bims-myxlip 2021-02-07 papers

bims-myxlip

Biomed News

on Myxoid liposarcoma

Issue of 2021–02–07
eight papers selected by
Laura Mannarino, Mario Negri Institute

Expression and prognostic significance of PDGF ligands and receptors across soft tissue sarcomas.
Candidate Biomarkers for Specific Intraoperative Near-Infrared Imaging of Soft Tissue Sarcomas: A Systematic Review.
The transcriptional regulator Zfat is essential for maintenance and differentiation of the adipocytes.
PROTACs: Promising Approaches for Epigenetic Strategies to Overcome Drug Resistance.
Cellular response to endogenous DNA damage: DNA base modifications in gene expression regulation.
Immunotherapy for sarcomas: new frontiers and unveiled opportunities.
Comparison of clinicopathological features and outcomes in patients with primary leiomyosarcoma of bone and soft tissue.
Adipose Tissue T Regulatory Cells: Implications for Health and Disease.

ESMO Open. 2021 Jan 29. pii: S2059-7029(20)32903-3. [Epub ahead of print]6(1): 100037

Expression and prognostic significance of PDGF ligands and receptors across soft tissue sarcomas.

M Brahmi, T Lesluyes, A Dufresne, M Toulmonde, A Italiano, O Mir, A Le Cesne, T Valentin, C Chevreau, S Bonvalot, N Penel, J-M Coindre, S Le Guellec, F Le Loarer, M Karanian, J-Y Blay, F Chibon.

   BACKGROUND: While the anti-PDGFRA antibody olaratumab failed to confirm an impact on survival in unselected advanced soft tissue sarcoma (STS) patients, the level of expression and the prognosis of platelet-derived growth factor (PDGF) receptors and ligands in STS remain unclear.
PATIENTS AND METHODS: We analyzed PDGF ligands and receptors' expression levels in a series of 255 patients with different histologies of STS [gastrointestinal stromal tumor (GIST), myxoid liposarcoma (MLPS), sarcoma with complex genomics, synovial sarcoma (SyS)] with Agilent single-color micro-arrays. We explored expression levels as prognostic values in univariate and multivariate analysis using R software (version 3.4.2).
RESULTS: Complex patterns of correlation of expression between ligands and receptors were observed for each histotype. PDGFA levels were highest in SyS and lowest in MLPS (P < 4 × 10-9), PDGFB and C levels were lower in GIST (P < 2 × 10-15 and P < 3 × 10-9) while PDGFD expression was similar across histological subtypes. PDGF receptor (PDGFR) A expression was lowest in MLPS (P < 0.002), whereas PDGFRB and L expressions were lowest in GIST and SyS (P < 0.0004). Interestingly, high PDGFA expression levels were associated with higher risk of metastasis (P = 0.006), whereas PDGFD levels above average were associated with a reduced risk of metastasis (P = 0.01) in univariate and multivariate analysis.
CONCLUSIONS: The expression of PDGF ligands and receptors varies across sarcoma histological subtypes. PDGFA and D expression levels independently and inversely correlate with the risk of metastatic relapse.

Keywords:  PDGF; PDGFR; expression level; prognostic factor; sarcoma

DOI:  https://doi.org/10.1016/j.esmoop.2020.100037
Cancers (Basel). 2021 Feb 01. pii: 557. [Epub ahead of print]13(3):

Candidate Biomarkers for Specific Intraoperative Near-Infrared Imaging of Soft Tissue Sarcomas: A Systematic Review.

Zeger Rijs, A Naweed Shifai, Sarah E Bosma, Peter J K Kuppen, Alexander L Vahrmeijer, Stijn Keereweer, Judith V M G Bovée, Michiel A J van de Sande, Cornelis F M Sier, Pieter B A A van Driel.

  Surgery is the mainstay of treatment for localized soft tissue sarcomas (STS). The curative treatment highly depends on complete tumor resection, as positive margins are associated with local recurrence (LR) and prognosis. However, determining the tumor margin during surgery is challenging. Real-time tumor-specific imaging can facilitate complete resection by visualizing tumor tissue during surgery. Unfortunately, STS specific tracers are presently not clinically available. In this review, STS-associated cell surface-expressed biomarkers, which are currently already clinically targeted with monoclonal antibodies for therapeutic purposes, are evaluated for their use in near-infrared fluorescence (NIRF) imaging of STS. Clinically targeted biomarkers in STS were extracted from clinical trial registers and a PubMed search was performed. Data on biomarker characteristics, sample size, percentage of biomarker-positive STS samples, pattern of biomarker expression, biomarker internalization features, and previous applications of the biomarker in imaging were extracted. The biomarkers were ranked utilizing a previously described scoring system. Eleven cell surface-expressed biomarkers were identified from which 7 were selected as potential biomarkers for NIRF imaging: TEM1, VEGFR-1, EGFR, VEGFR-2, IGF-1R, PDGFRα, and CD40. Promising biomarkers in common and aggressive STS subtypes are TEM1 for myxofibrosarcoma, TEM1, and PDGFRα for undifferentiated soft tissue sarcoma and EGFR for synovial sarcoma.

Keywords:  CD40; EGFR; IGF-1R; PDGFRα; TEM1; VEGFR-1; VEGFR-2; image guided surgery; near-infra red fluorescence; soft tissue sarcomas

DOI:  https://doi.org/10.3390/cancers13030557
J Cell Biochem. 2021 Feb 01.

The transcriptional regulator Zfat is essential for maintenance and differentiation of the adipocytes.

Shuhei Ishikura, Masayoshi Nagai, Toshiyuki Tsunoda, Kensuke Nishi, Yoko Tanaka, Midori Koyanagi, Senji Shirasawa.

  Adipocytes play crucial roles in the control of whole-body energy homeostasis. Differentiation and functions of the adipocytes are regulated by various transcription factors. Zfat (zinc-finger protein with AT-hook) is a transcriptional regulator that controls messenger RNA expression of specific genes through binding to their transcription start sites. Here we report important roles of Zfat in the adipocytes. We establish inducible Zfat-knockout (Zfat iKO) mice where treatment with tamoxifen causes a marked reduction in Zfat expression in various tissues. Tamoxifen treatment of Zfat iKO mice reduces the white adipose tissues (WATs) mass, accompanied by the decreased triglyceride levels. Zfat is expressed in both the adipose-derived stem cells (ADSCs) and mature adipocytes in the WATs. In ex vivo assays of the mature adipocytes differentiated from the Zfat iKO ADSCs, loss of Zfat in the mature adipocytes reduces the triglyceride levels, suggesting cell autonomous roles of Zfat in the maintenance of the mature adipocytes. Furthermore, we identify the Atg13, Brf1, Psmc3, and Timm22 genes as Zfat-target genes in the mature adipocytes. In contrast, loss of Zfat in the ADSCs impairs adipocyte differentiation with the decreased expression of C/EBPα and adiponectin. Thus, we propose that Zfat plays crucial roles in maintenance and differentiation of the adipocytes.

Keywords:  CCAAT-enhancer-binding protein (C/EBP); Zfat; adipocyte; lipid metabolism; transcription regulation; transgenic mice

DOI:  https://doi.org/10.1002/jcb.29890
Curr Cancer Drug Targets. 2021 Feb 02.

PROTACs: Promising Approaches for Epigenetic Strategies to Overcome Drug Resistance.

Sarah F Giardina, Elena Valdambrini, J David Warren, Francis Barany.

  Epigenetic modulation of gene expression is essential for tissue-specific development and maintenance in mammalian cells. Disruption of epigenetic processes, and the subsequent alteration of gene functions, can result in inappropriate activation or inhibition of various cellular signaling pathways and thus, lead to cancer. Recent advancements in the understanding of the role of epigenetics in cancer initiation and progression have uncovered functions for DNA methylation, histone modifications, nucleosome positioning, and non-coding RNAs. Epigenetic therapies have shown some promise for hematological malignancies, and a wide range of epigenetic-based drugs are undergoing clinical trials. However, in a dynamic survival strategy, cancer cells exploit their heterogeneous population which frequently results in the rapid acquisition of therapy resistance. Here, we describe novel approaches in drug discovery targeting the epigenome, highlighting recent advances the selective degradation of target proteins using Proteolysis Targeting Chimera (PROTAC) to address drug resistance.

Keywords:  Cancer; Oncology; PROTAC; drug resistance.; epigenetics

DOI:  https://doi.org/10.2174/1568009621666210203110857
DNA Repair (Amst). 2021 Jan 26. pii: S1568-7864(21)00005-7. [Epub ahead of print]99 103051

Cellular response to endogenous DNA damage: DNA base modifications in gene expression regulation.

Diana L Bordin, Lisa Lirussi, Hilde Nilsen.

  The integrity of the genetic information is continuously challenged by numerous genotoxic insults, most frequently in the form of oxidation, alkylation or deamination of the bases that result in DNA damage. These damages compromise the fidelity of the replication, and interfere with the progression and function of the transcription machineries. The DNA damage response (DDR) comprises a series of strategies to deal with DNA damage, including transient transcriptional inhibition, activation of DNA repair pathways and chromatin remodeling. Coordinated control of transcription and DNA repair is required to safeguardi cellular functions and identities. Here, we address the cellular responses to endogenous DNA damage, with a particular focus on the role of DNA glycosylases and the Base Excision Repair (BER) pathway, in conjunction with the DDR factors, in responding to DNA damage during the transcription process. We will also discuss functions of newly identified epigenetic and regulatory marks, such as 5-hydroxymethylcytosine and its oxidative products and 8-oxoguanine, that were previously considered only as DNA damages. In light of these resultsthe classical perception of DNA damage as detrimental for cellular processes are changing. and a picture emerges whereDNA glycosylases act as dynamic regulators of transcription, placing them at the intersection of DNA repair and gene expression modulation.

Keywords:  Base excision repair; DNA damage response; DNA glycosylases; Endogenous DNA damage; Epigenetic marks; Transcription regulation

DOI:  https://doi.org/10.1016/j.dnarep.2021.103051
J Immunother Cancer. 2021 Feb;pii: e001580. [Epub ahead of print]9(2):

Immunotherapy for sarcomas: new frontiers and unveiled opportunities.

Harsimrat Kaur Birdi, Anna Jirovec, Serena Cortés-Kaplan, Joel Werier, Carolyn Nessim, Jean-Simon Diallo, Michele Ardolino.

  Sarcomas are a rare malignancy of mesenchymal tissues, comprizing a plethora of unique subtypes, with more than 60 types. The sheer heterogeneity of disease phenotype makes this a particularly difficult cancer to treat. Radiotherapy, chemotherapy and surgery have been employed for over three decades and, although effective in early disease (stages I-II), in later stages, where metastatic tumors are present, these treatments are less effective. Given the spectacular results obtained by cancer immunotherapy in a variety of solid cancers and leukemias, there is now a great interest in appliying this new realm of therapy for sarcomas. The widespread use of immunotherapy for sarcoma relies on immuno-profiling of subtypes, immunomonitoring for prognosis, preclinical studies and insight into the safety profile of these novel therapies. Herein, we discuss preclinical and clinical data highlighting how immunotherapy is being used in soft tissue sarcoma and bone sarcomas.

Keywords:  immunotherapy; sarcoma

DOI:  https://doi.org/10.1136/jitc-2020-001580
J Surg Oncol. 2021 Feb 01.

Comparison of clinicopathological features and outcomes in patients with primary leiomyosarcoma of bone and soft tissue.

Charles A Gusho, Alan T Blank, Steven Gitelis.

   BACKGROUNDS AND OBJECTIVES: This investigation sought to describe the outcomes of primary leiomyosarcoma of bone (PLB) compared to soft tissue leiomyosarcoma (SLMS).
METHODS: This was a review of the Surveillance, Epidemiology, and End Results database from 1975 to 2016. Kaplan-Meier methods were used to estimate disease-specific survival (DSS), and a Cox regression model was used to identify prognostic factors.
RESULTS: Of the 7502 identifiable cases, 1% (n = 74) were PLB and 99% (n = 7428) were SLMS. Survival was the same between PLB and SLMS (p = .209). On multivariable analysis for high-grade SLMS, radiation (neoadjuvant: hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.4-0.8; p = .003; adjuvant: HR, 0.75; 95% CI, 0.6-0.9; p = .008) and surgery (procedure specific) improved DSS. For PLB, wide resection/limb salvage (HR, 0.40; 95% CI, 0.3-0.5; p = .018) and amputation (HR, 0.69; 95% CI, 0.5-0.9; p < .001) were positive prognostic factors. Neither radiation nor chemotherapy were prognostic factors for survival in PLB.
CONCLUSIONS: For SLMS, radiation portends a survival advantage. For PLB, however, neither chemotherapy nor radiation were significant prognostic factors, which suggests the optimal treatment for PLB, similar to other primary soft tissue sarcomas originating in bone, remains an unmet medical need.

Keywords:  leiomyosarcoma of bone; outcomes; prognosis; soft tissue leiomyosarcoma; survival

DOI:  https://doi.org/10.1002/jso.26404
Adv Exp Med Biol. 2021 ;1278 125-139

Adipose Tissue T Regulatory Cells: Implications for Health and Disease.

David Bradley, Dharti Shantaram, Alan Smith, Willa A Hsueh.

  Obesity dramatically increases the risk of numerous conditions, including type 2 diabetes mellitus and other components of the metabolic syndrome. Pro-inflammatory changes that occur in adipose tissue are critical to the pathogenesis of these obesity-induced complications. Adipose tissue is one of the body's largest endocrine organs, and the cells that comprise the adipose tissue immunoenvironment secrete multiple factors (including adipokines and cytokines) that impact systemic metabolism. In particular, immunosuppressive regulatory T cells (Tregs) decline in obesity, partly in response to its complex interaction with adipocytes, and this decline contributes to disruption of the typical homeostasis observed in lean adipose tissue. Although the regulation of Treg differentiation, function, and enrichment is incompletely understood, factors including various cell-surface co-stimulatory molecules, certain lipid species, and cytokines such as PPARγ, adiponectin, and leptin are important mediators. It is also clear that there may be depot-specific differences in Tregs, rendering adipose tissue Tregs distinct from lymphoid or circulating Tregs, with implications on maintenance and functionality. While most of these findings are derived from studies in murine models, comparatively little is known about the human adipose tissue Treg signature, which requires further investigation.

Keywords:  Adaptive immunity; Adipose tissue; Insulin resistance; Obesity; Regulatory T cells

DOI:  https://doi.org/10.1007/978-981-15-6407-9_8