Wound healing represents a complex and evolutionarily conserved process across vertebrates, encompassing a series of life-rescuing events. The healing process runs in three main phases: inflammation, proliferation, and maturation/remodelling. While acute inflammation is indispensable for cleansing the wound, removing infection, and eliminating dead tissue characterised by the prevalence of neutrophils, the proliferation phase is characterised by transition into the inflammatory cell profile, shifting towards the prevalence of macrophages. The proliferation phase involves development of granulation tissue, comprising fibroblasts, activated myofibroblasts, and inflammatory and endothelial cells. Communication among these cellular components occurs through intercellular contacts, extracellular matrix secretion, as well as paracrine production of bioactive factors and proteolytic enzymes. The proliferation phase of healing is intricately regulated by inflammation, particularly interleukin-6. Prolonged inflammation results in dysregulations during the granulation tissue formation and may lead to the development of chronic wounds or hypertrophic/keloid scars. Notably, pathological processes such as autoimmune chronic inflammation, organ fibrosis, the tumour microenvironment, and impaired repair following viral infections notably share morphological and functional similarities with granulation tissue. Consequently, wound healing emerges as a prototype for understanding these diverse pathological processes. The prospect of gaining a comprehensive understanding of wound healing holds the potential to furnish fundamental insights into modulation of the intricate dialogue between cancer cells and non-cancer cells within the cancer ecosystem. This knowledge may pave the way for innovative approaches to cancer diagnostics, disease monitoring, and anticancer therapy.

• Keywords
• IL-6, cancer-associated fibroblasts, granulation tissue, myofibroblasts, wound healing,
• MeSH
• Autoimmunity * MeSH
• Wound Healing * immunology   MeSH
• Interleukin-6 * metabolism   immunology   MeSH
• Humans MeSH
• Tumor Microenvironment * immunology   MeSH
• Neoplasms * immunology   metabolism   pathology   MeSH
• Aging * immunology   MeSH
• Inflammation * immunology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Interleukin-6 * MeSH

BACKGROUND: Interleukin-6 (IL-6) is a multifunctional cytokine that controls the immune response, and its role has been described in the development of autoimmune diseases. Signaling via its cognate IL-6 receptor (IL-6R) complex is critical in tumor progression and, therefore, IL-6R represents an important therapeutic target. METHODS: An albumin-binding domain-derived highly complex combinatorial library was used to select IL-6R alpha (IL-6Rα)-targeted small protein binders using ribosome display. Large-scale screening of bacterial lysates of individual clones was performed using ELISA, and their IL-6Rα blocking potential was verified by competition ELISA. The binding of proteins to cells was monitored by flow cytometry and confocal microscopy on HEK293T-transfected cells, and inhibition of signaling function was examined using HEK-Blue IL-6 reporter cells. Protein binding kinetics to living cells was measured by LigandTracer, cell proliferation and toxicity by iCELLigence and Incucyte, cell migration by the scratch wound healing assay, and prediction of binding poses using molecular modeling by docking. RESULTS: We demonstrated a collection of protein variants called NEF ligands, selected from an albumin-binding domain scaffold-derived combinatorial library, and showed their binding specificity to human IL-6Rα and antagonistic effect in HEK-Blue IL-6 reporter cells. The three most promising NEF108, NEF163, and NEF172 variants inhibited cell proliferation of malignant melanoma (G361 and A2058) and pancreatic (PaTu and MiaPaCa) cancer cells, and suppressed migration of malignant melanoma (A2058), pancreatic carcinoma (PaTu), and glioblastoma (GAMG) cells in vitro. The NEF binders also recognized maturation-induced IL-6Rα expression and interfered with IL-6-induced differentiation in primary human B cells. CONCLUSION: We report on the generation of small protein blockers of human IL-6Rα using directed evolution. NEF proteins represent a promising class of non-toxic anti-tumor agents with migrastatic potential.

• Keywords
• Cancer cell migration, GAMG glioblastoma, HEK-Blue IL-6, IL-6, IL-6R blockers, Malignant melanoma, Migrastatics, Pancreatic carcinoma, Protein engineering,
• MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Cell Movement * drug effects   MeSH
• Cell Proliferation * drug effects   MeSH
• Receptors, Interleukin-6 * metabolism   MeSH
• Protein Binding drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• IL6R protein, human MeSH Browser
• Receptors, Interleukin-6 * MeSH

BACKGROUND: The aim of this prospective study was to evaluate the role of serum IL-6 as a potential predictive biomarker of postoperative complications (POC) in elective colorectal surgery. METHOD: A total of 115 patients underwent colorectal surgery for malignancy. IL-6 was measured on the first and third postoperative days (POD1, POD3), and C-reactive protein (CRP) was measured on the POD3. POC was analysed in subgroups according to Clavien‒Dindo (CD), antibiotic (ATB) treatment, intensive care unit (ICU) and hospital length of stay. The predictive power of variables for evaluated endpoints was analysed using receiver-operating characteristic (ROC) analysis and described by area under the curve (AUC). ROC analysis was adopted for the identification of optimal cut-offs. Histological analysis was performed to verify IL-6 production by the tumour. RESULTS: Out of 115 patients who were analysed, 42% had POC. Patients with POC had significantly higher serum levels of IL-6 on POD1 (p < 0.001) and POD3 (p < 0.001). IL-6 early on POD1 as a predictor of antibiotic treatment, ICU stay and hospital stay (AUC 0.818; 0.811; 0.771) did not significantly differ from the AUC of CRP late on POD3 (0.879; 0.838, 0.752). A cut-off IL-6 value of 113 pg/ml on POD1 and 180.5 pg/ml on POD3 in severe complications (CD > 3a) resulted in 75% and 72% sensitivity, 78.6% and 99% specificity, negative predictive value 96.4% and 97% and positive predictive value 29% and 88.9%. CONCLUSION: The serum level of interleukin-6 can predict severe (CD > 3a) POC early on POD1. On POD3, IL-6 is superior to CRP in terms of high positive predictive power of severe POC. Interestingly, the advantage of IL-6 on POD1 is early prediction of the need for antibiotic treatment, ICU stay and hospital stay, which is comparable to the CRP serum level late on the third POD.

• Keywords
• Colorectal surgery, Infection, Interleukin-6, Postoperative complications,
• MeSH
• Anti-Bacterial Agents MeSH
• Biomarkers MeSH
• C-Reactive Protein analysis   MeSH
• Interleukin-6 * MeSH
• Colorectal Surgery * MeSH
• Humans MeSH
• Postoperative Complications etiology   MeSH
• Prospective Studies MeSH
• ROC Curve MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH
• Biomarkers MeSH
• C-Reactive Protein MeSH
• IL6 protein, human MeSH Browser
• Interleukin-6 * MeSH

Therapy for pancreatic ductal adenocarcinoma remains challenging, and the chances of a complete cure are very limited. As in other types of cancer, the expression and role of miRNAs in controlling the biological properties of this type of tumor have been extensively studied. A better insight into miRNA biology seems critical to refining diagnostics and improving their therapeutic potential. In this study, we focused on the expression of miR-21, -96, -196a, -210, and -217 in normal fibroblasts, cancer-associated fibroblasts prepared from a ductal adenocarcinoma of the pancreas, and pancreatic carcinoma cell lines. We compared these data with miRNAs in homogenates of paraffin-embedded sections from normal pancreatic tissues. In cancer-associated fibroblasts and cancer cell lines, miRNAs differed significantly from the normal tissue. In detail, miR-21 and -210 were significantly upregulated, while miR-217 was downregulated. Similar transcription profiles were earlier reported in cancer-associated fibroblasts exposed to hypoxia. However, the cells in our study were cultured under normoxic conditions. We also noted a relation to IL-6 production. In conclusion, cultured cancer-associated fibroblasts and carcinoma cells reflect miR-21 and -210 expression similarly to the cancer tissue samples harvested from the patients.

• Keywords
• IL-6, cancer-associated fibroblast, hypoxia, miR-21, miR-210, miRNA, pancreas,
• MeSH
• Diabetes Mellitus MeSH
• Carcinoma, Pancreatic Ductal * pathology   MeSH
• Facies MeSH
• Cancer-Associated Fibroblasts * metabolism   MeSH
• Humans MeSH
• MicroRNAs * genetics   MeSH
• Cerebellum abnormalities   MeSH
• Cell Line, Tumor MeSH
• Pancreatic Neoplasms * pathology   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Fetal Growth Retardation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• MicroRNAs * MeSH
• MIRN217 microRNA, human MeSH Browser

Interleukin 6 (IL-6) belongs to a broad class of cytokines involved in the regulation of various homeostatic and pathological processes. These activities range from regulating embryonic development, wound healing and ageing, inflammation, and immunity, including COVID-19. In this review, we summarise the role of IL-6 signalling pathways in cancer biology, with particular emphasis on cancer cell invasiveness and metastasis formation. Targeting principal components of IL-6 signalling (e.g., IL-6Rs, gp130, STAT3, NF-κB) is an intensively studied approach in preclinical cancer research. It is of significant translational potential; numerous studies strongly imply the remarkable potential of IL-6 signalling inhibitors, especially in metastasis suppression.

• Keywords
• IL-6, cancer, metastasis,
• MeSH
• Interleukin-6 metabolism   MeSH
• Humans MeSH
• Neoplasms * drug therapy   MeSH
• Antineoplastic Agents * therapeutic use   MeSH
• Signal Transduction MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• IL6 protein, human MeSH Browser
• Interleukin-6 MeSH
• Antineoplastic Agents * MeSH

Recent evidence indicates that targeting IL-6 provides broad therapeutic approaches to several diseases. In patients with cancer, autoimmune diseases, severe respiratory infections [e.g. coronavirus disease 2019 (COVID-19)] and wound healing, IL-6 plays a critical role in modulating the systemic and local microenvironment. Elevated serum levels of IL-6 interfere with the systemic immune response and are associated with disease progression and prognosis. As already noted, monoclonal antibodies blocking either IL-6 or binding of IL-6 to receptors have been used/tested successfully in the treatment of rheumatoid arthritis, many cancer types, and COVID-19. Therefore, in the present review, we compare the impact of IL-6 and anti-IL-6 therapy to demonstrate common (pathological) features of the studied diseases such as formation of granulation tissue with the presence of myofibroblasts and deposition of new extracellular matrix. We also discuss abnormal activation of other wound-healing-related pathways that have been implicated in autoimmune disorders, cancer or COVID-19.

• Keywords
• Cancer stroma, Granulation tissue, IL-6, Inflammation, Myofibroblast, Peripheral nerve injury, Rheumatoid arthritis, SARS-CoV-2, Wound healing,
• MeSH
• Autoimmunity MeSH
• Autoimmune Diseases * drug therapy   MeSH
• COVID-19 * MeSH
• Wound Healing MeSH
• Humans MeSH
• Tumor Microenvironment MeSH
• Neoplasms * drug therapy   MeSH
• Inflammation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Cancer represents an extremely complicated ecosystem where cancer cells communicate with non-cancer cells present in the tumour niche through intercellular contacts, paracrine production of bioactive factors and extracellular vesicles, such as exosomes [...].

• MeSH
• Ecosystem MeSH
• Exosomes * metabolism   MeSH
• Extracellular Vesicles * metabolism   MeSH
• Humans MeSH
• Cell Communication MeSH
• Tumor Microenvironment MeSH
• Neoplasms * metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Editorial MeSH