Cancer Research (CANCER RES )

Publisher: American Association for Cancer Research; International Cancer Research Foundation; William H. Donner Foundation, American Association for Cancer Research

Description

Cancer Research publishes significant, original studies in all areas of basic, clinical, translational, epidemiological, and prevention research devoted to the study of cancer and cancer-related biomedical sciences. Scientific topics include: biochemistry; chemical, physical, and viral carcinogenesis and mutagenesis; clinical investigations including clinical trials; endocrinology; epidemiology and prevention; experimental therapeutics; immunology and immunotherapy including biological therapy; molecular biology and genetics; radiobiology and radiation oncology; tumor biology; and virology. Thus its publication scope covers all subfields of cancer research. Papers are stringently reviewed and only those that report results of novel, timely, and significant research and meet high standards of scientific merit will be accepted for publication.

Impact factor 9.28

  • Hide impact factor history
     
    Impact factor
  • 5-year impact
    8.58
  • Cited half-life
    8.00
  • Immediacy index
    1.54
  • Eigenfactor
    0.30
  • Article influence
    3.08
  • Website
    Cancer Research website
  • Other titles
    Cancer chemotherapy screening data., Cancer research (Chicago, Ill.), Cancer research
  • ISSN
    0008-5472
  • OCLC
    1553285
  • Material type
    Periodical, Internet resource
  • Document type
    Journal / Magazine / Newspaper, Internet Resource

Publisher details

American Association for Cancer Research

  • Pre-print
    • Archiving status unclear
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • 12 months embargo
  • Conditions
    • NIH authors may post authors' own version in PubMed Central for release 12 months after publication
    • HHMI, Wellcome Trust, Cancer Research UK and UK Medical Research Council authors may deposit authors own version in Europe PMC for release 6 months after publication
    • AACR will deposit on behalf of these authors, if required
    • Authors final version may be deposited on institutional website or institutional repository if required by institution
    • Published source must be acknowledged
    • Must link to the publisher PDF of article on journal website
  • Classification
    ​ white

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: RAGE is a multi-functional receptor implicated in diverse processes including inflammation and cancer. In this study, we report that RAGE expression is upregulated widely in aggressive triple-negative breast cancer cells, both in primary tumors and lymph node metastases. In evaluating the functional contributions of RAGE in breast cancer, we found RAGE-deficient mice displayed a reduced propensity for breast tumor growth. In an established model of lung metastasis, systemic blockade by injection of a RAGE neutralizing antibody inhibited metastasis development. Mechanistic investigations revealed that RAGE bound to the pro-inflammatory ligand S100A7 and mediated its ability to activate ERK, NF-ĸB and cell migration. In an S100A7 transgenic mouse model of breast cancer (mS100a7a15 mice), administration of either RAGE neutralizing antibody or soluble RAGE was sufficient to inhibit tumor progression and metastasis. In this model, we found that RAGE/S100A7 conditioned the tumor microenvironment by driving the recruitment of MMP9-positive tumor-associated macrophages. Overall, our results highlight RAGE as a candidate biomarker for triple-negative breast cancers and they reveal a functional role for RAGE/S100A7 signaling in linking inflammation to aggressive breast cancer development. Copyright © 2015, American Association for Cancer Research.
    Cancer Research 01/2015;
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    ABSTRACT: Background: The tumor microenvironment (TME) is a 3D, dynamic interaction between tumor and stromal cells, extracellular matrix, and soluble factors which can promote tumor progression and resistance to therapy. Significant efforts are being made to develop long-term in vitro TME models to study cancer biology, improve drug development, and guide clinical decisions. We have developed a cost-effective micro-bioreactor culture device which enables a wide variety of dynamic cellular and TME interactions that can be monitored with in situ, label free, and non-lytic microscopic analysis. Using the 3DKUBE™, we developed a 3D breast cancer model composed of MCF-7 cells and fibroblasts in segregated co-culture and identified a highly active PI3K inhibitor that had limited activity in 2D monoculture. Based on a more complex morphologic and functional 3D mammary gland model that incorporates multiple human primary cells including epithelial cells (HuMEC), mammary fibroblasts, and adipocytes, our long-term 3D perfused tri-culture breast cancer model is designed to evaluate drug response continuously using non-lytic analysis. We theorize that different breast cancer epithelial cells will be supported in a standard 3D stromal platform which supports mammary gland function. Herein, we describe the 3DKUBE™ modifications and early optimization of a defined stromal TME which supports HuMECs in 3D perfusion. Materials & Methods: Primary human cells were used to optimize seeding conditions for silk fibroin scaffolds containing Matrigel™/collagen hydrogels, including, media composition, cellular ratios, flow rates, and analytical methods for the 3DKUBE™. Destructive analytical methods included morphology (H&E), phenotype (histology), viability & survival (CyQuant, TUNEL, Ki-67), and ER, PR, and casein expression (RT-PCR). Non-lytic assays included metabolism (resazurin reduction), cytotoxicity (LDH release), soluble biomarker expression (xMAP™), and two-photon emission fluorescence via multiphoton microscopy (MPM). Results: The 3DKUBE™ imaging window (1.25 mm thick with a refractive index of 1.590, transmittance (~90%) at wavelengths >290 nm) was replaced with a No. 1.5 glass, high resolution window allowing non-destructive, in situ microscopic imaging. MPM images obtained provided cellular detail (granularity, nuclear-cytoplasmic ratio, size). Optimization of the media conditions and cell numbers revealed that a tri-culture ratio of 1:1:1 was stable in the silk-Matrigel-collagen scaffold during prolonged static and perfusion culture in mixed media. Differentiation of adipocytes had to be performed separately from the tri-culture due to the cytotoxicity of the differentiation media to the epithelial cells. This was achieved via a serial seeding and differentiation method. Our initial drug studies revealed that cytotoxicity could be monitored over the course of a week by multiple methods, including LDH secretion, Presto blue, and CyQuant. Though non-specific drug binding (CPT-11) was seen in the complex 3D matrix, it did not materially impact total drug concentrations. Conclusions: Our current optimization results indicate our ability to grow a bioengineered 3D human breast tri-culture model under perfusion using the 3DKUBE™ while monitoring tissue structure, function, and drug response through both lytic and non-lytic methods. Future Development: The optimized perfused stroma will be used to develop ex vivo breast microtumors of clinically relevant subtypes (ER+, Her+, triple negative) validated against targeted agents. If validated, these 3D microtumors may be applied as predictive phenotypic screens to improve preclinical and clinical breast cancer drug development.
    Cancer Research 01/2015; 75.
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    ABSTRACT: Host responses are increasingly considered important for the efficacious response to experimental cancer therapies that employ viral vectors, but little is known about the specific nature of host responses required. In this study, we investigated the role of host type I interferons (IFN-I) in the efficacy of virally delivered therapeutic genes. Specifically, we used a Semliki Forest virus encoding interleukin-12 (SFV-IL-12) based on its promise as an RNA viral vector for cancer treatment. Intratumoral injection of SFV-IL-12 induced production of IFN-I as detected in serum. IFN-I production was abolished in mice deficient for the IFN-β transcriptional regulator IPS-1 and partially attenuated in mice deficient for the IFN-β signaling protein TRIF. Use of bone marrow chimeric hosts established that both hematopoietic and stromal cells were involved in IFN-I production. Macrophages, plasmacytoid and conventional dendritic cells were each implicated based on cell depletion experiments. Further, mice deficient in the IFN-I receptor abolished the therapeutic activity of SFV-IL-12, as did a specific antibody-mediated blockade of IFNAR signaling. Reduced efficacy was not caused by an impairment in IL-12 expression, because IFNAR-deficient mice expressed the viral IL-12 transgene even more strongly than wild-type hosts. Chimeric host analysis for the IFNAR involvement established a strict requirement in hematopoietic cells. Notably, while tumor-specific CD8 T lymphocytes expanded robustly after intratumoral injection of WT mice with SFV-IL-12, this did not occur in mice where IFNAR was inactivated genetically or pharmacologically. Overall, our results argued that the antitumor efficacy of a virally based transgene therapeutic relied strongly on a vector-induced IFN-I response, revealing an unexpected mechanism of action that is relevant to a broad array of current translational products in cancer research. Copyright © 2014, American Association for Cancer Research.
    Cancer Research 12/2014;
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    ABSTRACT: Carcinoma cells can transition from an epithelial-to-mesenchymal differentiation state through a process known as epithelial-mesenchymal transition (EMT). The process of EMT is characterized by alterations in the pattern of gene expression and is associated with a loss of cell polarity, an increase in invasiveness, and an increase in cells expressing cancer stem cell (CSC) markers. The reverse process of mesenchymal-to-epithelial transition (MET) can also occur, though the transitions characterizing EMT and MET can be incomplete. A growing number of transcription factors have been identified that influence the EMT/MET processes. Interestingly, SUMOylation regulates the functional activity of many of the transcription factors governing transitions between epithelial and mesenchymal states. In some cases, the transcription factor is a small ubiquitin-like modifier conjugated directly, thus altering its transcriptional activity or cell trafficking. In other cases, SUMOylation alters transcriptional mechanisms through secondary effects. This review explores the role of SUMOylation in controlling transcriptional mechanisms that regulate EMT/MET in cancer. Developing new drugs that specifically target SUMOylation offers a novel therapeutic approach to block tumor growth and metastasis. Cancer Res; 75(1); 1-5. ©2014 AACR. ©2014 American Association for Cancer Research.
    Cancer Research 12/2014;
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    ABSTRACT: Cancer immunotherapy has proven to be challenging as it depends on overcoming multiple mechanisms that mediate immune tolerance to self-antigens. A growing understanding of immune tolerance has been the foundation for new approaches to cancer immunotherapy. Adoptive transfer of immune effectors such as antitumor mAb and chimeric antigen receptor T cells bypasses many of the mechanisms involved in immune tolerance by allowing for expansion of tumor-specific effectors ex vivo. Vaccination with whole tumor cells, protein, peptide, or dendritic cells has proven challenging, yet may be more useful when combined with other cancer immunotherapeutic strategies. Immunomodulatory approaches to cancer immunotherapy include treatment with agents that enhance and maintain T-cell activation. Recent advances in the use of checkpoint blockade to block negative signals and to maintain the antitumor response are particularly exciting. With our growing knowledge of immune tolerance and ways to overcome it, combination treatments are being developed, tested, and have particular promise. One example is in situ immunization that is designed to break tolerance within the tumor microenvironment. Progress in all these areas is continuing based on clear evidence that cancer immunotherapy designed to overcome immune tolerance can be useful for a growing number of patients with cancer. Cancer Res; 75(1); 1-6. ©2014 AACR. ©2014 American Association for Cancer Research.
    Cancer Research 12/2014;
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    ABSTRACT: Translation initiation factor eIF4E mediates normal cell proliferation, yet induces tumorigenesis when overexpressed. The mechanisms by which eIF4E directs such distinct biological outputs remains unknown. We found that mouse mammary morphogenesis during pregnancy and lactation is accompanied by increased cap-binding capability of eIF4E and activation of the eIF4E-dependent translational apparatus, but only subtle oscillations in eIF4E abundance. Using a transgenic mouse model engineered so that lactogenic hormones stimulate a sustained increase in eIF4E abundance in stem/progenitor cells of lactogenic mammary epithelium during successive pregnancy/lactation cycles, eIF4E overexpression increased cell self-renewal, triggered DNA replication stress, and induced formation of pre-malignant and malignant lesions. Using complementary in vivo and ex vivo approaches, we found that increasing eIF4E levels rescued cells harboring oncogenic c-Myc or H-RasV12 from DNA replication stress and oncogene-induced replication catastrophe. Our findings indicate that distinct threshold levels of eIF4E govern its biological output in lactating mammary glands, and that eIF4E overexpression in the context of stem/progenitor cell population expansion can initiate malignant transformation by enabling cells to evade DNA damage checkpoints activated by oncogenic stimuli. Maintaining eIF4E levels below its pro-neoplastic threshold is an important anticancer defense in normal cells, with important implications for understanding pregnancy-associated breast cancer. Copyright © 2014, American Association for Cancer Research.
    Cancer Research 12/2014;
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    ABSTRACT: Lung cancer is the leading cause of cancer-related fatalities. Recent success developing genotypically-targeted therapies, with potency only in well-defined subpopulations of tumors, suggests a path to improving patient survival. We utilized a library of oligonucleotide inhibitors to microRNAs, a class of post-transcriptional gene regulators, to identify novel synthetic lethal interactions between miRNA inhibition and molecular mechanisms in NSCLC. Two inhibitors, those for miR-92a and miR-1226*, produced a toxicity distribution across a panel of 27 cell lines that correlated with loss of p53 protein expression. Notably, depletion of p53 was sufficient to confer sensitivity to otherwise resistant telomerase-immortalized bronchial epithelial cells. We found that both miR inhibitors cause sequence-specific down-regulation of the miR-17~92 polycistron, and this down-regulation was toxic only in the context of p53 loss. Mechanistic studies indicated the selective toxicity of miR-17~92 polycistron inactivation was the consequence of derepression of vitamin D signaling via suppression of CYP24A1; a rate limiting enzyme in the 1α,25-dihydroxyvitamin D3 metabolic pathway. Of note, high CYP24A1 expression significantly correlated with poor patient outcome in multiple lung cancer cohorts. Our results indicate that the screening approach utilized in this study can identify clinically relevant synthetic lethal interactions, and that vitamin D receptor agonists may show enhanced efficacy in p53-negative lung cancer patients. Copyright © 2014, American Association for Cancer Research.
    Cancer Research 12/2014;
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    ABSTRACT: Perinatal factors including high birth weight have been associated with childhood brain tumors in case-control studies. However, the specific contributions of gestational age and fetal growth remain unknown, and these issues have never been examined in large cohort studies with follow-up into adulthood. We conducted a national cohort study of 3,571,574 persons born in Sweden in 1973-2008, followed up for brain tumor incidence through 2010 (maximum age 38 years) to examine perinatal and familial risk factors. There were 2,809 brain tumors in 69.7 million person-years of follow-up. After adjusting for potential confounders, significant risk factors for brain tumors included high fetal growth (incidence rate ratio [IRR] per additional 1 standard deviation, 1.04; 95% CI, 1.01-1.08, P=0.02), first-degree family history of a brain tumor (IRR, 2.43; 95% CI, 1.86-3.18, P<0.001), parental country of birth (IRR for both parents born in Sweden vs. other countries, 1.21; 95% CI, 1.09-1.35, P<0.001), and high maternal education level (Ptrend=0.01). These risk factors did not vary by age at diagnosis. The association with high fetal growth appeared to involve pilocytic astrocytomas, but not other astrocytomas, medulloblastomas, or ependymomas. Gestational age at birth, birth order, multiple birth, and parental age were not associated with brain tumors. In this large cohort study, high fetal growth was associated with an increased risk of brain tumors (particularly pilocytic astrocytomas) independently of gestational age, not only in childhood but also into young adulthood, suggesting that growth factor pathways may play an important long-term role in the etiology of certain brain tumor subtypes. Copyright © 2014, American Association for Cancer Research.
    Cancer Research 12/2014;
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    ABSTRACT: Pan- or multi-drug resistance is a central problem in clinical oncology. Here we use a genetically engineered mouse model of BRCA2-associated hereditary breast cancer to study drug resistance to several types of chemotherapy and PARP inhibition. We found that multi-drug resistance was strongly associated with an EMT-like sarcomatoid phenotype and high expression of the Abcb1b gene, which encodes the drug efflux transporter P-glycoprotein. Inhibition of P-glycoprotein could partly re-sensitize sarcomatoid tumors to the PARP inhibitor olaparib, docetaxel and doxorubicin. We propose that multi-drug resistance is a multi-factorial process and that mouse models are useful to unravel this. Copyright © 2014, American Association for Cancer Research.
    Cancer Research 12/2014;
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    ABSTRACT: Breast cancer brain metastasis is resistant to therapy and a particularly poor prognostic feature in patient survival. Altered metabolism is a common feature of cancer cells but little is known as to what metabolic changes benefit breast cancer brain metastases. We found that brain-metastatic breast cancer cells evolved the ability to survive and proliferate independent of glucose due to enhanced gluconeogenesis and oxidations of glutamine and branched chain amino acids, which together sustain the non-oxidative pentose pathway for purine synthesis. Silencing expression of fructose-1,6-bisphosphatases (FBPs) in brain metastatic cells reduced their viability and improved the survival of metastasis-bearing immunocompetent hosts. Clinically, we showed that brain metastases from human breast cancer patients expressed higher levels of FBP and glycogen than the corresponding primary tumors. Together, our findings identify a critical metabolic condition required to sustain brain metastasis, and suggest that targeting gluconeogenesis may help eradicate this deadly feature in advanced breast cancer patients. Copyright © 2014, American Association for Cancer Research.
    Cancer Research 12/2014;
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    ABSTRACT: The prototypic chitinase-like protein Chi3l1 is induced in cancers and portends a poor prognosis, but whether it contributes to cancer progression is unknown. To address this gap in knowledge we investigated the production of Chi3l1 in melanoma lung metastases. We found that Chi3l1 was induced during pulmonary melanoma metastasis and that this induction was regulated by the semaphorin Sema7a, interacting in stimulatory or inhibitory ways with its β1 integrin or Plexin C1 receptors, respectively. In mouse strains with genetic deletions of Chi3l1 or Sema7a, there was a significant reduction in pulmonary metastasis. Notably, antiserum raised against Chi3l1 or Sema7a phenocopied the reduction produced by genetic deletions. Melanoma lung metastasis was also decreased in the absence of IL-13Rα2, a recently identified receptor for Chi3l1, consistent with a key role for Chi3l1 in melanoma spread. We confirmed roles for Sema7a and Chi3l1 in pulmonary metastasis of EMT6 breast cancer cells. Taken together, our studies establish a novel pathway through which Sem7a and its receptors regulate Chi3l1, revealing a host axis involving IL-13Rα2 that plays a critical role in generating a pulmonary microenvironment that is critical to license metastasis. Copyright © 2014, American Association for Cancer Research.
    Cancer Research 12/2014;
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    ABSTRACT: Many epithelial-mesenchymal transition (EMT)-promoting transcription factors have been implicated in tumorigenesis and metastasis, as well as chemoresistance of cancer. However, the underlying mechanisms mediating these processes are unclear. Here we report that Foxq1, a forkhead box-containing transcription factor and EMT-inducing gene, promotes stemness traits and chemoresistance in mammary epithelial cells. Using an expression profiling assay, we identified Twist1, Zeb2, and PDGFRα and β as Foxq1 downstream targets. We further show that PDGFRα and β can be directly regulated by Foxq1 or indirectly regulated through the Foxq1/Twist1 axis. Knockdown of both PDGFRα and β results in more significant effects on reversing Foxq1-promoted oncogenesis in vitro and in vivo than knockdown of either PDGFRα or β alone. In addition, PDGFRβ is a more potent mediator of Foxq1-promoted stemness traits than PDGFRα. Finally, pharmacological inhibition or gene silencing of PDGFRs sensitizes mammary epithelial cells to chemotherapeutic agents in vitro and in vivo. These findings collectively implicate PDGFRs as critical mediators of breast cancer oncogenesis and chemoresistance driven by Foxq1, with potential implications for developing novel therapeutic combinations to treat breast cancer.
    Cancer Research 12/2014; Cancer Res; Published OnlineFirst December 10, 2014;.
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    ABSTRACT: miR-155 is a regulator of immune cell development and function that is generally thought to be immunostimulatory. However, we report here that genetic ablation of miR-155 renders mice resistant to chemical carcinogenesis and the growth of several transplanted tumors, suggesting that miR-155 functions in immunosuppression and tumor promotion. Host miR-155 deficiency promoted overall antitumor immunity despite the finding of defective responses of miR-155-deficient dendritic cells and antitumor T cells. Further analysis of immune cell compartments revealed that miR-155 regulated the accumulation of functional myeloid-derived suppressive cells (MDSC) in the tumor microenvironment. Specifically, miR-155 mediated MDSC suppressor activity through at least two mechanisms, including SOCS1 repression and a reduced ability to license the generation of CD4+Foxp3+ regulatory T cells (Treg). Importantly, we demonstrated that miR-155 expression was required for MDSC to facilitate tumor growth. Thus, our results revealed a contextual function for miR-155 in antitumor immunity, with a role in MDSC support that appears to dominate in tumor-bearing hosts. Overall, the balance of these cellular effects appears to be a root determinant of whether miR-155 promotes or inhibits tumor growth. Copyright © 2014, American Association for Cancer Research.
    Cancer Research 12/2014;
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    ABSTRACT: Cancer metastasis can occur at early stages of tumor development due to facilitative alterations in the tumor microenvironment. While imaging techniques have considerably improved our understanding of metastasis, early events remain challenging to study due to the small numbers of malignant cells involved which are often undetectable. Using a novel zebrafish model to investigate this process, we discovered that tumor-associated macrophages (TAM) acted to facilitate metastasis by binding tumor cells and mediating their intravasation. Mechanistic investigations revealed that IL-6 and TNF-α promoted the ability of macrophages to mediate this step. M2 macrophages were particularly potent when induced by IL-4, IL-10 and TGF-β. In contrast, IFN-γ-LPS-induced M1 macrophages lacked the capability to function in the same way in the model. Confirming these observations, we found that human TAM isolated from primary breast, lung, colorectal and endometrial cancers exhibited a similar capability in invasion and metastasis. Taken together, our work shows how zebrafish can be used to study how host contributions can facilitate metastasis at its earliest stages, and they reveal a new macrophage-dependent mechanism of metastasis with possible prognostic implications. Copyright © 2014, American Association for Cancer Research.
    Cancer Research 12/2014;
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    ABSTRACT: Agr2 is a member of the endoplasmic reticulum (ER) protein disulfide isomerase, which physiologically regulates protein folding and plays a pivotal role in resistance to ER stress. Agr2 is expressed primarily in adenocarcinomas of various organs, and Agr2 protein overexpression participates in neoplastic transformation and metastasis, therefore acts as a pro-oncogenic protein. Besides the normal ER-localization, extracellular Agr2 is present in serum and urine of cancer patients. However, the physiological significance of extracellular Agr2 is poorly understood. In this study, we demonstrated a novel function of extracellular Agr2 that activated stromal fibroblasts and promoted fibroblast-associated cancer invasion. Agr2 is highly expressed in gastric signet-ring cell carcinoma (SRCC). Agr2 secreted from SRCC cells was incorporated by the surrounding gastric fibroblasts and promoted invasion by these cells. In turn, activated fibroblasts promote the coordinated invasion by fibroblasts and cancer cells. Thus Agr2 plays pivotal roles in the progression of gastric SRCC by exerting paracrine effects on the surrounding fibroblasts. Furthermore, Agr2 increased the growth and resistance of SRCC cells to oxidative and hypoxic stress as cell autonomous effects. Our results indicate that Agr2 may be a suitable therapeutic target for gastric SRCC. Copyright © 2014, American Association for Cancer Research.
    Cancer Research 12/2014;
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    ABSTRACT: Crosstalk between tumor and stromal cells in the tumor microenvironment alter its properties in ways that facilitate the invasive behavior of tumor cells. Here we demonstrate that cancer-associated fibroblasts (CAF) increase the stiffness of the extracellular matrix (ECM) and promote anisotropic fiber orientation, two mechanical signals generated through a Snail1/RhoA/alpha SMA-dependent mechanism that sustains oriented tumor cell migration and invasiveness. Snail1-depleted CAF failed to acquire myofibroblastic traits in response to TGF Beta, including RhoA activation, alpha-SMA-positive stress fibers, increased fibronectin fibrillogenesis and production of a stiff ECM with oriented fibers. Snail1 expression in human tumor-derived CAF was associated with an ability to organize the ECM. In co-culture, a relatively smaller number of Snail1-expressing CAF were capable of imposing an anisotropic ECM architecture, compared to non-activated fibroblasts. Pathologically, human breast cancers with Snail1+ CAF tended to exhibit desmoplastic areas with anisotropic fibers, lymph node involvement and poorer outcomes. Snail1 involvement in driving an ordered ECM was further confirmed in wound healing experiments in mice, with Snail1 depletion preventing the anisotropic organization of granulation tissue and delaying wound healing. Overall, our results showed that inhibiting Snail1 function in CAF could prevent tumor-driven ECM reorganization and cancer invasion. Copyright © 2014, American Association for Cancer Research.
    Cancer Research 12/2014;
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    ABSTRACT: The bradykinin receptor B1R is overexpressed in many human cancers where it might be used as a general target for cancer imaging. In this study, we evaluated the feasibility of using radiolabeled kallidin derivatives to visualize B1R expression in a preclinical model of B1R-positive tumors. Three synthetic derivatives were evaluated in vitro and in vivo for receptor binding and their ability to visualize tumors by positron emission tomography (PET). Enalaprilat and phosphoramidon were used to evaluate the impact of peptidases on tumor visualization. While we found that radiolabeled peptides based on the native kallidin sequence were ineffective at visualizing B1R-positive tumors, peptidase inhibition with phosphoramidon greatly enhanced B1R visualization in vivo. Two stabilized derivatives incorporating unnatural amino acids ((68)Ga-SH01078 and (68)Ga-P03034) maintained receptor-binding affinities that were effective, allowing excellent tumor visualization, minimal accumulation in normal tissues and rapid renal clearance. Tumor uptake was blocked in the presence of excess competitor, confirming that the specificity of tumor accumulation was receptor-mediated. Our results offer a preclinical proof of concept for non-invasive B1R detection by PET imaging as a general tool to visualize many human cancers. Copyright © 2014, American Association for Cancer Research.
    Cancer Research 12/2014;
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    ABSTRACT: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm associated with asbestos exposure. Although previous studies based on candidate gene approaches have identified important common somatic mutations in MPM, these studies have focused on small sets of genes and have provided a limited view of the genetic alterations underlying this disease. Here, we performed whole exome sequencing on DNA from 22 MPMs and matched blood samples, and identified 517 somatic mutations across 490 mutated genes. Integrative analysis of mutations and somatic copy number alterations (SCNAs) revealed frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1. Our study presents the first unbiased view of the genomic basis of MPM. Copyright © 2014, American Association for Cancer Research.
    Cancer Research 12/2014;