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Resolution of Gastric Cancer-Promoting Inflammation: A Novel Strategy for Anti-cancer Therapy.
Piazuelo MB, Riechelmann RP, Wilson KT, Algood HMS
(2019) Curr Top Microbiol Immunol 421: 319-359
MeSH Terms: Cytokines, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Inflammation, Stomach Neoplasms, Tumor Microenvironment
Show Abstract · Added June 6, 2019
The connection between inflammation and cancer was initially recognized by Rudolf Virchow in the nineteenth century. During the last decades, a large body of evidence has provided support to his hypothesis, and now inflammation is recognized as one of the hallmarks of cancer, both in etiopathogenesis and ongoing tumor growth. Infection with the pathogen Helicobacter pylori is the primary causal factor in 90% of gastric cancer (GC) cases. As we increase our understanding of how chronic inflammation develops in the stomach and contributes to carcinogenesis, there is increasing interest in targeting cancer-promoting inflammation as a strategy to treat GC. Moreover, once cancer develops and anti-cancer immune responses are suppressed, there is evidence of a substantial shift in the microenvironment and new targets for immune therapy emerge. In this chapter, we provide insight into inflammation-related factors, including T lymphocytes, macrophages, pro-inflammatory chemokines, and cytokines, which promote H. pylori-associated GC initiation and growth. While intervening with chronic inflammation is not a new practice in rheumatology or gastroenterology, this approach has not been fully explored for its potential to prevent carcinogenesis or to contribute to the treatment of GC. This review highlights current and possible strategies for therapeutic intervention including (i) targeting pro-inflammatory mediators, (ii) targeting growth factors and pathways involved in angiogenesis in the gastric tumor microenvironment, and (iii) enhancing anti-tumor immunity. In addition, we highlight a significant number of clinical trials and discuss the importance of individual tumor characterization toward offering personalized immune-related therapy.
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8 MeSH Terms
Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer.
Ferreira MA, Gamazon ER, Al-Ejeh F, Aittomäki K, Andrulis IL, Anton-Culver H, Arason A, Arndt V, Aronson KJ, Arun BK, Asseryanis E, Azzollini J, Balmaña J, Barnes DR, Barrowdale D, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Białkowska K, Blomqvist C, Bogdanova NV, Bojesen SE, Bolla MK, Borg A, Brauch H, Brenner H, Broeks A, Burwinkel B, Caldés T, Caligo MA, Campa D, Campbell I, Canzian F, Carter J, Carter BD, Castelao JE, Chang-Claude J, Chanock SJ, Christiansen H, Chung WK, Claes KBM, Clarke CL, EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, de la Hoya M, Dennis J, Devilee P, Diez O, Dörk T, Dunning AM, Dwek M, Eccles DM, Ejlertsen B, Ellberg C, Engel C, Eriksson M, Fasching PA, Fletcher O, Flyger H, Friedman E, Frost D, Gabrielson M, Gago-Dominguez M, Ganz PA, Gapstur SM, Garber J, García-Closas M, García-Sáenz JA, Gaudet MM, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Greene MH, Gronwald J, Guénel P, Haiman CA, Hall P, Hamann U, He W, Heyworth J, Hogervorst FBL, Hollestelle A, Hoover RN, Hopper JL, Hulick PJ, Humphreys K, Imyanitov EN, ABCTB Investigators, HEBON Investigators, BCFR Investigators, Isaacs C, Jakimovska M, Jakubowska A, James PA, Janavicius R, Jankowitz RC, John EM, Johnson N, Joseph V, Karlan BY, Khusnutdinova E, Kiiski JI, Ko YD, Jones ME, Konstantopoulou I, Kristensen VN, Laitman Y, Lambrechts D, Lazaro C, Leslie G, Lester J, Lesueur F, Lindström S, Long J, Loud JT, Lubiński J, Makalic E, Mannermaa A, Manoochehri M, Margolin S, Maurer T, Mavroudis D, McGuffog L, Meindl A, Menon U, Michailidou K, Miller A, Montagna M, Moreno F, Moserle L, Mulligan AM, Nathanson KL, Neuhausen SL, Nevanlinna H, Nevelsteen I, Nielsen FC, Nikitina-Zake L, Nussbaum RL, Offit K, Olah E, Olopade OI, Olsson H, Osorio A, Papp J, Park-Simon TW, Parsons MT, Pedersen IS, Peixoto A, Peterlongo P, Pharoah PDP, Plaseska-Karanfilska D, Poppe B, Presneau N, Radice P, Rantala J, Rennert G, Risch HA, Saloustros E, Sanden K, Sawyer EJ, Schmidt MK, Schmutzler RK, Sharma P, Shu XO, Simard J, Singer CF, Soucy P, Southey MC, Spinelli JJ, Spurdle AB, Stone J, Swerdlow AJ, Tapper WJ, Taylor JA, Teixeira MR, Terry MB, Teulé A, Thomassen M, Thöne K, Thull DL, Tischkowitz M, Toland AE, Torres D, Truong T, Tung N, Vachon CM, van Asperen CJ, van den Ouweland AMW, van Rensburg EJ, Vega A, Viel A, Wang Q, Wappenschmidt B, Weitzel JN, Wendt C, Winqvist R, Yang XR, Yannoukakos D, Ziogas A, Kraft P, Antoniou AC, Zheng W, Easton DF, Milne RL, Beesley J, Chenevix-Trench G
(2019) Nat Commun 10: 1741
MeSH Terms: Breast Neoplasms, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Quantitative Trait Loci
Show Abstract · Added July 17, 2019
Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
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MeSH Terms
Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer.
Formisano L, Lu Y, Servetto A, Hanker AB, Jansen VM, Bauer JA, Sudhan DR, Guerrero-Zotano AL, Croessmann S, Guo Y, Ericsson PG, Lee KM, Nixon MJ, Schwarz LJ, Sanders ME, Dugger TC, Cruz MR, Behdad A, Cristofanilli M, Bardia A, O'Shaughnessy J, Nagy RJ, Lanman RB, Solovieff N, He W, Miller M, Su F, Shyr Y, Mayer IA, Balko JM, Arteaga CL
(2019) Nat Commun 10: 1373
MeSH Terms: Aminopyridines, Animals, Antineoplastic Agents, Hormonal, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Circulating Tumor DNA, Cyclin D1, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Drug Resistance, Neoplasm, Female, Fulvestrant, High-Throughput Nucleotide Sequencing, Humans, MCF-7 Cells, Mice, Mutation, Naphthalenes, Piperazines, Progression-Free Survival, Proportional Hazards Models, Protein Kinase Inhibitors, Purines, Pyrazoles, Pyridines, Quinolines, Quinoxalines, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Fibroblast Growth Factor, Type 2, Receptors, Estrogen, Signal Transduction, Xenograft Model Antitumor Assays
Show Abstract · Added April 2, 2019
Using an ORF kinome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identified FGFR1 as a mechanism of drug resistance. FGFR1-amplified/ER+ breast cancer cells and MCF-7 cells transduced with FGFR1 were resistant to fulvestrant ± ribociclib or palbociclib. This resistance was abrogated by treatment with the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Addition of the FGFR TKI erdafitinib to palbociclib/fulvestrant induced complete responses of FGFR1-amplified/ER+ patient-derived-xenografts. Next generation sequencing of circulating tumor DNA (ctDNA) in 34 patients after progression on CDK4/6 inhibitors identified FGFR1/2 amplification or activating mutations in 14/34 (41%) post-progression specimens. Finally, ctDNA from patients enrolled in MONALEESA-2, the registration trial of ribociclib, showed that patients with FGFR1 amplification exhibited a shorter progression-free survival compared to patients with wild type FGFR1. Thus, we propose breast cancers with FGFR pathway alterations should be considered for trials using combinations of ER, CDK4/6 and FGFR antagonists.
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32 MeSH Terms
α-Difluoromethylornithine reduces gastric carcinogenesis by causing mutations in .
Sierra JC, Suarez G, Piazuelo MB, Luis PB, Baker DR, Romero-Gallo J, Barry DP, Schneider C, Morgan DR, Peek RM, Gobert AP, Wilson KT
(2019) Proc Natl Acad Sci U S A 116: 5077-5085
MeSH Terms: Animals, Bacterial Proteins, Carcinogenesis, DNA Damage, Eflornithine, Gene Deletion, Gene Rearrangement, Gerbillinae, Helicobacter pylori, Male, Mutation, Oxidative Stress, RNA, Messenger, Stomach Neoplasms, Virulence
Show Abstract · Added February 26, 2019
Infection by is the primary cause of gastric adenocarcinoma. The most potent virulence factor is cytotoxin-associated gene A (CagA), which is translocated by a type 4 secretion system (T4SS) into gastric epithelial cells and activates oncogenic signaling pathways. The gene encodes for a key component of the T4SS and can undergo gene rearrangements. We have shown that the cancer chemopreventive agent α-difluoromethylornithine (DFMO), known to inhibit the enzyme ornithine decarboxylase, reduces -mediated gastric cancer incidence in Mongolian gerbils. In the present study, we questioned whether DFMO might directly affect pathogenicity. We show that output strains isolated from gerbils treated with DFMO exhibit reduced ability to translocate CagA in gastric epithelial cells. Further, we frequently detected genomic modifications in the middle repeat region of the gene of output strains from DFMO-treated animals, which were associated with alterations in the CagY protein. Gerbils did not develop carcinoma when infected with a DFMO output strain containing rearranged or the parental strain in which the wild-type was replaced by with DFMO-induced rearrangements. Lastly, we demonstrate that in vitro treatment of by DFMO induces oxidative DNA damage, expression of the DNA repair enzyme MutS2, and mutations in , demonstrating that DFMO directly affects genomic stability. Deletion of abrogated the ability of DFMO to induce rearrangements directly. In conclusion, DFMO-induced oxidative stress in leads to genomic alterations and attenuates virulence.
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15 MeSH Terms
Metabolic plasticity meets gene regulation.
Paudel BB, Quaranta V
(2019) Proc Natl Acad Sci U S A 116: 3370-3372
MeSH Terms: Biochemical Phenomena, Gene Expression Regulation, Humans, Metabolic Networks and Pathways, Neoplasms, Neuronal Plasticity
Added March 23, 2019
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6 MeSH Terms
Linear Accelerator-Based Stereotactic Radiosurgery for Cranial Intraparenchymal Metastasis of a Malignant Peripheral Nerve Sheath Tumor: Case Report and Review of the Literature.
Fenlon JB, Khattab MH, Ferguson DC, Luo G, Keedy VL, Chambless LB, Kirschner AN
(2019) World Neurosurg 123: 123-127
MeSH Terms: Adult, Brain Neoplasms, Humans, Magnetic Resonance Imaging, Male, Nerve Sheath Neoplasms, Neurofibrosarcoma, Particle Accelerators, Positron-Emission Tomography, Radiosurgery
Show Abstract · Added April 2, 2019
BACKGROUND - Malignant peripheral nerve sheath tumors (MPNSTs) are rare, aggressive soft tissue sarcomas. MPNST intracranial metastasis is exceedingly rare with only 22 documented cases in the literature and, to our knowledge, only 1 case with intraparenchymal brain metastasis. Most have been managed surgically; however, 2 documented cases were treated with Gamma Knife radiosurgery. Excluding this case report, there are no other documented cases of linear accelerator-based stereotactic radiosurgery (SRS) to treat MPNST brain metastasis.
CASE DESCRIPTION - A 41-year-old man with MPNST of the lung initially underwent tumor resection. He developed multiple systemic metastases that were managed with directed radiation therapy. A parietal brain metastasis was treated with linear accelerator-based SRS. Following SRS therapy, the patient was treated with a tropomyosin receptor kinase inhibitor. Complete resolution of brain metastasis was seen on brain magnetic resonance imaging 5 months after treatment with SRS. At 11 months after SRS, there was no evidence of recurrence or progression of the intraparenchymal disease. The patient continued to have stable extracranial disease on his ninth cycle of systemic treatment.
CONCLUSIONS - This report provides important insights into efficacy of linear accelerator-based SRS to treat MPNST brain metastases.
Copyright © 2018 Elsevier Inc. All rights reserved.
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MeSH Terms
Single-Cell Mass Cytometry of Archived Human Epithelial Tissue for Decoding Cancer Signaling Pathways.
Scurrah CR, Simmons AJ, Lau KS
(2019) Methods Mol Biol 1884: 215-229
MeSH Terms: Animals, Cryopreservation, Epithelial Cells, Epithelium, Fixatives, Flow Cytometry, Formaldehyde, Humans, Mass Spectrometry, Mice, Neoplasms, Paraffin Embedding, Signal Transduction, Single-Cell Analysis, Tissue Fixation
Show Abstract · Added December 14, 2018
The emerging phenomenon of cellular heterogeneity in tissue requires single-cell resolution studies. A specific challenge for suspension-based single-cell analysis is the preservation of intact cell states when single cells are isolated from tissue contexts, in order to enable downstream analyses to extract accurate, native information. We have developed DISSECT (Disaggregation for Intracellular Signaling in Single Epithelial Cells from Tissue) coupled to mass cytometry (CyTOF: Cytometry by Time-of-Flight), an experimental approach for profiling intact signaling states of single cells from epithelial tissue specimens. We have previously applied DISSECT-CyTOF to fresh mouse intestinal samples and to Formalin-Fixed, Paraffin-Embedded (FFPE) human colorectal cancer specimens. Here, we present detailed protocols for each of these procedures, as well as a new method for applying DISSECT to cryopreserved tissue slices. We present example data for using DISSECT on a cryopreserved specimen of the human colon to profile its immune and epithelial composition. These techniques can be used for high-resolution studies for monitoring disease-related alternations in different cellular compartments using specimens stored in cryopreserved or FFPE tissue banks.
1 Communities
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15 MeSH Terms
Platelet-Based Drug Delivery for Cancer Applications.
Ortiz-Otero N, Mohamed Z, King MR
(2018) Adv Exp Med Biol 1092: 235-251
MeSH Terms: Blood Platelets, Drug Delivery Systems, Hemostasis, Humans, Male, Neoplasm Metastasis, Neoplasms
Show Abstract · Added April 15, 2019
Platelets can be considered as the "guardian of hemostasis" where their main function is to maintain vascular integrity. In pathological conditions, the hemostatic role of platelets may be hijacked to stimulate disease progression. In 1865, Armand Trousseau was a pioneer in establishing the platelet-cancer metastasis relationship, which he eventually termed as Trousseau's Syndrome to describe the deregulation of the hemostasis-associated pathways induced by cancer progression (Varki, Blood. 110(6):1723-9, 2007). Since these early studies, there has been an increase in experimental evidence not only to elucidate the role of platelets in cancer metastasis but also to create novel cancer therapies by targeting the platelet's impact in metastasis. In this chapter, we discuss the contribution of platelets in facilitating tumor cell transit from the primary tumor to distant metastatic sites as well as novel cancer therapies based on platelet interactions.
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7 MeSH Terms
Mechanical Forces in Tumor Angiogenesis.
Zanotelli MR, Reinhart-King CA
(2018) Adv Exp Med Biol 1092: 91-112
MeSH Terms: Biomechanical Phenomena, Endothelial Cells, Extracellular Fluid, Humans, Neoplasms, Neovascularization, Pathologic, Tumor Microenvironment
Show Abstract · Added April 10, 2019
A defining hallmark of cancer and cancer development is upregulated angiogenesis. The vasculature formed in tumors is structurally abnormal, not organized in the conventional hierarchical arrangement, and more permeable than normal vasculature. These features contribute to leaky, tortuous, and dilated blood vessels, which act to create heterogeneous blood flow, compression of vessels, and elevated interstitial fluid pressure. As such, abnormalities in the tumor vasculature not only affect the delivery of nutrients and oxygen to the tumor, but also contribute to creating an abnormal tumor microenvironment that further promotes tumorigenesis. The role of chemical signaling events in mediating tumor angiogenesis has been well researched; however, the relative contribution of physical cues and mechanical regulation of tumor angiogenesis is less understood. Growing research indicates that the physical microenvironment plays a significant role in tumor progression and promoting abnormal tumor vasculature. Here, we review how mechanical cues found in the tumor microenvironment promote aberrant tumor angiogenesis. Specifically, we discuss the influence of matrix stiffness and mechanical stresses in tumor tissue on tumor vasculature, as well as the mechanosensory pathways utilized by endothelial cells to respond to the physical cues found in the tumor microenvironment. We also discuss the impact of the resulting aberrant tumor vasculature on tumor progression and therapeutic treatment.
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7 MeSH Terms
Should Ki67 immunohistochemistry be performed on all lesions in multifocal small intestinal neuroendocrine tumours?
Numbere N, Huber AR, Shi C, Cates JMM, Gonzalez RS
(2019) Histopathology 74: 424-429
MeSH Terms: Adult, Aged, Aged, 80 and over, Biomarkers, Tumor, Disease-Free Survival, Female, Humans, Immunohistochemistry, Intestinal Neoplasms, Intestine, Small, Ki-67 Antigen, Male, Middle Aged, Neoplasm Grading, Neuroendocrine Tumors, Proportional Hazards Models
Show Abstract · Added November 1, 2018
AIMS - Well-differentiated small intestinal neuroendocrine tumours (SI-NETs) are often multifocal, and this has been suggested to impart worse disease-free survival. Practice guidelines have not been established for World Health Organisation (WHO) grading of multiple primary lesions.
METHODS AND RESULTS - We identified 68 patients with ileal/jejunal SI-NET for a combined total of 207 primary lesions. Each case was evaluated for patient age and sex; size of all tumours; presence of lymph node metastases, mesenteric tumour deposits or distant metastases; and disease-specific outcome. Ki67 staining was performed on all 207 primary lesions. The relationship between multifocality and clinicopathological factors was compared using Fisher's exact test. Outcome was tested using Cox proportional hazard regression. Forty-two patients had unifocal disease, and 26 had multifocal disease (median five lesions, range = 2-32). Most tumours were WHO grade 1 (201 of 207, 97%). Of the five patients with grades 2/3 tumours, three patients had unifocal disease, one patient had two subcentimetre grade 2 lesions (including the largest) and eight subcentimetre grade 1 lesions, and one patient had one 1.6-cm grade 3 lesion and one subcentimetre grade 1 lesion. There was a positive correlation between tumour size and Ki67 index (coefficient 0.28; 95% confidence interval 0.05-0.52, P = 0.017). There was no significant association between multifocality and nodal metastases, mesenteric tumour deposits, distant metastases or disease-specific survival.
CONCLUSIONS - In patients with multifocal SI-NET, unless a particular lesion has a high mitotic rate, only staining the largest lesion for Ki67 should serve to grade almost all cases accurately. Multifocality does not appear to significantly impact patient survival.
© 2018 John Wiley & Sons Ltd.
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16 MeSH Terms