The multi-factorial nature of clinical multidrug resistance in cancer

Drug Resistance Updates, Journal Year: 2019, Volume and Issue: 46, P. 100645 - 100645

Published: Sept. 1, 2019

Language: Английский

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Therapeutic targeting of the hypoxic tumour microenvironment

Nature Reviews Clinical Oncology, Journal Year: 2021, Volume and Issue: 18(12), P. 751 - 772

Published: July 29, 2021

Language: Английский

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Sarcoma treatment in the era of molecular medicine

EMBO Molecular Medicine, Journal Year: 2020, Volume and Issue: 12(11)

Published: Oct. 13, 2020

Review13 October 2020Open Access Sarcoma treatment in the era of molecular medicine Thomas GP Grünewald Corresponding Author [email protected] orcid.org/0000-0003-0920-7377 Max-Eder Research Group for Pediatric Biology, Institute Pathology, Faculty Medicine, LMU Munich, Germany Division Translational Research, German Cancer Center (DKFZ), Hopp Children's (KiTZ), Consortium (DKTK), Heidelberg, Heidelberg University Hospital, Search more papers by this author Marta Alonso orcid.org/0000-0002-7520-7351 Program Solid Tumors and Biomarkers, Foundation Applied Medical Navarra Pamplona, Spain Sofia Avnet Orthopedic Pathophysiology Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy Ana Banito Soft Tissue Group, Stefan Burdach Department Pediatrics (CCRC), Technische Universität München, Florencia Cidre-Aranaz orcid.org/0000-0002-0246-7179 Gemma Di Pompo Martin Distel Institute, Vienna, Austria Heathcliff Dorado-Garcia Oncology/Hematology, Charité-Universitätsmedizin Berlin, Javier Garcia-Castro Cellular Biotechnology Instituto de Salud Carlos III, Madrid, Laura González-González Agamemnon E Grigoriadis Centre Craniofacial King's College London, UK Merve Kasan Christian Koelsche Manuela Krumbholz Pediatrics, Erlangen, Fernando Lecanda Oncology, Adhesion Metastasis Laboratory, Navarra, Silvia Lemma Dario L Longo Biostructures Bioimaging (IBB), Italian National Council (CNR), Turin, Claudia Madrigal-Esquivel Oncology Metabolism, Sheffield, Álvaro Morales-Molina Julian Musa General, Visceral Transplantation Surgery, Shunya Ohmura Benjamin Ory Université Nantes, Inserm, U1238, France Miguel Pereira-Silva Pharmaceutical Technology, Pharmacy, Coimbra, Portugal Francesca Perut Rene Rodriguez orcid.org/0000-0002-0768-7306 Investigación Sanitaria del Principado Asturias, Oviedo, CIBER en oncología (CIBERONC), Carolin Seeling Ulm University, Ulm, Nada Al Shaaili Shabnam Shaabani Drug Design, Groningen, The Netherlands Kristina Shiavone Snehadri Sinha Oral Maxillofacial Diseases, Helsinki, Finland Eleni M Tomazou Marcel Trautmann orcid.org/0000-0002-5842-1196 Gerhard-Domagk-Institute Münster Münster, Maria Vela Hospital La Paz Health (IdiPAZ), Yvonne MH Versleijen-Jonkers Radboud Center, Nijmegen, Julia Visgauss Duke Durham, NC, USA Zalacain Sebastian J Schober Andrej Lissat Children′s Zurich – Eleonoren Foundation, Kanton Zürich, Switzerland William R English Nicola Baldini orcid.org/0000-0003-2228-3833 Biomedical Neuromotor Sciences, Dominique Heymann orcid.org/0000-0001-7777-0669 Institut Cancérologie l'Ouest, Tumor Heterogeneity Precision Saint-Herblain, Information *,1,2,3, Alonso4, Avnet5, Banito6, Burdach7, Cidre-Aranaz1, Pompo5, Distel8, Dorado-Garcia9, Garcia-Castro10, González-González10, Grigoriadis11, Kasan1, Koelsche3, Krumbholz12, Lecanda13, Lemma5, Longo14, Madrigal-Esquivel15, Morales-Molina10, Musa1,16, Ohmura1, Ory17, Pereira-Silva18, Perut5, Rodriguez19,20, Seeling21, Shaaili15, Shaabani22, Shiavone15, Sinha23, Tomazou8, Trautmann24, Vela25, Versleijen-Jonkers26, Visgauss27, Zalacain14, Schober7, Lissat28, English15, *,5,29 *,15,30 1Max-Eder 2Division 3Institute 4Program 5Orthopedic 6Pediatric 7Department 8Children's 9Department 10Cellular 11Centre 12Department 13Division 14Institute 15Department 16Department 17Université 18Department 19Instituto 20CIBER 21Institute 22Department 23Department 24Division 25Hospital 26Department 27Medical 28University 29Department 30Université *Corresponding author. Tel: +49 6221 42 3718; E-mail: +39 (0) 516 366 549; +33 240 679 841; EMBO Mol Med (2020)12:e11131https://doi.org/10.15252/emmm.201911131 See Glossary abbreviations used article. PDFDownload PDF article text main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Sarcomas are heterogeneous clinically challenging soft tissue bone cancers. Although constituting only 1% all human malignancies, sarcomas represent second most common type solid tumors children adolescents comprise an important group secondary malignancies. More than 100 histological subtypes have been characterized date, many being discovered due profiling. Owing their mostly aggressive biological behavior, relative rarity, occurrence at virtually every anatomical site, sarcoma particular difficult-to-treat categories. Current multimodal concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements enabled a precise characterization revealed novel therapeutic targets prognostic/predictive biomarkers. This review aims providing comprehensive overview latest advances biology effects on clinical oncology; it is meant broad readership ranging from novices experts field sarcoma. stem cells (CSCs) Cells within tumor found very small fractions that thought be responsible resistance cancer treatments thus relapse. Cell dormancy Stage progression during which cease dividing but survive quiescent state while waiting appropriate environmental conditions. Chorioallantoic Membrane (CAM) models Chick embryo CAM study formation, angiogenesis, metastasis. Circulating (CTCs) leak into vasculature or lymphatics primary carried around body blood circulation. Epigenomic alterations Heritable change does not affect DNA sequence results gene expression. Extracellular vesicles (EVs) Heterogeneous family generated different subcellular compartments released extracellular space Genomic Permanent modifications including somatic mutations, copy-number variations (CNVs), fusions. Immunotherapy Type aids immune system fight tumors. Oncolytic viruses Viruses that, intrinsic properties through genetic engineering, specifically replicate kill cells. Orthotopic xenografts Animal based injection cell lines location where typically appear humans. Patient-derived (PDXs) model transplantation biopsies encompass TME immunodeficient animals. arise between 0–14 years age. Approach patient care allows physicians select likely help patients understanding disease. Malignant neoplasms originate skeleton tissues. microenvironment (TME) environment reside encompassing matrix stromal (endothelial cells, fibroblasts, cells) Epidemiology rare among adult they 12–15% pediatric (Stiller et al, 2013). Despite implementation continuous optimization therapies, one-third still succumb Historically, clustered two large subgroups, according site occurrence—sarcomas tissues (hereafter referred as "bone sarcomas" "soft [STSs], respectively). Both subgroups variety subtypes, recent technological decipher constantly increasing number level (Fig 1; Baldauf 2018a; Watson 2018; Weidema 2020). Table 1 summarizes major discussed features. Figure 1. Diversity highlighted methylation profilingt-distributed stochastic neighbor embedding (t-SNE) plot n = 18 genome-wide profiling Illumina EPIC arrays (Koelsche 2018a,b). Web-link classifier: www.molecularsarcomapathology.org. Download figure PowerPoint Main characteristics subtype Abbreviation features Bone Chondrosarcomaa CHS Localization: Cartilage, surface, centrally Histopathology: Lobules composed malignant chondrocytes entrapped chondroid with calcified foci Identified mutations IDH1/2, EXT1/2 Ewing sarcomaa EwS Long flat bones (˜85%), extraskeletal sites (˜15%) Undifferentiated round cells; strong membranous CD99 immunoreactivity PAS-positive cytoplasm Harbor FET-ETS translocations (˜85% EWSR1-FLI1; ˜10% EWSR1-ERG; ˜5% subtypes) Osteosarcomaa OS surface Neoplastic mesenchymal morphology frequent polymorphism (epithelioid, fusiform, round, spindled, etc.) associated osteoid Various telangiectatic numerous hemorrhagic areas Complex highly aneuploidy karyotypes multiple chromosomal aberrations (numerical structural) Frequent TP53 RB other defining "BRCAness" signature (STSs) Fibrosarcomaa Deep extremities, trunk, head neck Composed monomorphic fibroblastic collagenous GastroIntestinal Stromal GIST Gastrointestinal track (main site: stomach intestine) morphological spectrum mainly spindle epithelioid (˜20% cases) mixed histology differentiation toward interstitial Cajal. Usually immunopositive CD117 (KIT) DOG1 activating KIT PDGFRA Leiomyosarcoma LMS Most commonly detected peritoneum uterus (rarely bone) Mesenchymal, spindle-shaped smooth muscle (SMA, desmin h-Caldesmon positivity) Highly complex genomic instability Liposarcomaa LPS Variable (most retroperitoneal space) variable adipocytic heterogenous embedded vascularized stroma (in case myxoid stroma) Rhabdomyosarcoma RMS Mesenchymal phenotype myogenic (usually positive myogenin MYOD) pleomorphic UPS frequently extremities high degree cellular atypia pleomorphism Synovial SS Mostly deep Spindle epithelial (i.e., monophasic/biphasic SS) specific SS18-SSX1/2/4 fusion oncogenes STS (WHO Classification Tumours: Tumours, Among sarcomas, osteosarcoma (OS) (Heymann, 2014). primarily affects young adults, first largest peak incidence age ~10–14 years. Coinciding pubertal growth spurt, rate 4 (3.5–4.6) range 5 (4.6–5.6) 0–19 per year million persons (Ottaviani Jaffe, 2009). current standard was introduced late 1970s remains largely unaltered despite efforts improve outcomes (Rosen 1976). Nowadays, localized disease face 5-year overall survival rates < 70%, 20% who develop metastatic relapse > 3 (Roberts 2019). (EwS) included because both (~85% (~15% cases), has similar OS. subgroup comprises ~70–80% 70 STSs cancers, highest Overall, estimated ~57–62% can vary widely depending stage interplay (Lyu Unfortunately, epidemiological data limited incomplete. initiatives ongoing databases, will benefit use "big data"

Language: Английский

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Dichloroacetate (DCA) and Cancer: An Overview towards Clinical Applications

Oxidative Medicine and Cellular Longevity, Journal Year: 2019, Volume and Issue: 2019, P. 1 - 14

Published: Nov. 14, 2019

An extensive body of literature describes anticancer property dichloroacetate (DCA), but its effective clinical administration in cancer therapy is still limited to trials. The occurrence side effects such as neurotoxicity well the suspicion DCA carcinogenicity restricts use DCA. However, last years, number reports supporting employment against increased also because great interest targeting metabolism tumour cells. Dissecting mechanism action helped understand bases selective efficacy A successful coadministration with conventional chemotherapy, radiotherapy, other drugs, or natural compounds has been tested several models. New drug delivery systems and multiaction containing drugs seem ameliorate bioavailability appear more efficient thanks a synergistic multiple agents. spread efficiency prompted additional studies that let find potential molecular targets Interestingly, could significantly affect stem cell fraction contribute eradication. Collectively, these findings provide strong rationale towards novel translational therapy.

Language: Английский

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Breast Cancer Stem Cells as Drivers of Tumor Chemoresistance, Dormancy and Relapse: New Challenges and Therapeutic Opportunities

Cancers, Journal Year: 2019, Volume and Issue: 11(10), P. 1569 - 1569

Published: Oct. 15, 2019

Breast cancer is the most frequent among women worldwide. Therapeutic strategies to prevent or treat metastatic disease are still inadequate although great progress has been made in treating early-stage breast cancer. Cancer stem-like cells (CSCs) that endowed with high plasticity and self-renewal properties have shown play a key role development, progression, metastasis. A subpopulation of CSCs combines tumor-initiating capacity dormant/quiescent/slow cycling status present throughout clinical history patients. Dormant/quiescent/slow component tumor heterogeneity they responsible for chemoresistance, migration, dormancy, defined as ability survive target organs generate metastasis up two decades after diagnosis. Understanding used by resist conventional targeted therapies, interact their niche, escape immune surveillance, finally awaken from dormancy importance This review summarizes current understanding mechanisms involved dissemination, cancer, particular focus on dormant cells. Finally, we discuss how advancements detection, molecular understanding, targeting will likely open new therapeutic avenues treatment.

Language: Английский

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Tumor-Associated Macrophages and Their Functional Transformation in the Hypoxic Tumor Microenvironment

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: Sept. 16, 2021

Tumor-associated macrophages (TAMs) are some of the most abundant immune cells within tumors and perform a broad repertoire functions via diverse phenotypes. On basis their functional differences in tumor growth, TAMs usually categorized into two subsets M1 M2. It is well established that microenvironment (TME) characterized by hypoxia along with progression. adopt an M1-like pro-inflammatory phenotype at early phases oncogenesis mediate response inhibits growth. As progress, anabatic TME gradually induces M2-like transformation means direct effects, metabolic influence, lactic acidosis, angiogenesis, remodeled stroma, then urges them to participate immunosuppression, angiogenesis other tumor-supporting procedure. Therefore, thorough comprehension internal mechanism this TAM hypoxic essence, might provide novel insights immunotherapeutic strategies.

Language: Английский

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The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer

Frontiers in Oncology, Journal Year: 2021, Volume and Issue: 11

Published: Sept. 3, 2021

Although chemotherapy can improve the overall survival and prognosis of cancer patients, chemoresistance remains an obstacle due to diversity, heterogeneity, adaptability environmental alters in clinic. To determine more possibilities for therapy, recent studies have begun explore changes metabolism, especially glycolysis. The Warburg effect is a hallmark that refers preference cells metabolize glucose anaerobically rather than aerobically, even under normoxia, which contributes chemoresistance. However, association between glycolysis molecular mechanisms glycolysis-induced unclear. This review describes mechanism from aspects process, signaling pathways, tumor microenvironment, their interactions. understanding how induces may provide new targets concepts therapy.

Language: Английский

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Engineering interferons and interleukins for cancer immunotherapy

Advanced Drug Delivery Reviews, Journal Year: 2022, Volume and Issue: 182, P. 114112 - 114112

Published: Jan. 24, 2022

Cytokines are a class of potent immunoregulatory proteins that secreted in response to various stimuli and act locally regulate many aspects human physiology disease. play important roles cancer initiation, progression, elimination, thus, there is long clinical history associated with the use recombinant cytokines treat cancer. However, as therapeutics has been limited by cytokine pleiotropy, complex biology, poor drug-like properties, severe dose-limiting toxicities. Nevertheless, crucial mediators innate adaptive antitumor immunity have potential enhance immunotherapeutic approaches Development immune checkpoint inhibitors combination immunotherapies reinvigorated interest therapeutics, variety engineering emerging improve safety effectiveness immunotherapy. In this review we highlight recent advances biology for

Language: Английский

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Tumor acidity: From hallmark of cancer to target of treatment

Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 12

Published: Aug. 29, 2022

Tumor acidity is one of the cancer hallmarks and associated with metabolic reprogramming use glycolysis, which results in a high intracellular lactic acid concentration. Cancer cells avoid stress major by activation expression proton lactate transporters exchangers have an inverted pH gradient (extracellular pHs are alkaline, respectively). The shift tumor acid-base balance promotes proliferation, apoptosis avoidance, invasiveness, metastatic potential, aggressiveness, immune evasion, treatment resistance. For example, weak-base chemotherapeutic agents may substantially reduced cellular uptake capacity due to "ion trapping". Lactic negatively affects functions activated effector T cells, stimulates regulatory them express programmed cell death receptor 1. On other hand, inversion could be weakness that will allow development new promising therapies, such as tumor-targeted pH-sensitive antibodies pH-responsible nanoparticle conjugates anticancer drugs. regulation levels pharmacological inhibition proteins (monocarboxylate transporters, H

Language: Английский

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Excited-state intramolecular proton transfer (ESIPT)-based fluorescent probes for biomarker detection: design, mechanism, and application

Chemical Communications, Journal Year: 2023, Volume and Issue: 59(15), P. 2056 - 2071

Published: Jan. 1, 2023

Biomarkers are essential in biology, physiology, and pharmacology; thus, their detection is of extensive importance.

Language: Английский

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