bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from miR-103/107 Promote Metastasis of Colorectal Cancer by Targeting the Metastasis Suppressors DAPK and KLF4
Authors: Chen Hsin-Yi , Lin Yu-Min , Chung Hsiang-Ching , Lang Yaw-Dong , Lin Ching-Jung , Huang John , Wang Wei-Chi , Lin Feng-Mao , Chen Zhen , Huang Hsien-Da , Shyy John Y.-J. , Liang Jin-Tung , Chen Ruey-Hwa
Published: March 2024

Abstract
Metastasis is the major cause of poor prognosis in colorectal cancer (CRC), and increasing evidence supports the contribution of miRNAs to cancer progression. Here, we found that high expression of miR-103 and miR-107 (miR-103/107) was associated with metastasis potential of CRC cell lines and poor prognosis in patients with CRC. We showed that miR-103/107 targeted the known metastasis suppressors death-associated protein kinase (DAPK) and Krüppel-like factor 4 (KLF4) in CRC cells, resulting in increased cell motility and cell–matrix adhesion and decreased cell–cell adhesion and epithelial marker expression. miR-103/107 expression was increased in the presence of hypoxia, thereby potentiating DAPK and KLF4 downregulation and hypoxia-induced motility and invasiveness. In mouse models of CRC, miR-103/107 overexpression potentiated local invasion and liver metastasis effects, which were suppressed by reexpression of DAPK or KLF4. miR-103/107–mediated downregulation of DAPK and KLF4 also enabled the colonization of CRC cells at a metastatic site. Clinically, the signature of a miR-103/107 high, DAPK low, and KLF4 low expression profile correlated with the extent of lymph node and distant metastasis in patients with CRC and served as a prognostic marker for metastasis recurrence and poor survival. Our findings therefore indicate that miR-103/107–mediated repression of DAPK and KLF4 promotes metastasis in CRC, and this regulatory circuit may contribute in part to hypoxia-stimulated tumor metastasis. Strategies that disrupt this regulation might be developed to block CRC metastasis. Cancer Res; 72(14); 3631–41. ©2012 AACR.
Data from Definition of Genetic Events Directing the Development of Distinct Types of Brain Tumors from Postnatal Neural Stem/Progenitor Cells
Authors: Hertwig Falk , Meyer Katharina , Braun Sebastian , Ek Sara , Spang Rainer , Pfenninger Cosima V. , Artner Isabella , Prost Gaëlle , Chen Xinbin , Biegel Jaclyn A. , Judkins Alexander R. , Englund Elisabet , Nuber Ulrike A.
Published: March 2024

Abstract
Although brain tumors are classified and treated based upon their histology, the molecular factors involved in the development of various tumor types remain unknown. In this study, we show that the type and order of genetic events directs the development of gliomas, central nervous system primitive neuroectodermal tumors, and atypical teratoid/rhabdoid-like tumors from postnatal mouse neural stem/progenitor cells (NSC/NPC). We found that the overexpression of specific genes led to the development of these three different brain tumors from NSC/NPCs, and manipulation of the order of genetic events was able to convert one established tumor type into another. In addition, loss of the nuclear chromatin-remodeling factor SMARCB1 in rhabdoid tumors led to increased phosphorylation of eIF2α, a central cytoplasmic unfolded protein response (UPR) component, suggesting a role for the UPR in these tumors. Consistent with this, application of the proteasome inhibitor bortezomib led to an increase in apoptosis of human cells with reduced SMARCB1 levels. Taken together, our findings indicate that the order of genetic events determines the phenotypes of brain tumors derived from a common precursor cell pool, and suggest that the UPR may represent a therapeutic target in atypical teratoid/rhabdoid tumors. Cancer Res; 72(13); 3381–92. ©2012 AACR.
Data from A Potent Vaccination Strategy That Circumvents Lymphodepletion for Effective Antitumor Adoptive T-cell Therapy
Authors: Cho Hyun-Il , Reyes-Vargas Eduardo , Delgado Julio C. , Celis Esteban
Published: March 2024

Abstract
Adoptive cell therapy using tumor-reactive T lymphocytes is a promising approach for treating advanced cancer. Successful tumor eradication depends primarily on the expansion and survival of the adoptively transferred T cells. Lymphodepletion using total body irradiation (TBI) and administering high-dose interleukin (IL)-2 have been used with adoptive cell therapy to promote T-cell expansion and survival to achieve maximal therapeutic effects. However, TBI and high-dose IL-2 increase the risk for major complications that impact overall survival. Here we describe an alternative approach to TBI and high-dose IL-2 for optimizing adoptive cell therapy, resulting in dramatic therapeutic effects against established melanomas in mice. Administration of a potent, noninfectious peptide vaccine after adoptive cell therapy dramatically increased antigen-specific T-cell numbers leading to enhancement in the survival of melanoma-bearing mice. Furthermore, combinations of peptide vaccination with PD1 blockade or IL-2/anti-IL-2 antibody complexes led to complete disease eradication and long-term survival in mice with large tumors receiving adoptive cell therapy. Our results indicate that PD1 blockade and IL-2/anti-IL-2 complexes enhance both the quantitative and qualitative aspects of the T-cell responses induced by peptide vaccination after adoptive cell therapy. These findings could be useful for the optimization of adoptive cell therapy in cancer patients without the need of toxic adjunct procedures. Cancer Res; 72(8); 1986–95. ©2012 AACR.
Data from Platelets and P-Selectin Control Tumor Cell Metastasis in an Organ-Specific Manner and Independently of NK Cells
Authors: Coupland Lucy A. , Chong Beng H. , Parish Christopher R.
Published: March 2024

Abstract
The prometastatic role of platelets has long been recognized with proposed mechanisms of action including shielding tumor cells from natural killer (NK) cell destruction and aiding endothelial attachment and extravasation of tumor cells with platelet P-selectin being implicated in these processes. However, many aspects of the prometastatic function of platelets remain unclear. In this study, we used mouse models of metastatic breast cancer and melanoma to investigate the platelet effect, focusing on organ specificity, the relationship with NK cells and the relative importance of platelet-derived versus endothelial-derived P-selectin. We found that platelets promote lung metastasis in the absence of NK cells in both acute and spontaneous metastasis models. In addition, the prometastatic action of platelets was found to be organ specific, clearly enhancing lung metastasis but not affecting B16F1 liver metastasis, in fact, liver metastasis was enhanced in the absence of platelets. Furthermore, the profound antimetastatic activity of NK cells was equally effective in the presence or absence of platelets and chronologically distinct from the prometastatic role of platelets. Finally, it was shown that endothelial-derived P-selectin is just as important as platelet-derived P-selectin in promoting lung metastasis and also plays an important role in liver metastasis. Taken together, our findings help clarify the roles of platelets, NK cells and P-selectin in metastasis, and they identify P-selectin as an attractive therapeutic target for preventing metastasis in multiple organs. Cancer Res; 72(18); 4662–71. ©2012 AACR.
Data from Stress-Regulated Transcription Factor ATF4 Promotes Neoplastic Transformation by Suppressing Expression of the INK4a/ARF Cell Senescence Factors
Authors: Horiguchi Michiko , Koyanagi Satoru , Okamoto Akinori , Suzuki Satoshi O. , Matsunaga Naoya , Ohdo Shigehiro
Published: March 2024

Abstract
Many cancers overexpress ATF4, a stress-induced transcription factor that promotes cell survival under hypoxic conditions and other stresses of the tumor microenvironment, but the potential contributions of ATF4 to oncogenesis itself have been little explored. Here, we report that ATF4 promotes oncogene-induced neoplastic transformation by suppressing the expression of cellular senescence-associated genes. Strikingly, primary embryo fibroblasts from ATF4-deficient mice were resistant to transformation by coexpression of H-rasV12 and SV40 large T antigen. In wild-type cells these oncogenes induced expression of the murine Atf4 gene along with the cyclin-dependent kinase inhibitor Cdkn2a, which encodes the cell senescence-associated proteins p16INK4 and p19ARF. Elevated levels of ATF4 were sufficient to suppress expression of these proteins and drive oncogenic transformation. Conversely, genetic ablation of ATF4 led to constitutive expression of p16INK4a and p19ARF, triggering cellular senescence. Our findings define a central function for ATF4 in promoting oncogenic transformation by suppressing a central pathway of cellular senescence. Cancer Res; 72(2); 395–401. ©2011 AACR.
Data from A Positive Feedback Signaling Loop between ATM and the Vitamin D Receptor Is Critical for Cancer Chemoprevention by Vitamin D
Authors: Ting Huei-Ju , Yasmin-Karim Sayeda , Yan Shian-Jang , Hsu Jong-Wei , Lin Tzu-Hua , Zeng Weisi , Messing James , Sheu Tzong-Jeng , Bao Bo-Ying , Li Willis X. , Messing Edward , Lee Yi-Fen
Published: March 2024

Abstract
Both epidemiologic and laboratory studies have shown the chemopreventive effects of 1α,25-dihydroxyvitamin D3 (1,25-VD) in tumorigenesis. However, understanding of the molecular mechanism by which 1,25-VD prevents tumorigenesis remains incomplete. In this study, we used an established mouse model of chemical carcinogenesis to investigate how 1,25-VD prevents malignant transformation. In this model, 1,25-VD promoted expression of the DNA repair genes RAD50 and ATM, both of which are critical for mediating the signaling responses to DNA damage. Correspondingly, 1,25-VD protected cells from genotoxic stress and growth inhibition by promoting double-strand break DNA repair. Depletion of the vitamin D receptor (VDR) reduced these genoprotective effects and drove malignant transformation that could not be prevented by 1,25-VD, defining an essential role for VDR in mediating the anticancer effects of 1,25-VD. Notably, genotoxic stress activated ATM and VDR through phosphorylation of VDR. Mutations in VDR at putative ATM phosphorylation sites impaired the ability of ATM to enhance VDR transactivation activity, diminishing 1,25-VD–mediated induction of ATM and RAD50 expression. Together, our findings identify a novel vitamin D–mediated chemopreventive mechanism involving a positive feedback loop between the DNA repair proteins ATM and VDR. Cancer Res; 72(4); 958–68. ©2011 AACR.
Data from Identification of Genes Upregulated in ALK-Positive and EGFR/KRAS/ALK-Negative Lung Adenocarcinomas
Authors: Okayama Hirokazu , Kohno Takashi , Ishii Yuko , Shimada Yoko , Shiraishi Kouya , Iwakawa Reika , Furuta Koh , Tsuta Koji , Shibata Tatsuhiro , Yamamoto Seiichiro , Watanabe Shun-ichi , Sakamoto Hiromi , Kumamoto Kensuke , Takenoshita Seiichi , Gotoh Noriko , Mizuno Hideaki , Sarai Akinori , Kawano Shuichi , Yamaguchi Rui , Miyano Satoru , Yokota Jun
Published: March 2024

Abstract
Activation of the EGFR, KRAS, and ALK oncogenes defines 3 different pathways of molecular pathogenesis in lung adenocarcinoma. However, many tumors lack activation of any pathway (triple-negative lung adenocarcinomas) posing a challenge for prognosis and treatment. Here, we report an extensive genome-wide expression profiling of 226 primary human stage I–II lung adenocarcinomas that elucidates molecular characteristics of tumors that harbor ALK mutations or that lack EGFR, KRAS, and ALK mutations, that is, triple-negative adenocarcinomas. One hundred and seventy-four genes were selected as being upregulated specifically in 79 lung adenocarcinomas without EGFR and KRAS mutations. Unsupervised clustering using a 174-gene signature, including ALK itself, classified these 2 groups of tumors into ALK-positive cases and 2 distinct groups of triple-negative cases (groups A and B). Notably, group A triple-negative cases had a worse prognosis for relapse and death, compared with cases with EGFR, KRAS, or ALK mutations or group B triple-negative cases. In ALK-positive tumors, 30 genes, including ALK and GRIN2A, were commonly overexpressed, whereas in group A triple-negative cases, 9 genes were commonly overexpressed, including a candidate diagnostic/therapeutic target DEPDC1, that were determined to be critical for predicting a worse prognosis. Our findings are important because they provide a molecular basis of ALK-positive lung adenocarcinomas and triple-negative lung adenocarcinomas and further stratify more or less aggressive subgroups of triple-negative lung ADC, possibly helping identify patients who may gain the most benefit from adjuvant chemotherapy after surgical resection. Cancer Res; 72(1); 100–11. ©2011 AACR.
Data from Common Variation at BARD1 Results in the Expression of an Oncogenic Isoform That Influences Neuroblastoma Susceptibility and Oncogenicity
Authors: Bosse Kristopher R. , Diskin Sharon J. , Cole Kristina A. , Wood Andrew C. , Schnepp Robert W. , Norris Geoffrey , Nguyen Le B. , Jagannathan Jayanti , Laquaglia Michael , Winter Cynthia , Diamond Maura , Hou Cuiping , Attiyeh Edward F. , Mosse Yael P. , Pineros Vanessa , Dizin Eva , Zhang Yongqiang , Asgharzadeh Shahab , Seeger Robert C. , Capasso Mario , Pawel Bruce R. , Devoto Marcella , Hakonarson Hakon , Rappaport Eric F. , Irminger-Finger Irmgard , Maris John M.
Published: March 2024

Abstract
The mechanisms underlying genetic susceptibility at loci discovered by genome-wide association study (GWAS) approaches in human cancer remain largely undefined. In this study, we characterized the high-risk neuroblastoma association at the BRCA1-related locus, BARD1, showing that disease-associated variations correlate with increased expression of the oncogenically activated isoform, BARD1β. In neuroblastoma cells, silencing of BARD1β showed genotype-specific cytotoxic effects, including decreased substrate-adherence, anchorage-independence, and foci growth. In established murine fibroblasts, overexpression of BARD1β was sufficient for neoplastic transformation. BARD1β stabilized the Aurora family of kinases in neuroblastoma cells, suggesting both a mechanism for the observed effect and a potential therapeutic strategy. Together, our findings identify BARD1β as an oncogenic driver of high-risk neuroblastoma tumorigenesis, and more generally, they illustrate how robust GWAS signals offer genomic landmarks to identify molecular mechanisms involved in both tumor initiation and malignant progression. The interaction of BARD1β with the Aurora family of kinases lends strong support to the ongoing work to develop Aurora kinase inhibitors for clinically aggressive neuroblastoma. Cancer Res; 72(8); 2068–78. ©2012 AACR.
Data from Biomarkers of HPV in Head and Neck Squamous Cell Carcinoma
Authors: Liang Caihua , Marsit Carmen J. , McClean Michael D. , Nelson Heather H. , Christensen Brock C. , Haddad Robert I. , Clark John R. , Wein Richard O. , Grillone Gregory A. , Houseman E. Andres , Halec Gordana , Waterboer Tim , Pawlita Michael , Krane Jeffrey F. , Kelsey Karl T.
Published: March 2024

Abstract
Human papillomavirus (HPV) is an accepted cause of head and neck squamous cell carcinoma (HNSCC), and patients with HPV-associated HNSCC have a favorable prognosis. Currently, there is no general guidance on the most appropriate biomarkers for clinical assessment of HPV in these malignancies. We compared PCR-based and serologic HPV assays, as well as p16 immunohistochemistry, individually and in combination in a single population-based study to assess their associations with overall survival among patients with HNSCC, and thus their potential value as biomarkers. HPV16 serology was determined for 488 patients; immunohistochemical detection of p16 expression in tumors was conducted in a subset of 233 cases, and PCR-based methods to assess the presence of HPV16 DNA in a subset of 179 cases of tumors. Considering each biomarker individually in the subset of patients studied for all endpoints, seropositivity for the E6 and E7 proteins was significantly associated with enhanced all-cause survival in oropharyngeal disease [HRE6/E7+ = 0.1, 95% confidence interval (CI) = 0.02–0.3]. Neither the presence of HPV16 DNA nor p16 immunostaining was associated with significant enhanced overall survival in oropharyngeal disease (HRDNA = 0.9, 95% CI = 0.3–2.9; HRp16 = 0.3, 95% CI = 0.1–1.1). However, the combination of HPV-positive DNA and E6 or E7 serology was associated with enhanced overall survival in oropharyngeal disease (HRDNA+/E6/E7+ = 0.1, 95% CI = 0.02–1.0), whereas E6/E7 seronegative patients with evidence of HPV in tumor DNA did not show any evidence of favorable survival (HRDNA+/E6-/E7- = 3.4, 95% CI = 0.6–18.1). Furthermore, patients with p16 staining and E6 or E7 seropositivity had favorable survival from oropharyngeal disease (HRp16+/E6/E7+ = 0.1, 95% CI = 0.02–0.4), whereas patients who were p16 positive and E6/E7 seronegative had significantly increased hazard of all causes of death (HRp16+/E6-/E7- = 3.1, 95% CI = 1.2–7.7). A stronger association of HPV presence with prognosis (assessed by all-cause survival) is observed when “HPV-associated” HNSCC is defined using tumor status (HPV DNA status or P16) and HPV E6/E7 serology in combination rather using tumor HPV status alone. Cancer Res; 72(19); 5004–13. ©2012 AACR.
Data from Genetic Variants in Oxidative Stress–Related Genes Predict Chemoresistance in Primary Breast Cancer: A Prospective Observational Study and Validation
Authors: Yu Ke-Da , Huang A-Ji , Fan Lei , Li Wen-Feng , Shao Zhi-Ming
Published: March 2024

Abstract
Chemotherapy response in patients with primary breast cancer is difficult to predict and the role of host genetic factors has not been thoroughly investigated. We hypothesized that polymorphisms in oxidative stress (OS)-related genes, including estrogen–quinone metabolizing enzymes NQO2 and GSTM1-5, may influence disease progression and treatment response. In this prospective observational study, nineteen polymorphisms tagging known variations in candidate genes were genotyped and analyzed in 806 patients with primary breast cancer. Three functional polymorphisms, which were shown to affect gene expression levels in experiments in vitro and ex vivo, modified the effect of chemotherapy on disease-free survival. There were significant interactions between chemotherapy and individual polymorphisms or combined genotypes (designated as genetic score). Patients harboring high genetic score had a 75% reduction in the hazard of disease progression compared with patients with low genetic score when no chemotherapy was administered (HR = 0.25, 95% CI: 0.10–0.63, P = 0.005); however, they received much less survival benefit from adjuvant chemotherapy compared with patients with low genetic score when chemotherapy was administered (HR = 4.60 for interaction, 95% CI: 1.63–13.3, P = 0.004). These findings were validated in another population (n = 339). In conclusion, germline polymorphisms in OS-related genes affect chemotherapy sensitivity in breast cancer patients. Although reduced OS levels might prevent breast cancer progression, they probably compromise the effectiveness of adjuvant chemotherapy. Our findings also indicate that host-related factors must be considered for individualized chemotherapy. Cancer Res; 72(2); 408–19. ©2011 AACR.
Data from Sensitivity of Glioblastomas to Clinically Available MEK Inhibitors Is Defined by Neurofibromin 1 Deficiency
Authors: See Wendy L. , Tan I-Li , Mukherjee Joydeep , Nicolaides Theodore , Pieper Russell O.
Published: March 2024

Abstract
Loss of neurofibromin 1 (NF1) leads to hyperactivation of RAS, which in turn signals through the RAF/MEK/ERK and phosphoinositide 3-kinase (PI3K)/mTOR pathways to regulate cell growth and survival. Because NF1-deficient acute myeloid leukemias are sensitive to MEK inhibitors, we investigated here whether NF1-deficient glioblastoma multiforme (GBM) would respond to MEK inhibition. In 19 GBM cell lines, we found that treatment with the clinically available MEK inhibitors PD0325901 or AZD6244 decreased levels of phospho-ERK, the downstream effector of MEK, regardless of NF1 status. However, growth inhibition occurred only in a subset of NF1-deficient cells, in association with decreased levels of cyclin D1, increased levels of p27, and G1 arrest. As a single agent, PD0325901 suppressed the growth of NF1-deficient, MEK inhibitor–sensitive cells in vivo as well. Mechanistically, NF1-deficient, MEK inhibitor–sensitive cells were dependent upon the RAF/MEK/ERK pathway for growth and did not activate the PI3K pathway as a mechanism of acquired resistance. Importantly, NF1-deficient cells intrinsically resistant to MEK inhibition were sensitized by the addition of the dual PI3K/mTOR inhibitor PI-103. Taken together, our findings indicate that a subset of NF1-deficient GBMs may respond to MEK inhibitors currently being tested in clinical trials. Cancer Res; 72(13); 3350–9. ©2012 AACR.
Data from Inhibition of HIF Prolyl Hydroxylase-2 Blocks Tumor Growth in Mice through the Antiproliferative Activity of TGFβ
Authors: Ameln Anne Klotzsche-von , Muschter Antje , Mamlouk Soulafa , Kalucka Joanna , Prade Ina , Franke Kristin , Rezaei Maryam , Poitz David M. , Breier Georg , Wielockx Ben
Published: March 2024

Abstract
Virtually all solid tumors are dependent on a vascular network to provide them with the right amount of nutrients and oxygen. In that sense, low oxygen tension or hypoxia leads to an adaptive response that is transcriptionally regulated by the hypoxia-inducible factors (HIF), which are tightly controlled by the HIF prolyl hydroxylases (PHD). In this study, we show that inhibition of the oxygen sensor PHD2 in tumor cells stimulates vessel formation but paradoxically results in a profound reduction of tumor growth. This effect relies on the antiproliferative nature of the TGFβ signaling pathway, in a largely HIF-independent manner. Moreover, our findings reveal that PHD2 has an essential function in controlling the dual nature of TGFβ during tumorigenesis and may offer an alternative opportunity for anticancer therapy. Cancer Res; 71(9); 3306–16. ©2011 AACR.
Data from Gene Immunotherapy of Chronic Lymphocytic Leukemia: A Phase I Study of Intranodally Injected Adenovirus Expressing a Chimeric CD154 Molecule
Authors: Castro Januario E. , Melo-Cardenas Johanna , Urquiza Mauricio , Barajas-Gamboa Juan S. , Pakbaz Ramin S. , Kipps Thomas J.
Published: March 2024

Abstract
New therapies for chronic lymphocytic leukemia (CLL) are needed, particularly those that can eradicate residual disease and elicit anti-CLL immune responses. CD40 ligation on CLL cells, which can be achieved using adenovirus encoding chimeric CD154 (Ad-ISF35), enhances their ability to function as antigen-presenting cells and increases their sensitivity to clearance by immune-effector mechanisms. In this study, we report the results of a first-in-man phase I trial of intranodal direct injection (IDI) of Ad-ISF35 in patients with CLL to evaluate toxicity, safety, and tolerability. Fifteen patients received a single IDI of 1 × 1010 to 33 × 1010 Ad-ISF35 viral particles (vp), with a defined maximum tolerated dose as 1 × 1011 vp. Although the most common adverse events were transient grade 1 to 2 pain at the injection site and flu-like symptoms following IDI, some patients receiving the highest dose had transient, asymptomatic grade 3 to 4 hypophosphatemia, neutropenia, or transaminitis. Increased expression of death receptor, immune costimulatory molecules, and Ad-ISF35 vector DNA was detected in circulating CLL cells. Notably, we also observed preliminary clinical responses, including reductions in leukemia cell counts, lymphadenopathy, and splenomegaly. Six patients did not require additional therapy for more than 6 months, and three achieved a partial remission. In conclusion, Ad-ISF35 IDI was safely delivered in patients with CLLs and induced systemic biologic and clinical responses. These results provide the rationale for phase II studies in CLLs, lymphomas, and CD40-expressing solid tumors. Cancer Res; 72(12); 2937–48. ©2012 AACR.
Data from Mithramycin Represses Basal and Cigarette Smoke–Induced Expression of ABCG2 and Inhibits Stem Cell Signaling in Lung and Esophageal Cancer Cells
Authors: Zhang Mary , Mathur Aarti , Zhang Yuwei , Xi Sichuan , Atay Scott , Hong Julie A. , Datrice Nicole , Upham Trevor , Kemp Clinton D. , Ripley R. Taylor , Wiegand Gordon , Avital Itzak , Fetsch Patricia , Mani Haresh , Zlott Daniel , Robey Robert , Bates Susan E. , Li Xinmin , Rao Mahadev , Schrump David S.
Published: March 2024

Abstract
Cigarette smoking at diagnosis or during therapy correlates with poor outcome in patients with lung and esophageal cancers, yet the underlying mechanisms remain unknown. In this study, we observed that exposure of esophageal cancer cells to cigarette smoke condensate (CSC) led to upregulation of the xenobiotic pump ABCG2, which is expressed in cancer stem cells and confers treatment resistance in lung and esophageal carcinomas. Furthermore, CSC increased the side population of lung cancer cells containing cancer stem cells. Upregulation of ABCG2 coincided with increased occupancy of aryl hydrocarbon receptor, Sp1, and Nrf2 within the ABCG2 promoter, and deletion of xenobiotic response elements and/or Sp1 sites markedly attenuated ABCG2 induction. Under conditions potentially achievable in clinical settings, mithramycin diminished basal as well as CSC-mediated increases in AhR, Sp1, and Nrf2 levels within the ABCG2 promoter, markedly downregulated ABCG2, and inhibited proliferation and tumorigenicity of lung and esophageal cancer cells. Microarray analyses revealed that mithramycin targeted multiple stem cell–related pathways in vitro and in vivo. Collectively, our findings provide a potential mechanistic link between smoking status and outcome of patients with lung and esophageal cancers, and support clinical use of mithramycin for repressing ABCG2 and inhibiting stem cell signaling in thoracic malignancies. Cancer Res; 72(16); 4178–92. ©2012 AACR.
Data from Coxsackievirus B3 Is an Oncolytic Virus with Immunostimulatory Properties That Is Active against Lung Adenocarcinoma
Authors: Miyamoto Shohei , Inoue Hiroyuki , Nakamura Takafumi , Yamada Meiko , Sakamoto Chika , Urata Yasuo , Okazaki Toshihiko , Marumoto Tomotoshi , Takahashi Atsushi , Takayama Koichi , Nakanishi Yoichi , Shimizu Hiroyuki , Tani Kenzaburo
Published: March 2024

Abstract
Although oncolytic virotherapy is a promising anticancer therapy, antitumor efficacy is hampered by low tumor selectivity. To identify a potent and selective oncolytic virotherapy, we carried out large-scale two-step screening of 28 enteroviral strains and found that coxsackievirus B3 (CVB3) possessed specific oncolytic activity against nine human non–small cell lung cancer (NSCLC) cell lines. CVB3-mediated cytotoxicity was positively correlated with the expression of the viral receptors, coxsackievirus and adenovirus receptor, and decay-accelerating factor, on NSCLC cells. In vitro assays revealed that the CVB3 induced apoptosis and phosphoinositide 3-kinase/Akt and mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) survival signaling pathways, leading to cytotoxicity and regulation of CVB3 replication. Intratumoral injections of CVB3 elicited remarkable regression of preestablished NSCLC tumors in vivo. Furthermore, administrations of CVB3 into xenografts on the right flank resulted in significantly durable regression of uninjected xenografts on the left flank, where replication-competent CVB3 was detected. All treatments with CVB3 were well tolerated without treatment-related deaths. In addition, after CVB3 infection, NSCLC cells expressed abundant cell surface calreticulin and secreted ATP as well as translocated extranuclear high-mobility group box 1, which are required for immunogenic cell death. Moreover, intratumoral CVB3 administration markedly recruited natural killer cells and granulocytes, both of which contributed to the antitumor effects as shown by depletion assays, macrophages, and mature dendritic cells into tumor tissues. Together, our findings suggest that CVB3 is a potent and well-tolerated oncolytic agent with immunostimulatory properties active against both localized and metastatic NSCLC. Cancer Res; 72(10); 2609–21. ©2012 AACR.
Data from Upregulation of miR-196a and HOTAIR Drive Malignant Character in Gastrointestinal Stromal Tumors
Authors: Niinuma Takeshi , Suzuki Hiromu , Nojima Masanori , Nosho Katsuhiko , Yamamoto Hiroyuki , Takamaru Hiroyuki , Yamamoto Eiichiro , Maruyama Reo , Nobuoka Takayuki , Miyazaki Yasuaki , Nishida Toshirou , Bamba Takeo , Kanda Tatsuo , Ajioka Yoichi , Taguchi Takahiro , Okahara Satoshi , Takahashi Hiroaki , Nishida Yasunori , Hosokawa Masao , Hasegawa Tadashi , Tokino Takashi , Hirata Koichi , Imai Kohzoh , Toyota Minoru , Shinomura Yasuhisa
Published: March 2024

Abstract
Large intergenic noncoding RNAs (lincRNA) have been less studied than miRNAs in cancer, although both offer considerable theranostic potential. In this study, we identified frequent upregulation of miR-196a and lincRNA HOTAIR in high-risk gastrointestinal stromal tumors (GIST). Overexpression of miR-196a was associated with high-risk grade, metastasis and poor survival among GIST specimens. miR-196a genes are located within the HOX gene clusters and microarray expression analysis revealed that the HOXC and HOTAIR gene were also coordinately upregulated in GISTs which overexpress miR-196a. In like manner, overexpression of HOTAIR was also strongly associated with high-risk grade and metastasis among GIST specimens. RNA interference–mediated knockdown of HOTAIR altered the expression of reported HOTAIR target genes and suppressed GIST cell invasiveness. These findings reveal concurrent overexpression of HOX genes with noncoding RNAs in human cancer in this setting, revealing miR-196a and HOTAIR as potentially useful biomarkers and therapeutic targets in malignant GISTs. Cancer Res; 72(5); 1126–36. ©2012 AACR.
Data from LRIG1 Modulates Cancer Cell Sensitivity to Smac Mimetics by Regulating TNFα Expression and Receptor Tyrosine Kinase Signaling
Authors: Bai Longchuan , McEachern Donna , Yang Chao-Yie , Lu Jianfeng , Sun Haiying , Wang Shaomeng
Published: March 2024

Abstract
Smac mimetics block inhibitor of apoptosis proteins to trigger TNFα-dependent apoptosis in cancer cells. However, only a small subset of cancer cells seem to be sensitive to Smac mimetics and even sensitive cells can develop resistance. Herein, we elucidated mechanisms underlying the intrinsic and acquired resistance of cancer cells to Smac mimetics. In vitro and in vivo investigations revealed that the expression of the cell surface protein LRIG1, a negative regulator of receptor tyrosine kinases (RTK), is downregulated in resistant derivatives of breast cancer cells sensitive to Smac mimetics. RNA interference–mediated downregulation of LRIG1 markedly attenuated the growth inhibitory activity of the Smac mimetic SM-164 in drug-sensitive breast and ovarian cancer cells. Furthermore, LRIG1 downregulation attenuated TNFα gene expression induced by Smac mimetics and increased the activity of multiple RTKs, including c-Met and Ron. The multitargeted tyrosine kinase inhibitors Crizotinib and GSK1363089 greatly enhanced the anticancer activity of SM-164 in all resistant cell derivatives, with the combination of SM-164 and GSK1363089 also completely inhibiting the outgrowth of resistant tumors in vivo. Together, our findings show that both upregulation of RTK signaling and attenuated TNFα expression caused by LRIG1 downregulation confers resistance to Smac mimetics, with implications for a rational combination strategy. Cancer Res; 72(5); 1229–38. ©2012 AACR.
Data from Integrative Genomic Analyses of Sporadic Clear Cell Renal Cell Carcinoma Define Disease Subtypes and Potential New Therapeutic Targets
Authors: Dondeti Vijay R. , Wubbenhorst Bradley , Lal Priti , Gordan John D. , D'Andrea Kurt , Attiyeh Edward F. , Simon M. Celeste , Nathanson Katherine L.
Published: March 2024

Abstract
Sporadic clear cell renal cell carcinoma (ccRCC), the most common type of adult kidney cancer, is often associated with genomic copy number aberrations on chromosomes 3p and 5q. Aberrations on chromosome 3p are associated with inactivation of the tumor suppressor gene von-Hippel Lindau (VHL), which activates the hypoxia-inducible factors HIF1α and HIF2α. In contrast, ccRCC genes on chromosome 5q remain to be defined. In this study, we conducted an integrated analysis of high-density copy number and gene expression data for 54 sporadic ccRCC tumors that identified the secreted glycoprotein STC2 (stanniocalcin 2) and the proteoglycan VCAN (versican) as potential 5q oncogenes in ccRCCs. In functional assays, STC2 and VCAN each promoted tumorigenesis by inhibiting cell death. Using the same approach, we also investigated the two VHL-deficient subtypes of ccRCC, which express both HIF1α and HIF2α (H1H2) or only HIF2α (H2). This analysis revealed a distinct pattern of genomic aberrations in each group, with the H1H2 group displaying, on average, a more aberrant genome than the H2 group. Together our findings provide a significant advance in understanding ccRCCs by offering a molecular definition of two subtypes with distinct characteristics as well as two potential chromosome 5q oncogenes, the overexpression of which is sufficient to promote tumorigenesis by limiting cell death. Cancer Res; 72(1); 112–21. ©2011 AACR.
Data from MiR-10b Downregulates the Stress-Induced Cell Surface Molecule MICB, a Critical Ligand for Cancer Cell Recognition by Natural Killer Cells
Authors: Tsukerman Pinchas , Stern-Ginossar Noam , Gur Chamutal , Glasner Ariella , Nachmani Daphna , Bauman Yoav , Yamin Rachel , Vitenshtein Alon , Stanietsky Noah , Bar-Mag Tomer , Lankry Dikla , Mandelboim Ofer
Published: March 2024

Abstract
Natural killer cells (NK) are a component of innate immunity well known for their potent ability to kill virus-infected or neoplastically transformed cells following stimulation of the NK cell receptor NKG2D. One of the various ligands of NKG2D is MICB, a stress-induced ligand that has been found to be upregulated on the surface of tumor cells. However, there is little knowledge about how this upregulation may occur or how it may be selected against in tumors as a mechanism of immune escape. Here, we report that the metastasis-associated microRNA (metastamir) miR-10b directly binds to the 3′ untranslated region of MICB and downregulates its expression. Notably, antagonizing miR-10b action enhanced NKG2D-mediated killing of tumor cells in vitro and enhanced clearance of tumors in vivo. Conversely, overexpression of miR-10b downregulated MICB and impaired elimination of tumor cells. Together, our results define MICB as a novel immune target of miR-10b, implying a direct link between metastasis capability and immune escape from NK cells. Cancer Res; 72(21); 5463–72. ©2012 AACR.
Data from CD8+ T Cells Specific for Tumor Antigens Can Be Rendered Dysfunctional by the Tumor Microenvironment through Upregulation of the Inhibitory Receptors BTLA and PD-1
Authors: Fourcade Julien , Sun Zhaojun , Pagliano Ornella , Guillaume Philippe , Luescher Immanuel F. , Sander Cindy , Kirkwood John M. , Olive Daniel , Kuchroo Vijay , Zarour Hassane M.
Published: March 2024

Abstract
Cytotoxic T cells that are present in tumors and capable of recognizing tumor epitopes are nevertheless generally impotent in eliciting tumor rejection. Thus, identifying the immune escape mechanisms responsible for inducing tumor-specific CD8+ T-cell dysfunction may reveal effective strategies for immune therapy. The inhibitory receptors PD-1 and Tim-3 are known to negatively regulate CD8+ T-cell responses directed against the well-characterized tumor antigen NY-ESO-1. Here, we report that the upregulation of the inhibitory molecule BTLA also plays a critical role in restricting NY-ESO-1–specific CD8+ T-cell expansion and function in melanoma. BTLA-expressing PD-1+Tim-3− CD8+ T cells represented the largest subset of NY-ESO-1–specific CD8+ T cells in patients with melanoma. These cells were partially dysfunctional, producing less IFN-γ than BTLA− T cells but more IFN-γ, TNF, and interleukin-2 than the highly dysfunctional subset expressing all three receptors. Expression of BTLA did not increase with higher T-cell dysfunction or upon cognate antigen stimulation, as it does with PD-1, suggesting that BTLA upregulation occurs independently of functional exhaustion driven by high antigen load. Added with PD-1 and Tim-3 blockades, BTLA blockade enhanced the expansion, proliferation, and cytokine production of NY-ESO-1–specific CD8+ T cells. Collectively, our findings indicate that targeting BTLA along with the PD-1 and Tim-3 pathways is critical to reverse an important mechanism of immune escape in patients with advanced melanoma. Cancer Res; 72(4); 887–96. ©2011 AACR.
Data from CXCL10 Promotes Osteolytic Bone Metastasis by Enhancing Cancer Outgrowth and Osteoclastogenesis
Authors: Lee Jong-Ho , Kim Ha-Neui , Kim Kyung-Ok , Jin Won Jong , Lee Seungbok , Kim Hong-Hee , Ha Hyunil , Lee Zang Hee
Published: March 2024

Abstract
Amplification of the chemokines CXCL10 and RANKL has been suggested to promote osteoclast differentiation and osteolytic bone metastasis, but a function for endogenous CXCL10 in these processes is not well established. In this study, we show that endogenous CXCL10 is critical to recruit cancer cells to bone, support osteoclast differentiation and promote for the formation of osteolytic bone metastases. Neutralizing CXCL10 antibody reduced migration of cancer cells expressing the CXCL10 receptor CXCR3, and loss of CXCR3 or CXCL10 decreased bone tumor burden in vivo. Bone colonization augmented host production of CXCL10, which was required for cancer growth and subsequent osteolysis. Direct interactions between cancer cells and macrophages further stimulated CXCL10 production from macrophages. Growth of bone metastases required CXCL10-stimulated adhesion of cancer cells to type I collagen as well as RANKL-mediated osteoclast formation. Together, our findings show that CXCL10 facilitates trafficking of CXCR3-expressing cancer cells to bone, which augments its own production and promotes osteoclastic differentiation. CXCL10 therefore may represent a therapeutic target for osteolytic bone metastasis. Cancer Res; 72(13); 3175–86. ©2012 AACR.
Data from Mammographic Breast Density and Breast Cancer: Evidence of a Shared Genetic Basis
Authors: Varghese Jajini S. , Thompson Deborah J. , Michailidou Kyriaki , Lindström Sara , Turnbull Clare , Brown Judith , Leyland Jean , Warren Ruth M.L. , Luben Robert N. , Loos Ruth J. , Wareham Nicholas J. , Rommens Johanna , Paterson Andrew D. , Martin Lisa J. , Vachon Celine M. , Scott Christopher G. , Atkinson Elizabeth J. , Couch Fergus J. , Apicella Carmel , Southey Melissa C. , Stone Jennifer , Li Jingmei , Eriksson Louise , Czene Kamila , Boyd Norman F. , Hall Per , Hopper John L. , Tamimi Rulla M. , Rahman Nazneen , Easton Douglas F.
Published: March 2024

Abstract
Percent mammographic breast density (PMD) is a strong heritable risk factor for breast cancer. However, the pathways through which this risk is mediated are still unclear. To explore whether PMD and breast cancer have a shared genetic basis, we identified genetic variants most strongly associated with PMD in a published meta-analysis of five genome-wide association studies (GWAS) and used these to construct risk scores for 3,628 breast cancer cases and 5,190 controls from the UK2 GWAS of breast cancer. The signed per-allele effect estimates of single-nucleotide polymorphisms (SNP) were multiplied with the respective allele counts in the individual and summed over all SNPs to derive the risk score for an individual. These scores were included as the exposure variable in a logistic regression model with breast cancer case–control status as the outcome. This analysis was repeated using 10 different cutoff points for the most significant density SNPs (1%–10% representing 5,222–50,899 SNPs). Permutation analysis was also conducted across all 10 cutoff points. The association between risk score and breast cancer was significant for all cutoff points from 3% to 10% of top density SNPs, being most significant for the 6% (2-sided P = 0.002) to 10% (P = 0.001) cutoff points (overall permutation P = 0.003). Women in the top 10% of the risk score distribution had a 31% increased risk of breast cancer [OR = 1.31; 95% confidence interval (CI), 1.08–1.59] compared with women in the bottom 10%. Together, our results show that PMD and breast cancer have a shared genetic basis that is mediated through a large number of common variants. Cancer Res; 72(6); 1478–84. ©2012 AACR.
Data from AMPKα Modulation in Cancer Progression: Multilayer Integrative Analysis of the Whole Transcriptome in Asian Gastric Cancer
Authors: Kim Yon Hui , Liang Han , Liu Xiuping , Lee Ju-Seog , Cho Jae Yong , Cheong Jae-Ho , Kim Hoguen , Li Min , Downey Thomas J. , Dyer Matthew D. , Sun Yongming , Sun Jingtao , Beasley Ellen M. , Chung Hyun Cheol , Noh Sung Hoon , Weinstein John N. , Liu Chang-Gong , Powis Garth
Published: March 2024

Abstract
Gastric cancer is the most common cancer in Asia and most developing countries. Despite the use of multimodality therapeutics, it remains the second leading cause of cancer death in the world. To identify the molecular underpinnings of gastric cancer in the Asian population, we applied an RNA-sequencing approach to gastric tumor and noncancerous specimens, generating 680 million informative short reads to quantitatively characterize the entire transcriptome of gastric cancer (including mRNAs and miRNAs). A multilayer analysis was then developed to identify multiple types of transcriptional aberrations associated with different stages of gastric cancer, including differentially expressed mRNAs, recurrent somatic mutations, and key differentially expressed miRNAs. Through this approach, we identified the central metabolic regulator AMP-activated protein kinase (AMPK)α as a potential functional target in Asian gastric cancer. Furthermore, we experimentally showed the translational relevance of this gene as a potential therapeutic target for early-stage gastric cancer in Asian patients. Together, our findings not only provide a valuable information resource for identifying and elucidating the molecular mechanisms of Asian gastric cancer, but also represent a general integrative framework to develop more effective therapeutic targets. Cancer Res; 72(10); 2512–21. ©2012 AACR.
Data from CXCR4 Activation Defines a New Subgroup of Sonic Hedgehog–Driven Medulloblastoma
Authors: Sengupta Rajarshi , Dubuc Adrian , Ward Stacey , Yang Lihua , Northcott Paul , Woerner B. Mark , Kroll Kirsten , Luo Jingqin , Taylor Michael D. , Wechsler-Reya Robert J. , Rubin Joshua B.
Published: March 2024

Abstract
Medulloblastoma prognosis tends to be poor, despite aggressive therapy, but defining molecular subgroups may identify patients who could benefit from targeted therapies. This study used human gene array and associated clinical data to identify a new molecular subgroup of medulloblastoma characterized by coactivation of the Sonic hedgehog (SHH) and CXCR4 pathways. SHH–CXCR4 tumors were more common in the youngest patients where they were associated with desmoplastic histology. In contrast to tumors activating SHH but not CXCR4, coactivated tumors exhibited greater expression of Math1 and cyclin D1. Treatment with the CXCR4 antagonist AMD3100 inhibited cyclin D1 expression and maximal tumor growth in vivo. Mechanistic investigations revealed that SHH activation stimulated CXCR4 cell surface localization and effector signaling activity, whereas SHH absence caused CXCR4 to assume an intracellular localization. Taken together, our findings define a new medulloblastoma subgroup characterized by a functional interaction between the SHH and CXCR4 pathways, and they provide a rationale to clinically evaluate combined inhibition of SHH and CXCR4 for medulloblastoma treatment. Cancer Res; 72(1); 122–32. ©2011 AACR.
Data from Radiotherapy Increases the Permissiveness of Established Mammary Tumors to Rejection by Immunomodulatory Antibodies
Authors: Verbrugge Inge , Hagekyriakou Jim , Sharp Leslie L. , Galli Mara , West Alison , McLaughlin Nicole M. , Duret Hélène , Yagita Hideo , Johnstone Ricky W. , Smyth Mark J. , Haynes Nicole M.
Published: March 2024

Abstract
It is becoming increasingly evident that radiotherapy may benefit from coincident or subsequent immunotherapy. In this study, we examined whether the antitumor effects of radiotherapy, in established triple-negative breast tumors could be enhanced with combinations of clinically relevant monoclonal antibodies (mAb), designed to stimulate immunity [anti-(α)-CD137, α-CD40] or relieve immunosuppression [α-programmed death (PD)-1]. While the concomitant targeting of the costimulatory molecules CD137 and CD40 enhanced the antitumor effects of radiotherapy and promoted the rejection of subcutaneous BALB/c-derived 4T1.2 tumors, this novel combination was noncurative in mice bearing established C57BL/6-derived AT-3 tumors. We identified PD-1 signaling within the AT-3 tumors as a critical limiting factor to the therapeutic efficacy of α-CD137 therapy, alone and in combination with radiotherapy. Strikingly, all mice bearing established orthotopic AT-3 mammary tumors were cured when α-CD137 and α-PD-1 mAbs were combined with single- or low-dose fractionated radiotherapy. CD8+ T cells were essential for curative responses to this combinatorial regime. Interestingly, CD137 expression on tumor-associated CD8+ T cells was largely restricted to a subset that highly expressed PD-1. These CD137+PD-1High CD8+ T cells, persisted in irradiated AT-3 tumors, expressed Tim-3, granzyme B and Ki67 and produced IFN-γ ex vivo in response to phorbol 12-myristate 13-acetate (PMA) and ionomycin stimulation. Notably, radiotherapy did not deplete, but enriched tumors of functionally active, tumor-specific effector cells. Collectively, these data show that concomitant targeting of immunostimulatory and inhibitory checkpoints with immunomodulatory mAbs can enhance the curative capacity of radiotherapy in established breast malignancy. Cancer Res; 72(13); 3163–74. ©2012 AACR.