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Cancer Research

Ayesha A Shafi, Karen E Knudsen
The circadian clock is a master regulator of mammalian physiology, regulating daily oscillations of crucial biological processes and behaviors. Notably, circadian disruption has recently been identified as an independent risk factor for cancer and classified as a carcinogen. As such, it is imperative to discern the underpinning mechanisms by which circadian disruption alters cancer risk. Emergent data, reviewed herein, demonstrate that circadian regulatory functions play critical roles in several hallmarks of cancer, including control of cell proliferation, cell death, DNA repair, and metabolic alteration...
July 12, 2019: Cancer Research
Hsi-Wen Yeh, Szu-Shuo Lee, Chieh-Yu Chang, Yaw-Dong Lang, Yuh-Shan Jou
The TGFβ cytokine plays dichotomous roles during tumor progression. In normal and premalignant cancer cells, the TGFβ signaling pathway inhibits proliferation and promotes cell-cycle arrest and apoptosis. However, the activation of this pathway in late-stage cancer cells could facilitate the epithelial-to-mesenchymal transition, stemness, and mobile features to enhance tumorigenesis and metastasis. The opposite functions of TGFβ signaling during tumor progression make it a challenging target to develop anticancer interventions...
July 12, 2019: Cancer Research
Lenard M Lichtenberger, K Vinod Vijayan
Aspirin, when administered at low doses, has emerged as a powerful anticancer drug due to both chemopreventive activity against many forms of cancer and its ability to block metastases when administered postdiagnosis. Platelets, which are often elevated in circulation during the latter stages of cancer, are known to promote epithelial-mesenchymal transition, cancer cell growth, survival in circulation, and angiogenesis at sites of metastases. Low-dose aspirin has been demonstrated to block this procarcinogenic action of platelets...
July 12, 2019: Cancer Research
Saurabh V Laddha, Edaise M da Silva, Kenneth Robzyk, Brian R Untch, Hua Ke, Natasha Rekhtman, John T Poirier, William D Travis, Laura H Tang, Chang S Chan
Lung carcinoids (LCs) are rare and slow growing primary lung neuroendocrine tumors. We performed targeted exome sequencing, mRNA sequencing and DNA methylation array analysis on macro-dissected lung carcinoids. Recurrent mutations were enriched for genes involved in covalent histone modification/chromatin remodeling (34.5%; MEN1, ARID1A, KMT2C and KMT2A) as well as DNA repair (17.2%) pathways. Unsupervised clustering and principle component analysis on gene expression and DNA methylation profiles showed three robust molecular subtypes (LC1, LC2, LC3) with distinct clinical features...
July 12, 2019: Cancer Research
Rohit Sachdeva, Megan Wu, Sandra Smiljanic, Oleksandra Kaskun, Kimia Ghannad-Zadeh, Angela Celebre, Keren Isaev, A Sorana Morrissy, Jennifer Guan, Jiefei Tong, Jeffrey Chan, Taylor M Wilson, Sayf Al-Omaishi, David G Munoz, Peter B Dirks, Michael F Moran, Michael D Taylor, Jüri Reimand, Sunit Das
Glioblastoma is the most common primary brain tumor in adults. While the introduction of temozolomide chemotherapy has increased long-term survivorship, treatment failure and rapid tumor recurrence remains universal. The transcriptional regulatory protein, inhibitor of DNA-binding-1 (ID1), is a key regulator of cell phenotype in cancer. We show that CRISPR-mediated knockout of ID1 in glioblastoma cells, breast adenocarcinoma cells, and melanoma cells dramatically reduced tumor progression in all three cancer systems through transcriptional downregulation of EGF, which resulted in decreased EGFR phosphorylation...
July 10, 2019: Cancer Research
Santanu Bhattacharya, Xun Gong, Enfeng Wang, Shamit K Dutta, Joseph R Caplette, Manki Son, Freddy T Nguyen, Michael S Strano, Debabrata Mukhopadhyay
Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic cancer with limited treatment options. There is an urgent need for tools that monitor therapeutic responses in real-time. Drugs such as gemcitabine (GEM) and irinotecan elicit their therapeutic effect in cancer cells by producing hydrogen peroxide (H2O2). In this study, specific DNA- wrapped single-walled carbon nanotubes (SWCNTs), which precisely monitor H2O2, were used to determine the therapeutic response of PDAC cells in vitro and tumors in vivo...
July 10, 2019: Cancer Research
Xuanmao Jiao, Omar Nawab, Tejal Patel, Andrew V Kossenkov, Niels Halama, Dirk Jaeger, Richard G Pestell
Experiments of nature have revealed the peculiar importance of the G protein coupled receptor CCR5 in human disease since ancient times. The resurgence of interest in heterotypic signals in the onset and progression of tumorigenesis has led to the current focus of CCR5 as an exciting new therapeutic target for metastatic cancer with clinical trials now targeting breast and colon cancer. The eutopic expression of CCR5 activates calcium signaling and thereby augments Treg differentiation and migration to sites of inflammation...
July 10, 2019: Cancer Research
Xingyu Wu, Huwate Yeerna, Yusuke Goto, Toshinori Ando, Victoria H Wu, Xuefeng Zhang, Zhiyong Wang, Panomwat Amornphimoltham, Anne N Murphy, Pablo Tamayo, Qianming Chen, Scott M Lippman, J Silvio Gutkind
Metformin may reduce the progression of head and neck squamous cell carcinoma (HNSCC), however, whether metformin acts by altering the host metabolism or targets cancer initiating cells remains poorly understood. This gap in knowledge has prevented the stratification of patient populations that are most likely to benefit from metformin treatment. Here, we explored whether metformin acts directly on HNSCC cells to inhibit aberrant cell growth. To investigate the tumor cell autonomous effects of metformin, we engineered representative HPV- and HPV+ HNSCC cells harboring typical genetic alternations to express the yeast mitochondrial NADH dehydrogenase (NDI1) protein, which is insensitive to metformin...
July 10, 2019: Cancer Research
Isha Sethi, Zhenying Cai, Thomas M Roberts, Guo-Cheng Yuan
Aberrant activation of the PI3K pathway is a common alteration in human cancers. Therapeutic intervention targeting the PI3K pathway has achieved limited success due to the intricate balance of its different components and isoforms. Here, we systematically investigated the genomic and transcriptomic signatures associated with response to KIN-193, a compound specifically targeting the p110β isoform. By integrating genomic, transcriptomic, and drug response profiles from the GDSC database, we identified mutational and transcriptomic signatures associated with KIN193 and further created statistical models to predict the treatment effect of KIN-193 in cell lines which may eventually be clinically valuable...
July 10, 2019: Cancer Research
Carmen Morcelle, Sandra Menoyo, Francisco D Morón-Duran, Albert Tauler, Sara C Kozma, George Thomas, Antonio Gentilella
The role of MYC in regulating p53 stability as a function of increased ribosome biogenesis is controversial. On one hand, it was suggested that MYC drives the overexpression of ribosomal proteins (RP)L5 and RPL11, which bind and inhibit HDM2, stabilizing p53. On the other, it has been proposed that increased ribosome biogenesis leads the consumption of RPL5/RPL11 into nascent ribosomes, reducing p53 levels and enhancing tumorigenesis. Here we show that the components that make-up the recently described impaired ribosome biogenesis checkpoint (IRBC) complex, RPL5, RPL11 and 5S rRNA, are reduced following MYC silencing...
July 10, 2019: Cancer Research
Xiaoling Kuai, Long Li, Ran Chen, Kangjunjie Wang, Min Chen, Binghai Cui, Yuxue Zhang, Junqiang Li, Hongwen Zhu, Hu Zhou, Jianfei Huang, Jun Qin, Zhiwei Wang, Wenyi Wei, Daming Gao
Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. The regulatory mechanisms underlying GC cell proliferation are largely unclear. Here, we showed that the transcription factor GFI1 is associated with advanced clinical gastric cancer progression and promoted GC cell proliferation partially through inhibition of Gastrokine-2 (GKN2) transcription. GFI1 was a degrading substrate of FBXW7, whose loss was observed in GC. Mechanistically, GSK3β-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7 resulting in SCFFBXW7-mediated ubiquitination and degradation...
July 9, 2019: Cancer Research
Marta Prieto-Vila, Wataru Usuba, Ryou-U Takahashi, Iwao Shimomura, Hideo Sasaki, Takahiro Ochiya, Yusuke Yamamoto
Drug resistance is a major obstacle in the treatment of breast cancer. Surviving cells lead to tumor recurrence and metastasis, which remains the main cause of cancer-related mortality. Breast cancer is also highly heterogeneous which hinders the identification of individual cells with the capacity to survive anticancer treatment. To address this, we performed extensive single-cell gene expression profiling of the luminal-type breast cancer cell line MCF7 and its derivatives, including docetaxel-resistant cells...
July 9, 2019: Cancer Research
Lingli He, Liang Yuan, Yang Sun, Pingyang Wang, Hailin Zhang, Xue Feng, Zuoyun Wang, Wenxiang Zhang, Chuanyu Yang, Yi Arial Zeng, Yun Zhao, Ceshi Chen, Lei Zhang
Hippo pathway plays a critical role in cell growth and tumorigenesis. The activity of TEA domain transcription factor 4 (TEAD4) determines the output of Hippo signaling, however, the regulation and function of TEAD4 has not been explored extensively. Here, we identified glucocorticoids (GCs) as novel activators of TEAD4. GC treatment facilitated glucocorticoid receptor (GR)-dependent nuclear accumulation and transcriptional activation of TEAD4. TEAD4 positively correlated with GR expression in human breast cancer, and high expression of TEAD4 predicted poor survival of breast cancer patients...
July 9, 2019: Cancer Research
Laila-Sara Arroyo-Mühr, Camilla Lagheden, Emilie Hultin, Carina Eklund, Hans-Olov Adami, Joakim Dillner, Karin Sundström
The human papillomavirus (HPV) rate of evolution is essential for cancer-preventive strategies targeting HPV. We analyzed variability over time in a prospective, population-based nested case-control study of in situ (CIS) and invasive squamous cervical cancer (SCC). Among 757690 women who participated in cervical screening in Sweden during 1969-2002, 94 women who had HPV16 persistence in two serial cervical screening samples (median 24 months apart, range 0.5-178 months) and later were diagnosed with CIS (n=59), SCC (n=32) or remained healthy (n=3)...
July 9, 2019: Cancer Research
Rui Zhang, Fan Zhang, Zeguo Sun, Pengpeng Liu, Xiao Zhang, Yingnan Ye, Beiqi Cai, Martin J Walsh, Xiubao Ren, Xishan Hao, Weijia Zhang, Jinpu Yu
Somatic Long Interspersed element-1 (LINE-1) retrotransposition (RT) is a genomic process that relates to gene disruption and tumor occurrence. However, the expression and function of LINE-1 RT in lung squamous cell carcinoma (LUSC) remains unclear. We analyzed the transcriptomes of LUSC samples in The Cancer Genome Atlas (TCGA) and observed LINE-1 RT in 90% of tumor samples. Thirteen LINE-1 RTs of high occurrence were identified and further validated from an independent Chinese LUSC cohort. Among them, LINE-1-FGGY (L1-FGGY) was identified as the most frequent LINE-1 RT in the Chinese cohort and significantly correlated with poor clinical outcome...
July 9, 2019: Cancer Research
A-Rum Yoon, JinWoo Hong, Yan Li, Ha Chul Shin, Hyunah Lee, Hyun Soo Kim, Chae-Ok Yun
Oncolytic virotherapy is a promising alternative to conventional treatment, yet systemic delivery of these viruses to tumors remains a major challenge. In this regard, mesenchymal stem cells (MSCs) with well-established tumor-homing properties could serve as a promising systemic delivery tool. In this study, we examined the feasibility of using human mesenchymal stem cells as a carrier to systemically deliver a hepatocellular carcinoma (HCC)-specific oncolytic adenovirus (HCC-oAd) in an HCC orthotopic tumor model...
July 9, 2019: Cancer Research
Aditi Jain, Lebaron C Agostini, Grace A McCarthy, Saswati N Chand, AnnJosette Ramirez, Avinoam Nevler, Joseph Cozzitorto, Christopher W Schultz, Cinthya Y Lowder, Kate M Smith, Ian D Waddell, Maria Raitses-Gurevich, Chani Stossel, Yulia Glick Gorman, Dikla Atias, Charles J Yeo, Jordan M Winter, Kenneth P Olive, Talia Golan, Michael J Pishvaian, Donald Ogilvie, Dominic I James, Allan M Jordan, Jonathan R Brody
Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have an average survival of less than one year, underscoring the importance of evaluating novel targets with matched targeted agents. We recently identified that poly (ADP) ribose glycohydrolase (PARG) is a strong candidate target due to its dependence on the pro-oncogenic mRNA stability factor HuR (ELAVL1). Here, we evaluated PARG as a target in PDAC models using both genetic silencing of PARG and established small molecule PARG inhibitors, PDDX-001/004 (PARGi)...
July 4, 2019: Cancer Research
Jeffrey H Becker, Yandi Gao, Margaret Soucheray, Ines Pulido, Eiki Kikuchi, María L Rodríguez, Rutu Gandhi, Aranzazu Lafuente-Sanchis, Miguel Aupí, Javier Alcácer Fernández-Coronado, Paloma Martín-Martorell, Antonio Cremades, José M Galbis-Caravajal, Javier Alcácer, Camilla L Christensen, Patricia Simms, Ashley Hess, Hajime Asahina, Michael P Kahle, Fatima Al-Shahrour, Jeffrey A Borgia, Agustín Lahoz, Amelia Insa, Oscar Juan, Pasi A Janne, Kwok-Kin Wong, Julian Carretero, Takeshi Shimamura
Although EGFR mutant-selective TKIs are clinically effective, acquired resistance can occur by reactivating ERK. We show using in vitro models of acquired EGFR TKI resistance with a mesenchymal phenotype that CXCR7, an atypical GPCR, activates the MAPK-ERK pathway via β-arrestin. Depletion of CXCR7 inhibited the MAPK pathway, significantly attenuated EGFR TKI resistance and resulted in mesenchymal to epithelial transition. CXCR7 overexpression was essential in reactivation of ERK1/2 for the generation of EGFR TKI resistant persister cells...
July 4, 2019: Cancer Research
Julie Ross, Marissa Rashkovan, Jennifer Fraszczak, Charles Joly Beauparlant, Charles Vadnais, René Winkler, Arnaud Droit, Christian Kosan, Tarik Möröy
Acute lymphoblastic leukemia (ALL) is an aggressive blood cancer that mainly affects children. Relapse rates are high and toxic chemotherapies that block DNA replication and induce DNA damage lead to health problems later in life, underlining the need for improved therapies. c-Myc is a transcription factor that is hyperactive in a large proportion of cancers including leukemia but is difficult to target in therapy. We show that ablation of the function of the BTB/POZ domain factor Miz-1, an important co-factor of c-Myc, significantly delayed T- and B-ALL/lymphoma in mice and interfered with the oncogenic transcriptional activity of c-Myc...
July 4, 2019: Cancer Research
Christopher B Jackson, Seth I Noorbakhsh, Ranjini K Sundaram, Aravind N Kalathil, Sachita Ganesa, Lanqi Jia, Hank Breslin, Danielle M Burgenske, Oren Gilad, Jann N Sarkaria, Ranjit S Bindra
O6-methylguanine-DNA methyltransferase (MGMT) is an enzyme that removes alkyl groups at the O6-position of guanine in DNA. MGMT expression is reduced or absent in many tumor types derived from a diverse range of tissues, most notably in glioma. Low MGMT expression confers significant sensitivity to DNA alkylating agents such as temozolomide (TMZ), providing a natural therapeutic index over normal tissue. In this study, we sought to identify novel approaches which could maximally exploit the therapeutic index between tumor cells and normal tissues based on MGMT expression, as a means to enhance selective tumor cell killing...
July 4, 2019: Cancer Research
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