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Cancer Research

Yuki Fujiwara, Yi Sun, Robert J Torphy, Jiadai He, Katsuhiko Yanaga, Barish H Edil, Richard D Schulick, Yuwen Zhu
Thalidomide-like drugs have been approved for the treatment of human multiple myeloma (MM), with their direct antitumor effects and immunomodulatory functions well documented. However, the exact molecular mechanisms that govern these effects remain unclear. Here we demonstrate that pomalidomide (POM) promotes immune response by inhibiting expression of PD-L1. POM inhibited PD-L1 expression on tumor cells to promote cytotoxic T lymphocyte (CTL) activity in vitro and suppressed PD-L1 upregulation on antigen-presenting cells (APC) to prevent peptide-induced T cell tolerance...
October 12, 2018: Cancer Research
Jordan A Torok, Patrick Oh, Katherine D Castle, Michael Reinsvold, Yan Ma, Lixia Luo, Chang-Lung Lee, David G Kirsch
Stereotactic body radiation therapy is utilized to treat lung cancer. The mechanism of tumor response to high dose RT (HDRT) is controversial, with competing hypotheses of increased direct tumor cell killing vs indirect effects on stroma including endothelial cells. Here we used dual recombinase technology in a primary murine lung cancer model to test whether tumor cells or endothelial cells are critical HDRT targets. Lenti-Cre deleted one or two copies of Atm (KPAFL/+ or KPAFL/FL), whereas adeno-FlpO infected mice expressed Cre in endothelial cells to delete one or both copies of Atm (KPVAFL/+ or KPVAFL/FL) to modify tumor cell or endothelial cell radiosensitivity, respectively...
October 12, 2018: Cancer Research
Ting La, Guang Zhi Liu, Margaret Farrelly, Nicole Cole, Yu Chen Feng, Yuan Yuan Zhang, Simonne K Sherwin, Hamed Yari, Hessam Tabatabaee, Xu Guang Yan, Su Tang Guo, Tao Liu, Rick F Thorne, Lei Jin, Xu Dong Zhang
Cancer cells in quiescence (G0 phase) are resistant to death, and re-entry of quiescent cancer cells into the cell cycle plays an important role in cancer recurrence. Here we show that two p53-responsive microRNAs (miRNAs) utilize distinct but complementary mechanisms to promote cancer cell quiescence by facilitating stabilization of p27. Purified quiescent B16 mouse melanoma cells expressed higher levels of miRNA-27b-3p and miRNA-455-3p relative to their proliferating counterparts. Induction of quiescence resulted in increased levels of these miRNAs in diverse types of human cancer cell lines...
October 9, 2018: Cancer Research
Daisuke Eino, Yohei Tsukada, Hisamichi Naito, Yonehiro Kanemura, Tomohiro Iba, Taku Wakabayashi, Fumitaka Muramatsu, Hiroyasu Kidoya, Hideyuki Arita, Naoki Kagawa, Yasunori Fujimoto, Kazuhiro Takara, Haruhiko Kishima, Nobuyuki Takakura
The structure and function of tumor blood vessels profoundly impacts the tumor microenvironment. Signals mediated through the lysophosphatidic acid receptor 4 (LPA4) promote vascular network formation to restore normal vascular barrier function in subcutaneous tumors and thus improve drug delivery. However, the characteristics of the vasculature vary by organ and tumor types, and how drug delivery and leukocyte trafficking are affected by modification of vascular function by LPA in different cancers is unclear...
October 9, 2018: Cancer Research
Yoichi Takakusagi, Sarwat Naz, Kaori Takakusagi, Masahiro Ishima, Hiroshi Murata, Keisuke Ohta, Masahiko Miura, Fumio Sugawara, Kengo Sakaguchi, Shun Kishimoto, Jeeva P Munasinghe, James B Mitchell, Murali C Krishna
Hypoxic zones in solid tumors contribute to radioresistance, and pharmacological agents that increase tumor oxygenation prior to radiation, including anti-angiogenic drugs, can enhance treatment response to radiotherapy. Although such strategies have been applied, imaging assessments of tumor oxygenation to identify an optimum time window for radiotherapy have not been fully explored. In this study, we investigated the effects of alpha-sulfoquinovosylacyl-1,3-propanediol (SQAP; a synthetic derivative of an anti-angiogenic agent) on the tumor microenvironment in terms of oxygen partial pressure (pO2), oxyhemoglobin saturation (sO2), blood perfusion, and microvessel density using electron paramagnetic resonance imaging, photoacoustic imaging, dynamic contrast-enhanced MRI with Gd-DTPA injection, and T2*-weighted imaging with ultrasmall superparamagnetic iron oxide (USPIO) contrast...
October 9, 2018: Cancer Research
Dinoop Ravindran Menon, Yuchun Luo, John J Arcaroli, Sucai Liu, Lekha Nair KrishnanKutty, Douglas G Osborne, Yang Li, Jenny Mae Samson, Stacey Bagby, Aik-Choon Tan, William A Robinson, Wells A Messersmith, Mayumi Fujita
Cancers are comprised of heterogeneous subpopulations with various tumor-initiating capacities, yet key stem cell genes associated with enhanced tumor initiating capacities and their regulatory mechanisms remain elusive. Here we analyzed patient-derived xenografts from melanoma, colon, and pancreatic cancer tissues and identified enrichment of tumor-initiating cells in MHC class I-hi cells, where CDK1, a master regulator of the cell cycle, was upregulated. Overexpression of CDK1, but not its kinase-dead variant, in melanoma cells increased their spheroid forming ability, tumorigenic potential, and tumor-initiating capacity; inhibition of CDK1 with pharmacological agents reduced these characteristics, which was unexplained by the role of CDK1 in regulating the cell cycle...
October 8, 2018: Cancer Research
Zebin Wang, Shaun E Grosskurth, Tony Cheung, Philip Petteruti, Jingwen Zhang, Xin Wang, Wenxian Wang, Farzin Gharahdaghi, Jiaquan Wu, Nancy Su, Ryan T Howard, Michele Mayo, Dan Widzowski, David A Scott, Jeffrey W Johannes, Michelle L Lamb, Deborah Lawson, Jonathan R Dry, Paul D Lyne, Edward W Tate, Michael Zinda, Keith Mikule, Stephen E Fawell, Corinne Reimer, Huawei Chen
PARP (poly ADP-ribose polymerase) proteins represent a class of post-translational modification enzymes with diverse cellular functions. Targeting PARPs has proven to be efficacious clinically, but exploration of the therapeutic potential of PARP inhibition has been limited to targeting poly(ADP-ribose) (PAR) generating PARP including PARP1/2/3 and tankyrases. The cancer-related functions of mono(ADP-ribose) (MAR) generating PARP, including PARP6, remain largely uncharacterized. Here, we report a novel therapeutic strategy targeting PARP6 using the first reported PARP6 inhibitors...
October 8, 2018: Cancer Research
Yang Xu, Paul Taylor, Joshua Andrade, Beatrix Ueberheide, Brian Shuch, Peter M Glazer, Ranjit S Bindra, Michael F Moran, W Marston Linehan, Benjamin G Neel
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an inherited cancer syndrome associated with a highly aggressive form of type 2 papillary renal cell carcinoma (PRCC). Germline inactivating alterations in fumarate hydratase (FH) cause HLRCC and result in elevated levels of reactive oxygen species (ROS). Recent work indicates that FH-/- PRCC cells have increased activation of ABL1, which promotes tumor growth, but how ABL1 is activated remains unclear. Given that oxidation can regulate protein-tyrosine phosphatase (PTP) catalytic activity, inactivation of an ABL-directed PTP by ROS might account for ABL1 activation in this malignancy...
October 8, 2018: Cancer Research
Reem Ali, Abdulbaqi Al-Kawaz, Michael S Toss, Andrew R Green, Islam M Miligy, Katia A Mesquita, Claire Seedhouse, Sameer Mirza, Vimla Band, Emad A Rakha, Srinivasan Madhusudan
Targeting PARP1 for synthetic lethality is a new strategy for breast cancers harboring germline mutations in BRCA. However, these mutations are rare, and reactivation of BRCA-mediated pathways may result in eventual resistance to PARP1 inhibitor therapy. Alternative synthetic lethality approaches targeting more common sporadic breast cancers and pre-invasive ductal carcinoma in situ (DCIS) are desirable. Here we show that downregulation of XRCC1, which interacts with PARP1 and coordinates base excision repair, is an early event in human breast cancer pathogenesis...
October 8, 2018: Cancer Research
Ryan P Barnes, Wei-Chung Tsao, George-Lucian Moldovan, Kristin A Eckert
Neoplastic transformation and genome instability are enhanced by replication stress, conditions that slow or stall DNA replication forks. Consequently, cancer cells require multiple enzymes and checkpoint signaling pathways to mitigate replication stress for their viability and proliferation. Targeting proteins that enhance cancer cell survival during replication stress is a recent approach in clinical strategies, especially when targets produce synthetic lethality. DNA polymerase eta (Pol η) has many key functions in genome stability, particularly for translesion synthesis...
October 8, 2018: Cancer Research
Alfonso R Sanchez-Paulete, Alvaro Teijeira, Jose I Quetglas, Maria E Rodriguez-Ruiz, Alvaro Sanchez-Arraez, Sara Labiano, Inaki Etxeberria, Arantza Azpilikueta, Elixabet Bolaños, Maria Cristina Ballesteros-Briones, Noelia Casares, Sergio A Quezada, Pedro Berraondo, David Sancho, Cristian Smerdou, Ignacio Melero
Multiple lines of evidence indicate a critical role for antigen cross-presentation by conventional BATF3-dependent type 1 classical dendritic cells (cDC1) in CD8-mediated antitumor immunity. Flt3L and XCL1 respectively constitute a key growth/differentiation factor and a potent and specific chemoattractant for cDC1. To exploit their antitumor functions in local immunotherapy, we prepared Semliki Forest Virus (SFV)-based vectors encoding XCL1 and soluble Flt3L (sFlt3L). These vectors readily conferred transgene expression to tumor cells in culture and when engrafted as subcutaneous mouse tumor models...
October 8, 2018: Cancer Research
Georg E Luebeck, William D Hazelton, Kit Curtius, Sean K Maden, Ming Yu, Kelly T Carter, Wynn Burke, Paul D Lampe, Christopher I Li, Cornelia M Ulrich, Polly A Newcomb, Maria Westerhoff, Andrew M Kaz, Yanxin Luo, John M Inadomi, William M Grady
Many normal tissues undergo age-related drift in DNA methylation, providing a quantitative measure of tissue age. Here we identify and validate 781 CpG-islands (CGI) that undergo significant methylomic drift in 232 normal colorectal tissues and show that these CGI continue to drift in neoplasia while retaining significant correlations across samples. However, compared with normal colon, this drift advanced (~3-4 fold) faster in neoplasia, consistent with increased cell proliferation during neoplastic progression...
October 5, 2018: Cancer Research
Elizabeth K Duperret, Aspen Trautz, Regina Stoltz, Ami Patel, Megan C Wise, Alfredo Perales-Puchalt, Trevor Smith, Kate E Broderick, Emma L Masteller, J Joseph Kim, Laurent Humeau, Kar Muthumani, David B Weiner
Antibody-based immune therapies targeting the T cell checkpoint molecules CTLA-4 and PD-1 have impacted cancer therapy. However, this immune therapy requires complex manufacturing and frequent dosing, limiting the global use of this treatment. Here we focused on the development of a DNA-encoded monoclonal antibody (DMAb) approach for delivery of anti-CTLA-4 monoclonal antibodies in vivo. With this technology, engineered and formulated DMAb plasmids encoding IgG inserts were directly injected into muscle and delivered intracellularly by electroporation, leading to in vivo expression and secretion of the encoded IgG...
October 4, 2018: Cancer Research
Joanna L Birch, Karen Strathdee, Lesley Gilmour, Antoine Vallatos, Laura McDonald, Ariadni Kouzeli, Richa Vasan, Abdulrahman Hussain Qaisi, Daniel R Croft, Diane Crighton, Kathryn Gill, Christopher H Gray, Jennifer Konczal, Mokdad Mezna, Duncan McArthur, Alexander W Schüttelkopf, Patricia McConnell, Mairi Sime, William M Holmes, Justin Bower, Heather J McKinnon, Martin Drysdale, Michael F Olson, Anthony J Chalmers
Glioblastoma (GBM) is an aggressive and incurable primary brain tumor that causes severe neurological, cognitive, and psychological symptoms. Symptoms are caused and exacerbated by the infiltrative properties of GBM cells, which enable them to pervade the healthy brain and disrupt normal function. Recent research has indicated that, while radiotherapy (RT) remains the most effective component of multimodality therapy for GBM patients, it can provoke a more infiltrative phenotype in GBM cells that survive treatment...
October 2, 2018: Cancer Research
Wei Zhao, Jiancheng Yang, Yingli Sun, Cheng Li, Weilan Wu, Liang Jin, Zhiming Yang, Bingbing Ni, Pan Gao, Peijun Wang, Yanqing Hua, Ming Li
Identification of early-stage pulmonary adenocarcinomas prior to surgery, especially in cases of sub-centimeter cancers, would be clinically important and could provide guidance to clinical decision making. In this study, we developed a deep learning system based on 3D convolutional neural networks and multi-task learning, which automatically predicts tumor invasiveness, together with 3D nodule segmentation masks. The system processes a 3D nodule-centered patch of pre-processed CT and learns a deep representation of a given nodule without the need for any additional information...
October 2, 2018: Cancer Research
Wenwen Wu, Nana Rokutanda, Jun Takeuchi, Yongqiang Lai, Reo Maruyama, Yukiko Togashi, Hiroyuki Nishikawa, Naoko Arai, Yasuo Miyoshi, Nao Suzuki, Yasushi Saeki, Keiji Tanaka, Tomohiko Ohta
BLM and WRN are RecQ DNA helicases essential for genomic stability. Here we demonstrate that HERC2, a HECT E3 ligase, is critical for their functions to suppress G-quadruplex (G4) DNA. HERC2 interacted with BLM, WRN, and replication protein A (RPA) complexes during the S-phase of the cell cycle. Depletion of HERC2 dissociated RPA from BLM and WRN complexes and significantly increased G4 formation. Triple depletion revealed that HERC2 has an epistatic relationship with BLM and WRN in their G4-suppressing function...
October 2, 2018: Cancer Research
Mark R Goldstein, Luca Mascitelli
No abstract text is available yet for this article.
October 1, 2018: Cancer Research
Jesus Duque-Afonso, Chiou-Hong Lin, Kyuho Han, David W Morgens, Edwin E Jeng, Ziming Weng, Johan Jeong, Stephen H K Wong, Li Zhu, Michael C Wei, Hee-Don Chae, Martin Schrappe, Gunnar Cario, Justus Duyster, Kathleen M Sakamoto, Michael C Bassik, Michael L Cleary
Dasatinib is a multi-tyrosine kinase inhibitor approved for treatment of Ph+ acute lymphoblastic leukemia (ALL), but its efficacy is limited by resistance. Recent preclinical studies suggest that dasatinib may be a candidate therapy in additional ALL subtypes including pre-BCR+ ALL. Here we utilized shRNA library screening and global transcriptomic analysis to identify several novel genes and pathways that may enhance dasatinib efficacy or mitigate potential resistance in human pre-BCR+ ALL. Depletion of the transcriptional co-activator CBP increased dasatinib sensitivity by activating transcription of the pre-BCR signaling pathway previously associated with dasatinib sensitivity...
September 27, 2018: Cancer Research
Alan M Elder, Beth Aj Tamburini, Lyndsey S Crump, Sarah A Black, Veronica M Wessells, Pepper J Schedin, Virginia F Borges, Traci R Lyons
Postpartum mammary gland involution is a tissue remodeling event that occurs in all mammals in the absence of nursing or after weaning to return the gland to the pre-pregnant state. The tissue microenvironment created by involution has proven to be tumor promotional. Here we report that the GPI-linked protein semaphorin 7a (SEMA7A) is expressed on mammary epithelial cells during involution and use preclinical models to demonstrate that tumors induced during involution express high levels of SEMA7A. Overexpression of SEMA7A promoted the presence of myeloid-derived podoplanin (PDPN)-expressing cells in the tumor microenvironment and during involution...
September 25, 2018: Cancer Research
Ruhi S Deshmukh, Shalakha Sharma, Sanjeev Das
Cyclin F is a substrate recognition subunit of Skp1-Cul1-F-box protein (SCF) E3 ubiquitin ligase complex. Although there have been reports describing the role of cyclin F in the genotoxic stress response, its function under conditions of altered metabolic homeostasis remain unexplored. Here we report that cyclin F is induced upon metabolic stress in a FOXO1-dependent manner. Under metabolic stress conditions, cyclin F mediated polyubiquitylation of RBPJ at Lys315, leading to its proteasomal degradation. RBPJ regulated the expression of IDH1, which is often mutated to an oncogenic form IDH1R132H in cancers...
September 25, 2018: Cancer Research
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