journal

Cancer Research

journal
https://read.qxmd.com/read/31941699/activation-of-canonical-bmp4-smad7-signaling-suppresses-breast-cancer-metastasis
#1
Bedrich L Eckhardt, Yuan Cao, Andrew D Redfern, Lap Hing Chi, Allan D Burrows, Suraya Roslan, Erica K Sloan, Belinda S Parker, Sherene Loi, Naoto T Ueno, Peter K H Lau, Bruce Latham, Robin L Anderson
Metastasis is the major cause of death in cancer patients; with no therapeutic cure, treatments remain largely palliative. As such, new targets and therapeutic strategies are urgently required. Here we show that bone morphogenetic protein-4 (BMP4) blocks metastasis in animal models of breast cancer and predicts improved survival in patients. In preclinical models of spontaneous metastasis, BMP4 acted as an autocrine mediator to modulate a range of known metastasis-regulating genes, including SMAD7, via activation of canonical BMP-SMAD signaling...
January 15, 2020: Cancer Research
https://read.qxmd.com/read/31941698/increased-tumor-penetration-of-single-domain-antibody-drug-conjugates-improves-in-vivo-efficacy-in-prostate-cancer-models
#2
Ian Nessler, Eshita Khera, Steven Vance, Anna Kopp, Qifeng Qiu, Thomas A Keating, Adnan O Abu-Yousif, Thomas Sandal, James Legg, Lorraine Thompson, Normann Goodwin, Greg M Thurber
Targeted delivery of chemotherapeutics aims to increase efficacy and lower toxicity by concentrating drugs at the site-of-action, a method embodied by the seven current FDA approved antibody-drug conjugates (ADCs). However, a variety of pharmacokinetic challenges result in relatively narrow therapeutic windows for these agents, hampering the development of new drugs. Here, we use a series of Prostate-Specific Membrane Antigen (PSMA)-binding single-domain (Humabody®) ADC constructs to demonstrate that tissue penetration of protein-drug conjugates plays a major role in therapeutic efficacy...
January 15, 2020: Cancer Research
https://read.qxmd.com/read/31932457/lymphoma-angiogenesis-is-orchestrated-by-noncanonical-signaling-pathways
#3
Marleen Gloger, Lutz Menzel, Michael Grau, Anne-Clemence Vion, Ioannis Anagnostopoulos, Myroslav Zapukhlyak, Kerstin Gerlach, Thomas Kammertöns, Thomas Hehlgans, Maria Zschummel, Georg Lenz, Holger Gerhardt, Uta E Höpken, Armin Rehm
Tumor-induced remodeling of the microenvironment relies on the formation of blood vessels, which go beyond the regulation of metabolism, shaping a maladapted survival niche for tumor cells. In high-grade B-cell lymphoma, angiogenesis correlates with poor prognosis, but attempts to target established pro-angiogenic pathways within the vascular niche have been inefficient. Here, we analyzed Myc-driven B-cell lymphoma-induced angiogenesis in mice. A few lymphoma cells were sufficient to activate the angiogenic switch in lymph nodes...
January 13, 2020: Cancer Research
https://read.qxmd.com/read/31932456/metabolic-reprogramming-in-cancer-is-induced-to-increase-proton-production
#4
Huiyan Sun, Yi Zhou, Michael Francis Skaro, Yiran Wu, Zexing Qu, Fenglou Mao, Suwen Zhao, Ying Xu
Considerable metabolic reprogramming has been observed in a conserved manner across multiple cancer types, but their true causes remain elusive. We present an analysis of around 50 such reprogrammed metabolisms (RMs) including the Warburg effect, nucleotide de novo synthesis and sialic acid biosynthesis in cancer. Analyses of the biochemical reactions conducted by these RMs, coupled with gene expression data of their catalyzing enzymes, in 7,011 tissues of 14 cancer types, revealed that all RMs produce more H+ than their original metabolisms...
January 13, 2020: Cancer Research
https://read.qxmd.com/read/31932455/the-risk-of-ovarian-cancer-increases-with-an-increase-in-the-lifetime-number-of-ovulatory-cycles-an-analysis-from-the-ovarian-cancer-cohort-consortium-oc3
#5
Britton Trabert, Shelley S Tworoger, Katie M O'Brien, Mary K Townsend, Renée T Fortner, Edwin S Iversen, Patricia Hartge, Emily White, Pilar Amiano, Alan A Arslan, Leslie Bernstein, Louise A Brinton, Julie E Buring, Laure Dossus, Gary E Fraser, Mia M Gaudet, Graham G Giles, Inger T Gram, Holly R Harris, Judith Hoffman Bolton, Annika Idahl, Michael E Jones, Rudolf Kaaks, Victoria A Kirsh, Synnove F Knutsen, Marina Kvaskoff, James V Lacey, I-Min Lee, Roger L Milne, N Charlotte Onland-Moret, Kim Overvad, Alpa V Patel, Ulrike Peters, Jenny N Poynter, Elio Riboli, Kim Robien, Thomas E Rohan, Dale P Sandler, Catherine Schairer, Leo J Schouten, Veronica Wendy Setiawan, Anthony J Swerdlow, Ruth C Travis, Antonia Trichopoulou, Piet A van den Brandt, Kala Visvanathan, Lynne R Wilkens, Alicja Wolk, Anne Zeleniuch-Jacquotte, Nicolas Wentzensen
Repeated exposure to the acute pro-inflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted hazard ratios (HR) between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype...
January 13, 2020: Cancer Research
https://read.qxmd.com/read/31932454/host-wnt5a-potentiates-microenvironmental-regulation-of-ovarian-cancer-metastasis
#6
Marwa Asem, Allison M Young, Carlysa Oyama, Alejandro G Claure De La Zerda, Yueying Liu, Jing Yang, Tyvette S Hilliard, Jeffery Johnson, Elizabeth I Harper, Ian Guldner, Siyuan Zhang, Toni M Page-Mayberry, William J Kaliney, M Sharon Stack
The non-canonical Wnt ligand Wnt5a is found in high concentrations in ascites of women with ovarian cancer. In this study, we elucidated the role of Wnt5a in ovarian cancer metastasis. Wnt5a promoted ovarian tumor cell adhesion to peritoneal mesothelial cells as well as migration and invasion, leading to colonization of peritoneal explants. Host components of the ovarian tumor microenvironment, notably peritoneal mesothelial cells and visceral adipose, secreted Wnt5a. Conditional knockout of host WNT5A significantly reduced peritoneal metastatic tumor burden...
January 13, 2020: Cancer Research
https://read.qxmd.com/read/31932453/therapy-induced-senescence-drives-bone-loss
#7
Sheila A Stewart, Zhangting Yao, Bhavna Murali, Qihao Ren, Xianmin Luo, Douglas V Faget, Tom Cole, Biancamaria Ricci, Dinesh Thotala, Joseph Monahan, Jan M van Deursen, Darren Baker, Roberta Faccio, Julie K Schwarz
Chemotherapy is important for cancer treatment; however, toxicities limit its use. While great strides have been made to ameliorate the acute toxicities induced by chemotherapy, long-term comorbidities including bone loss remain a significant problem. Chemotherapy-driven estrogen loss is postulated to drive bone loss, but significant data suggests the existence of an estrogen-independent mechanism of bone loss. Using clinically relevant mouse models, we showed that senescence and its senescence-associated secretory phenotype (SASP) contribute to chemotherapy-induced bone loss that can be rescued by depleting senescent cells...
January 13, 2020: Cancer Research
https://read.qxmd.com/read/31919242/bach1-promotes-pancreatic-cancer-metastasis-by-repressing-epithelial-genes-and-enhancing-epithelial-mesenchymal-transition
#8
Masaki Sato, Mitsuyo Matsumoto, Yuriko Saiki, Mahabub Alam, Hironari Nishizawa, Masahiro Rokugo, Andrey Brydun, Shinji Yamada, Mika K Kaneko, Ryo Funayama, Mamoru Ito, Yukinari Kato, Keiko Nakayama, Michiaki Unno, Kazuhiko Igarashi
Pancreatic ductal adenocarcinoma (PDAC) is among the cancers with the poorest prognoses due to its highly malignant features. BTB and CNC homology 1 (BACH1) has been implicated in RAS-driven tumor formation. We focused on the role of BACH1 in PDAC, more than 90% of which have KRAS mutation. Knockdown of BACH1 in PDAC cell lines reduced cell migration and invasion in part by increasing E-cadherin expression, whereas its overexpression showed opposite effects. BACH1 directly repressed the expression of FOXA1 which is known to activate the expression of CDH1 encoding E-cadherin and to inhibit epithelial-mesenchymal transition...
January 9, 2020: Cancer Research
https://read.qxmd.com/read/31915130/tumor-cell-derived-il-1%C3%AE-promotes-desmoplasia-and-immune-suppression-in-pancreatic-cancer
#9
Shipra Das, Beny Shapiro, Emily A Vucic, Sandra Vogt, Dafna Bar-Sagi
Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy typified by a highly stromal and weakly immunogenic tumor microenvironment that promotes tumor evolution and contributes to therapeutic resistance. Here, we demonstrate that PDA tumor cell-derived pro-inflammatory cytokine, interleukin-1β (IL-1β) is essential for the establishment of the pro-tumorigenic PDA microenvironment. Tumor cell-derived IL-1β promoted the activation and secretory phenotype of quiescent pancreatic stellate cells (PSC) and established an immunosuppressive milieu mediated by M2 macrophages, MDSCs, CD1dhiCD5+ regulatory B cells and Th17 cells...
January 8, 2020: Cancer Research
https://read.qxmd.com/read/31915129/computational-staining-of-pathology-images-to-study-the-tumor-microenvironment-in-lung-cancer
#10
Shidan Wang, Ruichen Rong, Donghan M Yang, Junya Fujimoto, Shirley Yan, Ling Cai, Lin Yang, Danni Luo, Carmen Behrens, Edwin R Parra, Bo Yao, Lin Xu, Tao Wang, Xiaowei Zhan, Ignacio I Wistuba, John Minna, Yang Xie, Guanghua Xiao
The spatial organization of different types of cells in tumor tissues reveals important information about the tumor microenvironment (TME). In order to facilitate the study of cellular spatial organization and interactions, we developed Histology-based Digital (HD)-Staining, a deep learning-based computation model, to segment the nuclei of tumor, stroma, lymphocyte, macrophage, karyorrhexis and red blood cells from standard Hematoxylin and Eosin (H&E)-stained pathology images in lung adenocarcinoma (ADC)...
January 8, 2020: Cancer Research
https://read.qxmd.com/read/31911557/the-immunosuppressive-microenvironment-in-brca1-iris-overexpressing-tnbc-tumors-is-induced-by-bidirectional-interaction-with-tumor-associated-macrophages
#11
Wael M ElShamy, Eman Sami, Bibbin T Paul, James A Koziol
Tumor-associated macrophages (TAMs) promote triple-negative breast cancer (TNBC) progression. Here, we report BRCA1-IRIS overexpressing (IRISOE) TNBC cells secrete high levels of GM-CSF in a HIF-1a- and a NF-kB-dependent manner to recruit macrophages to IRISOE cells and polarize them to pro-tumor M2 TAMs. GM-CSF triggered TGF-b1 expression by M2 TAMs by activating STAT5, NF-kB and/or ERK signaling. Despite expressing high levels of TGF-b1 receptors on their surface, IRISOE TNBC cells channeled TGF-b1/TbRI/II signaling towards AKT, not SMAD, which activated stemness/EMT-phenotypes...
January 7, 2020: Cancer Research
https://read.qxmd.com/read/31911556/in-situ-desi-msi-lipidomic-profiles-of-breast-cancer-molecular-subtypes-and-precursor-lesions
#12
Adriana Leandra Santoro, Rodrigo D Drummond, Israel Tojal da Silva, Severino Silva Ferreira, Luiz Juliano, Pedro Henrique Vendramini, Monique Batista da Costa Lemos, Marcos N Eberlin, Victor Piana de Andrade
Clinically meaningful molecular subtypes for classification of breast cancers have been established, however, initiation and progression of these subtypes remain poorly understood. The recent development of desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) facilitates the convergence of analytical chemistry and traditional pathology, allowing chemical profiling with minimal tissue pre-treatment in frozen samples. Here we characterized the chemical composition of molecular subtypes of breast cancer with DESI-MSI...
January 7, 2020: Cancer Research
https://read.qxmd.com/read/31911555/mir-149-suppresses-breast-cancer-metastasis-by-blocking-paracrine-interactions-with-macrophages
#13
Monilola A Olayioye, Ismael Sánchez-González, Anja Bobien, Christian Molnar, Simone Schmid, Michaela Strotbek, Melanie Boerries, Hauke Busch
Paracrine activation of cells contained in the tumor microenvironment promotes tumor progression and metastasis. In breast cancer, malignant cells recruit and educate macrophages into a M2 tumor-promoting phenotype that supports the metastatic spread of cancer cells. Here, we show that miR-149 functions as a metastasis-suppressing microRNA in breast cancer cells by limiting colony-stimulating factor-1 (CSF1)-dependent recruitment and M2 polarization of macrophages. In lymph node-positive, triple-negative breast cancer (TNBC) tissues, low miR-149 expression correlated with reduced macrophage infiltration and patient survival...
January 7, 2020: Cancer Research
https://read.qxmd.com/read/31911554/a-bis-indole-derived-nr4a1-antagonist-induces-pd-l1-degradation-and-enhances-anti-tumor-immunity
#14
Keshav Karki, Gus A Wright, Kumaravel Mohankumar, Un-Ho Jin, Xing-Han Zhang, Stephen Safe
PD-L1 is expressed in tumor cells and its interaction with PD-1 plays an important role in evading immune surveillance; this can be overcome using PD-L1 or PD-1 immunotherapy antibodies. This study reports a novel approach for targeting PD-L1. In human breast cancer cell lines and 4T1 mouse mammary tumor cells PD-L1 expression was regulated by the nuclear receptor NR4A1/Sp1 complex bound to the proximal GC-rich region of the PD-L1 gene promoter. Treatment of breast cancer cells with bis-indole-derived NR4A1 antagonists including 1,1-bis(3'-indolyl)-1-(3-chloro-4-hydroxy-5-methoxyphenyl)methane (Cl-OCH3) decreased expression of PD-L1 mRNA, promoter-dependent luciferase activity and protein...
January 7, 2020: Cancer Research
https://read.qxmd.com/read/31911553/inhibiting-translation-elongation-with-svc112-suppresses-cancer-stem-cells-and-inhibits-growth-in-head-and-neck-squamous-carcinoma
#15
Stephen B Keysar, Nathan Gomes, Bettina Miller, Brian C Jackson, Phuong N Le, J Jason Morton, Julie Reisinger, Tugs-Saikhan Chimed, Karina E Gomez, Cera Nieto, Barbara Frederick, Gijsbertus J Pronk, Hilary L Somerset, Aik-Choon Tan, Xiao-Jing Wang, David Raben, Tin Tin Su, Antonio Jimeno
Cancer stem cells (CSCs) drive growth, therapy resistance, and recurrence in head and neck squamous cell carcinoma (HNSCC). Regulation of protein translation is crucial for normal stem cells and CSCs; its inhibition could disrupt stemness properties, but translation inhibitors are limited clinically due to toxicity. SVC112 is a synthetic derivative of bouvardin, a plant-derived translation elongation inhibitor. SVC112 had greater anti-proliferative effects on HNSCC cells compared to the FDA-approved translation inhibitor omacetaxine mepesuccinate (HHT)...
January 7, 2020: Cancer Research
https://read.qxmd.com/read/31911552/runx2-deficiency-in-osteoblasts-promotes-myeloma-progression-by-altering-the-bone-microenvironment-at-new-bone-sites
#16
Xiaoxuan Xu, Chao Zhang, Timothy N Trotter, Pramod S Gowda, Yun Lu, Selvarangan Ponnazhagan, Amjad Javed, Juan Li, Yang Yang
Multiple myeloma (MM) is a plasma cell malignancy that thrives in the bone marrow (BM), with frequent progression to new local and distant bone sites. Our previous studies demonstrated that MM cells at primary sites secrete soluble factors and suppress osteoblastogenesis via the inhibition of Runt-related transcription factor 2 (Runx2) in pre- and immature osteoblasts (OBs) in new bone sites, prior to the arrival of metastatic tumor cells. However, it is unknown whether OB-Runx2 suppression in new bone sites feeds back to promote MM dissemination to and progression in these areas...
January 7, 2020: Cancer Research
https://read.qxmd.com/read/31911551/nudix-hydrolase-nudt16-regulates-53bp1-protein-by-reversing-53bp1-adp-ribosylation
#17
Fan Zhang, Lihong Lou, Bo Peng, Xiaotian Song, Ofer Reizes, Alexandru Almasan, Zihua Gong
53BP1 controls two downstream sub-pathways, one mediated by PTIP and Artemis and the other by RIF1 and MAD2L2/Shieldin, to coordinate DNA repair pathway choices. However, the upstream regulator(s) of 53BP1 function in DNA repair remain unknown. We and others recently reported that TIRR associates with 53BP1 to stabilize it and prevents 53BP1 localization to DNA damage sites by blocking 53BP1 Tudor domain binding to H4K20me2 sites. Here, we report that the Nudix hydrolase NUDT16, a TIRR homolog, regulates 53BP1 stability...
January 7, 2020: Cancer Research
https://read.qxmd.com/read/31911550/undermining-glutaminolysis-bolsters-chemotherapy-while-nrf2-promotes-chemoresistance-in-kras-driven-pancreatic-cancers
#18
Suman Mukhopadhyay, Debanjan Goswami, Pavan P Adiseshaiah, William Burgan, Ming Yi, Theresa M Guerin, Serguei V Kozlov, Dwight V Nissley, Frank McCormick
Pancreatic cancer is a disease with limited therapeutic options. Resistance to chemotherapies poses a significant clinical challenge for pancreatic cancer patients and contributes to a high rate of recurrence. Here we showed that oncogenic KRAS, a critical driver of pancreatic cancer, promotes metabolic reprogramming and upregulates NRF2, a master regulator of the antioxidant network. NRF2 contributed to chemoresistance and was associated with a poor prognosis in pancreatic cancer patients. NRF2 activation metabolically rewired and elevated pathways involved in glutamine metabolism...
January 7, 2020: Cancer Research
https://read.qxmd.com/read/31911549/combined-mek-and-pi3k-p110b-inhibition-as-a-novel-targeted-therapy-for-malignant-mesothelioma-displaying-sarcomatoid-features
#19
Miriam Marqués, Robin Tranchant, Blanca Risa-Ebrí, María L Suárez-Solís, Luis C Fernández, Enrique Carrillo-de-Santa-Pau, Natalia Del Pozo, Jaime Martínez de Villarreal, Clément Meiller, Yves Allory, Yuna Blum, Christine Pirker, Balazs Hegedus, Simon T Barry, Amancio Carnero, Walter Berger, Didier Jean, Francisco X Real
Among malignant mesotheliomas (MM) the sarcomatoid subtype is associated with higher chemoresistance and worst survival. Due to its low incidence, there has been little progress in the knowledge of the molecular mechanisms associated with sarcomatoid MM, which might help to define novel therapeutic targets. In this work, we show that loss of PTEN expression is frequent in human sarcomatoid MM and PTEN expression levels are lower in sarcomatoid MM than in the biphasic and epithelioid subtypes. Combined Pten and Trp53 deletion in mouse mesothelium led to non-epithelioid MM development...
January 7, 2020: Cancer Research
https://read.qxmd.com/read/31900260/long-noncoding-rna-draic-inhibits-prostate-cancer-progression-by-interacting-with-ikk-to-inhibit-nf-%C3%AE%C2%BAb-activation
#20
Shekhar Saha, Manjari Kiran, Canan Kuscu, Ajay Chatrath, David Wotton, Marty W Mayo, Anindya Dutta
DRAIC is a 1.7 kb spliced long noncoding RNA downregulated in castration-resistant advanced prostate cancer. Decreased DRAIC expression predicts poor patient outcome in prostate and seven other cancers, while increased DRAIC represses growth of xenografted tumors. Here we show that cancers with decreased DRAIC expression have increased NF-κB target gene expression. DRAIC downregulation increased cell invasion and soft agar colony formation; this was dependent on NF-κB activation. DRAIC interacted with subunits of the IκB kinase (IKK) complex to inhibit their interaction with each other, the phosphorylation of IκBα and the activation of NF-κB...
January 3, 2020: Cancer Research
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