Fibroblasts, the most abundant cell type in the human body, play crucial roles in biological processes such as inflammation and cancer progression. They originate from the mesoderm or neural-crest-derived ectomesenchyme. Ectomesenchyme-derived fibroblasts contribute to facial formation and do not express HOX genes during development. The expression and role of the HOX genes in adult fibroblasts is not known. We investigated whether the developmental pattern persists into adulthood and under pathological conditions, such as cancer. We collected adult fibroblasts of ectomesenchymal and mesodermal origins from distinct body parts. The isolated fibroblasts were characterised by immunocytochemistry, and their transcriptome was analysed by whole genome profiling. Significant differences were observed between normal fibroblasts from the face (ectomesenchyme) and upper limb (mesoderm), particularly in genes associated with limb development, including HOX genes, e.g., HOXA9 and HOXD9. Notably, the pattern of HOX gene expression remained consistent postnatally, even in fibroblasts from pathological tissues, including inflammatory states and cancer-associated fibroblasts from primary and metastatic tumours. Therefore, the distinctive HOX gene expression pattern can serve as an indicator of the topological origin of fibroblasts. The influence of cell position and HOX gene expression in fibroblasts on disease progression warrants further investigation.

• Klíčová slova
• Cancer-associated fibroblasts, Ectomesenchyme, Expression pattern, Fibroblasts, Homeobox genes, Mesoderm,
• MeSH
• dospělí MeSH
• fibroblasty * metabolismus   cytologie   MeSH
• homeoboxové geny * MeSH
• homeodoménové proteiny * genetika   MeSH
• kultivované buňky MeSH
• lidé MeSH
• mezoderm * metabolismus   cytologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• homeodoménové proteiny * MeSH

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.

• Klíčová slova
• IL-6, cancer-associated fibroblasts, granulation tissue, myofibroblasts, wound healing,
• MeSH
• autoimunita * MeSH
• hojení ran * imunologie   MeSH
• interleukin-6 * metabolismus   imunologie   MeSH
• lidé MeSH
• nádorové mikroprostředí * imunologie   MeSH
• nádory * imunologie   metabolismus   patologie   MeSH
• stárnutí * imunologie   MeSH
• zánět * imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• interleukin-6 * MeSH

Head and neck cancers (HNC) are aggressive, difficult-to-treat tumors that can be caused by genetic factors but mainly by lifestyle or infection caused by the human papillomavirus. As the sixth most common malignancy, it presents a formidable therapeutic challenge with limited therapeutic modalities. Curcumin, a natural polyphenol, is appearing as a promising multitarget anticancer and antimetastatic agent. Numerous studies have shown that curcumin and its derivatives have the potential to affect signaling pathways (NF-κB, JAK/STAT, and EGFR) and molecular mechanisms that are crucial for the growth and migration of head and neck tumors. Furthermore, its ability to interact with the tumor microenvironment and trigger the immune system may significantly influence the organism's immune response to the tumor. Combining curcumin with conventional therapies such as chemotherapy or radiotherapy may improve the efficacy of treatment and reduce the side effects of treatment, thereby increasing its therapeutic potential. This review is a comprehensive overview that discusses both the benefits and limitations of curcumin and its therapeutic effects in the context of tumor biology, with an emphasis on molecular mechanisms in the context of HNC. This review also includes possibilities to improve the limiting properties of curcumin both in terms of the development of new derivatives, formulations, or combinations with conventional therapies that have potential as a new type of therapy for the treatment of HNC and subsequent use in clinical practice.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Embryos are regeneration and wound healing masters. They rapidly close wounds and scarlessly remodel and regenerate injured tissue. Regeneration has been extensively studied in many animal models using new tools such as single-cell analysis. However, until now, they have been based primarily on experiments assessing from 1 day post injury. RESULTS: In this paper, we reveal that critical steps initiating regeneration occur within hours after injury. We discovered the regeneration initiating cells (RICs) using single-cell and spatial transcriptomics of the regenerating Xenopus laevis tail. RICs are formed transiently from the basal epidermal cells, and their expression signature suggests they are important for modifying the surrounding extracellular matrix thus regulating development. The absence or deregulation of RICs leads to excessive extracellular matrix deposition and defective regeneration. CONCLUSION: RICs represent a newly discovered transient cell state involved in the initiation of the regeneration process.

• Klíčová slova
• Xenopus laevis, RICs, ROCs, Regeneration,
• MeSH
• analýza jednotlivých buněk MeSH
• extracelulární matrix metabolismus   MeSH
• hojení ran MeSH
• ocas * MeSH
• regenerace * MeSH
• transkriptom MeSH
• Xenopus laevis * MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Immune checkpoints regulate the immune system response. Recent studies suggest that flavonoids, known as phytoestrogens, may inhibit the PD-1/PD-L1 axis. We explored the potential of estrogens and 17 Selective Estrogen Receptor Modulators (SERMs) as inhibiting ligands for immune checkpoint proteins (CTLA-4, PD-L1, PD-1, and CD80). Our docking studies revealed strong binding energy values for quinestrol, quercetin, and bazedoxifene, indicating their potential to inhibit PD-1 and CTLA-4. Quercetin and bazedoxifene, known to modulate EGFR and IL-6R alongside estrogen receptors, can influence the immune checkpoint functionality. We discuss the impact of SERMs on PD-1 and CTLA-4, suggesting that these SERMs could have therapeutic effects through immune checkpoint inhibition. This study highlights the potential of SERMs as inhibitory ligands for immune checkpoint proteins, emphasizing the importance of considering PD-1 and CTLA-4 inhibition when evaluating SERMs as therapeutic agents. Our findings open new avenues for cancer immunotherapy by exploring the interaction between various SERMs and immune checkpoint pathways.

• MeSH
• antigen CTLA-4 MeSH
• antigeny CD274 MeSH
• antigeny CD279 MeSH
• imunoterapie MeSH
• lidé MeSH
• modulátory estrogenních receptorů MeSH
• nádory * terapie   MeSH
• proteiny kontrolních bodů imunitní reakce * MeSH
• quercetin MeSH
• selektivní modulátory estrogenních receptorů farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigen CTLA-4 MeSH
• antigeny CD274 MeSH
• antigeny CD279 MeSH
• modulátory estrogenních receptorů MeSH
• proteiny kontrolních bodů imunitní reakce * MeSH
• quercetin MeSH
• selektivní modulátory estrogenních receptorů 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.

• Klíčová slova
• Carcinoma, Hypertrophic scar, Keloid, Melanoma, Stroma, Tumor microenvironment,
• MeSH
• fibroblasty metabolismus   MeSH
• hojení ran MeSH
• jizva hypertrofická * metabolismus   patologie   MeSH
• karcinogeneze metabolismus   patologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• nádorová transformace buněk metabolismus   MeSH
• protein - isoformy metabolismus   MeSH
• transformující růstový faktor beta metabolismus   MeSH
• transformující růstový faktor beta1 * farmakologie   metabolismus   MeSH
• transformující růstový faktor beta3 metabolismus   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• protein - isoformy MeSH
• transformující růstový faktor beta MeSH
• transformující růstový faktor beta1 * MeSH
• transformující růstový faktor beta3 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.

• Klíčová slova
• IL-6, cancer-associated fibroblast, hypoxia, miR-21, miR-210, miRNA, pancreas,
• MeSH
• diabetes mellitus MeSH
• duktální karcinom slinivky břišní * patologie   MeSH
• faciální stigmatizace MeSH
• fibroblasty asociované s nádorem * metabolismus   MeSH
• lidé MeSH
• mikro RNA * genetika   MeSH
• mozeček abnormality   MeSH
• nádorové buněčné linie MeSH
• nádory slinivky břišní * patologie   MeSH
• regulace genové exprese u nádorů MeSH
• růstová retardace plodu MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• mikro RNA * MeSH
• MIRN217 microRNA, human MeSH Prohlížeč

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.

• Klíčová slova
• IL-6, cancer, metastasis,
• MeSH
• interleukin-6 metabolismus   MeSH
• lidé MeSH
• nádory * farmakoterapie   MeSH
• protinádorové látky * terapeutické užití   MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• IL6 protein, human MeSH Prohlížeč
• interleukin-6 MeSH
• protinádorové látky * MeSH