Breast cancer is the most frequently diagnosed cancer in women worldwide. Although dramatically increased survival rates of early diagnosed cases have been observed, late diagnosed patients and metastatic cancer may still be considered fatal. The present study's main focus was on cancer‑associated fibroblasts (CAFs) which is an active component of the tumor microenvironment (TME) regulating the breast cancer ecosystem. Transcriptomic profiling and analysis of CAFs isolated from breast cancer skin metastasis, cutaneous basal cell carcinoma, and squamous cell carcinoma unravelled major gene candidates such as IL6, VEGFA and MFGE8 that induced co‑expression of keratins‑8/‑14 in the EM‑G3 cell line derived from infiltrating ductal breast carcinoma. Western blot analysis of selected keratins (keratin‑8, ‑14, ‑18, ‑19) and epithelial‑mesenchymal transition‑associated markers (SLUG, SNAIL, ZEB1, E‑/N‑cadherin, vimentin) revealed specific responses pointing to certain heterogeneity of the studied CAF populations. Experimental in vitro treatment using neutralizing antibodies against IL-6, VEGF‑A and MFGE8 attenuated the modulatory effect of CAFs on EM‑G3 cells. The present study provided novel data in characterizing and understanding the interactions between CAFs and EM‑G3 cells in vitro. CAFs of different origins support the pro‑inflammatory microenvironment and influence the biology of breast cancer cells. This observation potentially holds significant interest for the development of novel, clinically relevant approaches targeting the TME in breast cancer. Furthermore, its implications extend beyond breast cancer and have the potential to impact a wide range of other cancer types.
- Klíčová slova
- breast cancer, cell differentiation, epithelial‑mesenchymal interaction, neutralizing antibody, tumor microenvironment,
- MeSH
- antigeny povrchové MeSH
- fibroblasty asociované s nádorem * metabolismus MeSH
- fibroblasty metabolismus MeSH
- keratiny genetika metabolismus MeSH
- lidé MeSH
- maligní melanom kůže MeSH
- MFC-7 buňky MeSH
- mléčné bílkoviny genetika metabolismus MeSH
- nádorové buněčné linie MeSH
- nádorové mikroprostředí genetika MeSH
- nádory prsu * farmakoterapie genetika metabolismus MeSH
- prognóza MeSH
- transkriptom MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antigeny povrchové MeSH
- keratiny MeSH
- MFGE8 protein, human MeSH Prohlížeč
- mléčné bílkoviny MeSH
Soft tissue sarcomas are aggressive mesenchymal-origin malignancies. Undifferentiated pleomorphic sarcoma (UPS) belongs to the aggressive, high-grade, and least characterized sarcoma subtype, affecting multiple tissues and metastasizing to many organs. The treatment of localized UPS includes surgery in combination with radiation therapy. Metastatic forms are treated with chemotherapy. Immunotherapy is a promising treatment modality for many cancers. However, the development of immunotherapy for UPS is limited due to its heterogeneity, antigenic landscape variation, lower infiltration with immune cells, and a limited number of established patient-derived UPS cell lines for preclinical research. In this study, we established and characterized a novel patient-derived UPS cell line, JBT19. The JBT19 cells express PD-L1 and collagen, a ligand of the immune checkpoint molecule LAIR-1. JBT19 cells can form spheroids in vitro and solid tumors in immunodeficient nude mice. We found JBT19 cells induce expansion of JBT19-reactive autologous and allogeneic NK, T, and NKT-like cells, and the reactivity of the expanded cells was associated with cytotoxic impact on JBT19 cells. The PD-1 and LAIR-1 ligand-expressing JBT19 cells show ex vivo immunogenicity and effective in vivo xenoengraftment properties that can offer a unique resource in the preclinical research developing novel immunotherapeutic interventions in the treatment of UPS.
- MeSH
- antigeny CD274 metabolismus MeSH
- buněčné linie MeSH
- imunoterapie MeSH
- lidé MeSH
- ligandy MeSH
- maligní fibrózní histiocytom * MeSH
- myši nahé MeSH
- myši MeSH
- sarkom * patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antigeny CD274 MeSH
- ligandy MeSH
IL-6 signaling is involved in the pathogenesis of a number of serious diseases, including chronic inflammation and cancer. Targeting of IL-6 receptor (IL-6R) by small molecules is therefore an intensively studied strategy in cancer treatment. We describe the design, synthesis, and characteristics of two new bis-pentamethinium salts 5 and 6 (meta and para) bearing indole moieties. Molecular docking studies showed that both compounds have the potential to bind IL-6R (free energy of binding -9.5 and -8.1 kcal/mol). The interaction with IL-6R was confirmed using microscale thermophoresis analyses, which revealed that both compounds had strong affinity for the IL-6R (experimentally determined dissociation constants 26.5 ± 2.5 nM and 304 ± 27.6 nM, respectively). In addition, both compounds were cytotoxic for a broad spectrum of cancer cell lines in micromolar concentrations, most likely due to their accumulation in mitochondria and inhibition of mitochondrial respiration. In summary, the structure motif of bis-pentamethinium salts represents a promising starting point for the design of novel multitargeting compounds with the potential to inhibit IL-6 signaling and simultaneously target mitochondrial metabolism in cancer cells.
- Klíčová slova
- IL-6R synthetic inhibitors, cancer, mitochondria,
- Publikační typ
- časopisecké články MeSH
BACKGROUND/AIM: We have previously shown that the water extract of Agrimonia eupatoria L. (AE) is a valuable source of polyphenols with excellent antioxidant properties and has clinical potential for the prevention and/or adjuvant therapy of cardiovascular complications associated with diabetes. Inspired by our previously published data, in the present study we examined whether AE improves skin wound healing in a series of in vitro and in vivo experiments. MATERIALS AND METHODS: In detail, we investigated the ability of the AE extract to induce fibroblast to myofibroblast conversion, extracellular matrix (ECM) deposition, and keratinocyte proliferation/differentiation, in vitro. In parallel, in an animal model, we measured wound tensile strength (TS) and assessed the progression of open wounds using basic histology and immunofluorescence. RESULTS: The AE extract induced the myofibroblast-like phenotype and enhanced ECM deposition, both in vitro and in vivo. Furthermore, the wound TS of skin incisions and the contraction rates of open excisions were significantly increased in the AE-treated group. CONCLUSION: The present data show that AE water extract significantly improves the healing of open and sutured skin wounds. Therefore, our data warrant further testing in animal models that are physiologically and evolutionarily closer to humans.
- Klíčová slova
- Skin tissue, extracellular matrix, phytotherapy, regeneration, repair,
- MeSH
- Agrimonia * MeSH
- fibroblasty MeSH
- hojení ran MeSH
- keratinocyty MeSH
- krysa rodu Rattus MeSH
- modely nemocí na zvířatech MeSH
- rostlinné extrakty farmakologie MeSH
- voda MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- rostlinné extrakty MeSH
- voda MeSH
The incidence of cutaneous malignant melanoma is increasing worldwide. While the treatment of initial stages of the disease is simple, the advanced disease frequently remains fatal despite novel therapeutic options . This requires identification of novel therapeutic targets in melanoma. Similarly to other types of tumours, the cancer microenvironment plays a prominent role and determines the biological properties of melanoma. Importantly, melanoma cell-produced exosomes represent an important tool of intercellular communication within this cancer ecosystem. We have focused on potential differences in the activity of exosomes produced by melanoma cells towards melanoma-associated fibroblasts and normal dermal fibroblasts. Cancer-associated fibroblasts were activated by the melanoma cell-produced exosomes significantly more than their normal counterparts, as assessed by increased transcription of genes for inflammation-supporting cytokines and chemokines, namely IL-6 or IL-8. We have observed that the response is dependent on the duration of the stimulus via exosomes and also on the quantity of exosomes. Our study demonstrates that melanoma-produced exosomes significantly stimulate the tumour-promoting proinflammatory activity of cancer-associated fibroblasts. This may represent a potential new target of oncologic therapy .
- Klíčová slova
- Cancer-associated fibroblasts, Exosomes, IL-6, IL-8, Melanoma, Proinflammatory cytokine,
- MeSH
- exozómy metabolismus MeSH
- fibroblasty metabolismus patologie MeSH
- lidé MeSH
- melanom experimentální metabolismus patologie MeSH
- nádorové buňky kultivované MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Interleukin-6 (IL-6) is a highly potent cytokine involved in multiple biological processes. It was previously reported to play a distinct role in inflammation, autoimmune and psychiatric disorders, ageing and various types of cancer. Furthermore, it is understood that IL-6 and its signaling pathways are substantial players in orchestrating the cancer microenvironment. Thus, they appear to be potential targets in anti-tumor therapy. The aim of this article is to elucidate the role of IL-6 in the tumor ecosystem and to review the possible therapeutic approaches in head and neck cancer.
- Klíčová slova
- IL-6, cancer microenvironment, head and neck cancer, targeted therapy,
- MeSH
- interleukin-6 imunologie metabolismus MeSH
- lidé MeSH
- nádorové mikroprostředí * MeSH
- nádory hlavy a krku imunologie terapie MeSH
- signální transdukce MeSH
- zánět MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- interleukin-6 MeSH
COVID-19 is a pandemic respiratory disease caused by the SARS-CoV-2 coronavirus. The worldwide epidemiologic data showed higher mortality in males compared to females, suggesting a hypothesis about the protective effect of estrogens against severe disease progression with the ultimate end being patient's death. This article summarizes the current knowledge regarding the potential effect of estrogens and other modulators of estrogen receptors on COVID-19. While estrogen receptor activation shows complex effects on the patient's organism, such as an influence on the cardiovascular/pulmonary/immune system which includes lower production of cytokines responsible for the cytokine storm, the receptor-independent effects directly inhibits viral replication. Furthermore, it inhibits the interaction of IL-6 with its receptor complex. Interestingly, in addition to natural hormones, phytestrogens and even synthetic molecules are able to interact with the estrogen receptor and exhibit some anti-COVID-19 activity. From this point of view, estrogen receptor modulators have the potential to be included in the anti-COVID-19 therapeutic arsenal.
- Klíčová slova
- COVID-19, IL-6, SARS−CoV−2, cytokine storm, estrogen, estrogen receptor, viral replication,
- MeSH
- COVID-19 komplikace patologie virologie MeSH
- internalizace viru účinky léků MeSH
- lidé MeSH
- modulátory estrogenních receptorů metabolismus farmakologie terapeutické užití MeSH
- nádory prsu komplikace farmakoterapie patologie MeSH
- proteiny virové matrix antagonisté a inhibitory metabolismus MeSH
- receptory pro estrogeny chemie metabolismus MeSH
- replikace viru účinky léků MeSH
- SARS-CoV-2 účinky léků izolace a purifikace fyziologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- membrane protein, SARS-CoV-2 MeSH Prohlížeč
- modulátory estrogenních receptorů MeSH
- proteiny virové matrix MeSH
- receptory pro estrogeny MeSH
Excessive connective tissue accumulation, a hallmark of hypertrophic scaring, results in progressive deterioration of the structure and function of organs. It can also be seen during tumor growth and other fibroproliferative disorders. These processes result from a wide spectrum of cross-talks between mesenchymal, epithelial and inflammatory/immune cells that have not yet been fully understood. In the present review, we aimed to describe the molecular features of fibroblasts and their interactions with immune and epithelial cells and extracellular matrix. We also compared different types of fibroblasts and their roles in skin repair and regeneration following burn injury. In summary, here we briefly review molecular changes underlying hypertrophic scarring following burns throughout all basic wound healing stages, i.e. during inflammation, proliferation and maturation.
- Klíčová slova
- burn, cell interaction, pathological scar, skin, stem cell, wound healing,
- MeSH
- epitelové buňky metabolismus patologie MeSH
- extracelulární matrix metabolismus patologie MeSH
- fibroblasty metabolismus patologie MeSH
- hojení ran genetika MeSH
- jizva hypertrofická genetika imunologie patologie MeSH
- lidé MeSH
- popálení genetika patologie MeSH
- proliferace buněk genetika MeSH
- zánět genetika patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Heterogeneous spheroids have recently acquired a prominent position in melanoma research because they incorporate microenvironmental cues relevant for melanoma. In this study, we focused on the analysis of microenvironmental factors introduced in melanoma heterogeneous spheroids by different dermal fibroblasts. We aimed to map the fibroblast diversity resulting from previously acquired damage caused by exposure to extrinsic and intrinsic stimuli. To construct heterogeneous melanoma spheroids, we used normal dermal fibroblasts from the sun-protected skin of a juvenile donor. We compared them to the fibroblasts from the sun-exposed photodamaged skin of an adult donor. Further, we analysed the spheroids by single-cell RNA sequencing. To validate transcriptional data, we also compared the immunohistochemical analysis of heterogeneous spheroids to melanoma biopsies. We have distinguished three functional clusters in primary human fibroblasts from melanoma spheroids. These clusters differed in the expression of (a) extracellular matrix-related genes, (b) pro-inflammatory factors, and (c) TGFβ signalling superfamily. We observed a broader deregulation of gene transcription in previously photodamaged cells. We have confirmed that pro-inflammatory cytokine IL-6 significantly enhances melanoma invasion to the extracellular matrix in our model. This supports the opinion that the aspects of ageing are essential for reliable melanoma 3D modelling in vitro.
- Klíčová slova
- Interleukin-6, cytokine, extracellular matrix, fibroblasts, heterogeneity, melanoma, senescence-associated secretory phenotype, single-cell sequencing, spheroids, subpopulation,
- Publikační typ
- časopisecké články MeSH
Interleukin-6 (IL-6) is a cytokine with multifaceted effects playing a remarkable role in the initiation of the immune response. The increased level of this cytokine in the elderly seems to be associated with the chronic inflammatory setting of the microenvironment in aged individuals. IL-6 also represents one of the main signals in communication between cancer cells and their non-malignant neighbours within the tumour niche. IL-6 also participates in the development of a premetastatic niche and in the adjustment of the metabolism in terminal-stage patients suffering from a malignant disease. IL-6 is a fundamental factor of the cytokine storm in patients with severe COVID-19, where it is responsible for the fatal outcome of the disease. A better understanding of the role of IL-6 under physiological as well as pathological conditions and the preparation of new strategies for the therapeutic control of the IL-6 axis may help to manage the problems associated with the elderly, cancer, and serious viral infections.
- Klíčová slova
- COVID-19, IL-6, ageing, cancer ecosystem, cancer-associated fibroblasts, cytokine, cytokine storm, tumour microenvironment,
- MeSH
- COVID-19 MeSH
- interleukin-6 genetika metabolismus MeSH
- koronavirové infekce metabolismus patologie MeSH
- lidé MeSH
- nádory metabolismus patologie MeSH
- pandemie MeSH
- signální transdukce MeSH
- stárnutí metabolismus patologie MeSH
- virová pneumonie metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- interleukin-6 MeSH
