bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Proinflammatory Homeobox Gene, ISX, Regulates Tumor Growth and Survival in Hepatocellular Carcinoma
Authors: Hsu Shih-Hsien , Wang Li-Ting , Lee King-Teh , Chen Yao-Li , Liu Kwei-Yan , Suen Jau-Ling , Chai Chee-Yin , Wang Shen-Nien
Published: March 2024

Abstract
Chronic inflammation drives initiation of hepatocellular carcinoma (HCC), but the underlying mechanisms linking inflammation and tumor formation remain obscure. In this study, we compared the expression of interleukin (IL)-6 and cyclin D1 (CCND1) with the IL-6–induced homeobox gene ISX (intestine-specific homeobox) in 119 paired specimens of HCCs and adjacent normal tissues and also in paired specimens from 11 patients with non-HCCs. In pathologic analysis, ISX exhibited a tumor-specific expression pattern and a high correlation to patient survival time, tumor size, tumor number, and progression stage. Enforced expression of ISX accelerated cell proliferation and tumorigenic activity in hepatoma cells through CCND1 induction. In contrast, short hairpin RNA–mediated attenuation of ISX in hepatoma cells decreased cell proliferation and malignant transformation in vitro and in vivo. A high positive correlation existed in human hepatoma tumors between ISX and CCND1 expression. Together, our results highlight ISX as an important regulator in hepatoma progression with significant potential as a prognostic and therapeutic target in HCCs. Cancer Res; 73(2); 508–18. ©2012 AACR.
Data from Resistance to Irreversible EGF Receptor Tyrosine Kinase Inhibitors through a Multistep Mechanism Involving the IGF1R Pathway
Authors: Cortot Alexis B. , Repellin Claire E. , Shimamura Takeshi , Capelletti Marzia , Zejnullahu Kreshnik , Ercan Dalia , Christensen James G. , Wong Kwok-Kin , Gray Nathanael S. , Jänne Pasi A.
Published: March 2024

Abstract
The clinical efficacy of EGF receptor (EGFR) kinase inhibitors gefitinib and erlotinib is limited by the development of drug resistance. The most common mechanism of drug resistance is the secondary EGFR T790M mutation. Strategies to overcome EGFR T790M-mediated drug resistance include the use of mutant selective EGFR inhibitors, including WZ4002, or the use of high concentrations of irreversible quinazoline EGFR inhibitors such as PF299804. In the current study, we develop drug-resistant versions of the EGFR-mutant PC9 cell line, which reproducibly develops EGFR T790M as a mechanism of drug resistance to gefitinib. Neither PF299804-resistant nor WZ4002-resistant clones of PC9 harbor EGFR T790M. Instead, they have shown activated insulin-like growth factor receptor (IGF1R) signaling as a result of loss of expression of IGFBP3 with the IGF1R inhibitor, BMS 536924, restoring EGFR inhibitor sensitivity. Intriguingly, prolonged exposure to either PF299804 or WZ4002 results in the emergence of a more drug-resistant subclone that exhibits ERK activation. A MEK inhibitor, CI-1040, partially restores sensitivity to the EGFR/IGF1R inhibitor combination. Moreover, an IGF1R or MEK inhibitor used in combination with either PF299804 or WZ4002 completely prevents the emergence of drug-resistant clones in this model system. Our studies suggest that more effective means of inhibiting EGFR T790M will prevent the emergence of this common drug resistance mechanism in EGFR-mutant non–small cell lung cancer. However, multiple drug resistance mechanisms can still emerge. Preventing the emergence of drug resistance, by targeting pathways that become activated in resistant cancers, may be a more effective clinical strategy. Cancer Res; 73(2); 834–43. ©2012 AACR.
Data from Distinct FAK Activities Determine Progenitor and Mammary Stem Cell Characteristics
Authors: Luo Ming , Zhao Xiaofeng , Chen Song , Liu Suling , Wicha Max S. , Guan Jun-Lin
Published: March 2024

Abstract
Mammary stem cells (MaSC) and progenitor cells are important for mammary gland development and maintenance and may give rise to mammary cancer stem cells (MaCSC). Yet, there remains limited understanding of how these cells contribute to tumorigenesis. Here, we show that conditional deletion of focal adhesion kinase (FAK) in embryonic mammary epithelial cells (MaEC) decreases luminal progenitors and basal MaSCs, reducing their colony-forming and regenerative potentials in a cell-autonomous manner. Loss of FAK kinase activity in MaECs specifically impaired luminal progenitor proliferation and alveologenesis, whereas a kinase-independent activity of FAK supported ductal invasion and basal MaSC activity. Deficiency in luminal progenitors suppressed tumorigenesis and MaCSC formation in a mouse model of breast cancer. In contrast with the general inhibitory effect of FAK attenuation, inhibitors of FAK kinase preferentially inhibited proliferation and tumorsphere formation of luminal progenitor-like, but not MaSC-like, human breast cancer cells. Our findings establish distinct kinase-dependent and -independent activities of FAK that differentially regulate luminal progenitors and basal MaSCs. We suggest that targeting these distinct functions may tailor therapeutic strategies to address breast cancer heterogeneity more effectively. Cancer Res; 73(17); 5591–602. ©2013 AACR.
Data from IL-18–Primed Helper NK Cells Collaborate with Dendritic Cells to Promote Recruitment of Effector CD8+ T Cells to the Tumor Microenvironment
Authors: Wong Jeffrey L. , Berk Erik , Edwards Robert P. , Kalinski Pawel
Published: March 2024

Abstract
Chemokine-driven interactions of immune cells are essential for effective antitumor immunity. Human natural killer (NK) cells can be primed by the interleukin (IL)-1–related proinflammatory cytokine IL-18 for unique helper activity, which promotes dendritic cell (DC) activation and DC-mediated induction of type-1 immune responses against cancer. Here, we show that such IL-18–primed "helper" NK cells produce high levels of the immature DC (iDC)–attracting chemokines CCL3 and CCL4 upon exposure to tumor cells or the additional inflammatory signals IFN-α, IL-15, IL-12, or IL-2. These "helper" NK cells potently attract iDCs in a CCR5-dependent mechanism and induce high DC production of CXCR3 and CCR5 ligands (CXCL9, CXCL10, and CCL5), facilitating the subsequent recruitment of type-1 effector CD8+ T (Teff) cells. Using cells isolated from the malignant ascites of patients with advanced ovarian cancer, we show that "helper" NK cell-inducing factors can be used to enhance local production of Teff cell-recruiting chemokines. Our findings reveal the unique chemokine expression profile of "helper" NK cells and highlight the potential for using two-signal–activated NK cells to promote homing of type-1 immune effectors to the human tumor environment. Cancer Res; 73(15); 4653–62. ©2013 AACR.
Data from Werner Syndrome Helicase Has a Critical Role in DNA Damage Responses in the Absence of a Functional Fanconi Anemia Pathway
Authors: Aggarwal Monika , Banerjee Taraswi , Sommers Joshua A. , Iannascoli Chiara , Pichierri Pietro , Shoemaker Robert H. , Brosh Robert M.
Published: March 2024

Abstract
Werner syndrome is genetically linked to mutations in WRN that encodes a DNA helicase-nuclease believed to operate at stalled replication forks. Using a newly identified small-molecule inhibitor of WRN helicase (NSC 617145), we investigated the role of WRN in the interstrand cross-link (ICL) response in cells derived from patients with Fanconi anemia, a hereditary disorder characterized by bone marrow failure and cancer. In FA-D2−/− cells, NSC 617145 acted synergistically with very low concentrations of mitomycin C to inhibit proliferation in a WRN-dependent manner and induce double-strand breaks (DSB) and chromosomal abnormalities. Under these conditions, ataxia–telangiectasia mutated activation and accumulation of DNA-dependent protein kinase, catalytic subunit pS2056 foci suggested an increased number of DSBs processed by nonhomologous end-joining (NHEJ). Rad51 foci were also elevated in FA-D2−/− cells exposed to NSC 617145 and mitomycin C, suggesting that WRN helicase inhibition interferes with later steps of homologous recombination at ICL-induced DSBs. Thus, when the Fanconi anemia pathway is defective, WRN helicase inhibition perturbs the normal ICL response, leading to NHEJ activation. Potential implication for treatment of Fanconi anemia–deficient tumors by their sensitization to DNA cross-linking agents is discussed. Cancer Res; 73(17); 5497–507. ©2013 AACR.
Data from Novel DNA Damage Checkpoints Mediating Cell Death Induced by the NEDD8-Activating Enzyme Inhibitor MLN4924
Authors: Blank Jonathan L. , Liu Xiaozhen J. , Cosmopoulos Katherine , Bouck David C. , Garcia Khristofer , Bernard Hugues , Tayber Olga , Hather Greg , Liu Ray , Narayanan Usha , Milhollen Michael A. , Lightcap Eric S.
Published: March 2024

Abstract
MLN4924 is an investigational small-molecule inhibitor of the NEDD8-activating enzyme (NAE) in phase I clinical trials. NAE inhibition prevents the ubiquitination and proteasomal degradation of substrates for cullin-RING ubiquitin E3 ligases that support cancer pathophysiology, but the genetic determinants conferring sensitivity to NAE inhibition are unknown. To address this gap in knowledge, we conducted a genome-wide siRNA screen to identify genes and pathways that affect the lethality of MLN4924 in melanoma cells. Of the 154 genes identified, approximately one-half interfered with components of the cell cycle, apoptotic machinery, ubiquitin system, and DNA damage response pathways. In particular, genes involved in DNA replication, p53, BRCA1/BRCA2, transcription-coupled repair, and base excision repair seemed to be important for MLN4924 lethality. In contrast, genes within the G2–M checkpoint affected sensitivity to MLN4924 in colon cancer cells. Cell-cycle analysis in melanoma cells by flow cytometry following RNAi-mediated silencing showed that MLN4924 prevented the transition of cells from S–G2 phase after induction of rereplication stress. Our analysis suggested an important role for the p21-dependent intra-S-phase checkpoint and extensive rereplication, whereas the ATR-dependent intra-S-phase checkpoint seemed to play a less dominant role. Unexpectedly, induction of the p21-dependent intra-S-phase checkpoint seemed to be independent of both Cdt1 stabilization and ATR signaling. Collectively, these data enhance our understanding of the mechanisms by which inhibition of NEDD8-dependent ubiquitination causes cell death, informing clinical development of MLN4924. Cancer Res; 73(1); 225–34. ©2012 AACR.
Data from Potent Immunomodulatory Effects of the Trifunctional Antibody Catumaxomab
Authors: Goéré Diane , Flament Caroline , Rusakiewicz Sylvie , Poirier-Colame Vichnou , Kepp Oliver , Martins Isabelle , Pesquet Julien , Eggermont Alexander , Elias Dominique , Chaput Nathalie , Zitvogel Laurence
Published: March 2024

Abstract
Catumaxomab (CatmAb), a trifunctional bispecific antibody directed against the epithelial cell adhesion molecule (EpCAM) and the T-cell antigen CD3, is approved as intraperitoneal therapy for the treatment of malignant ascites in patients with EpCAM-positive carcinomas. The immunomonitoring results of a phase II/III study using CatmAb revealed a tumoricidal effect associated with reduced VEGF levels, CD69-expressing T cells, and the release of T-helper cell (TH)-1 cytokines. We comprehensively dissected the immunomodulatory effects of the CatmAb on the major subsets of malignant ascites-infiltrating leukocytes and the molecular fingerprint of tumor cell death. Herein we show that in the presence of EpCAM-positive tumor targets, CatmAb markedly enhanced T-cell activation [CD69, CD107A (LAMP1), HLA-DR and PD-1(PDCD1) expression] and stimulated inflammatory CD4+ TH1 and CD8+ TH1 to release IFN-γ but failed to trigger TH17 cells. Engagement of CD16-expressing cells caused upregulation of TRAIL (TNFSF10) and costimulatory CD40 and CD80 molecules. CatmAb promoted tumor cell death associated with ATP release and strongly synergized with oxaliplatin for the exposure of the three hallmarks of immunogenic cell death (calreticulin, HMGB1, and ATP). These findings warrant validation as potential biomarkers of efficacy of CatmAb. Cancer Res; 73(15); 4663–73. ©2013 AACR.
Data from Single-Molecule Genomic Data Delineate Patient-Specific Tumor Profiles and Cancer Stem Cell Organization
Authors: Sottoriva Andrea , Spiteri Inmaculada , Shibata Darryl , Curtis Christina , Tavaré Simon
Published: March 2024

Abstract
Substantial evidence supports the concept that cancers are organized in a cellular hierarchy with cancer stem cells (CSC) at the apex. To date, the primary evidence for CSCs derives from transplantation assays, which have known limitations. In particular, they are unable to report on the fate of cells within the original human tumor. Because of the difficulty in measuring tumor characteristics in patients, cellular organization and other aspects of cancer dynamics have not been quantified directly, although they likely play a fundamental role in tumor progression and therapy response. As such, new approaches to study CSCs in patient-derived tumor specimens are needed. In this study, we exploited ultradeep single-molecule genomic data derived from multiple microdissected colorectal cancer glands per tumor, along with a novel quantitative approach to measure tumor characteristics, define patient-specific tumor profiles, and infer tumor ancestral trees. We show that each cancer is unique in terms of its cellular organization, molecular heterogeneity, time from malignant transformation, and rate of mutation and apoptosis. Importantly, we estimate CSC fractions between 0.5% and 4%, indicative of a hierarchical organization responsible for long-lived CSC lineages, with variable rates of symmetric cell division. We also observed extensive molecular heterogeneity, both between and within individual cancer glands, suggesting a complex hierarchy of mitotic clones. Our framework enables the measurement of clinically relevant patient-specific characteristics in vivo, providing insight into the cellular organization and dynamics of tumor growth, with implications for personalized patient care. Cancer Res; 73(1); 41–49. ©2012 AACR.
Data from Substance P Autocrine Signaling Contributes to Persistent HER2 Activation That Drives Malignant Progression and Drug Resistance in Breast Cancer
Authors: Garcia-Recio Susana , Fuster Gemma , Fernandez-Nogueira Patricia , Pastor-Arroyo Eva M. , Park So Yeon , Mayordomo Cristina , Ametller Elisabet , Mancino Mario , Gonzalez-Farre Xavier , Russnes Hege G. , Engel Pablo , Costamagna Domiziana , Fernandez Pedro L. , Gascón Pedro , Almendro Vanessa
Published: March 2024

Abstract
ERBB receptor transmodulation by heterologous G-protein–coupled receptors (GPCR) generates functional diversity in signal transduction. Tachykinins are neuropeptides and proinflammatory cytokines that promote cell survival and cancer progression by activating several GPCRs. In this work, we found that the pain-associated tachykinin Substance P (SP) contributes to persistent transmodulation of the ERBB receptors, EGFR and HER2, in breast cancer, acting to enhance malignancy and therapeutic resistance. SP and its high-affinity receptor NK-1R were highly expressed in HER2+ primary breast tumors (relative to the luminal and triple-negative subtypes) and were overall correlated with poor prognosis factors. In breast cancer cell lines and primary cultures derived from breast cancer samples, we found that SP could activate HER2. Conversely, RNA interference-mediated attenuation of NK-1R, or its chemical inhibition, or suppression of overall GPCR-mediated signaling, all strongly decreased steady-state expression of EGFR and HER2, establishing that their basal activity relied upon transdirectional activation by GPCR. Thus, SP exposure affected cellular responses to anti-ERBB therapies. Our work reveals an important oncogenic cooperation between NK-1R and HER2, thereby adding a novel link between inflammation and cancer progression that may be targetable by SP antagonists that have been clinically explored. Cancer Res; 73(21); 6424–34. ©2013 AACR.
Data from Androgen Glucuronidation: An Unexpected Target for Androgen Deprivation Therapy, with Prognosis and Diagnostic Implications
Authors: Grosse Laurent , Pâquet Sophie , Caron Patrick , Fazli Ladan , Rennie Paul S. , Bélanger Alain , Barbier Olivier
Published: March 2024

Abstract
Androgen deprivation therapy (ADTh) remains a mainstay of prostate cancer treatment, but its efficacy is bypassed by mechanisms that are not fully understood. In human prostate cancer cells, androgen glucuronidation, catalyzed by the two UDP-glucuronosyltransferase (UGT) enzymes UGT2B15 and UGT2B17, is the major androgen inactivation pathway. In this study, we investigated the effect of ADTh on androgen glucuronidation to evaluate its potential clinical utility for prostate cancer prognosis or therapy. UGT2B15 and UGT2B17 expression was evaluated in prostate cancer specimens from untreated or treated patients and in cell models of prostate cancer exposed to clinically relevant antiandrogens. UGT2B15 and UGT2B17 protein levels in prostate were increased after 5 months of ADTh when compared with specimens from untreated patients. UGT2B15 expression remained elevated for up to 12 months, but UGT2B17 returned to initial levels as soon as after 6 months. Several androgen receptor (AR) antagonists tested caused a dose- and time-dependent stimulation of UGT2B15 and UGT2B17 expression and androgen glucuronidation in prostate cancer cell lines. The role of AR in these regulatory events was confirmed using AR-deficient LNCaP cells, in which UGT2B attenuation reduced the antiproliferative effects of AR pharmacologic antagonists. Through this combination of clinical and functional investigations, our work revealed that ADTh stimulates a local androgen metabolism in prostate cells, establishing a foundation to evaluate the potential of UGT2B15 and UGT2B17 as drug targets and/or molecular markers for ADTh responsiveness and maintenance in prostate cancer. Cancer Res; 73(23); 6963–71. ©2013 AACR.
Data from mTOR Complex 2 Is Involved in Regulation of Cbl-Dependent c-FLIP Degradation and Sensitivity of TRAIL-Induced Apoptosis
Authors: Zhao Liqun , Yue Ping , Khuri Fadlo R. , Sun Shi-Yong
Published: March 2024

Abstract
The mTOR positively regulates cell proliferation and survival through forming 2 complexes with raptor (mTOR complex 1; mTORC1) or rictor (mTOR complex 2; mTORC2). Compared with the mTORC1, relatively little is known about the biologic functions of mTORC2. This study focuses on addressing whether mTORC2 regulates apoptosis, particularly induced by TRAIL (TNFSF10). Using the mTOR kinase inhibitor, PP242, as a research tool, we found that it synergized with TRAIL to augment apoptosis of cancer cells. PP242 reduced the abundance of the short form of c-FLIP (FLIPS, CFLARS) and survivin (BIRC5). Enforced expression of ectopic FLIPS, but not survivin, attenuated augmented apoptosis induced by PP242 plus TRAIL. Thus, it is FLIPS downregulation that contributes to synergistic induction of apoptosis by PP242 plus TRAIL. PP242 decreased FLIPS stability, increased FLIPS ubiquitination, and facilitated FLIPS degradation. Moreover, knockdown of the E3 ligase Cbl (CBL) abolished PP242-induced FLIPS reduction. Thus, PP242 induces Cbl-dependent degradation of FLIPS, leading to FLIPS downregulation. Consistently, knockdown of rictor or mTOR, but not raptor, mimicked PP242 in decreasing FLIPS levels and sensitizing cells to TRAIL. Rictor knockdown decreased FLIPS stability, whereas enforced expression of rictor stabilized FLIPS. Moreover, silencing of Cbl abrogated FLIPS reduction induced by rictor knockdown. Collectively we conclude that it is mTORC2 inhibition that results in FLIPS downregulation and subsequent sensitization of TRAIL-induced apoptosis. Our findings provide the first evidence showing that mTORC2 stabilizes FLIPS, hence connecting mTORC2 signaling to the regulation of death receptor-mediated apoptosis. Cancer Res; 73(6); 1946–57. ©2012 AACR.
Data from Mature Cytotoxic CD56bright/CD16+ Natural Killer Cells Can Infiltrate Lymph Nodes Adjacent to Metastatic Melanoma
Authors: Messaoudene Meriem , Fregni Giulia , Fourmentraux-Neves Emmanuelle , Chanal Johan , Maubec Eve , Mazouz-Dorval Sarra , Couturaud Benoit , Girod Angelique , Sastre-Garau Xavier , Albert Sebastien , Guédon Charles , Deschamps Lydia , Mitilian Delphine , Cremer Isabelle , Jacquelot Nicolas , Rusakiewicz Sylvie , Zitvogel Laurence , Avril Marie-Francoise , Caignard Anne
Published: March 2024

Abstract
Melanomas are characterized by high metastatic potential, with regional lymph node representing the most frequent site of early dissemination in this disease. These regional lymph nodes also represent the primary site for differentiation of natural killer (NK) cells. Although blood-derived NK cells can efficiently lyse melanoma cells isolated from metastatic lymph node (M-LN), there has been no study of the properties of the most disease-relevant NK cells isolated from M-LN in patients with melanoma. Here, we report that M-LN contains 0.5% to 11% of CD56bright NK cells among CD45+ hematopoietic cells present and that this cell population surrounds tumor cell clusters in M-LN. This NK cell population was characterized by expression of CD62L, chemokine receptors, and high levels of natural cytotoxicity receptors (NCR), NK group 2 D (NKG2D), and DNAX accessory molecule 1 (DNAM-1). Expression of NCR-NKp30 and NKG2D correlated negatively with percentages of tumor cells in M-LN. Interestingly, M-LN contained a unique subset of mature CD56brightCD16+ NK cells displaying coregulated expression of NCR and NKG2D activating receptors. Ex vivo analyses suggested that M-LN–derived NK cells were inactive but could be activated by appropriate cytokine signals [interleukin (IL)-2 or IL-15], and could lyse metastatic melanoma cells in a highly efficient manner compared with blood-derived NK cells. Taken together, the results offer evidence that adjuvant immunotherapy that targets NK cells in M-LN for activation may improve treatment of patients with sentinel lymph node–positive melanoma. Cancer Res; 74(1); 81–92. ©2013 AACR.
Data from Endogenous Two-Photon Fluorescence Imaging Elucidates Metabolic Changes Related to Enhanced Glycolysis and Glutamine Consumption in Precancerous Epithelial Tissues
Authors: Varone Antonio , Xylas Joanna , Quinn Kyle P. , Pouli Dimitra , Sridharan Gautham , McLaughlin-Drubin Margaret E. , Alonzo Carlo , Lee Kyongbum , Münger Karl , Georgakoudi Irene
Published: March 2024

Abstract
Alterations in the balance between different metabolic pathways used to meet cellular bioenergetic and biosynthetic demands are considered hallmarks of cancer. Optical imaging relying on endogenous fluorescence has been used as a noninvasive approach to assess tissue metabolic changes during cancer development. However, quantitative correlations of optical assessments with variations in the concentration of relevant metabolites or in the specific metabolic pathways that are involved have been lacking. In this study, we use high-resolution, depth-resolved imaging, relying entirely on endogenous two-photon excited fluorescence in combination with invasive biochemical assays and mass spectrometry to demonstrate the sensitivity and quantitative nature of optical redox ratio tissue assessments. We identify significant differences in the optical redox ratio of live, engineered normal and precancerous squamous epithelial tissues. We establish that while decreases in the optical redox ratio are associated with enhanced levels of glycolysis relative to oxidative phosphorylation, increases in glutamine consumption to support energy production are associated with increased optical redox ratio values. Such mechanistic insights in the origins of optical metabolic assessments are critical for exploiting fully the potential of such noninvasive approaches to monitor and understand important metabolic changes that occur in live tissues at the onset of cancer or in response to treatment. Cancer Res; 74(11); 3067–75. ©2014 AACR.
Data from Childhood Height and Body Mass Index Were Associated with Risk of Adult Thyroid Cancer in a Large Cohort Study
Authors: Kitahara Cari M. , Gamborg Michael , Berrington de González Amy , Sørensen Thorkild I.A. , Baker Jennifer L.
Published: March 2024

Abstract
Taller stature and obesity in adulthood have been consistently associated with an increased risk of thyroid cancer, but few studies have investigated the role of childhood body size. Using data from a large prospective cohort, we examined associations for height and body mass index (BMI) at ages 7 to 13 years with risk of thyroid cancer in later life. The study population included 321,085 children from the Copenhagen School Health Records Register, born between 1930 and 1989 in Copenhagen, Denmark, with measurements of height and weight from 7 to 13 years of age. These data were linked with the Danish Cancer Registry to identify incident thyroid cancer cases (1968–2010). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for age- and sex-specific height and BMI SD scores (SDS) using proportional hazards models stratified by birth cohort and sex. During follow-up (median = 38.6 years), 171 women and 64 men were diagnosed with thyroid cancer. Both height and BMI were positively associated with thyroid cancer risk, and these associations were similar by age at measurement. Using age 10 as an example, HRs per 1 unit increase in SDS for height (∼6–7 cm) and BMI (∼ 1.5–2 kg/m2) were 1.22 (95% CI, 1.07–1.40) and 1.15 (95% CI, 1.00–1.34), respectively. These results, together with the relatively young ages at which thyroid cancers are diagnosed compared with other malignancies, suggest a potential link between early-life factors related to growth and body weight and thyroid carcinogenesis. Cancer Res; 74(1); 235–42. ©2013 AACR.
Data from Natural Human Plasmacytoid Dendritic Cells Induce Antigen-Specific T-Cell Responses in Melanoma Patients
Authors: Tel Jurjen , Aarntzen Erik H.J.G. , Baba Tetsuro , Schreibelt Gerty , Schulte Barbara M. , Benitez-Ribas Daniel , Boerman Otto C. , Croockewit Sandra , Oyen Wim J.G. , van Rossum Michelle , Winkels Gregor , Coulie Pierre G. , Punt Cornelis J.A. , Figdor Carl G. , de Vries I. Jolanda M.
Published: March 2024

Abstract
Vaccination against cancer by using dendritic cells has for more than a decade been based on dendritic cells generated ex vivo from monocytes or CD34+ progenitors. Here, we report on the first clinical study of therapeutic vaccination against cancer using naturally occurring plasmacytoid dendritic cells (pDC). Fifteen patients with metastatic melanoma received intranodal injections of pDCs activated and loaded with tumor antigen-associated peptides ex vivo. In vivo imaging showed that administered pDCs migrated and distributed over multiple lymph nodes. Several patients mounted antivaccine CD4+ and CD8+ T-cell responses. Despite the limited number of administered pDCs, an IFN signature was observed after each vaccination. These results indicate that vaccination with naturally occurring pDC is feasible with minimal toxicity and that in patients with metastatic melanoma, it induces favorable immune responses. Cancer Res; 73(3); 1063–75. ©2012 AACR.
Data from Tissue Damage–Associated “Danger Signals” Influence T-cell Responses That Promote the Progression of Preneoplasia to Cancer
Authors: He Ying , Zha Jikun , Wang Yamin , Liu Wenhua , Yang Xuanming , Yu Ping
Published: March 2024

Abstract
T-cell responses may be shaped by sterile “danger signals” that are constituted by damage-associated molecular patterns (DAMP). However, whether and what type of adaptive immune responses are triggered in vivo by DAMPs induced by tumor progression are not well characterized. In this study, we report that the production of HMGB1, an established DAMP released by dying cells, was critical for tumor progression in an established mouse model of prostate cancer. HMGB1 was required for the activation and intratumoral accumulation of T cells that expressed cytokine lymphotoxinα1β2 (LT) on their surface. Intriguingly, these tumor-activated T cells recruited macrophages to the lesion and were essential to promote the preneoplasia to invasive carcinoma in an LTβ receptor (LTβR)-dependent manner. Taken together, our findings suggest that the release of HMGB1 as an endogenous danger signal is important for priming an adaptive immune response that promotes malignant progression, with implications for cancer prevention and therapy. Cancer Res; 73(2); 629–39. ©2012 AACR.
Data from Identification of an Aurora Kinase Inhibitor Specific for the Aurora B Isoform
Authors: Xie Hua , Lee Mee-Hyun , Zhu Feng , Reddy Kanamata , Peng Cong , Li Yan , Lim Do Young , Joon Kim Dong , Li Xiang , Kang Soouk , Li Haitao , Ma Weiya , Lubet Ronald A. , Ding Jian , Bode Ann M. , Dong Zigang
Published: March 2024

Abstract
Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. In the present study, we used a ligand docking method to explore the novel scaffold of potential Aurora B inhibitors. One thousand compounds from our in-house compound library were screened against the Aurora B structure and one compound, (E)-3-((E)-4-(benzo[d][1,3]dioxol-5-yl)-2-oxobut-3-en-1-ylidene)indolin-2-one (designated herein as HOI-07) was selected for further study. HOI-07 potently inhibited in vitro Aurora B kinase activity in a dose-dependent manner, without obvious inhibition of another 49 kinases, including Aurora A. This compound suppressed Aurora B kinase activity in lung cancer cells, evidenced by the inhibition of the phosphorylation of histone H3 on Ser10 in a dose- and time-dependent manner. This inhibition resulted in apoptosis induction, G2–M arrest, polyploidy cells, and attenuation of cancer cell anchorage-independent growth. Moreover, knocking down the expression of Aurora B effectively reduced the sensitivity of cancer cells to HOI-07. Results of an in vivo xenograft mouse study showed that HOI-07 treatment effectively suppressed the growth of A549 xenografts, without affecting the body weight of mice. The expression of phospho-histone H3, phospho-Aurora B, and Ki-67 was also suppressed in the HOI-07 treatment group. Taken together, we identified HOI-07 as a specific Aurora B inhibitor, which deserves further investigation. Cancer Res; 73(2); 716–24. ©2012 AACR.
Data from An Inducible Hepatocellular Carcinoma Model for Preclinical Evaluation of Antiangiogenic Therapy in Adult Mice
Authors: Runge Anja , Hu Junhao , Wieland Matthias , Bergeest Jan-Philip , Mogler Carolin , Neumann André , Géraud Cyrill , Arnold Bernd , Rohr Karl , Komljenovic Dorde , Schirmacher Peter , Goerdt Sergij , Augustin Hellmut G.
Published: March 2024

Abstract
The limited availability of experimental tumor models that faithfully mimic the progression of human tumors and their response to therapy remains a major bottleneck to the clinical translation and application of novel therapeutic principles. To address this challenge in hepatocellular carcinoma (HCC), one of the deadliest and most common cancers in the world, we developed and validated an inducible model of hepatocarcinogenesis in adult mice. Tumorigenesis was triggered by intravenous adenoviral delivery of Cre recombinase in transgenic mice expressing the hepatocyte-specific albumin promoter, a loxP-flanked stop cassette, and the SV40 large T-antigen (iAST). Cre recombinase–mediated excision of the stop cassette led to a transient viral hepatitis and resulted in multinodular tumorigenesis within 5 to 8 weeks. Tumor nodules with histologic characteristics of human HCC established a functional vasculature by cooption, remodeling, and angiogenic expansion of the preexisting sinusoidal liver vasculature with increasing signs of vascular immaturity during tumor progression. Treatment of mice with sorafenib rapidly resulted in the induction of vascular regression, inhibition of tumor growth, and enhanced overall survival. Vascular regression was characterized by loss of endothelial cells leaving behind avascular type IV collagen–positive empty sleeves with remaining pericytes. Sorafenib treatment led to transcriptional changes of Igf1, Id1, and cMet over time, which may reflect the emergence of potential escape mechanisms. Taken together, our results established the iAST model of inducible hepatocarcinogenesis as a robust and versatile preclinical model to study HCC progression and validate novel therapies. Cancer Res; 74(15); 4157–69. ©2014 AACR.
Data from SRC Signaling Is Crucial in the Growth of Synovial Sarcoma Cells
Authors: Michels Sebastian , Trautmann Marcel , Sievers Elisabeth , Kindler Dagmar , Huss Sebastian , Renner Marcus , Friedrichs Nicolaus , Kirfel Jutta , Steiner Susanne , Endl Elmar , Wurst Peter , Heukamp Lukas , Penzel Roland , Larsson Olle , Kawai Akira , Tanaka Shinya , Sonobe Hiroshi , Schirmacher Peter , Mechtersheimer Gunhild , Wardelmann Eva , Büttner Reinhard , Hartmann Wolfgang
Published: March 2024

Abstract
Synovial sarcoma is a soft-tissue malignancy characterized by a reciprocal t(X;18) translocation encoding a chimeric transcriptional modifier. Several receptor tyrosine kinases have been found activated in synovial sarcoma; however, no convincing therapeutic concept has emerged from these findings. On the basis of the results of phosphokinase screening arrays, we here investigate the functional and therapeutic relevance of the SRC kinase in synovial sarcoma. Immunohistochemistry of phosphorylated SRC and its regulators CSK and PTP1B (PTPN1) was conducted in 30 synovial sarcomas. Functional aspects of SRC, including dependence of SRC activation on the SS18/SSX fusion proteins, were analyzed in vitro. Eventually, synovial sarcoma xenografts were treated with the SRC inhibitor dasatinib in vivo. Activated phospho (p)-(Tyr416)-SRC was detected in the majority of tumors; dysregulation of CSK or PTP1B was excluded as the reason for the activation of the kinase. Expression of the SS18/SSX fusion proteins in T-REx-293 cells was associated with increased p-(Tyr416)-SRC levels, linked with an induction of the insulin-like growth factor pathway. Treatment of synovial sarcoma cells with dasatinib led to apoptosis and inhibition of cellular proliferation, associated with reduced phosphorylation of FAK (PTK2), STAT3, IGF-IR, and AKT. Concurrent exposure of cells to dasatinib and chemotherapeutic agents resulted in additive effects. Cellular migration and invasion were dependent on signals transmitted by SRC involving regulation of the Rho GTPases Rac and RhoA. Treatment of nude mice with SYO-1 xenografts with dasatinib significantly inhibited tumor growth in vivo. In summary, SRC is of crucial biologic importance and represents a promising therapeutic target in synovial sarcoma. Cancer Res; 73(8); 2518–28. ©2013 AACR.
Data from Integrin-Free Tetraspanin CD151 Can Inhibit Tumor Cell Motility upon Clustering and Is a Clinical Indicator of Prostate Cancer Progression
Authors: Palmer Trenis D. , Martínez Carlos H. , Vasquez Catalina , Hebron Katie E. , Jones-Paris Celestial , Arnold Shanna A. , Chan Susanne M. , Chalasani Venu , Gomez-Lemus Jose A. , Williams Andrew K. , Chin Joseph L. , Giannico Giovanna A. , Ketova Tatiana , Lewis John D. , Zijlstra Andries
Published: March 2024

Abstract
Normal physiology relies on the organization of transmembrane proteins by molecular scaffolds, such as tetraspanins. Oncogenesis frequently involves changes in their organization or expression. The tetraspanin CD151 is thought to contribute to cancer progression through direct interaction with the laminin-binding integrins α3β1 and α6β1. However, this interaction cannot explain the ability of CD151 to control migration in the absence of these integrins or on non-laminin substrates. We demonstrate that CD151 can regulate tumor cell migration without direct integrin binding and that integrin-free CD151 (CD151free) correlates clinically with tumor progression and metastasis. Clustering CD151free through its integrin-binding domain promotes accumulation in areas of cell–cell contact, leading to enhanced adhesion and inhibition of tumor cell motility in vitro and in vivo. CD151free clustering is a strong regulator of motility even in the absence of α3 expression but requires PKCα, suggesting that CD151 can control migration independent of its integrin associations. The histologic detection of CD151free in prostate cancer correlates with poor patient outcome. When CD151free is present, patients are more likely to recur after radical prostatectomy and progression to metastatic disease is accelerated. Multivariable analysis identifies CD151free as an independent predictor of survival. Moreover, the detection of CD151free can stratify survival among patients with elevated prostate-specific antigen levels. Cumulatively, these studies demonstrate that a subpopulation of CD151 exists on the surface of tumor cells that can regulate migration independent of its integrin partner. The clinical correlation of CD151free with prostate cancer progression suggests that it may contribute to the disease and predict cancer progression. Cancer Res; 74(1); 173–87. ©2013 AACR.
Data from HTLV-1 bZIP Factor Suppresses Apoptosis by Attenuating the Function of FoxO3a and Altering Its Localization
Authors: Tanaka-Nakanishi Azusa , Yasunaga Jun-ichirou , Takai Ken , Matsuoka Masao
Published: March 2024

Abstract
As the infectious agent causing human adult T-cell leukemia (ATL), the human T-cell leukemia virus type 1 (HTLV-1) virus spreads in vivo primarily by cell-to-cell transmission. However, the factors that determine its transmission efficiency are not fully understood. The viral genome encodes the HTLV-1 bZIP factor (HBZ), which is expressed in all ATL cases and is known to promote T-cell proliferation. In this study, we investigated the hypothesis that HBZ also influences the survival of T cells. Through analyzing the transcriptional profile of HBZ-expressing cells, we learned that HBZ suppressed transcription of the proapoptotic gene Bim (Bcl2l11) and that HBZ-expressing cells were resistant to activation-induced apoptosis. Mechanistic investigations into how HBZ suppresses Bim expression revealed that HBZ perturbs the localization and function of FoxO3a, a critical transcriptional activator of the genes encoding Bim and also Fas ligand (FasL). By interacting with FoxO3a, HBZ not only attenuated DNA binding by FoxO3a but also sequestered the inactive form of FoxO3a in the nucleus. In a similar manner, HBZ also inhibited FasL transcription induced by T-cell activation. Further study of ATL cells identified other Bim perturbations by HBZ, including at the level of epigenetic alteration, histone modification in the promoter region of the Bim gene. Collectively, our results indicated that HBZ impairs transcription of the Bim and FasL genes by disrupting FoxO3a function, broadening understanding of how HBZ acts to promote proliferation of HTLV-1–infected T cells by blocking their apoptosis. Cancer Res; 74(1); 188–200. ©2013 AACR.
Data from CD40-Mediated Activation of Chronic Lymphocytic Leukemia Cells Promotes Their CD44-Dependent Adhesion to Hyaluronan and Restricts CCL21-Induced Motility
Authors: Girbl Tamara , Hinterseer Elisabeth , Grössinger Eva Melanie , Asslaber Daniela , Oberascher Karin , Weiss Lukas , Hauser-Kronberger Cornelia , Neureiter Daniel , Kerschbaum Hubert , Naor David , Alon Ronen , Greil Richard , Hartmann Tanja Nicole
Published: March 2024

Abstract
Microenvironmental interactions are crucial for the survival and proliferation of chronic lymphocytic leukemia (CLL) cells. CD4+ T cells that express CD40 ligand (CD40L), along with other accessory immune and stromal cells within CLL lymph nodes, provide signals needed for activation and outgrowth of the tumor clone. Furthermore, correct positioning of CLL cells within lymphoid subcompartments is essential for the transmission of these supportive signals. Thereby, interstitial cell migration and adhesion events, influenced by activational stimuli, determine CLL cell localization. CD44 has been implicated in cell activation, migration, and tissue retention via binding to its extracellular matrix ligand hyaluronan (HA). In this study, we investigated the role of CD44–HA interactions for CLL positioning and interaction with supportive microenvironments in peripheral lymph nodes, focusing on its regulation via CD40L-dependent, T-cell–mediated activation of CLL cells. We found that hyaluronan triggered a robust CCL21-induced motility of resting CLL cells. However, CD40L stimulation promoted the firm, CD44-mediated adhesion of CLL cells to hyaluronan, antagonizing their motile behavior. N-linked glycosylations of CD44, particularly associated with the variant isoform CD44v6 after CD40L activation, seemed to facilitate hyaluronan recognition by CD44. We propose that the CD40L–CD40 signaling axis provides a stop signal to motile CLL cells within lymph node compartments by inducing high avidity CD44–HA adhesion. This might retain CLL cells close to T-cell stimuli and facilitate essential interactions with hyaluronan-bearing stromal cells, collectively promoting CLL cell proliferation and survival. Cancer Res; 73(2); 561–70. ©2012 AACR.
Data from Polo-like Kinase 1: A Potential Therapeutic Option in Combination with Conventional Chemotherapy for the Management of Patients with Triple-Negative Breast Cancer
Authors: Maire Virginie , Némati Fariba , Richardson Marion , Vincent-Salomon Anne , Tesson Bruno , Rigaill Guillem , Gravier Eléonore , Marty-Prouvost Bérengère , De Koning Leanne , Lang Guillaume , Gentien David , Dumont Aurélie , Barillot Emmanuel , Marangoni Elisabetta , Decaudin Didier , Roman-Roman Sergio , Pierré Alain , Cruzalegui Francisco , Depil Stéphane , Tucker Gordon C. , Dubois Thierry
Published: March 2024

Abstract
Breast cancers are composed of molecularly distinct subtypes with different clinical outcomes and responses to therapy. To discover potential therapeutic targets for the poor prognosis-associated triple-negative breast cancer (TNBC), gene expression profiling was carried out on a cohort of 130 breast cancer samples. Polo-like kinase 1 (PLK1) was found to be significantly overexpressed in TNBC compared with the other breast cancer subtypes. High PLK1 expression was confirmed by reverse phase protein and tissue microarrays. In triple-negative cell lines, RNAi-mediated PLK1 depletion or inhibition of PLK1 activity with a small molecule (BI-2536) induced an increase in phosphorylated H2AX, G2–M arrest, and apoptosis. A soft-agar colony assay showed that PLK1 silencing impaired clonogenic potential of TNBC cell lines. When cells were grown in extracellular matrix gels (Matrigel), and exposed to BI-2536, apoptosis was observed specifically in TNBC cancerous cells, and not in a normal cell line. When administrated as a single agent, the PLK1 inhibitor significantly impaired tumor growth in vivo in two xenografts models established from biopsies of patients with TNBC. Most importantly, the administration of BI-2536, in combination with doxorubicin + cyclophosphamide chemotherapy, led to a faster complete response compared with the chemotherapy treatment alone and prevented relapse, which is the major risk associated with TNBC. Altogether, our observations suggest PLK1 inhibition as an attractive therapeutic approach, in association with conventional chemotherapy, for the management of patients with TNBC. Cancer Res; 73(2); 813–23. ©2012 AACR.
Data from Selection of Personalized Patient Therapy through the Use of Knowledge-Based Computational Models That Identify Tumor-Driving Signal Transduction Pathways
Authors: Verhaegh Wim , van Ooijen Henk , Inda Márcia A. , Hatzis Pantelis , Versteeg Rogier , Smid Marcel , Martens John , Foekens John , van de Wiel Paul , Clevers Hans , van de Stolpe Anja
Published: March 2024

Abstract
Increasing knowledge about signal transduction pathways as drivers of cancer growth has elicited the development of “targeted drugs,” which inhibit aberrant signaling pathways. They require a companion diagnostic test that identifies the tumor-driving pathway; however, currently available tests like estrogen receptor (ER) protein expression for hormonal treatment of breast cancer do not reliably predict therapy response, at least in part because they do not adequately assess functional pathway activity. We describe a novel approach to predict signaling pathway activity based on knowledge-based Bayesian computational models, which interpret quantitative transcriptome data as the functional output of an active signaling pathway, by using expression levels of transcriptional target genes. Following calibration on only a small number of cell lines or cohorts of patient data, they provide a reliable assessment of signaling pathway activity in tumors of different tissue origin. As proof of principle, models for the canonical Wnt and ER pathways are presented, including initial clinical validation on independent datasets from various cancer types. Cancer Res; 74(11); 2936–45. ©2014 AACR.
Data from The Noncoding RNA MALAT1 Is a Critical Regulator of the Metastasis Phenotype of Lung Cancer Cells
Authors: Gutschner Tony , Hämmerle Monika , Eißmann Moritz , Hsu Jeff , Kim Youngsoo , Hung Gene , Revenko Alexey , Arun Gayatri , Stentrup Marion , Groß Matthias , Zörnig Martin , MacLeod A. Robert , Spector David L. , Diederichs Sven
Published: March 2024

Abstract
The long noncoding RNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), also known as MALAT-1 or NEAT2 (nuclear-enriched abundant transcript 2), is a highly conserved nuclear noncoding RNA (ncRNA) and a predictive marker for metastasis development in lung cancer. To uncover its functional importance, we developed a MALAT1 knockout model in human lung tumor cells by genomically integrating RNA destabilizing elements using zinc finger nucleases. The achieved 1,000-fold MALAT1 silencing provides a unique loss-of-function model. Proposed mechanisms of action include regulation of splicing or gene expression. In lung cancer, MALAT1 does not alter alternative splicing but actively regulates gene expression including a set of metastasis-associated genes. Consequently, MALAT1-deficient cells are impaired in migration and form fewer tumor nodules in a mouse xenograft. Antisense oligonucleotides (ASO) blocking MALAT1 prevent metastasis formation after tumor implantation. Thus, targeting MALAT1 with ASOs provides a potential therapeutic approach to prevent lung cancer metastasis with this ncRNA serving as both predictive marker and therapeutic target. Finally, regulating gene expression, but not alternative splicing, is the critical function of MALAT1 in lung cancer metastasis. In summary, 10 years after the discovery of the lncRNA MALAT1 as a biomarker for lung cancer metastasis, our loss-of-function model unravels the active function of MALAT1 as a regulator of gene expression governing hallmarks of lung cancer metastasis. Cancer Res; 73(3); 1180–9. ©2012 AACR.