of prostate-specific antigen. CRPC progression also correlated with increased expression of IRS-2 and insulin receptor in vivo. Taken together, our findings support the hypothesis that the elevated insulin levels associated with therapeutic castration may exacerbate progression of prostate cancer to incurable CRPC in part by enhancing steroidogenesis. Cancer Res; 71(17); 5754–64. ©2011 AACR.
Data from Hypoxia Induces Escape from Innate Immunity in Cancer Cells via Increased Expression of ADAM10: Role of Nitric Oxide
Authors: Barsoum Ivraym B. , Hamilton Thomas K. , Li Xin , Cotechini Tiziana , Miles Ellen A. , Siemens D. Robert , Graham Charles H.
Published: March 2024

Abstract
One key to malignant progression is the acquired ability of tumor cells to escape immune-mediated lysis. Whereas tumor hypoxia is known to play a causal role in cancer metastasis and resistance to therapy, the link between hypoxia and immune escape in cancer remains poorly understood. Here, we show that hypoxia induces tumor cell resistance to lysis mediated by immune effectors and that this resistance to lysis occurs via a hypoxia-inducible factor-1 (HIF-1)–dependent pathway linked to increased expression of the metalloproteinase ADAM10. This enzyme is required for the hypoxia-induced shedding of MHC class I chain–related molecule A (MICA), a ligand that triggers the cytolytic action of immune effectors, from the surface of tumor cells. Indeed, our findings show a mechanistic link between hypoxia-induced accumulation of the α-subunit of HIF-1 (HIF-1α), increased expression of ADAM10, and decreased surface MICA levels leading to tumor cell resistance to lysis mediated by innate immune effectors. Nitric oxide mimetic agents interfered with the hypoxia-induced accumulation of HIF-1α and with the hypoxia-induced upregulation of ADAM10 expression required for decreased surface MICA expression and resistance to lysis. Furthermore, treatment of tumor-bearing mice with nitroglycerin, a nitric oxide mimetic, attenuated tumor growth by a mechanism that relied upon innate immune effector cells. Together, these findings reveal a novel mechanism by which the hypoxic tumor microenvironment contributes to immune escape in cancer, lending support to potential immunotherapeutic strategies involving the use of nitric oxide mimetics. Cancer Res; 71(24); 7433–41. ©2011 AACR.
Data from SMAC Mimetic (JP1201) Sensitizes Non–Small Cell Lung Cancers to Multiple Chemotherapy Agents in an IAP-Dependent but TNF-α–Independent Manner
Authors: Greer Rachel M. , Peyton Michael , Larsen Jill E. , Girard Luc , Xie Yang , Gazdar Adi F. , Harran Patrick , Wang Lai , Brekken Rolf A. , Wang Xiaodong , Minna John D.
Published: March 2024

Abstract
Inhibitors of apoptosis proteins (IAP) are key regulators of apoptosis and are inhibited by the second mitocondrial activator of caspases (SMAC). Previously, a small subset of TNF-α–expressing non–small cell lung cancers (NSCLC) was found to be sensitive to SMAC mimetics alone. In this study, we determined if a SMAC mimetic (JP1201) could sensitize nonresponsive NSCLC cell lines to standard chemotherapy. We found that JP1201 sensitized NSCLCs to doxorubicin, erlotinib, gemcitabine, paclitaxel, vinorelbine, and the combination of carboplatin with paclitaxel in a synergistic manner at clinically achievable drug concentrations. Sensitization did not occur with platinum alone. Furthermore, sensitization was specific for tumor compared with normal lung epithelial cells, increased in NSCLCs harvested after chemotherapy treatment, and did not induce TNF-α secretion. Sensitization also was enhanced in vivo with increased tumor inhibition and increased survival of mice carrying xenografts. These effects were accompanied by caspase 3, 4, and 9 activation, indicating that both mitochondrial and endoplasmic reticulum stress-induced apoptotic pathways are activated by the combination of vinorelbine and JP1201. Chemotherapies that induce cell death through the mitochondrial pathway required only inhibition of X-linked IAP (XIAP) for sensitization, whereas chemotherapies that induce cell death through multiple apoptotic pathways required inhibition of cIAP1, cIAP2, and XIAP. Therefore, the data suggest that IAP-targeted therapy using a SMAC mimetic provides a new therapeutic strategy for synergistic sensitization of NSCLCs to standard chemotherapy agents, which seems to occur independently of TNF-α secretion. Cancer Res; 71(24); 7640–8. ©2011 AACR.
Data from Cell-Cycle Regulator Cks1 Promotes Hepatocellular Carcinoma by Supporting NF-κB–Dependent Expression of Interleukin-8
Authors: Lee Eun-Kyoung , Kim Dae-Ghon , Kim Jang-Seong , Yoon Yeup
Published: March 2024

Abstract
The cell-cycle regulator Cks1 has recently been implicated in Skp2-mediated ubiquitination of the tumor suppressor protein p27. In this article, we report that Cks1 exerts a Skp2-independent regulation of NF-κB that promotes interleukin-8 (IL-8) expression, which is critical to hepatocellular carcinoma (HCC) growth. Cks1 was upregulated frequently in human HCC tissues and cell lines. Cks1 knockdown in HCC cells elevated p27 levels and decreased tumorigenicity in a manner that was also associated with a strong downregulation of IL-8 expression. IL-8 downregulation was not phenocopied by either RNAi-mediated knockdown of Skp2 or ectopic overexpression of p27. However, attenuation of IL-8 expression itself was sufficient to blunt HCC growth. Mechanistic investigations revealed that IL-8 was controlled at a transcriptional level by Cks1 targeting of the NF-κB regulator IκBα, which led to NF-κB activation and IL-8 expression, through a p27-independent regulation of IκB kinase complex components. Collectively, our findings support the hypothesis that Cks1 supports hepatocarcinogenesis by NF-κB–mediated regulation of IL-8 expression, broadening the function of Cks1 in cancer beyond its role as a Skp2 cofactor in p27 ubiquitination. Cancer Res; 71(21); 6827–35. ©2011 AACR.
Data from TRPM7 Is Required for Breast Tumor Cell Metastasis
Authors: Middelbeek Jeroen , Kuipers Arthur J. , Henneman Linda , Visser Daan , Eidhof Ilse , van Horssen Remco , Wieringa Bé , Canisius Sander V. , Zwart Wilbert , Wessels Lodewyk F. , Sweep Fred C.G.J. , Bult Peter , Span Paul N. , van Leeuwen Frank N. , Jalink Kees
Published: March 2024

Abstract
TRPM7 encodes a Ca2+-permeable nonselective cation channel with kinase activity. TRPM7 has been implicated in control of cell adhesion and migration, but whether TRPM7 activity contributes to cancer progression has not been established. Here we report that high levels of TRPM7 expression independently predict poor outcome in breast cancer patients and that it is functionally required for metastasis formation in a mouse xenograft model of human breast cancer. Mechanistic investigation revealed that TRPM7 regulated myosin II–based cellular tension, thereby modifying focal adhesion number, cell–cell adhesion and polarized cell movement. Our findings therefore suggest that TRPM7 is part of a mechanosensory complex adopted by cancer cells to drive metastasis formation. Cancer Res; 72(16); 4250–61. ©2012 AACR.
Data from Iodide Transporter NIS Regulates Cancer Cell Motility and Invasiveness by Interacting with the Rho Guanine Nucleotide Exchange Factor LARG
Authors: Lacoste Claire , Hervé Julie , Bou Nader Myriam , Dos Santos Alexandre , Moniaux Nicolas , Valogne Yannick , Montjean Rodrick , Dorseuil Olivier , Samuel Didier , Cassio Doris , Portulano Carla , Carrasco Nancy , Bréchot Christian , Faivre Jamila
Published: March 2024

Abstract
A number of solute carrier (SLC) proteins are subject to changes in expression and activity during carcinogenesis. Whether these changes play a role in carcinogenesis is unclear, except for some nutrients and ion carriers whose deregulation ensures the necessary reprogramming of energy metabolism in cancer cells. In this study, we investigated the functional role in tumor progression of the sodium/iodide symporter (NIS; aka SLC5A5), which is upregulated and mislocalized in many human carcinomas. Notably, we found that NIS enhanced cell migration and invasion without ion transport being involved. These functions were mediated by NIS binding to leukemia-associated RhoA guanine exchange factor, a Rho guanine exchange factor that activates the small GTPase RhoA. Sequestering NIS in intracellular organelles or impairing its targeting to the cell surface (as observed in many cancers) led to a further increase in cell motility and invasiveness. In sum, our results established NIS as a carrier protein that interacts with a major cell signaling hub to facilitate tumor cell locomotion and invasion. Cancer Res; 72(21); 5505–15. ©2012 AACR.
Data from NF-κB Hyperactivation in Tumor Tissues Allows Tumor-Selective Reprogramming of the Chemokine Microenvironment to Enhance the Recruitment of Cytolytic T Effector Cells
Authors: Muthuswamy Ravikumar , Berk Erik , Junecko Beth Fallert , Zeh Herbert J. , Zureikat Amer H. , Normolle Daniel , Luong The Minh , Reinhart Todd A. , Bartlett David L. , Kalinski Pawel
Published: March 2024

Abstract
Tumor infiltration with effector CD8+ T cells (Teff) predicts longer recurrence-free survival in many types of human cancer, illustrating the broad significance of Teff for effective immunosurveillance. Colorectal tumors with reduced accumulation of Teff express low levels of Teff-attracting chemokines such as CXCL10/IP10 and CCL5/RANTES. In this study, we investigated the feasibility of enhancing tumor production of Teff-attracting chemokines as a cancer therapeutic strategy using a tissue explant culture system to analyze chemokine induction in intact tumor tissues. In different tumor explants, we observed highly heterogeneous responses to IFNα or poly-I:C (a TLR3 ligand) when they were applied individually. In contrast, a combination of IFNα and poly-I:C uniformly enhanced the production of CXCL10 and CCL5 in all tumor lesions. Moreover, these effects could be optimized by the further addition of COX inhibitors. Applying this triple combination also uniformly suppressed the production of CCL22/MDC, a chemokine associated with infiltration of T regulatory cells (Treg). The Teff-enhancing effects of this treatment occurred selectively in tumor tissues, as compared with tissues derived from tumor margins. These effects relied on the increased propensity of tumor-associated cells (mostly fibroblasts and infiltrating inflammatory cells) to hyperactivate NF-κB and produce Teff-attracting chemokines in response to treatment, resulting in an enhanced ability of the treated tumors to attract Teff cells and reduced ability to attract Treg cells. Together, our findings suggest the feasibility of exploiting NF-κB hyperactivation in the tumor microenvironment to selectively enhance Teff entry into colon tumors. Cancer Res; 72(15); 3735–43. ©2012 AACR.
Data from Estrogen Promotes ER-Negative Tumor Growth and Angiogenesis through Mobilization of Bone Marrow–Derived Monocytes
Authors: Iyer Vandana , Klebba Ina , McCready Jessica , Arendt Lisa M. , Betancur-Boissel Monica , Wu Meng-Fen , Zhang Xiaomei , Lewis Michael T. , Kuperwasser Charlotte
Published: March 2024

Abstract
Estrogen has a central role in the genesis and progression of breast cancers whether they are positive or negative for the estrogen receptor (ER). While therapies that disrupt estrogen biosynthesis or ER activity can treat these diseases in postmenopausal women, in younger women where ovarian function remains intact, these anti-estrogen therapies are not as effective. Moreover, emerging clinical evidence suggests that estrogen may promote other cancers. Thus, circulating estrogens may participate in cancer pathogenesis in ways that are not yet understood. In this study, we show that estrogen can promote the outgrowth of murine xenograft tumors established from patient-derived ER-negative breast cancer cells by influencing the mobilization and recruitment of a proangiogenic population of bone marrow–derived myeloid cells. ERα expression was necessary and sufficient in the bone marrow–derived cells themselves to promote tumor formation in response to estrogen. Our findings reveal a novel way in which estrogen promotes tumor formation, with implications for the development and application of anti-estrogen therapies to treat cancer in premenopausal women. Cancer Res; 72(11); 2705–13. ©2012 AACR.
Data from CXCR6 Upregulation Contributes to a Proinflammatory Tumor Microenvironment That Drives Metastasis and Poor Patient Outcomes in Hepatocellular Carcinoma
Authors: Gao Qiang , Zhao Ying-Jun , Wang Xiao-Ying , Qiu Shuang-Jian , Shi Ying-Hong , Sun Jian , Yi Yong , Shi Jie-Yi , Shi Guo-Ming , Ding Zhen-Bin , Xiao Yong-Sheng , Zhao Zhong-Hua , Zhou Jian , He Xiang-Huo , Fan Jia
Published: March 2024

Abstract
CXC chemokines and their cognate receptors have been implicated widely in cancer pathogenesis. In this study, we report a critical causal relationship between CXCR6 expression and tumorigenesis in the setting of human hepatocellular carcinoma (HCC). Among the CXC chemokine receptors, only CXCR6 was detected in all the hepatoma cell lines studied. Moreover, in HCC tissue, CXCR6 expression was significantly higher than in noncancerous liver tissues. Reduction of CXCR6 or its ligand CXCL16 in cancer cells reduced cell invasion in vitro and tumor growth, angiogenesis, and metastases in vivo. Importantly, loss of CXCR6 led to reduced Gr-1+ neutrophil infiltration and decreased neoangiogenesis in hepatoma xenografts via inhibition of proinflammatory cytokine production. Clinically, high expression of CXCR6 was an independent predictor of increased recurrence and poor survival in HCCs. Human HCC samples expressing high levels of CXCR6 also contained an increased number of CD66b+ neutrophils and microvessels, and the combination of CXCR6 and neutrophils was a superior predictor of recurrence and survival than either marker used alone. Together, our findings suggest that elevated expression of CXCR6 promotes HCC invasiveness and a protumor inflammatory environment and is associated with poor patient outcome. These results support the concept that inhibition of the CXCR6–CXCL16 pathway may improve prognosis after HCC treatment. Cancer Res; 72(14); 3546–56. ©2012 AACR.
Data from Monocytic CCR2+ Myeloid-Derived Suppressor Cells Promote Immune Escape by Limiting Activated CD8 T-cell Infiltration into the Tumor Microenvironment
Authors: Lesokhin Alexander M. , Hohl Tobias M. , Kitano Shigehisa , Cortez Czrina , Hirschhorn-Cymerman Daniel , Avogadri Francesca , Rizzuto Gabrielle A. , Lazarus John J. , Pamer Eric G. , Houghton Alan N. , Merghoub Taha , Wolchok Jedd D.
Published: March 2024

Abstract
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that accumulate during tumor formation, facilitate immune escape, and enable tumor progression. MDSCs are important contributors to the development of an immunosuppressive tumor microenvironment that blocks the action of cytotoxic antitumor T effector cells. Heterogeneity in these cells poses a significant barrier to studying the in vivo contributions of individual MDSC subtypes. Herein, we show that granulocyte-macrophage colony stimulating factor, a cytokine critical for the numeric and functional development of MDSC populations, promotes expansion of a monocyte-derived MDSC population characterized by expression of CD11b and the chemokine receptor CCR2. Using a toxin-mediated ablation strategy to target CCR2-expressing cells, we show that these monocytic MDSCs regulate entry of activated CD8 T cells into the tumor site, thereby limiting the efficacy of immunotherapy. Our results argue that therapeutic targeting of monocytic MDSCs would enhance outcomes in immunotherapy. Cancer Res; 72(4); 876–86. ©2011 AACR.
Data from Circulating Insulin-Like Growth Factors and IGF-Binding Proteins in PSA-Detected Prostate Cancer: The Large Case–Control Study ProtecT
Authors: Rowlands Mari-Anne , Holly Jeff M.P. , Gunnell David , Donovan Jenny , Lane J. Athene , Hamdy Freddie , Neal David E. , Oliver Steven , Smith George Davey , Martin Richard M.
Published: March 2024

Abstract
Circulating insulin-like growth factor-I (IGF-I) has been studied extensively in prostate cancer, but there is still little information about IGFs and IGF-binding proteins (IGFBP) in cancers detected by the prostate-specific antigen (PSA) test. Here, we report the findings of a U.K.-based case–control study to investigate circulating IGFs and IGFBPs in PSA-detected prostate cancer with regard to their potential associations with different cancer stages or grades. PSA testing was offered to 110,000 men aged 50 to 69 years from 2002 to 2009. Participants with an elevated level of PSA (≥3.0 ng/mL) underwent prostate biopsy and measurements of blood serum IGF-I, IGF-II, IGFBP-2, and IGFBP-3 obtained at recruitment. We found that serum levels of IGF-II (OR per SD increase: 1.16; 95% CI: 1.08–1.24; Ptrend < 0.001), IGFBP-2 (1.18; 1.06–1.31; Ptrend < 0.01) and IGFBP-3 (1.27; 1.19–1.36; Ptrend < 0.001), but not IGF-I (0.99; 0.93–1.04; Ptrend = 0.62), were associated with PSA-detected prostate cancer. After controlling for IGFBP-3, IGF-II was no longer associated (0.99; 0.91–1.08; Ptrend = 0.62) and IGF-I was inversely associated (0.85; 0.79–0.91; Ptrend < 0.001) with prostate cancer. In addition, no strong associations existed with cancer stage or grade. Overall, these findings suggest potentially important roles for circulating IGF-II, IGFBP-2, and IGFBP-3 in PSA-detected prostate cancer, in support of recent in vitro evidence. Although our findings for IGF-I agree with previous results from PSA screening trials, they contrast with positive associations in routinely detected disease, suggesting that reducing levels of circulating IGF-I might not prevent the initiation of prostate cancer but might, nonetheless, prevent its progression. Cancer Res; 72(2); 503–15. ©2011 AACR.
Data from A Novel Tankyrase Inhibitor Decreases Canonical Wnt Signaling in Colon Carcinoma Cells and Reduces Tumor Growth in Conditional APC Mutant Mice
Authors: Waaler Jo , Machon Ondrej , Tumova Lucie , Dinh Huyen , Korinek Vladimir , Wilson Steven Ray , Paulsen Jan Erik , Pedersen Nina Marie , Eide Tor J. , Machonova Olga , Gradl Dietmar , Voronkov Andrey , von Kries Jens Peter , Krauss Stefan
Published: March 2024

Abstract
Increased nuclear accumulation of β-catenin, a mediator of canonical Wnt signaling, is found in numerous tumors and is frequently associated with tumor progression and metastasis. Inhibition of Wnt/β-catenin signaling therefore is an attractive strategy for anticancer drugs. In this study, we have identified a novel small molecule inhibitor of the β-catenin signaling pathway, JW55, that functions via inhibition of the PARP domain of tankyrase 1 and tankyrase 2 (TNKS1/2), regulators of the β-catenin destruction complex. Inhibition of TNKS1/2 poly(ADP-ribosyl)ation activity by JW55 led to stabilization of AXIN2, a member of the β-catenin destruction complex, followed by increased degradation of β-catenin. In a dose-dependent manner, JW55 inhibited canonical Wnt signaling in colon carcinoma cells that contained mutations in either the APC (adenomatous polyposis coli) locus or in an allele of β-catenin. In addition, JW55 reduced XWnt8-induced axis duplication in Xenopus embryos and tamoxifen-induced polyposis formation in conditional APC mutant mice. Together, our findings provide a novel chemotype for targeting canonical Wnt/β-catenin signaling through inhibiting the PARP domain of TNKS1/2. Cancer Res; 72(11); 2822–32. ©2012 AACR.