scholarly journals Profiling Cancer-Associated Fibroblasts in Melanoma

2021 ◽  
Vol 22 (14) ◽  
pp. 7255
Author(s):  
Federica Papaccio ◽  
Daniela Kovacs ◽  
Barbara Bellei ◽  
Silvia Caputo ◽  
Emilia Migliano ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Stromal Cells ◽  
Treatment Options ◽  
Matrix Remodeling ◽  
Cancer Associated Fibroblasts ◽  
Dynamic Interactions ◽  
Low Passage ◽  
Pleiotropic Functions ◽  
Tumoral Cells ◽  
Cell Crosstalk

Solid tumors are complex systems characterized by dynamic interactions between neoplastic cells, non-tumoral cells, and extracellular components. Among all the stromal cells that populate tumor microenvironment, fibroblasts are the most abundant elements and are critically involved in disease progression. Cancer-associated fibroblasts (CAFs) have pleiotropic functions in tumor growth and extracellular matrix remodeling implicated in local invasion and distant metastasis. CAFs additionally participate in the inflammatory response of the tumor site by releasing a variety of chemokines and cytokines. It is becoming clear that understanding the dynamic, mutual melanoma–fibroblast relationship would enable treatment options to be amplified. To better characterize melanoma-associated fibroblasts, here we analyzed low-passage primary CAFs derived from advanced-stage primary skin melanomas, focusing on the immuno-phenotype. Furthermore, we assessed the expression of several CAF markers and the production of growth factors. To deepen the study of CAF–melanoma cell crosstalk, we employed CAF-derived supernatants and trans-well co-culture systems to evaluate the influences of CAFs on (i) the motogenic ability of melanoma cells, (ii) the chemotherapy-induced cytotoxicity, and (iii) the release of mediators active in modulating tumor growth and spread.

Theranostic radiopharmaceuticals targeting cancer-associated fibroblasts

2020 ◽  
Vol 13 ◽  
Author(s):  
Fedor Zhuravlev
Keyword(s):  
Extracellular Matrix ◽  
Immune Evasion ◽  
Stromal Cells ◽  
Tumor Stroma ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Cancer Associated Fibroblasts ◽  
Malignant Cells ◽  
Anti Cancer ◽  
Tumor Growth And Metastasis

The tumor microenvironment is a dynamic ecosystem where malignant cells interact with the stromal cells sustaining and promoting tumor growth and metastasis. Cancer-associated fibroblasts (CAFs) are the major component of tumor stroma. CAFs control key tumorigenic activities by participating in immune evasion and suppression, extracellular matrix remodeling, neo-angiogenesis, and drug resistance. Therefore, targeting CAFs emerges as an attractive anti-cancer strategy. This review summarized recent advancements in targeting CAFs with diagnostic and therapeutic radiopharmaceuticals using clinically-promising biomarkers. The efforts to improve clinical outcomes via application of new radiotheranostic compounds are discussed in the context of radionuclide, the pharmacophore, and, more generally, in terms of biomarker specificity and expression across different cancers and CAF phenotypes.

scholarly journals Made to Measure: Patient-Tailored Treatment of Multiple Sclerosis Using Cell-Based Therapies

2021 ◽  
Vol 22 (14) ◽  
pp. 7536
Author(s):  
Inez Wens ◽  
Ibo Janssens ◽  
Judith Derdelinckx ◽  
Megha Meena ◽  
Barbara Willekens ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Autoimmune Diseases ◽  
Stromal Cells ◽  
Mononuclear Cells ◽  
Treatment Options ◽  
Cell Types ◽  
Peripheral Blood Mononuclear ◽  
Tailored Treatment ◽  
Key Issues ◽  
The Central Nervous System

Currently, there is still no cure for multiple sclerosis (MS), which is an autoimmune and neurodegenerative disease of the central nervous system. Treatment options predominantly consist of drugs that affect adaptive immunity and lead to a reduction of the inflammatory disease activity. A broad range of possible cell-based therapeutic options are being explored in the treatment of autoimmune diseases, including MS. This review aims to provide an overview of recent and future advances in the development of cell-based treatment options for the induction of tolerance in MS. Here, we will focus on haematopoietic stem cells, mesenchymal stromal cells, regulatory T cells and dendritic cells. We will also focus on less familiar cell types that are used in cell therapy, including B cells, natural killer cells and peripheral blood mononuclear cells. We will address key issues regarding the depicted therapies and highlight the major challenges that lie ahead to successfully reverse autoimmune diseases, such as MS, while minimising the side effects. Although cell-based therapies are well known and used in the treatment of several cancers, cell-based treatment options hold promise for the future treatment of autoimmune diseases in general, and MS in particular.

scholarly journals Cancer-Associated Fibroblasts: Their Characteristics and Their Roles in Tumor Growth

Cancers ◽  
2015 ◽  
Vol 7 (4) ◽  
pp. 2443-2458 ◽  
Author(s):  
Kazuyoshi Shiga ◽  
Masayasu Hara ◽  
Takaya Nagasaki ◽  
Takafumi Sato ◽  
Hiroki Takahashi ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cancer Associated Fibroblasts

scholarly journals Augmentation of Dermal Wound Healing by Adipose Tissue-Derived Stromal Cells (ASC)

2018 ◽  
Vol 5 (4) ◽  
pp. 91 ◽  
Author(s):  
Joris van Dongen ◽  
Martin Harmsen ◽  
Berend van der Lei ◽  
Hieronymus Stevens
Keyword(s):  
Extracellular Matrix ◽  
Wound Healing ◽  
Adipose Tissue ◽  
Stromal Cells ◽  
Randomized Clinical Trials ◽  
Cell Types ◽  
Matrix Remodeling ◽  
Skin Wound Healing ◽  
Dermal Wound Healing ◽  
Dermal Wound

The skin is the largest organ of the human body and is the first line of defense against physical and biological damage. Thus, the skin is equipped to self-repair and regenerates after trauma. Skin regeneration after damage comprises a tightly spatial-temporally regulated process of wound healing that involves virtually all cell types in the skin. Wound healing features five partially overlapping stages: homeostasis, inflammation, proliferation, re-epithelization, and finally resolution or fibrosis. Dysreguled wound healing may resolve in dermal scarring. Adipose tissue is long known for its suppressive influence on dermal scarring. Cultured adipose tissue-derived stromal cells (ASCs) secrete a plethora of regenerative growth factors and immune mediators that influence processes during wound healing e.g., angiogenesis, modulation of inflammation and extracellular matrix remodeling. In clinical practice, ASCs are usually administered as part of fractionated adipose tissue i.e., as part of enzymatically isolated SVF (cellular SVF), mechanically isolated SVF (tissue SVF), or as lipograft. Enzymatic isolation of SVF obtained adipose tissue results in suspension of adipocyte-free cells (cSVF) that lack intact intercellular adhesions or connections to extracellular matrix (ECM). Mechanical isolation of SVF from adipose tissue destructs the parenchyma (adipocytes), which results in a tissue SVF (tSVF) with intact connections between cells, as well as matrix. To date, due to a lack of well-designed prospective randomized clinical trials, neither cSVF, tSVF, whole adipose tissue, or cultured ASCs can be indicated as the preferred preparation procedure prior to therapeutic administration. In this review, we present and discuss current literature regarding the different administration options to apply ASCs (i.e., cultured ASCs, cSVF, tSVF, and lipografting) to augment dermal wound healing, as well as the available indications for clinical efficacy.

scholarly journals BRAF inhibitors reprogram cancer-associated fibroblasts to drive matrix remodeling and therapeutic escape in melanoma

2021 ◽  
Author(s):  
Tianyi Liu ◽  
Linli Zhou ◽  
Yao Xiao ◽  
Thomas Andl ◽  
Yuhang Zhang
Keyword(s):  
Resistance Mechanism ◽  
Tumor Stroma ◽  
Melanoma Cells ◽  
Biological Properties ◽  
Nuclear Accumulation ◽  
Matrix Remodeling ◽  
Cancer Associated Fibroblasts ◽  
Braf Inhibitors ◽  
Downstream Effector ◽  
Cellular Components

ABSTRACTThe tumor stroma and its cellular components are known to play an important role in tumor resilience towards treatment. Here, we report a novel resistance mechanism in melanoma that is elicited by BRAF inhibitors (BRAFi)-induced non-canonical nuclear β-catenin signaling in cancer-associated fibroblasts (CAFs). Our study reveals that BRAFi leads to an expanded CAF population with increased β-catenin nuclear accumulation and enhances their biological properties. This CAF subpopulation is essential for melanoma cells to grow and resist to BRAFi/MEK inhibitors (MEKi). Mechanistically, BRAFi induces BRAF and CRAF dimerization and subsequently the activation of ERK signaling in CAFs, leading to the inactivation of the β-catenin destruction complex. By RNA-Seq, periostin (POSTN) is identified as a major downstream effector of β catenin in CAFs and can compensate for the loss of β-catenin in CAFs in conferring melanoma cell BRAFi/MEKi resistance. Moreover, POSTN reactivates the ERK pathway, which is inhibited by BRAFi/MEKi, in melanoma cells through PI3K/AKT signaling. Our data underscore the roles of BRAFi-induced CAF reprogramming in matrix remodeling and therapeutic escape of melanoma cells and reveal POSTN as an important matrix target to eliminate BRAFi/MEKi resistance in melanoma.

scholarly journals USP7 Inhibition Alleviates H2O2-Induced Injury in Chondrocytes via Inhibiting NOX4/NLRP3 Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Gang Liu ◽  
Qingbai Liu ◽  
Bin Yan ◽  
Ziqiang Zhu ◽  
Yaozeng Xu
Keyword(s):  
Treatment Options ◽  
Current Treatment ◽  
Pathological Process ◽  
Joint Disease ◽  
Matrix Remodeling ◽  
Ros Production ◽  
Caspase 1 ◽  
Enhanced Production

Osteoarthritis (OA), the most common form of arthritis, is a very common joint disease that often affects middle-aged to elderly people. However, current treatment options for OA are predominantly palliative. Thus, understanding its pathological process and exploring its potential therapeutic approaches are of great importance. Rat chondrocytes were isolated and exposed to hydrogen peroxide (H2O2) to mimic OA. The effects of H2O2 on ubiquitin-specific protease 7 (USP7) expression, reactive oxygen species (ROS) levels, proliferation, inflammatory cytokine release, and pyroptosis were measured. USP7 was knocked down (KD) or overexpressed to investigate the role of USP7 in OA. Co-immunoprecipitation (Co-IP) was used to study the interaction between USP7 and NAD(P)H oxidases (NOX)4 as well as NOX4 ubiquitination. NOX4 inhibitor was applied to study the involvement of NOX4 in USP7-mediated OA development. USP7 inhibitor was given to OA animals to further investigate the role of USP7 in OA in vivo. Moreover, H2O2 treatment significantly increased USP7 expression, enhanced ROS levels, and inhibited proliferation in rat chondrocytes. The overexpression of USP7 enhanced pyroptosis, ROS production, interleukin (IL)-1β and IL-18 levels, and the expression level of NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, matrix metalloproteinases (MMP) 1, and MMP13, which was abolished by ROS inhibition. The USP7 KD protected rat chondrocytes against H2O2-induced injury. Co-IP results showed that USP7 interacted with NOX4, and USP7 KD enhanced NOX4 ubiquitinylation. The inhibition of NOX4 blocked the pro-OA effect of USP7. Moreover, the USP7 inhibitor given to OA animals suppressed OA in vivo. USP7 inhibited NOX4 ubiquitination for degradation which leads to elevated ROS production. ROS subsequently activates NLPR3 inflammasome, leading to enhanced production of IL-1β and IL-18, GSDMD-N-dependent pyroptosis, and extracellular matrix remodeling. Thus, UPS7 contributes to the progression of OA via NOX4/ROS/NLPR3 axis.

scholarly journals TLR4 signaling drives mesenchymal stromal cells commitment to promote tumor microenvironment transformation in multiple myeloma

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Cesarina Giallongo ◽  
Daniele Tibullo ◽  
Giuseppina Camiolo ◽  
Nunziatina L. Parrinello ◽  
Alessandra Romano ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Immune Escape ◽  
In Vivo Model ◽  
Th2 Response ◽  
Tlr4 Signaling

Abstract Inflammation represents a key feature and hallmark of tumor microenvironment playing a major role in the interaction with mesenchymal stromal cells (MSC) in cancer progression. The aim of the present study was to investigate the crosstalk between MSCs and myeloma cells (MM) in the pro-inflammatory microenvironment promoting immune evasion and tumor growth. MSC were collected from patients with diagnosis of MGUS (n = 10), smoldering myeloma (n = 7), multiple myeloma at diagnosis (n = 16), relapse (n = 5) or refractory (n = 3), and from age-matched healthy controls (HC, n = 10) and cultured with peripheral blood mononucleated cells (PBMC) from healthy volunteer donors. Similarly to MM, we showed that MSC from smoldering multiple myeloma (SMM) patients activated neutrophils and conferred an immunosuppressive and pro-angiogenic phenotype. Furthermore, co-cultures of plasma cells (PC) and HC-MSC suggested that such activation is driven by MM cells through the switching into a pro-inflammatory phenotype mediated by toll-like receptor 4 (TLR4). These results were further confirmed using a zebrafish as an immunocompetent in vivo model, showing the role of MM–MSC in supporting PCs engraftment and Th2 response. Such effect was abolished following inhibition of TLR4 signaling in MM–MSC before co-injection with PC. Moreover, the addition of a TLR4 inhibitor in the co-culture of HC-MSC with MM cells prevented the activation of the pro-tumor activity in PC-educated MSC. In conclusion, our study provides evidence that TLR4 signaling plays a key role in MSC transformation by inducing a pro-tumor phenotype associated with a permissive microenvironment allowing immune escape and tumor growth.

scholarly journals Cancer-associated fibroblasts stimulate primary tumor growth and metastatic spread in an orthotopic prostate cancer xenograft model

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Johannes Linxweiler ◽  
Turkan Hajili ◽  
Christina Körbel ◽  
Carolina Berchem ◽  
Philip Zeuschner ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Primary Tumor ◽  
Xenograft Model ◽  
Metastatic Spread ◽  
Cancer Associated Fibroblasts ◽  
Primary Tumor Growth

scholarly journals Gallbladder cancer-associated fibroblasts promote vasculogenic mimicry formation and tumor growth in gallbladder cancer via upregulating the expression of NOX4, a poor prognosis factor, through IL-6-JAK-STAT3 signal pathway

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Mu-Su Pan ◽  
Hui Wang ◽  
Kamar Hasan Ansari ◽  
Xin-Ping Li ◽  
Wei Sun ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Gallbladder Cancer ◽  
Molecular Mechanism ◽  
Poor Prognosis ◽  
Vasculogenic Mimicry ◽  
Tube Formation ◽  
Signal Pathway ◽  
Cancer Associated Fibroblasts

Abstract Background Cancer-associated fibroblasts (CAFs) and vasculogenic mimicry (VM) play important roles in the occurrence and development of tumors. However, the relationship between CAFs and VM formation, especially in gallbladder cancer (GBC) has not been clarified. In this study, we investigated whether gallbladder CAFs (GCAFs) can promote VM formation and tumor growth and explored the underlying molecular mechanism. Methods A co-culture system of human GBC cells and fibroblasts or HUVECs was established. VM formation, proliferation, invasion, migration, tube formation assays, CD31-PAS double staining, optic/electron microscopy and tumor xenograft assay were used to detect VM formation and malignant phenotypes of 3-D co-culture matrices in vitro, as well as the VM formation and tumor growth of xenografts in vivo, respectively. Microarray analysis was used to analyze gene expression profile in GCAFs/NFs and VM (+)/VM (−) in vitro. QRT-PCR, western blotting, IHC and CIF were used to detected NOX4 expression in GCAFs/NFs, 3-D culture/co-culture matrices in vitro, the xenografts in vivo and human gallbladder tissue/stroma samples. The correlation between NOX4 expression and clinicopathological and prognostic factors of GBC patients was analyzed. And, the underlying molecular mechanism of GCAFs promoting VM formation and tumor growth in GBC was explored. Results GCAFs promote VM formation and tumor growth in GBC; and the finding was confirmed by facts that GCAFs induced proliferation, invasion, migration and tube formation of GBC cells in vitro, and promoted VM formation and tumor growth of xenografts in vivo. NOX4 is highly expressed in GBC and its stroma, which is the key gene for VM formation, and is correlated with tumor aggression and survival of GBC patients. The GBC patients with high NOX4 expression in tumor cells and stroma have a poor prognosis. The underlying molecular mechanism may be related to the upregulation of NOX4 expression through paracrine IL-6 mediated IL-6/JAK/STAT3 signaling pathway. Conclusions GCAFs promote VM formation and tumor growth in GBC via upregulating NOX4 expression through the activation of IL-6-JAK-STAT3 signal pathway. NOX4, as a VM-related gene in GBC, is overexpressed in GBC cells and GCAFs, which is related to aggression and unfavorable prognosis of GBC patients.

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