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

Identification of therapeutic targets for treating fibrotic diseases and cancer remains challenging. Our study aimed to investigate the effects of TGF-β1 and TGF-β3 on myofibroblast differentiation and extracellular matrix deposition in different types of fibroblasts, including normal/dermal, cancer-associated, and scar-derived fibroblasts. When comparing the phenotype and signaling pathways activation we observed extreme heterogeneity of studied markers across different fibroblast populations, even within those isolated from the same tissue. Specifically, the presence of myofibroblast and deposition of extracellular matrix were dependent on the origin of the fibroblasts and the type of treatment they received (TGF-β1 vs. TGF-β3). In parallel, we detected activation of canonical signaling (pSMAD2/3) across all studied fibroblasts, albeit to various extents. Treatment with TGF-β1 and TGF-β3 resulted in the activation of canonical and several non-canonical pathways, including AKT, ERK, and ROCK. Among studied cells, cancer-associated fibroblasts displayed the most heterogenic response to TGF-β1/3 treatments. In general, TGF-β1 demonstrated a more potent activation of signaling pathways compared to TGF-β3, whereas TGF-β3 exhibited rather an inhibitory effect in keloid- and hypertrophic scar-derived fibroblasts suggesting its clinical potential for scar treatment. In summary, our study has implications for comprehending the role of TGF-β signaling in fibroblast biology, fibrotic diseases, and cancer. Future research should focus on unraveling the mechanisms beyond differential fibroblast responses to TGF-β isomers considering inherent fibroblast heterogeneity.

• Keywords
• Carcinoma, Hypertrophic scar, Keloid, Melanoma, Stroma, Tumor microenvironment,
• MeSH
• Fibroblasts metabolism   MeSH
• Wound Healing MeSH
• Cicatrix, Hypertrophic * metabolism   pathology   MeSH
• Carcinogenesis metabolism   pathology   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Cell Transformation, Neoplastic metabolism   MeSH
• Protein Isoforms metabolism   MeSH
• Transforming Growth Factor beta metabolism   MeSH
• Transforming Growth Factor beta1 * pharmacology   metabolism   MeSH
• Transforming Growth Factor beta3 metabolism   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Protein Isoforms MeSH
• Transforming Growth Factor beta MeSH
• Transforming Growth Factor beta1 * MeSH
• Transforming Growth Factor beta3 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

Melanoma represents a malignant disease with steadily increasing incidence. UV-irradiation is a recognized key factor in melanoma initiation. Therefore, the efficient prevention of UV tissue damage bears a critical potential for melanoma prevention. In this study, we tested the effect of UV irradiation of normal keratinocytes and their consequent interaction with normal and cancer-associated fibroblasts isolated from melanoma, respectively. Using this model of UV influenced microenvironment, we measured melanoma cell migration in 3-D collagen gels. These interactions were studied using DNA microarray technology, immunofluorescence staining, single cell electrophoresis assay, viability (dead/life) cell detection methods, and migration analysis. We observed that three 10 mJ/cm2 fractions at equal intervals over 72 h applied on keratinocytes lead to a 50% increase (p < 0.05) in in vitro invasion of melanoma cells. The introduction cancer-associated fibroblasts to such model further significantly stimulated melanoma cells in vitro invasiveness to a higher extent than normal fibroblasts. A panel of candidate gene products responsible for facilitation of melanoma cells invasion was defined with emphasis on IL-6, IL-8, and CXCL-1. In conclusion, this study demonstrates a synergistic effect between cancer microenvironment and UV irradiation in melanoma invasiveness under in vitro condition.

• Keywords
• Cancer microenvironment, Cancer-associated fibroblasts, Chemokine, Cytokine, Keratinocytes, Melanoma,
• MeSH
• Fibroblasts cytology   pathology   MeSH
• Immunohistochemistry MeSH
• Neoplasm Invasiveness * MeSH
• Keratinocytes pathology   radiation effects   MeSH
• Coculture Techniques MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Melanoma pathology   MeSH
• Ultraviolet Rays * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

The nonsyndromic cleft is one of the most frequent congenital defects in humans. Clinical data demonstrated improved and almost scarless neonatal healing of reparative surgery. Based on our previous results on crosstalk between neonatal fibroblasts and adult keratinocytes, the present study focused on characterization of fibroblasts prepared from cleft lip tissue samples of neonates and older children, and compared them with samples isolated from normal adult skin (face and breast) and scars. Although subtle variances in expression profiles of children and neonates were observed, the two groups differed significantly from adult cells. Compared with adult cells, differences were observed in nestin and smooth muscle actin (SMA) expression at the protein and transcript level. Furthermore, fibroblast to myofibroblast differentiation drives effective wound healing and is largely regulated by the cytokine, transforming growth factor-β1 (TGF-β1). Dysregulation of the TGF-β signalling pathway, including low expression of the TGF-β receptor II, may contribute to reducing scarring in neonates. Fibroblasts of facial origin also exhibited age independent differences from the cells prepared from the breast, reflecting the origin of the facial cells from neural crest-based ectomesenchyme.

• MeSH
• Actins genetics   metabolism   MeSH
• Biomarkers MeSH
• Models, Biological MeSH
• Cell Differentiation MeSH
• Cytokines genetics   metabolism   pharmacology   MeSH
• Child MeSH
• Adult MeSH
• Fibroblasts cytology   drug effects   metabolism   MeSH
• Immunohistochemistry MeSH
• Infant MeSH
• Skin cytology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Nestin genetics   metabolism   MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Cell Proliferation drug effects   MeSH
• Cleft Lip pathology   surgery   MeSH
• Aged MeSH
• Signal Transduction MeSH
• Gene Expression Profiling MeSH
• Transforming Growth Factor beta genetics   metabolism   MeSH
• Plastic Surgery Procedures MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Actins MeSH
• Biomarkers MeSH
• Cytokines MeSH
• Nestin MeSH
• Transforming Growth Factor beta MeSH

Incidence of malignant melanoma is increasing globally. While the initial stages of tumors can be easily treated by a simple surgery, the therapy of advanced stages is rather limited. Melanoma cells spread rapidly through the body of a patient to form multiple metastases. Consequently, the survival rate is poor. Therefore, emphasis in melanoma research is given on early diagnosis and development of novel and more potent therapeutic options. The malignant melanoma is arising from melanocytes, cells protecting mitotically active keratinocytes against damage caused by UV light irradiation. The melanocytes originate in the neural crest and consequently migrate to the epidermis. The relationship between the melanoma cells, the melanocytes, and neural crest stem cells manifests when the melanoma cells are implanted to an early embryo: they use similar migratory routes as the normal neural crest cells. Moreover, malignant potential of these melanoma cells is overdriven in this experimental model, probably due to microenvironmental reprogramming. This observation demonstrates the crucial role of the microenvironment in melanoma biology. Indeed, malignant tumors in general represent complex ecosystems, where multiple cell types influence the growth of genetically mutated cancer cells. This concept is directly applicable to the malignant melanoma. Our review article focuses on possible strategies to modify the intercellular crosstalk in melanoma that can be employed for therapeutic purposes.

• Keywords
• Cancer-associated fibroblast, Cytokine, Keratinocyte, Melanocyte, Melanoma cells, Melanoma ecosystem,
• MeSH
• Early Detection of Cancer methods   MeSH
• Neural Crest cytology   pathology   MeSH
• Indoles therapeutic use   MeSH
• Keratinocytes MeSH
• Humans MeSH
• Melanoma, Cutaneous Malignant MeSH
• Melanocytes pathology   MeSH
• Melanoma drug therapy   epidemiology   pathology   MeSH
• Tumor Microenvironment physiology   MeSH
• Skin Neoplasms MeSH
• Antineoplastic Agents therapeutic use   MeSH
• Sulfonamides therapeutic use   MeSH
• Ultraviolet Rays adverse effects   MeSH
• Vemurafenib MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Indoles MeSH
• Antineoplastic Agents MeSH
• Sulfonamides MeSH
• Vemurafenib MeSH