scholarly journals Glypicans specifically regulate Hedgehog signaling through their interaction with Ihog in cytonemes

2020 ◽  
Author(s):  
Eléanor Simon ◽  
Carlos Jiménez-Jiménez ◽  
Irene Seijo-Barandiarán ◽  
Gustavo Aguilar ◽  
David Sánchez-Hernández ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Tissue Repair ◽  
Hedgehog Signaling ◽  
Cell Communication ◽  
Target Cells ◽  
Signaling Proteins ◽  
Signaling Mechanism ◽  
Protein Levels ◽  
High Affinity ◽  
Hh Signaling

AbstractThe conserved family of Hedgehog (Hh) signaling proteins plays a key role in cell-cell communication in development, tissue repair and cancer progression. These proteins can act as morphogens, inducing responses dependent on the ligand concentration in target cells located at a distance. Hh proteins are lipid modified and thereby have high affinity for membranes, which hinders the understanding of their spreading across tissues. Direct contact between cell membranes by filopodia-like structures (also known as cytonemes) could be the simplest explanation for Hh dispersal. To better understand this signaling mechanism, we have analyzed in Drosophila the interaction between the glypicans that, besides for other pathways, are necessary for Hh signaling, plus the adhesion molecules and Hh coreceptors Ihog and Boi. We describe that glypicans (Dally and Dally-like protein) are required to maintain Ihog, but not Boi, protein levels. We also show that ectopic Ihog stabilizes cytonemes through its interaction with glypicans, and we determine that two Ihog fibronectin III domains are essential for this interaction. Our data suggest that this interaction with Ihog in cytonemes confers the specificity of glypicans for Hh signaling.

scholarly journals Glypicans define unique roles for the Hedgehog co-receptors Boi and Ihog in cytoneme-mediated gradient formation

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Eleanor Simon ◽  
Carlos Jiménez-Jiménez ◽  
Irene Seijo-Barandiarán ◽  
Gustavo Aguilar ◽  
David Sánchez-Hernández ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Direct Contact ◽  
Tissue Repair ◽  
Cell Communication ◽  
Target Cells ◽  
Signaling Proteins ◽  
Long Distance Dispersal ◽  
Long Distance ◽  
Gradient Formation ◽  
Hh Signaling

The conserved family of Hedgehog (Hh) signaling proteins plays a key role in cell-cell communication during development, tissue repair and cancer progression, inducing distinct concentration-dependent responses in target cells located at short and long distances. One simple mechanism for long distance dispersal of the lipid modified Hh is the direct contact between cell membranes through filopodia-like structures known as cytonemes. Here we have analyzed in Drosophila the interaction between the glypicans Dally and Dally-like protein, necessary for Hh signaling, and the adhesion molecules and Hh coreceptors Ihog and Boi. We describe that glypicans are required to maintain the levels of Ihog, but not of Boi. We also show that the overexpression of Ihog, but not of Boi, regulates cytoneme dynamics through their interaction with glypicans, the Ihog fibronectin III domains being essential for this interaction. Our data suggest that the regulation of glypicans over Hh signaling is specifically given by their interaction with Ihog in cytonemes. Contrary to previous data, we also show that there is no redundancy of Ihog and Boi functions in Hh gradient formation, being Ihog, but not of Boi, essential for the long-range gradient.

scholarly journals CEND1 and GJB6 co-expression as a prognostic factor in colorectal cancer

2021 ◽  
Author(s):  
Rui Chen ◽  
Zhan Wang ◽  
Dong Ma ◽  
Yijiang Han ◽  
Junsong Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Perineural Invasion ◽  
Patient Survival ◽  
Colorectal Cancer Patient ◽  
Cell Communication ◽  
Tumor Location ◽  
Protein Levels ◽  
Kaplan Meier ◽  
Clinicopathological Findings

Abstract Background: Perineural invasion is an important mechanism of cancer progression that is not well understood at present. The present study explored the relationship between GJB6, CEND1, and cell-cell communication as regulators of colorectal cancer patient survival and clinicopathological findings.Method: Immunohistochemical staining was performed to assess CEND1 and GJB6 expression levels in CRC patient samples, while survival outcomes were assessed using Kaplan-Meier curves and log-rank tests.Results: Elevated CEND1 expression was associated with tumor location, poor differentiation, and perineural invasion, while GJB6 expression was positively correlated with TNM stage, distant metastasis, and perineural invasion. In addition, GJB6 and CEND1 protein levels were correlated with one another in CRC patient tissues, and high expression of both of these proteins was associated with a higher risk of perineural invasion. CEND1+/GJB6+ status was also associated with poorer patient survival, highlighting both of these proteins as prognostic biomarkers in CRC patients.Conclusion: Elevated levels of CEND1 and GJB6 are independent predictors of poorer CRC patient prognosis.

Emerging role of extracellular vesicles in mediating cancer cachexia

2018 ◽  
Vol 46 (5) ◽  
pp. 1129-1136 ◽  
Author(s):  
Sai V. Chitti ◽  
Pamali Fonseka ◽  
Suresh Mathivanan
Keyword(s):  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Tissue Repair ◽  
Skeletal Muscles ◽  
Cancer Cachexia ◽  
Cell Communication ◽  
Rapid Weight Loss ◽  
Rapid Loss ◽  
Patients Experience

Cancer cachexia is a multifactorial metabolic syndrome characterized by the rapid loss of skeletal muscle mass with or without the loss of fat mass. Nearly 50–80% of all cancer patients' experience rapid weight loss results in ∼20% of cancer-related deaths. The levels of pro-inflammatory and pro-cachectic factors were significantly up-regulated in cachexia patients when compared with the patients who were without cachexia. It is becoming evident that these factors work synergistically to induce cancer cachexia. Extracellular vesicles (EVs) including exosomes and microvesicles are implicated in cell–cell communication, immune response, tissue repair, epigenetic regulation, and in various diseases including cancer. It has been reported that these EVs regulate cancer progression, metastasis, organotropism and chemoresistance. In recent times, the role of EVs in regulating cancer cachexia is beginning to unravel. The aim of this mini article is to review the recent knowledge gained in the field of EVs and cancer cachexia. Specifically, the role of tumour cell-derived EVs in promoting catabolism in distally located skeletal muscles and adipose tissue will be discussed.

scholarly journals Defining the Role of GLI/Hedgehog Signaling in Chemoresistance: Implications in Therapeutic Approaches

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4746
Author(s):  
Jian Yi Chai ◽  
Vaisnevee Sugumar ◽  
Ahmed F. Alshanon ◽  
Won Fen Wong ◽  
Shin Yee Fung ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cancer Progression ◽  
Hedgehog Signaling ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Treatment Strategies ◽  
Cancer Treatments ◽  
Mesenchymal Transition ◽  
Hh Signaling

Insight into cancer signaling pathways is vital in the development of new cancer treatments to improve treatment efficacy. A relatively new but essential developmental signaling pathway, namely Hedgehog (Hh), has recently emerged as a major mediator of cancer progression and chemoresistance. The evolutionary conserved Hh signaling pathway requires an in-depth understanding of the paradigm of Hh signaling transduction, which is fundamental to provide the necessary means for the design of novel tools for treating cancer related to aberrant Hh signaling. This review will focus substantially on the canonical Hh signaling and the treatment strategies employed in different studies, with special emphasis on the molecular mechanisms and combination treatment in regard to Hh inhibitors and chemotherapeutics. We discuss our views based on Hh signaling’s role in regulating DNA repair machinery, autophagy, tumor microenvironment, drug inactivation, transporters, epithelial-to-mesenchymal transition, and cancer stem cells to promote chemoresistance. The understanding of this Achilles’ Heel in cancer may improve the therapeutic outcome for cancer therapy.

scholarly journals Cholesterol activates the G-protein coupled receptor Smoothened to promote Hedgehog signaling

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Giovanni Luchetti ◽  
Ria Sircar ◽  
Jennifer H Kong ◽  
Sigrid Nachtergaele ◽  
Andreas Sagner ◽  
...  
Keyword(s):  
Structural Analysis ◽  
G Protein ◽  
Hedgehog Signaling ◽  
Cell Communication ◽  
G Protein Coupled Receptors ◽  
Rich Domain ◽  
Hh Signaling ◽  
G Protein Coupled ◽  
Orphan Gpcr ◽  
Cysteine Rich Domain

Cholesterol is necessary for the function of many G-protein coupled receptors (GPCRs). We find that cholesterol is not just necessary but also sufficient to activate signaling by the Hedgehog (Hh) pathway, a prominent cell-cell communication system in development. Cholesterol influences Hh signaling by directly activating Smoothened (SMO), an orphan GPCR that transmits the Hh signal across the membrane in all animals. Unlike many GPCRs, which are regulated by cholesterol through their heptahelical transmembrane domains, SMO is activated by cholesterol through its extracellular cysteine-rich domain (CRD). Residues shown to mediate cholesterol binding to the CRD in a recent structural analysis also dictate SMO activation, both in response to cholesterol and to native Hh ligands. Our results show that cholesterol can initiate signaling from the cell surface by engaging the extracellular domain of a GPCR and suggest that SMO activity may be regulated by local changes in cholesterol abundance or accessibility.

scholarly journals Resveratrol increases the sensitivity of multiple myeloma cells against bortezomib via Hedgehog signaling pathway

2021 ◽  
Vol 18 (10) ◽  
pp. 2133-2138
Author(s):  
Riyong Zhou ◽  
Ruye Ma ◽  
Zhenlin Jin ◽  
Liyuan Tang ◽  
Ying Zhou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Cell Model ◽  
Annexin V ◽  
Underlying Mechanism ◽  
Signaling Proteins ◽  
Regulation Of Expression ◽  
Model Cell ◽  
Hh Signaling

Purpose: To investigate the effect of resveratrol (RSV) on bortezomib (BTZ)-resistant multiple myeloma (MM) cells, and to elucidate the underlying mechanism of action. Methods: H929 cell lines were exposed to BTZ for 8 months to establish BTZ-resistant MM cell model. Cell proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was measured using annexin V/propidium iodide (PI) staining while cell cycle analysis was evaluated by flow cytometry. The expression of Hedgehog (Hh) signaling proteins (sonic hedgehog (SHH), smoothened (SMO), and glioma-associated oncogene homolog (GLI)) was analyzed by western blot. Results: H929R was confirmed as a MM cell line that is resistant to BTZ. RSV enhanced the sensitivity of H929R cells against BTZ via inhibition of cell viability and colony formation, induction of cell apoptosis and regulation of expression of apoptosis-related proteins. Furthermore, RSV inhibited the expression of Hh signaling proteins (p < 0.05. Conclusion: RSV enhances the sensitivity of MM cells to BTZ, partly via Hh signaling pathway. Thus, Hh pathway is a probable target for MM treatment, and RSV has potentials for use in the clinical management of MM.

scholarly journals A Comprehensive Picture of Extracellular Vesicles and Their Contents. Molecular Transfer to Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 298 ◽  
Author(s):  
Ancuta Jurj ◽  
Oana Zanoaga ◽  
Cornelia Braicu ◽  
Vladimir Lazar ◽  
Ciprian Tomuleasa ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Tumor Development ◽  
Cell Communication ◽  
Cancer Diagnostics ◽  
Target Cells ◽  
Chemotherapeutic Response ◽  
Non Coding Rna ◽  
Comprehensive Picture

Critical processes such as growth, invasion, and metastasis of cancer cells are sustained via bidirectional cell-to-cell communication in tissue complex environments. Such communication involves the secretion of soluble factors by stromal cells and/or cancer cells within the tumor microenvironment (TME). Both stromal and cancer cells have been shown to export bilayer nanoparticles: encapsulated regulatory molecules that contribute to cell-to-cell communication. These nanoparticles are known as extracellular vesicles (EVs) being classified into exosomes, microvesicles, and apoptotic bodies. EVs carry a vast repertoire of molecules such as oncoproteins and oncopeptides, DNA fragments from parental to target cells, RNA species (mRNAs, microRNAs, and long non-coding RNA), and lipids, initiating phenotypic changes in TME. According to their specific cargo, EVs have crucial roles in several early and late processes associated with tumor development and metastasis. Emerging evidence suggests that EVs are being investigated for their implication in early cancer detection, monitoring cancer progression and chemotherapeutic response, and more relevant, the development of novel targeted therapeutics. In this study, we provide a comprehensive understanding of the biophysical properties and physiological functions of EVs, their implications in TME, and highlight the applicability of EVs for the development of cancer diagnostics and therapeutics.

scholarly journals SHED-Dependent Oncogenic Signaling of the PEAK3 Pseudo-Kinase

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6344
Author(s):  
Youcef Ounoughene ◽  
Elise Fourgous ◽  
Yvan Boublik ◽  
Estelle Saland ◽  
Nathan Guiraud ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Protein Tyrosine Kinase ◽  
Akt Signaling ◽  
Leukemic Cells ◽  
Evolutionary Divergence ◽  
Signaling Proteins ◽  
Oncogenic Signaling ◽  
Signaling Mechanism ◽  
Family Based ◽  
Sarcoma Cells

The PEAK1 and Pragmin/PEAK2 pseudo-kinases have emerged as important components of the protein tyrosine kinase pathway implicated in cancer progression. They can signal using a scaffolding mechanism that involves a conserved split helical dimerization (SHED) module. We recently identified PEAK3 as a novel member of this family based on structural homology; however, its signaling mechanism remains unclear. In this study, we found that, although it can self-associate, PEAK3 shows higher evolutionary divergence than PEAK1/2. Moreover, the PEAK3 protein is strongly expressed in human hematopoietic cells and is upregulated in acute myeloid leukemia. Functionally, PEAK3 overexpression in U2OS sarcoma cells enhanced their growth and migratory properties, while its silencing in THP1 leukemic cells reduced these effects. Importantly, an intact SHED module was required for these PEAK3 oncogenic activities. Mechanistically, through a phosphokinase survey, we identified PEAK3 as a novel inducer of AKT signaling, independent of growth-factor stimulation. Then, proteomic analyses revealed that PEAK3 interacts with the signaling proteins GRB2 and ASAP1/2 and the protein kinase PYK2, and that these interactions require the SHED domain. Moreover, PEAK3 activated PYK2, which promoted PEAK3 tyrosine phosphorylation, its association with GRB2 and ASAP1, and AKT signaling. Thus, the PEAK1-3 pseudo-kinases may use a conserved SHED-dependent mechanism to activate specific signaling proteins to promote oncogenesis.

scholarly journals Proteomic Analysis of Exosomes from Adipose-Derived Mesenchymal Stem Cells: A Novel Therapeutic Strategy for Tissue Injury

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Xin Xing ◽  
Shuang Han ◽  
Gu Cheng ◽  
Yifeng Ni ◽  
Zhi Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Proteomic Analysis ◽  
Tissue Repair ◽  
Tissue Injury ◽  
Protein Profile ◽  
Cell Communication ◽  
Average Diameter ◽  
Target Cells ◽  
General Function

Exosomes are extracellular membranous nanovesicles that mediate local and systemic cell-to-cell communication by transporting functional molecules, such as proteins, into target cells, thereby affecting the behavior of receptor cells. Exosomes originating from adipose-derived mesenchymal stem cells (ADSCs) are considered a multipotent and abundant therapeutic tool for tissue injury. To investigate ADSC-secreted exosomes and their potential function in tissue repair, we isolated exosomes from the supernatants of ADSCs via ultracentrifugation, characterized them via transmission electron microscopy, nanoparticle tracking analysis, and Western blot analysis. Then, we determined their protein profile via proteomic analysis. Results showed that extracellular vesicles, which have an average diameter of 116 nm, exhibit a cup-shaped morphology and express exosomal markers. A total of 1,185 protein groups were identified in the exosomes. Gene Ontology analysis indicated that exosomal proteins are mostly derived from cells mainly involved in protein binding. Protein annotation via the Cluster of Orthologous Groups system indicated that most proteins were involved in general function prediction, posttranslational modification, protein turnover, and chaperoning. Further, pathway analysis revealed that most of the proteins obtained participated in metabolic pathways, focal adhesion, regulation of the actin cytoskeleton, and microbial metabolism. Some tissue repair-related signaling pathways were also discovered. The identified molecules might serve as potential therapeutic targets for future studies.

scholarly journals Pathophysiological Role and Potential Therapeutic Exploitation of Exosomes in Ovarian Cancer

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 814 ◽  
Author(s):  
Aasa Shimizu ◽  
Kenjiro Sawada ◽  
Tadashi Kimura
Keyword(s):  
Ovarian Cancer ◽  
Cancer Progression ◽  
Immune Therapy ◽  
Cell Communication ◽  
Target Cells ◽  
Cancer Treatments ◽  
Bioactive Materials ◽  
Advanced Stages ◽  
Application Potential ◽  
Functional Features

Exosomes are extracellular vesicles involved in several biological and pathological molecules and can carry many bioactive materials to target cells. They work as important mediators of cell-cell communication and play essential roles in many diseases, especially in cancer. Ovarian cancer is one of the most common gynecological malignancies. Most patients are diagnosed at advanced stages involving widespread peritoneal dissemination, resulting in poor prognosis. Emerging evidence has shown that exosomes play vital roles throughout the progression of ovarian cancer. Moreover, the development of engineered exosome-based therapeutic applications— including drug delivery systems, biomolecular targets and immune therapy—has increased drastically. Herein, we review the functional features of exosomes in ovarian cancer progression and the therapeutic application potential of exosomes as novel cancer treatments.

Sign in / Sign up

Export Citation Format

Share Document