scholarly journals Is YKL-40 (CHI3-L1) a new possible biomarker prognosticator in high grade glioma?

2015 ◽  
Vol 29 (3) ◽  
pp. 247-253
Author(s):  
A. Oslobanu ◽  
St.I. Florian
Keyword(s):  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Serum Level ◽  
Imaging Techniques ◽  
High Grade Glioma ◽  
Cancer Cell Proliferation ◽  
High Grade ◽  
Antitumor Therapy ◽  
Severity Of Disease ◽  
Naturally Occurring

Abstract A biomarker is “a naturally occurring molecule, gene, or characteristic by which a particular pathological or physiological process, disease, etc. can be identified” and it could be used a measurable indicator for the presence or severity of disease state. YKL-40 is a secreted glycoprotein associated with extracellular matrix, a member of the mammalian chitinase-like proteins that is expressed in a several types of solid tumors. Although the implication of this biomarker in tissue remodeling processes or the role in cancer cell proliferation, invasiveness, angiogenesis, and remodeling of the extracellular matrix is going to be well recognized, the regulation and role in glioblastoma multiforme (GBM) progression remains unknown. Using the serum level of YKL-40 as a single screening test in cancer cannot be used, but in association with other tumoral biomarkers and imaging techniques can be a useful tool as a “prognosticator.” Moreover, elucidation of the YKL-40 functions could be an attractive target for antitumor therapy.

scholarly journals High-grade Ovarian Cancer Associated H/ACA snoRNAs Promote Cancer Cell Proliferation and Survival

2021 ◽  
Author(s):  
Laurence Faucher-Giguere ◽  
Audrey Roy ◽  
Gabrielle Deschamps-Francoeur ◽  
Sonia Couture ◽  
Ryan M Nottingham ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Cell Proliferation ◽  
High Grade ◽  
Ovarian Carcinomas ◽  
Ovarian Cancer Cell Lines ◽  
Nucleolar Rnas ◽  
Host Genes

Small nucleolar RNAs (snoRNAs) are an omnipresent class of non-coding RNAs involved in the modification and processing of ribosomal RNA (rRNA). As snoRNAs are required for ribosome production, the increase of which is a hallmark of cancer development, their expression would be expected to increase in proliferating cancer cells. However, the nature and extent of snoRNAs contribution to the biology of cancer cells remain largely unexplored. In this study, we examined the abundance patterns of snoRNA in high-grade serous ovarian carcinomas (HGSC) and serous borderline tumours (SBT) and identified a subset of snoRNA associated with increased invasiveness. This subgroup of snoRNA accurately discriminates between SBT and HGSC underlining their potential as biomarkers of tumour aggressiveness. Remarkably, knockdown of HGSC-associated H/ACA snoRNAs, but not their host genes, inhibits cell proliferation and induces apoptosis of model ovarian cancer cell lines. Wound healing and cell migration assays confirmed the requirement of these HGSC-associated snoRNA for cell invasion and increased tumour aggressiveness. Together our data indicate that H/ACA snoRNAs promote tumour aggressiveness through the induction of cell proliferation and resistance to apoptosis.

scholarly journals Sox2-dependent maintenance of mouse oligodendroglioma involves the Sox2-mediated downregulation of Cdkn2b, Ebf1, Zfp423 and Hey2

2020 ◽  
Author(s):  
Cristiana Barone ◽  
Mariachiara Buccarelli ◽  
Francesco Alessandrini ◽  
Miriam Pagin ◽  
Laura Rigoldi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Cancer Stem Cells ◽  
Regulatory Network ◽  
Glioma Cells ◽  
High Grade Glioma ◽  
High Grade

AbstractCancer stem cells (CSC) are essential for tumorigenesis. The transcription factor Sox2 is overexpressed in brain tumors. In gliomas, Sox2 is essential to maintain CSC. In mouse high-grade glioma pHGG, Sox2 deletion causes cell proliferation arrest and inability to reform tumors in vivo; 134 genes are significantly derepressed. To identify genes mediating the effects of Sox2 deletion, we overexpressed into pHGG cells nine among the most derepressed genes, and identified four genes, Cdkn2b, Ebf1, Zfp423 and Hey2, that strongly reduced cell proliferation in vitro and brain tumorigenesis in vivo. CRISPR/Cas9 mutagenesis, or pharmacological inactivation, of each of these genes, individually, showed that their activity is essential for the proliferation arrest caused by Sox2 deletion. These Sox2-inhibited antioncogenes also inhibited clonogenicity in primary human glioblastoma-derived cancer stem-like cell lines. These experiments identify critical anti-oncogenic factors whose inhibition by Sox2 is involved in CSC maintenance, defining new potential therapeutic targets for gliomas.Table of Contents ImageMain PointsSox2 maintains glioma tumorigenicity by repressing the antioncogenic activity of a regulatory network involving the Ebf1, Hey2, Cdkn2b and Zfp423 genes.Mutation of these genes prevents the cell proliferation arrest of Sox2-deleted glioma cells.

scholarly journals BTP-7, a novel peptide for therapeutic targeting of malignant brain tumors

2020 ◽  
Author(s):  
Niklas von Spreckelsen ◽  
Yarah Ghotmi ◽  
Colin M. Fadzen ◽  
Justin M. Wolfe ◽  
Nina Hartrampf ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Extracellular Matrix ◽  
Brain Cancer ◽  
Targeted Therapies ◽  
Glioma Cells ◽  
High Grade Glioma ◽  
Clinical Activity ◽  
High Grade ◽  
High Affinity ◽  
Anti Cancer

AbstractBackgroundTargeted therapies for malignant brain cancer that are currently available have little clinical activity, highlighting an urgent need for the development of novel precision medicines. Brevican (Bcan), a central nervous system (CNS)-specific extracellular matrix protein is upregulated in glioma cells. A brevican isoform lacking glycosylation, dg-Bcan, is a unique glioma marker and thus represents a valuable target for anti-cancer therapy. In this study, we aimed to find a versatile dg-Bcan specific ligand to facilitate glioma targeting.MethodsWe screened a D-peptide library to identify dg-Bcan-Targeting Peptide (BTP) candidates, which were characterized extensively through binding kinetic analyses, cell uptake tests and animal studies.ResultsThe top candidate, BTP-7 binds dg-Bcan with high affinity and specificity, is preferentially internalized by Bcan-expressing glioma cells and can cross the blood-brain barrier in vitro and in mice. Functionalization of camptothecin with BTP-7 led to increased drug delivery to intracranial glioblastoma and cytotoxicity in tumor tissues, as well as prolonged survival in tumor-bearing mice.Conclusiondg-Bcan is an attractive therapeutic target for high-grade gliomas, and BTP-7 represents a promising lead candidate for further development into novel targeted therapeutics.Key pointsBTP-7 is a high affinity peptide ligand for the dg-Bcan protein and Bcan-expressing cells.BTP-7 targets human intracranial GBM xenografts in mice.Functionalization of a toxic anti-cancer drug with BTP-7 enables targeted delivery of the therapeutic to intracranial GBM in miceImportance of the StudyTargeted therapies for malignant brain cancer that are currently available have little clinical activity, highlighting an urgent need for the development of novel precision medicines that can selectively recognize and kill high-grade glioma tissues. A protein called dg-Bcan is an ideal target because it is present only in the extracellular matrix of high-grade glioma cells and is absent from normal brain tissues. Here, we describe the discovery of a novel dg-Bcan-Targeting Peptide, called BTP-7 that can bind specifically to high-grade glioma cells/tissues, and thus serve as a promising drug delivery vehicle.

scholarly journals MR-guided focused ultrasound increases antibody delivery to nonenhancing high-grade glioma

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Caterina Brighi ◽  
Lee Reid ◽  
Alison L White ◽  
Laura A Genovesi ◽  
Marija Kojic ◽  
...  
Keyword(s):  
Mouse Model ◽  
Focused Ultrasound ◽  
Imaging Techniques ◽  
High Grade Glioma ◽  
Clinical Problem ◽  
Antibody Concentration ◽  
High Grade ◽  
Orthotopic Mouse Model ◽  
Dynamic Contrast Enhancement ◽  
Antibody Uptake

Abstract Background High-grade glioma (HGG) remains a recalcitrant clinical problem despite many decades of research. A major challenge in improving prognosis is the inability of current therapeutic strategies to address a clinically significant burden of infiltrating tumor cells that extend beyond the margins of the primary tumor mass. Such cells cannot be surgically excised nor efficiently targeted by radiation therapy. Therapeutic targeting of this tumor cell population is significantly hampered by the presence of an intact blood–brain barrier (BBB). In this study, we performed a preclinical investigation of the efficiency of MR-guided Focused Ultrasound (FUS) to temporarily disrupt the BBB to allow selective delivery of a tumor-targeting antibody to infiltrating tumor. Methods Structural MRI, dynamic-contrast enhancement MRI, and histology were used to fully characterize the MR-enhancing properties of a patient-derived xenograft (PDX) orthotopic mouse model of HGG and to develop a reproducible, robust model of nonenhancing HGG. PET–CT imaging techniques were then used to evaluate the efficacy of FUS to increase 89Zr-radiolabeled antibody concentration in nonenhancing HGG regions and adjacent non-targeted tumor tissue. Results The PDX mouse model of HGG has a significant tumor burden lying behind an intact BBB. Increased antibody uptake in nonenhancing tumor regions is directly proportional to the FUS-targeted volume. FUS locally increased antibody uptake in FUS-targeted regions of the tumor with an intact BBB, while leaving untargeted regions unaffected. Conclusions FUS exposure successfully allowed temporary BBB disruption, localized to specifically targeted, nonenhancing, infiltrating tumor regions and delivery of a systemically administered antibody was significantly increased.

scholarly journals TP53 exon-6 truncating mutations produce separation of function isoforms with pro-tumorigenic functions

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Nitin H Shirole ◽  
Debjani Pal ◽  
Edward R Kastenhuber ◽  
Serif Senturk ◽  
Joseph Boroda ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Cancer Cell ◽  
Splice Variant ◽  
Human Tumors ◽  
Null Alleles ◽  
Cancer Cell Proliferation ◽  
Cyclophilin D ◽  
Naturally Occurring ◽  
Pore Permeability

TP53 truncating mutations are common in human tumors and are thought to give rise to p53-null alleles. Here, we show that TP53 exon-6 truncating mutations occur at higher than expected frequencies and produce proteins that lack canonical p53 tumor suppressor activities but promote cancer cell proliferation, survival, and metastasis. Functionally and molecularly, these p53 mutants resemble the naturally occurring alternative p53 splice variant, p53-psi. Accordingly, these mutants can localize to the mitochondria where they promote tumor phenotypes by binding and activating the mitochondria inner pore permeability regulator, Cyclophilin D (CypD). Together, our studies reveal that TP53 exon-6 truncating mutations, contrary to current beliefs, act beyond p53 loss to promote tumorigenesis, and could inform the development of strategies to target cancers driven by these prevalent mutations.

scholarly journals Naturally-occurring spinosyn A and its derivatives function as argininosuccinate synthase activator and tumor inhibitor

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zizheng Zou ◽  
Xiyuan Hu ◽  
Tiao Luo ◽  
Zhengnan Ming ◽  
Xiaodan Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cancer Cell Proliferation ◽  
Down Regulation ◽  
Pyrimidine Synthesis ◽  
Naturally Occurring ◽  
Argininosuccinate Synthase ◽  
Tumor Inhibitor ◽  
Therapeutic Avenue

AbstractArgininosuccinate synthase (ASS1) is a ubiquitous enzyme in mammals that catalyzes the formation of argininosuccinate from citrulline and aspartate. ASS1 genetic deficiency in patients leads to an autosomal recessive urea cycle disorder citrullinemia, while its somatic silence or down-regulation is very common in various human cancers. Here, we show that ASS1 functions as a tumor suppressor in breast cancer, and the pesticide spinosyn A (SPA) and its derivative LM-2I suppress breast tumor cell proliferation and growth by binding to and activating ASS1. The C13-C14 double bond in SPA and LM-2I while the Cys97 (C97) site in ASS1 are critical for the interaction between ASS1 and SPA or LM-2I. SPA and LM-2I treatment results in significant enhancement of ASS1 enzymatic activity in breast cancer cells, particularly in those cancer cells with low ASS1 expression, leading to reduced pyrimidine synthesis and consequently the inhibition of cancer cell proliferation. Thus, our results establish spinosyn A and its derivative LM-2I as potent ASS1 enzymatic activator and tumor inhibitor, which provides a therapeutic avenue for tumors with low ASS1 expression and for those non-tumor diseases caused by down-regulation of ASS1.

NF-κB regulates colon cancer cell proliferation and tumorigenicity

2001 ◽  
Vol 120 (5) ◽  
pp. A615-A615
Author(s):  
S KUWADA ◽  
C SCAIFE ◽  
J KUANG ◽  
R DAYNES
Keyword(s):  
Colon Cancer ◽  
Cell Proliferation ◽  
Cancer Cell ◽  
Colon Cancer Cell ◽  
Cancer Cell Proliferation
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