Microenvironment Plasticity Research Articles

Zinc-based Polyoxometalate Nanozyme Functionalized Hydrogels for optimizing the Hyperglycemic-Immune Microenvironment to Promote Diabetic Wound Regeneration.

In diabetic wounds, hyperglycemia-induced cytotoxicity and impaired immune microenvironment plasticity directly hinder the wound healing process. Regulation of the hyperglycemic microenvironment and remodeling of the immune microenvironment are crucial. Here, we developed a nanozymatic functionalized regenerative microenvironmental regulator (AHAMA/CS-GOx@Zn-POM) for the effective repair of diabetic wounds. This novel construct integrated an aldehyde and methacrylic anhydride-modified hyaluronic acid hydrogel (AHAMA) and chitosan nanoparticles (CS NPs) encapsulating zinc-based polymetallic oxonate nanozyme (Zn-POM) and glucose oxidase (GOx), facilitating a sustained release of release of both enzymes. The GOx catalyzed glucose to gluconic acid and (H₂O₂), thereby alleviating the effects of the hyperglycemic microenvironment on wound healing. Zn-POM exhibited catalase and superoxide dismutase activities to scavenge reactive oxygen species and H₂O₂, a by-product of glucose degradation. Additionally, Zn-POM induced M1 macrophage reprogramming to the M2 phenotype by inhibiting the MAPK/IL-17 signaling diminishing pro-inflammatory cytokines, and upregulating the expression of anti-inflammatory mediators, thus remodeling the immune microenvironment and enhancing angiogenesis and collagen regeneration within wounds. In a rat diabetic wound model, the application of AHAMA/CS-GOx@Zn-POM enhanced neovascularization and collagen deposition, accelerating the wound healing process. Therefore, the regenerative microenvironment regulator AHAMA/CS-GOx@Zn-POM can achieve the effective conversion of a pathological microenvironment to regenerative microenvironment through integrated control of the hyperglycemic-immune microenvironment, offering a novel strategy for the treatment of diabetic wounds.

Cetuximab in locally advanced head and neck squamous cell carcinoma: Biological mechanisms involved in efficacy, toxicity and resistance.

Since its introduction, the use of cetuximab in the treatment of head and neck squamous cell carcinoma (HNSCC) has experienced an evolution. Currently, cetuximab associated with radiotherapy is limited to the treatment of patients affected by a locally advanced malignancy and unfit for cisplatin. However, reliable biomarkers of cetuximab efficacy in this cancer setting are still lacking. This review focuses on the mechanisms of action of cetuximab, highlighting, in particular, the consequences of the binding to EGFR, and the pathways involved in the development of adverse events or acquired resistance. Indeed, adverse events, such as skin rash, have been associated with cetuximab efficacy in HNSCC several times. Acquired resistance is associated with microenvironment plasticity, which is, in turn, characterized by an increased immune infiltrate. The better definition of patients eligible for this kind of therapy could improve HNSCC management, possibly proposing a combined treatment with radiotherapy, cetuximab and immune checkpoint inhibitors as recently investigated.

Extracellular Vesicle-Mediated Purinergic Signaling Contributes to Host Microenvironment Plasticity and Metastasis in Triple Negative Breast Cancer.

Metastasis accounts for over 90% of cancer-related deaths, yet the mechanisms guiding this process remain unclear. Secreted nucleoside diphosphate kinase A and B (NDPK) support breast cancer metastasis. Proteomic evidence confirms their presence in breast cancer-derived extracellular vesicles (EVs). We investigated the role of EV-associated NDPK in modulating the host microenvironment in favor of pre-metastatic niche formation. We measured NDPK expression and activity in EVs isolated from triple-negative breast cancer (MDA-MB-231) and non-tumorigenic mammary epithelial (HME1) cells using flow cytometry, western blot, and ATP assay. We evaluated the effects of EV-associated NDPK on endothelial cell migration, vascular remodeling, and metastasis. We further assessed MDA-MB-231 EV-induced proteomic changes in support of pre-metastatic lung niche formation. NDPK-B expression and phosphotransferase activity were enriched in MDA-MB-231 EVs that promote vascular endothelial cell migration and disrupt monolayer integrity. MDA-MB-231 EV-treated mice demonstrate pulmonary vascular leakage and enhanced experimental lung metastasis, whereas treatment with an NDPK inhibitor or a P2Y1 purinoreceptor antagonist blunts these effects. We identified perturbations to the purinergic signaling pathway in experimental lungs, lending evidence to support a role for EV-associated NDPK-B in lung pre-metastatic niche formation and metastatic outgrowth. These studies prompt further evaluation of NDPK-mediated EV signaling using targeted genetic silencing approaches.

Relevance of Non-Targeted Effects for Radiotherapy and Diagnostic Radiology; A Historical and Conceptual Analysis of Key Players.

Non-targeted effects (NTE) such as bystander effects or genomic instability have been known for many years but their significance for radiotherapy or medical diagnostic radiology are far from clear. Central to the issue are reported differences in the response of normal and tumour tissues to signals from directly irradiated cells. This review will discuss possible mechanisms and implications of these different responses and will then discuss possible new therapeutic avenues suggested by the analysis. Finally, the importance of NTE for diagnostic radiology and nuclear medicine which stems from the dominance of NTE in the low-dose region of the dose–response curve will be presented. Areas such as second cancer induction and microenvironment plasticity will be discussed.

Microenvironment plasticity confers cetuximab resistance.

Microenvironment plasticity confers cetuximab resistance.

Spatiotemporal dynamics of the biological interface between cancer and the microenvironment: a fractal anomalous diffusion model with microenvironment plasticity

BackgroundThe invasion-metastasis cascade of cancer involves a process of parallel progression. A biological interface (module) in which cells is linked with ECM (extracellular matrix) by CAMs (cell adhesion molecules) has been proposed as a tool for tracing cancer spatiotemporal dynamics.MethodsA mathematical model was established to simulate cancer cell migration. Human uterine leiomyoma specimens, in vitro cell migration assay, quantitative real-time PCR, western blotting, dynamic viscosity, and an in vivo C57BL6 mouse model were used to verify the predictive findings of our model.ResultsThe return to origin probability (RTOP) and its related CAM expression ratio in tumors, so-called "tumor self-seeding", gradually decreased with increased tumor size, and approached the 3D Pólya random walk constant (0.340537) in a periodic structure. The biphasic pattern of cancer cell migration revealed that cancer cells initially grew together and subsequently began spreading. A higher viscosity of fillers applied to the cancer surface was associated with a significantly greater inhibitory effect on cancer migration, in accordance with the Stokes-Einstein equation.ConclusionThe positional probability and cell-CAM-ECM interface (module) in the fractal framework helped us decipher cancer spatiotemporal dynamics; in addition we modeled the methods of cancer control by manipulating the microenvironment plasticity or inhibiting the CAM expression to the Pólya random walk, Pólya constant.

Epithelial Framework Reorganization during Human Thymus Involution

Background: The thymus undergoes age-related (physiological) involution in the course of normal ontogenetic development. In addition to this chronic involution, the thymus can also undergo an acute (age-independent) regression, defined as spontaneous, transient involution. This process is induced by either exogenous or endogenous factors, including some infections (infection-type involution). Objective: The purpose of the present work was to undertake a comparative study of the epithelial framework organization and cytokeratin immunoreactivity of human thymic epithelial cells during age-related and infection-induced involution. Methods: Routine methods for light and transmission electron microscopy, as well as indirect immunoperoxidase staining and immunogold electron microscopy, were applied. Results: The epithelial thymocyte microenvironment was of a generally similar cellular composition in both chronically and acutely involuted thymus. Structurally, aged thymus glands and infection-affected thymus glands displayed a large mass of adipose tissue containing scattered islands composed of epithelial cells, lymphocytes and reticular connective tissue. Correlation between thymus involution and regional peculiarities in the presence and distribution of cytokeratin-immunopositive cells and their intermediate filaments was investigated. Conclusion: The epithelial framework of the thymus undergoes reorganization during both age-related and infection-induced thymus involution. The involutionary processes demonstrated essential regional and intracellular (structural and immunocytochemical) differences. The epithelial cell rearrangement and cytokeratin modulation that we observed might be involved in thymic microenvironment plasticity and reorganization in the course of these processes.