scholarly journals Impact of MMP-2 and MMP-9 activation on wound healing, tumor growth and RACPP cleavage

2018 ◽  
Author(s):  
Dina V. Hingorani ◽  
Csilla N. Lippert ◽  
Jessica L. Crisp ◽  
Elamprakash N. Savariar ◽  
Jonathan P.C. Hasselmann ◽  
...  
Keyword(s):  
Wound Healing ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Mammary Tumorigenesis ◽  
Cell Penetrating Peptides ◽  
Double Knockout ◽  
Mendelian Genetics ◽  
A Site

AbstractMatrix metalloproteinases-2 and -9 (MMP-2/-9) are key tissue remodeling enzymes that have multiple overlapping activities critical for wound healing and tumor progression in vivo. To overcome issues of redundancy, we created MMP-2/-9 double knockout (DKO) mice in the C57BL/6 background to examine wound healing. We then bred the DKO mice into the polyomavirus middle T (PyVmT) model of breast cancer to analyze the role of these enzymes in tumorigenesis. Breeding analyses indicated that significantly fewer DKO mice were born than predicted by Mendelian genetics and weaned DKO mice were growth compromised compared with wild type (WT) cohorts. Epithelial wound healing was dramatically delayed in adult DKO mice and when the DKO was combined with the PyVmT oncogene, we found that the biologically related process of mammary tumorigenesis was inhibited in a site-specific manner. To further examine the role of MMP-2/-9 in tumor progression, tumor cells derived from WT or DKO PyVmT transgenic tumors were grown in WT or DKO mice. Ratiometric activatable cell penetrating peptides (RACPPs) previously used to image cancer based on MMP-2/-9 activity were used to understand differences in MMP activity in WT or knockout syngeneic tumors in WT and KO animals. Analysis of an MMP-2 selective RACPP in WT or DKO mice bearing WT and DKO PyVmT tumor cells indicated that the genotype of the tumor cells was more important than the host stromal genotype in promoting MMP-2/-9 activity in the tumors in this model system. Additional complexities were revealed as the recruitment of host macrophages by the tumor cells was found to be the source of the tumor MMP-2/-9 activity and it is evident that MMP-2/-9 from both host and tumor is required for maximum signal using RACPP imaging for detection. We conclude that in the PyVmT model, the majority of MMP-2/-9 activity in mammary tumors is associated with host macrophages recruited into the tumor rather than that produced by the tumor cells themselves. Thus therapies that target tumor-associated macrophage functions have the potential to slow tumor progression.

scholarly journals Macrophages in Tumor-Associated Adipose Microenvironment Accelerate Tumor Progression

2020 ◽  
Author(s):  
Bei Li ◽  
Qi Wu ◽  
Qian Yang ◽  
Zhiyu Li ◽  
Juanjuan Li ◽  
...  
Keyword(s):  
Western Blot ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Tumor Burden ◽  
Migration Assay ◽  
Novel Target ◽  
Pathway Inhibition ◽  
Exosomal Mirna

Abstract BackgroundAdipose tissue macrophages (ATMs) particularly contribute to the progression of obesity-related tumor. However, the mechanisms that the tumor-adipocyte crosstalk may enable the properties and plasticity of macrophages remain still unclear. MethodsSurvival probabilities for recurrence-free survival (RFS) were estimated by the Kaplan–Meier method based on immunohistochemistry and immunofluorescence images. 3T3-L1 cells were co-cultivated with 4T1 and MDA-MB-231 cells. Then the co-cultivated media were used to treat THP-1/RAW264.7 cells. The ATMs markers were detected by immunofluorescence and Western blot. Transwell migration assay, was conducted to determine the migration capability of ATMs. RT-PCR and ELISA were used to detect the expression and secretion level of chemokines, respectively. Immunofluorescence imaging and Western blot were used to investigate the role of SOCS6/STAT3 signaling pathway in the polarization of ATMs. microRNA mimic and inhibitor, and xenograft models were used to explore the role of miR-155 in the polarization of ATMs.ResultsWe demonstrate that CD163-positive macrophages aggregated to surround adipocytes in breast cancer tissues, which was associated with tumor relapse. Thereafter, the eliminated macrophages partially inhibited adipocytes-induced tumor proliferation. The expression of chemokines, CCL2 and CCL5, elevated in tumor-adipocyte microenvironment and contributed to macrophage recruit and M2-like polarization via phosphorylating STAT3. Consistently, inhibiting chemokines and their receptors or suppressing the phosphorylation of STAT3 significantly decreased tumor burden in vivo. In coculture of tumor cells and adipocytes, the level of exosomal miRNA-155 was high, then it promoted the generation and release of CCL2 and CCL5 from adipocytes through targeting SOCS6/STAT3 pathway. Inhibition of exosomal miRNA-155 in tumor cells reduced the CCL2 and CCL5 levels in tumor-adipocytes coculture, and further retarded tumor growth. Likewise, the exosomes stimulated autophagy in macrophages in TFE3-depending way. ConclusionThese results suggest a novel target of tumor-adipocyte-macrophage interconnect that could facilitate obesity-induced tumor progression.

scholarly journals Macrophages in Tumor-Associated Adipose Microenvironment Accelerate Tumor progression

2020 ◽  
Author(s):  
Bei Li ◽  
Qi Wu ◽  
Qian Yang ◽  
Zhiyu Li ◽  
Juanjuan Li ◽  
...  
Keyword(s):  
Western Blot ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Tumor Burden ◽  
Migration Assay ◽  
Novel Target ◽  
Pathway Inhibition ◽  
Exosomal Mirna

Abstract Background: Macrophages particularly contribute to the progression of obesity-related tumor. However, the mechanisms that the tumor-adipocyte crosstalk may enable the properties and plasticity of macrophages remain still unclear. Methods: Survival probabilities for recurrence-free survival (RFS) were estimated by the Kaplan–Meier method based on immunohistochemistry and immunofluorescence images. 3T3-L1 cells were co-cultivated with 4T1 and MDA-MB-231 cells. Then the co-cultivated media were used to treat THP-1/RAW264.7 cells. The markers of macrophages were detected by immunofluorescence and Western blot. Transwell migration assay, was conducted to determine the migration capability of macrophages. RT-PCR and ELISA were used to detect the expression and secretion level of chemokines, respectively. Immunofluorescence imaging and Western blot were used to investigate the role of SOCS6/STAT3 signaling pathway in the polarization of macrophages. microRNA mimic and inhibitor, and xenograft models were used to explore the role of miR-155 in the polarization of macrophages.Results: We demonstrate that CD163-positive macrophages aggregated to surround adipocytes in breast cancer tissues, which was associated with tumor relapse. In tumor-adipocyte microenvironment, CD163-positive macrophages are recruited and polarized via the elevated expression of CCL2 and CCL5. Consistently, the eliminated macrophages partially inhibited adipocytes-induced tumor proliferation. Likewise, inhibiting chemokines and their receptors or suppressing the phosphorylation of STAT3 significantly decreased tumor burden in vivo. Finally, the source of CCL2 and CCL5 mainly derived from adipocytes. In coculture of tumor cells and adipocytes, the level of exosomal miRNA-155 was high, then it promoted the generation and release of CCL2 and CCL5 from adipocytes through targeting SOCS6/STAT3 pathway. Inhibition of exosomal miRNA-155 in tumor cells reduced the CCL2 and CCL5 levels in tumor-adipocytes coculture, and further retarded tumor growth. Conclusion: These results suggest a novel target of tumor-adipocyte-macrophage interconnect that could facilitate obesity-induced tumor progression.

scholarly journals EphA2 super-enhancer promotes tumor progression by recruiting FOSL2 and TCF7L2 to activate the target gene EphA2

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Shuang Cui ◽  
Qiong Wu ◽  
Ming Liu ◽  
Mu Su ◽  
ShiYou Liu ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Tumor Cells ◽  
Target Gene ◽  
Super Enhancer ◽  
Proliferation And Metastasis ◽  
Active Transcription ◽  
Hct 116 ◽  
Large Clusters

AbstractSuper-enhancers or stretch enhancers (SEs) consist of large clusters of active transcription enhancers which promote the expression of critical genes that define cell identity during development and disease. However, the role of many super-enhancers in tumor cells remains unclear. This study aims to explore the function and mechanism of a new super-enhancer in various tumor cells. A new super-enhancer that exists in a variety of tumors named EphA2-Super-enhancer (EphA2-SE) was found using multiple databases and further identified. CRISPR/Cas9-mediated deletion of EphA2-SE results in the significant downregulation of its target gene EphA2. Mechanistically, we revealed that the core active region of EphA2-SE comprises E1 component enhancer, which recruits TCF7L2 and FOSL2 transcription factors to drive the expression of EphA2, induce cell proliferation and metastasis. Bioinformatics analysis of RNA-seq data and functional experiments in vitro illustrated that EphA2-SE deletion inhibited cell growth and metastasis by blocking PI3K/AKT and Wnt/β-catenin pathway in HeLa, HCT-116 and MCF-7 cells. Overexpression of EphA2 in EphA2-SE−/− clones rescued the effect of EphA2-SE deletion on proliferation and metastasis. Subsequent xenograft animal model revealed that EphA2-SE deletion suppressed tumor proliferation and survival in vivo. Taken together, these findings demonstrate that EphA2-SE plays an oncogenic role and promotes tumor progression in various tumors by recruiting FOSL2 and TCF7L2 to drive the expression of oncogene EphA2.

scholarly journals Iron-Bound Lipocalin-2 from Tumor-Associated Macrophages Drives Breast Cancer Progression Independent of Ferroportin

Metabolites ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 180
Author(s):  
Christina Mertens ◽  
Matthias Schnetz ◽  
Claudia Rehwald ◽  
Stephan Grein ◽  
Eiman Elwakeel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Lung Metastases ◽  
Expression Profiles ◽  
The Cancer Genome Atlas ◽  
Lipocalin 2 ◽  
Tumor Associated Macrophages

Macrophages supply iron to the breast tumor microenvironment by enforced secretion of lipocalin-2 (Lcn-2)-bound iron as well as the increased expression of the iron exporter ferroportin (FPN). We aimed at identifying the contribution of each pathway in supplying iron for the growing tumor, thereby fostering tumor progression. Analyzing the expression profiles of Lcn-2 and FPN using the spontaneous polyoma-middle-T oncogene (PyMT) breast cancer model as well as mining publicly available TCGA (The Cancer Genome Atlas) and GEO Series(GSE) datasets from the Gene Expression Omnibus database (GEO), we found no association between tumor parameters and Lcn-2 or FPN. However, stromal/macrophage-expression of Lcn-2 correlated with tumor onset, lung metastases, and recurrence, whereas FPN did not. While the total iron amount in wildtype and Lcn-2−/− PyMT tumors showed no difference, we observed that tumor-associated macrophages from Lcn-2−/− compared to wildtype tumors stored more iron. In contrast, Lcn-2−/− tumor cells accumulated less iron than their wildtype counterparts, translating into a low migratory and proliferative capacity of Lcn-2−/− tumor cells in a 3D tumor spheroid model in vitro. Our data suggest a pivotal role of Lcn-2 in tumor iron-management, affecting tumor growth. This study underscores the role of iron for tumor progression and the need for a better understanding of iron-targeted therapy approaches.

scholarly journals Arginase Activity in Eisenia andrei Coelomocytes: Function in the Earthworm Innate Response

2021 ◽  
Vol 22 (7) ◽  
pp. 3687
Author(s):  
Joanna Homa ◽  
Alina Klosowska ◽  
Magdalena Chadzinska
Keyword(s):  
Immune Response ◽  
Wound Healing ◽  
Arginase Activity ◽  
Eisenia Andrei ◽  
Heavy Metals Ions ◽  
First Time ◽  
Important Marker

Arginase is the manganese metalloenzyme catalyzing the conversion of l-arginine to l-ornithine and urea. In vertebrates, arginase is involved in the immune response, tissue regeneration, and wound healing and is an important marker of alternative anti-inflammatory polarization of macrophages. In invertebrates, data concerning the role of arginase in these processes are very limited. Therefore, in the present study, we focused on the changes in arginase activity in the coelomocytes of Eisenia andrei. We studied the effects of lipopolysaccharide (LPS), hydrogen peroxide (H2O2), heavy metals ions (e.g., Mn2+), parasite infection, wound healing, and short-term fasting (5 days) on arginase activity. For the first time in earthworms, we described arginase activity in the coelomocytes and found that it can be up-regulated upon in vitro stimulation with LPS and H2O2 and in the presence of Mn2+ ions. Moreover, arginase activity was also up-regulated in animals in vivo infected with nematodes or experiencing segment amputation, but not in fasting earthworms. Furthermore, we confirmed that the activity of coelomocyte arginase can be suppressed by l-norvaline. Our studies strongly suggest that similarly to the vertebrates, also in the earthworms, coelomocyte arginase is an important element of the immune response and wound healing processes.

scholarly journals Differentiated glioblastoma cells accelerate tumor progression by shaping the tumor microenvironment via CCN1-mediated macrophage infiltration

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Atsuhito Uneda ◽  
Kazuhiko Kurozumi ◽  
Atsushi Fujimura ◽  
Kentaro Fujii ◽  
Joji Ishida ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Tumor Cells ◽  
In Silico ◽  
Tumor Tissue ◽  
The Cancer Genome Atlas ◽  
Macrophage Infiltration ◽  
Macrophage Migration

AbstractGlioblastoma (GBM) is the most lethal primary brain tumor characterized by significant cellular heterogeneity, namely tumor cells, including GBM stem-like cells (GSCs) and differentiated GBM cells (DGCs), and non-tumor cells such as endothelial cells, vascular pericytes, macrophages, and other types of immune cells. GSCs are essential to drive tumor progression, whereas the biological roles of DGCs are largely unknown. In this study, we focused on the roles of DGCs in the tumor microenvironment. To this end, we extracted DGC-specific signature genes from transcriptomic profiles of matched pairs of in vitro GSC and DGC models. By evaluating the DGC signature using single cell data, we confirmed the presence of cell subpopulations emulated by in vitro culture models within a primary tumor. The DGC signature was correlated with the mesenchymal subtype and a poor prognosis in large GBM cohorts such as The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project. In silico signaling pathway analysis suggested a role of DGCs in macrophage infiltration. Consistent with in silico findings, in vitro DGC models promoted macrophage migration. In vivo, coimplantation of DGCs and GSCs reduced the survival of tumor xenograft-bearing mice and increased macrophage infiltration into tumor tissue compared with transplantation of GSCs alone. DGCs exhibited a significant increase in YAP/TAZ/TEAD activity compared with GSCs. CCN1, a transcriptional target of YAP/TAZ, was selected from the DGC signature as a candidate secreted protein involved in macrophage recruitment. In fact, CCN1 was secreted abundantly from DGCs, but not GSCs. DGCs promoted macrophage migration in vitro and macrophage infiltration into tumor tissue in vivo through secretion of CCN1. Collectively, these results demonstrate that DGCs contribute to GSC-dependent tumor progression by shaping a mesenchymal microenvironment via CCN1-mediated macrophage infiltration. This study provides new insight into the complex GBM microenvironment consisting of heterogeneous cells.

scholarly journals A reassessment of the role of B7-1 expression in tumor rejection.

1995 ◽  
Vol 182 (5) ◽  
pp. 1415-1421 ◽  
Author(s):  
T C Wu ◽  
A Y Huang ◽  
E M Jaffee ◽  
H I Levitsky ◽  
D M Pardoll
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Tumor Rejection ◽  
Type B ◽  
Wild Type ◽  
Systemic Immunity ◽  
Murine Tumor

Introduction of the B7-1 gene into murine tumor cells can result in rejection of the B7-1 transductants and, in some cases, systemic immunity to subsequent challenge with the nontransduced tumor cells. These effects have been largely attributed to the function of B7-1 as a costimulator in directly activating tumor specific, major histocompatibility class I-restricted CD8+ T cells. We examined the role of B7-1 expression in the direct rejection as well as in the induction of systemic immunity to a nonimmunogenic murine tumor. B-16 melanoma cells with high levels of B7-1 expression did not grow in C57BL/6 recipient mice, while wild-type B-16 cells and cells with low B7-1 expression grew progressively within 21 d. In mixing experiments with B7-1hi and wild-type B-16 cells, tumors grew out in vivo even when a minority of cells were B7-1-. Furthermore, the occasional tumors that grew out after injection of 100% B-16 B7-1hi cells showed markedly decreased B7-1 expression. In vivo antibody depletions showed that NK1.1 and CD8+ T cells, but not CD4+ T cells, were essential for the in vivo rejection of tumors. Animals that rejected B-16 B7-1hi tumors did not develop enhanced systemic immunity against challenge with wild-type B-16 cells. These results suggest that a major role of B7-1 expression by tumors is to mediate direct recognition and killing by natural killer cells. With an intrinsically nonimmunogenic tumor, this direct killing does not lead to enhanced systemic immunity.

scholarly journals Peroxiredoxin 6 is required for blood vessel integrity in wounded skin

2007 ◽  
Vol 179 (4) ◽  
pp. 747-760 ◽  
Author(s):  
Angelika Kümin ◽  
Matthias Schäfer ◽  
Nikolas Epp ◽  
Philippe Bugnon ◽  
Christiane Born-Berclaz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Wound Healing ◽  
Endothelial Cells ◽  
Ultrastructural Level ◽  
Peroxiredoxin 6 ◽  
Severe Hemorrhage ◽  
Vessel Integrity ◽  
Knockout Animals

Peroxiredoxin 6 (Prdx6) is a cytoprotective enzyme with largely unknown in vivo functions. Here, we use Prdx6 knockout mice to determine its role in UV protection and wound healing. UV-mediated keratinocyte apoptosis is enhanced in Prdx6-deficient mice. Upon skin injury, we observe a severe hemorrhage in the granulation tissue of knockout animals, which correlates with the extent of oxidative stress. At the ultrastructural level endothelial cells appear highly damaged, and their rate of apoptosis is enhanced. Knock-down of Prdx6 in cultured endothelial cells also increases their susceptibility to oxidative stress, thus confirming the sensitivity of this cell type to loss of Prdx6. Wound healing studies in bone marrow chimeric mice demonstrate that Prdx6-deficient inflammatory and endothelial cells contribute to the hemorrhage phenotype. These results provide insight into the cross-talk between hematopoietic and resident cells at the wound site and the role of reactive oxygen species in this interplay.

scholarly journals Chitosan from Lucilia cuprina (Diptera: Calliphoridae) enhances sensitization to insulin treatment in a diabetic burn mice of wound healing

2020 ◽  
Vol 1 (1) ◽  
pp. 1-15
Author(s):  
Lamia M. El-Samad ◽  
◽  
Azza A. Attia ◽  
Basant A. Bakr ◽  
◽  
...  
Keyword(s):  
Wound Healing ◽  
Wound Closure ◽  
Lucilia Cuprina ◽  
Diabetic Mice ◽  
Burn Wound ◽  
Time Intervals ◽  
Burn Wound Healing ◽  
High Degree

Chitosan is recognized as a multipurpose biomaterial because of its low allergenicity, non-toxicity, biodegradability and biocompatibility. The present study was designed to estimate the role of chitosan derived from Lucilia cuprina on burn healing in diabetic mice; using histopathological and microbiological studies at different time intervals. Chitosan was prepared from L. cuprina with high molecular weight (MW) and high degree of deacetylation (DD) to evaluate its burn wound healing potential; skin burn closure assessment, histological and microbiological studies in vivo in male diabetic mice. Chitosan topical treatment was superior in wound closure acceleration; mainly in insulin injected group at all the time intervals. Additionally, earlier epidermal remodelling with mature and intense collagen deposition was encountered in all chitosan treated animals as well as non-diabetic burned animals. There was a significant delay in hair growth and poor epidermal remodelling with impairment of wound closure in diabetic groups. Moreover, chitosan treated groups assert the chitosan antibacterial effects with protecting the burn against contamination that hinders healing especially in this diabetic condition. Further researches needed to interpret effects of possible synergistic combination therapy.

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