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Cancer Research

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https://www.readbyqxmd.com/read/29055020/subtype-specific-cancer-associated-fibroblasts-contribute-to-the-pathogenesis-of-uterine-leiomyoma
#1
Xin Wu, Vanida Ann Serna, Justin Thomas, Wenan Qiang, Michael L Blumenfeld, Takeshi Kurita
Recent genomic studies have identified subtypes of uterine leiomyoma (LM) with distinctive genetic alterations. Here we report the elucidation of the biological characteristics of the two most prevalent LM subtypes, MED12 mutant (MED12-LM) and HMGA2-overexpressing (HMGA2-LM) LM. Since each tumor carries only one genetic alteration, both subtypes are considered to be monoclonal. Approximately 90% of cells in HMGA2-LM were smooth muscle cells (SMC) with HMGA2 overexpression. In contrast, MED12-LM consisted of similar numbers of SMC and non-SMC, which were mostly tumor-associated fibroblasts (TAF)...
October 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/29055019/-18-f-fluorothymidine-positron-emission-tomography-informs-the-synergistic-efficacy-of-capecitabine-and-trifluridine-tipiracil-in-colon-cancer
#2
Seog-Young Kim, Jin Hwa Jung, Haeng Jung Lee, Hyunsu Soh, Sang Ju Lee, Seung Jun Oh, Sun Young Chae, Jai Hyuen Lee, Seung Jin Lee, Yong Sang Hong, Tae Won Kim, Dae Hyuk Moon
In cancer therapy, enhanced thymidine uptake by the salvage pathway can bypass dTMP depletion, thereby conferring resistance to thymidylate synthase inhibition. We investigated whether sequential combination therapy of capecitabine and trifluridine/tipiracil (TAS-102) could synergistically enhance antitumor efficacy in colon cancer xenograft models. We also examined 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) positron emission tomography (PET) as a means to predict therapeutic response to a sequential combination of capecitabine and trifluridine/tipiracil...
October 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/29055018/runx1-upregulation-by-cytotoxic-drugs-promotes-apoptosis
#3
Daniel Speidel, Jasmin Wellbrock, Melissa Abas
Mutations in the RUNX1 gene have been associated with chemotherapy resistance and poor prognosis in patients with acute myeloid leukemia (AML), T cell acute lymphoblastic leukemia (T-ALL) and myelodysplastic syndromes (MDS). However, the underlying mechanisms connecting RUNX1 to the success of therapy remain elusive. Here we explore the hypothesis that RUNX1 is directly involved in the response of hematopoietic cells to cytotoxic agents. RUNX1 was upregulated post-transcriptionally by cytotoxic agents in C57BL/6 mice in vivo and hematopoietic cell lines...
October 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/29055017/new-generation-nanomedicines-constructed-from-self-assembling-small-molecule-prodrugs-alleviate-cancer-drug-toxicity
#4
Hangxiang Wang, Zhongjie Lu, Lijiang Wang, Tingting Guo, Jiaping Wu, Jianqin Wan, Liqian Zhou, Hui Li, Zhen Li, Donghai Jiang, Penghong Song, Haiyang Xie, Lin Zhou, Xiao Xu, Shusen Zheng
The therapeutic index for chemotherapeutic drugs is determined in part by systemic toxicity, so strategies for dose intensification to improve efficacy must also address tolerability. In addressing this issue, we have investigated a novel combinatorial strategy of reconstructing a drug molecule and using sequential drug-induced nanoassembly to fabricate supramolecular nanomedicines (SNM). Using cabazitaxel (CTX) as a target agent, we established that individual synthetic prodrugs tethered with polyunsaturated fatty acids were capable of recapitulating self-assembly behavior independent of exogenous excipients...
October 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/29055016/sgk1-is-a-critical-component-of-an-akt-independent-pathway-essential-for-pi3k-mediated-tumor-development-and-maintenance
#5
Arturo Orlacchio, Michela Ranieri, Martina Brave, Valeria Antico Arciuch, Toni Forde, Daniela De Martino, Karen E Anderson, Phillip Hawkins, Antonio Di Cristofano
Activation of the PI3K-AKT signaling cascade is a common critical event during malignant transformation. In this study, we used thyroid gland epithelial cells and a series of genetically engineered mouse strains as model systems to demonstrate that, while necessary, AKT activation is not sufficient for PI3K-driven transformation. Instead, transformation requires the activity of the PDK1-regulated AGC family of protein kinases. In particular, SGK1 was found to be essential for proliferation and survival of thyroid cancer cells harboring PI3K-activating mutations...
October 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/29055015/small-molecule%C3%A2-inhibition-of-pd-1-transcription-is-an-effective-alternative-to-antibody-blockade-in-cancer-therapy
#6
Alison Taylor, David Rothstein, Christopher Rudd
The impact of PD-1 immune checkpoint therapy prompts exploration of other strategies to downregulate PD-1 for cancer therapy. We previously showed that the serine/threonine kinase, glycogen synthase kinase GSK-3α/β, is a central regulator of PD-1 transcription in CD8+ T cells. Here, we show that the use of small molecule inhibitors of GSK-3α/β (GSK-3i) to reduce pcdc1 (PD-1) transcription and expression was as effective as anti-PD-1 and PDL-1 blocking antibodies in the control of B16 melanoma, or EL4 lymphoma, in primary tumor and metastatic settings...
October 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/29055014/protein-acyltransferase-dhhc3-regulates-breast-tumor-growth-oxidative-stress-and-senescence
#7
Martin E Hemler, Chandan Sharma, Hong-Xing Wang, Qinglin Li, Konstantin Knoblich, Emily S Reisenbichler, Andrea L Richardson
DHHC-type protein acyltransferases may regulate the localization, stability and/or activity of their substrates. In this study, we show that the protein palmitoyltransferase DHHC3 is upregulated in malignant and metastatic human breast cancer. Elevated expression of DHHC3 correlated with diminished patient survival in breast cancer and six other human cancer types. ZDHHC3 ablation in human MDA-MB-231 mammary tumor cell xenografts reduced the sizes of both the primary tumor and metastatic lung colonies. Gene array data and fluorescence dye assays documented increased oxidative stress and senescence in ZDHHC3-ablated cells...
October 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/29055013/a-synthetic-cd8%C3%AE-myd88-co-receptor-enhances-cd8-t-cell-responses-to-weakly-immunogenic-and-lowly-expressed-tumor-antigens
#8
Sabina Kaczanowska, Ann Mary Joseph, Jitao Guo, Alexander K Tsai, Jackline Joy M Lasola, Kenisha Younger, Yuji Zhang, Cruz Velasco Gonzalez, Eduardo Davila
T cell-based immunotherapies are a promising approach for patients with advanced cancers. However, various obstacles limit T cell efficacy, including suboptimal T cell receptor (TCR) activation and an immunosuppressive tumor environment. Here we developed a fusion protein by linking CD8α and MyD88 (CD8α:MyD88) to enhance CD8+ T cell responses to weakly immunogenic and poorly expressed tumor antigens. CD8α:MyD88-engineered T cells exhibited increased proliferation and expression of effector and co-stimulatory molecules in a tumor antigen-dependent manner...
October 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/29051178/tlr4-mediated-inflammation-promotes-kshv-induced-cellular-transformation-and-tumorigenesis-by-activating-the-stat3-pathway
#9
Marion Gruffaz, Karthik Vasan, Brandon Tan, Suzane Ramos da Silva, Shou-Jiang Gao
Toll-like receptors (TLR) are conserved immune sensors mediating antimicrobial and antitumoral responses, but recent evidence implicates them in promoting carcinogenesis in certain cancers. Kaposi's sarcoma (KS) is caused by infection of Kaposi's sarcoma-associated herpesvirus (KSHV) and is characterized by uncontrolled neoangiogenesis and inflammation. Here we show that TLR4 is upregulated in KSHV-infected spindle tumor cells in human KS lesions. In a model of KSHV-induced cellular transformation, KSHV upregulated expression of TLR4, its adaptor MyD88, and coreceptors CD14 and MD2...
October 19, 2017: Cancer Research
https://www.readbyqxmd.com/read/29046337/cathepsin-b-is-dispensable-for-cellular-processing-of-cathepsin-b-cleavable-antibody-drug-conjugates
#10
Niña G Caculitan, Josefa Dela Cruz Chuh, Yong Ma, Donglu Zhang, Katherine R Kozak, Yichin Liu, Thomas H Pillow, Jack Sadowsky, Tommy K Cheung, Qui Phung, Benjamin Haley, Byoung-Chul Lee, Robert Akita, Mark X Sliwkowski, Andrew G Polson
Antibody-drug conjugates (ADCs) are designed to selectively bind to tumor antigens via the antibody and release their cytotoxic payload upon internalization. Controllable payload release through judicious design of the linker has been an early technological milestone. Here, we examine the effect of the protease-cleavable valine-citrulline (VC(S)) linker on ADC efficacy. The VC(S) linker was designed to be cleaved by cathepsin B, a lysosomal cysteine protease. Surprisingly, suppression of cathepsin B expression via CRISPR-Cas9 gene deletion or shRNA knockdown had no effect on the efficacy of ADCs with VC(S) linkers armed with a monomethyl auristatin E (MMAE) payload...
October 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/29046336/pp2a-inactivation-mediated-by-ppp2r4-haploinsufficiency-promotes-cancer-development
#11
Ward Sents, Bob Meeusen, Petar Kalev, Enrico Radaelli, Xavier Sagaert, Eline Miermans, Dorien Haesen, Caroline Lambrecht, Mieke Dewerchin, Peter Carmeliet, Jukka Westermarck, Anna Sablina, Veerle Janssens
Protein phosphatase 2A (PP2A) complexes counteract many oncogenic kinase pathways. In cancer cells, PP2A function can be compromised by several mechanisms, including sporadic mutations in its scaffolding A and regulatory B subunits or more frequently through overexpression of cellular PP2A inhibitors. Here we identify a novel genetic mechanism by which PP2A function is recurrently affected in human cancer, involving haploinsufficiency of PPP2R4, a gene encoding the cellular PP2A activator PTPA. Notably, up to 70% of cancer patients showed a heterozygous deletion or missense mutations in PPP2R4 Cancer-associated PTPA mutants exhibited decreased abilities to bind the PP2A-C subunit or activate PP2A and failed to reverse the tumorigenic phenotype induced by PTPA suppression, indicating they function as null alleles...
October 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/29042418/socs1-gene-therapy-improves-radiosensitivity-and-enhances-irradiation-induced-dna-damage-in-esophageal-squamous-cell-carcinoma
#12
Takahito Sugase, Tsuyoshi Takahashi, Satoshi Serada, Minoru Fujimoto, Kosuke Hiramatsu, Tomoharu Ohkawara, Koji Tanaka, Yasuhiro Miyazaki, Tomoki Makino, Yukinori Kurokawa, Makoto Yamasaki, Kiyokazu Nakajima, Tadamitsu Kishimoto, Masaki Mori, Yuichiro Doki, Tetsuji Naka
STAT3 has been implicated recently in radioresistance in cancer. In this study, we investigated the association between STAT3 and radioresistance in esophageal squamous cell carcinoma (ESCC). Strong expression of activated phospho-STAT3 (p-STAT3) was observed in 16/22 ESCC patients with preoperative chemoradiotherapy (CRT), compared to 9/24 patients with surgery alone, where the prognosis of those with CRT was poor. Expression of p-STAT3 and the anti-apoptotic proteins Mcl-1 and survivin was strongly induced in ESCC cells by irradiation...
October 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/29042417/restoration-of-natural-killer-cell-anti-metastatic-activity-by-il-12-and-checkpoint-blockade
#13
Isabel Ohs, Laura Ducimetiere, Joana Marinho, Paulina Kulig, Burkhard Becher, Sonia Tugues
Immune checkpoint therapies target tumor antigen-specific T cells, but less is known about their effects on natural killer (NK) cells, which help control metastasis. In studying the development of lung metastases, we found that NK cells lose their cytotoxic capacity and acquire a molecular signature defined by the expression of co-inhibitory receptors. In an effort to overcome this suppressive mechanism, we evaluated NK cell responses to the immunostimulatory cytokine IL-12. Exposure to IL-12 rescued the cytotoxicity of NK cells but also led to the emergence of an immature NK cell population which expressed high levels of the co-inhibitory molecules PD-1, Lag-3 and TIGIT, thereby limiting NK cell-mediated control of pulmonary metastases...
October 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/29038348/stk33-promotes-growth-and-progression-of-pancreatic-cancer-as-a-critical-downstream-mediator-of-hif-1%C3%AE
#14
Fanyang Kong, Xiangyu Kong, Yiqi Du, Ying Chen, Xuan Deng, Jianwei Zhu, Jiawei Du, Lei Li, Zhiliang Jia, Dacheng Xie, Zhaoshen Li, Keping Xie
The serine/threonine kinase STK33 has been implicated in cancer cell proliferation. Here we provide evidence of a critical role for STK33 in the pathogenesis and metastatic progression of pancreatic ductal adenocarcinoma (PDAC). STK33 expression in PDAC was regulated by the hypoxia-inducible transcription factor HIF-1α. In human PDAC specimens, STK33 was overexpressed and associated with poor prognosis. Enforced STK33 expression promoted PDAC proliferation, migration, invasion and tumor growth, whereas STK33 depletion exerted opposing effects...
October 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/29038347/an-akt3-splice-variant-lacking-the-serine-472-phosphorylation-site-promotes-apoptosis-and-suppresses-mammary-tumorigenesis
#15
Kimita Suyama, Jiahong Yao, Huizhi Liang, Outhiriaradjou Benard, Olivier D Loudig, Dulguun Amgalan, Wendy M McKimpson, Greg R Phillips, Jeffrey E Segall, Yihong Wang, Susan Fineberg, Larry Norton, Richard N Kitsis, Rachel B Hazan
The Akt pathway is a well-known promoter of tumor malignancy. Akt3 is expressed as two alternatively spliced variants, one of which lacks the key regulatory serine 472 phosphorylation site. Whereas the function of full-length Akt3 isoform (Akt3/+S472) is well-characterized, that of Akt3/-S472 isoform remains unknown. Despite being expressed at a substantially lower level than Akt3/+S472 in triple negative breast cancer cells, specific ablation of Akt3/-S472, enhanced, whereas overexpression, suppressed mammary tumor growth-consistent with a significant association with patient survival duration relative to Akt3/+S472...
October 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/29038346/atr-is-a-therapeutic-target-in-synovial-sarcoma
#16
Samuel E Jones, Emmy D G Fleuren, Jessica Frankum, Asha Konde, Chris T Williamson, Dragomir B Krastev, Helen N Pemberton, James Campbell, Aditi Gulati, Richard Elliott, Malini Menon, Joanna L Selfe, Rachel Brough, Stephen J Pettitt, Wojciech Niedzwiedz, Winette T A van der Graaf, Janet Shipley, Alan Ashworth, Christopher J Lord
Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterised by expression of SS18-SSX fusions, where treatment options are limited. To identify therapeutically actionable genetic dependencies in SS, we performed a series of parallel, high-throughput small interfering RNA (siRNA) screens and compared genetic dependencies in SS tumor cells to those in >130 non-SS tumour cell lines. This approach revealed a reliance of SS tumor cells upon the DNA damage response serine/threonine protein kinase ATR...
October 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/29038345/administering-xct-inhibitors-based-on-circadian-clock-improves-antitumor-effects
#17
Fumiyasu Okazaki, Naoya Matsunaga, Kengo Hamamura, Kayoko Suzuki, Takaharu Nakao, Hiroyuki Okazaki, Masahiko Kutsukake, Shiro Fukumori, Yasuhiro Tsuji, Hideto To
Clock genes encoding transcription factors that regulate circadian rhythms may inform chrono-modulated chemotherapy, where time-dependent dose alterations might affect drug efficacy and reduce side effects. For example, inhibiting the essential cystine transporter xCT with sulfasalazine induces growth arrest in cancer cells. Although the anticancer effects of sulfasalazine have been studied extensively, its effects on transcriptional control of xCT expression have not been studied. Here we show that sulfasalazine administration during the period of increased xCT expression improves its anticancer effects, and that the Clock gene itself induces xCT expression and regulates its circadian rhythm...
October 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/29038344/blocking-myristoylation-of-src-inhibits-its-kinase-activity-and-suppresses-prostate-cancer-progression
#18
Sungjin Kim, Omar Awad Alsaidan, Octavia Goodwin, Qianjin Li, Essilvo Sulejmani, Zhen Han, Aiping Bai, Thomas Albers, Zanna Beharry, Y George G Zheng, James S Norris, Zdzislaw M Szulc, Alicja Bielawska, Iryna Lebedyeva, Scott D Pegan, Houjian Cai
Protein N-myristoylation enables localization to membranes and helps maintain protein conformation and function. N-myristoyltransferases (NMT) catalyze co- or post-translational myristoylation of Src family kinases and other oncogenic proteins, thereby regulating their function. In this study, we provide genetic and pharmacological evidence that inhibiting the N-myristoyltransferase NMT1 suppresses cell cycle progression, proliferation and malignant growth of prostate cancer cells. Loss of myristoylation abolished the tumorigenic potential of Src and its synergy with androgen receptor in mediating tumor invasion...
October 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/29021139/paxillin-binding-to-the-cytoplasmic-domain-of-cd103-promotes-cell-adhesion-and-effector-functions-for-cd8-resident-memory-t-cells-in-tumors
#19
Ludiane Gauthier, Stephanie Corgnac, Marie Boutet, Gwendoline Gros, Pierre Validire, Georges Bismuth, Fathia Mami-Chouaib
CD8+/CD103+ tissue resident memory T cells (TRM cells) accumulate in several human solid tumors where they have been associated with a favorable prognosis. However, the role of CD103 - the α subunit of the integrin αEβ7 (also known as CD103) - in the retention and functions of these TRM is undefined. In this report, we investigated the role of CD103 cytoplasmic domain and the focal adhesion-associated protein paxillin (Pxn) in downstream signaling and functional activities triggered through αE/CD103 chain...
October 11, 2017: Cancer Research
https://www.readbyqxmd.com/read/29021138/glutamine-addiction-in-kidney-cancer-suppresses-oxidative-stress-and-can-be-exploited-for-real-time-imaging
#20
Omran Abu Aboud, Samy Habib, Josephine F Trott, Benjamin Stewart, Sitai Liang, Abhijit J Chaudhari, Julie L Sutcliffe, Robert H Weiss
Many cancers appear to activate intrinsic antioxidant systems as a means to counteract oxidative stress. Some cancers, such as clear cell renal cell carcinoma (ccRCC), require exogenous glutamine for growth and exhibit reprogrammed glutamine metabolism, at least in part due to the glutathione pathway, an efficient cellular buffering system that counteracts reactive oxygen species (ROS) and other oxidants. We show here that ccRCC xenograft tumors under the renal capsule exhibit enhanced oxidative stress compared to adjacent normal tissue and the contralateral kidney...
October 11, 2017: Cancer Research
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