Cancer-associated fibroblasts (CAFs) are an essential component of the tumour microenvironment. They represent a heterogeneous group of cells that are under the control of cancer cells and can reversely influence the cancer cell population. They affect the cancer cell differentiation status, and the migration and formation of metastases. This is achieved through the production of the extracellular matrix and numerous bioactive factors. IL-6 seems to play the central role in the communication of noncancerous and cancer cells in the tumour. This review outlines the role of exosomes in cancer cells and cancer-associated fibroblasts. Available data on the exosomal cargo, which can significantly intensify interactions in the tumour, are summarised. The role of exosomes as mediators of the dialogue between cancer cells and cancer-associated fibroblasts is discussed together with their therapeutic relevance. The functional unity of the paracrine- and exosome-mediated communication of cancer cells with the tumour microenvironment represented by CAFs is worthy of attention.

• Klíčová slova
• IL-6, cancer ecosystem, cancer microenvironment, cancer-associated fibroblast, exosome,
• MeSH
• exozómy metabolismus   MeSH
• fibroblasty asociované s nádorem metabolismus   MeSH
• interleukin-6 metabolismus   MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• nádory metabolismus   MeSH
• parakrinní signalizace MeSH
• pohyb buněk MeSH
• proliferace buněk MeSH
• regulace genové exprese u nádorů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• IL6 protein, human MeSH Prohlížeč
• interleukin-6 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

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

The steadily increasing incidence of malignant melanoma (MM) and its aggressive behaviour makes this tumour an attractive cancer research topic. The tumour microenvironment is being increasingly recognised as a key factor in cancer biology, with an impact on proliferation, invasion, angiogenesis and metastatic spread, as well as acquired therapy resistance. Multiple bioactive molecules playing cooperative roles promote the chronic inflammatory milieu in tumours, making inflammation a hallmark of cancer. This specific inflammatory setting is evident in the affected tissue. However, certain mediators can leak into the systemic circulation and affect the whole organism. The present study analysed the complex inflammatory response in the sera of patients with MM of various stages. Multiplexed proteomic analysis (Luminex Corporation) of 31 serum proteins was employed. These targets were observed in immunohistochemical profiles of primary tumours from the same patients. Furthermore, these proteins were analysed in MM cell lines and the principal cell population of the melanoma microenvironment, cancer‑associated fibroblasts. Growth factors such as hepatocyte growth factor, granulocyte‑colony stimulating factor and vascular endothelial growth factor, chemokines RANTES and interleukin (IL)‑8, and cytokines IL‑6, interferon‑α and IL‑1 receptor antagonist significantly differed in these patients compared with the healthy controls. Taken together, the results presented here depict the inflammatory landscape that is altered in melanoma patients, and highlight potentially relevant targets for therapy improvement.

• MeSH
• chemokiny krev   MeSH
• dospělí MeSH
• fibroblasty asociované s nádorem metabolismus   MeSH
• krevní proteiny analýza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• melanom krev   metabolismus   MeSH
• nádorové biomarkery krev   MeSH
• nádorové buněčné linie MeSH
• pilotní projekty MeSH
• prognóza MeSH
• proteomika metody   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• chemokiny MeSH
• krevní proteiny MeSH
• nádorové biomarkery MeSH

The incidence of malignant melanoma is rapidly increasing and current medicine is offering only limited options for treatment of the advanced disease. For B‑Raf mutated melanomas, treatment with mutation‑specific drug inhibitors may be used. Unfortunately, tumors frequently acquire resistance to the treatment. Tumor microenvironment, namely cancer‑associated fibroblasts, largely influence this acquired resistance. In the present study, fibroblasts were isolated from a patient suffering from acrolentiginous melanoma (Breslow, 4.0 mm; Clark, IV; B‑Raf V600E mutated). The present study focused on the expression of structural and functional markers of fibroblast activation in melanoma‑associated fibroblasts (MAFs; isolated prior to therapy initiation) as well as in autologous control fibroblasts (ACFs) of the same patient isolated during B‑Raf inhibitor therapy, yet before clinical progression of the disease. Analysis of gene transcription was also performed, as well as DNA methylation status analysis at the genomic scale of both isolates. MAFs were positive for smooth muscle actin (SMA), which is a marker of myofibroblasts and the hallmark of cancer stoma. Surprisingly, ACF isolated from the distant uninvolved skin of the same patient also exhibited strong SMA expression. A similar phenotype was also observed in control dermal fibroblasts (CDFs; from different donors) exclusively following stimulation by transforming growth factor (TGF)‑β1. Immunohistochemistry confirmed that melanoma cells potently produce TGF‑β1. Significant differences were also identified in gene transcription and in DNA methylation status at the genomic scale. Upregulation of SMA was observed in ACF cells at the protein and transcriptional levels. The present results support recent experimental findings that tumor microenvironment is driving resistance to B‑Raf inhibition in patients with melanoma. Such an activated microenvironment may be viable for the growth of circulating melanoma cells.

• MeSH
• bodová mutace MeSH
• chemorezistence * MeSH
• fibroblasty asociované s nádorem účinky léků   metabolismus   patologie   MeSH
• lidé MeSH
• maligní melanom kůže MeSH
• melanom farmakoterapie   genetika   patologie   MeSH
• metylace DNA MeSH
• nádorové buňky kultivované MeSH
• nádorové mikroprostředí * MeSH
• nádory kůže farmakoterapie   genetika   patologie   MeSH
• protoonkogenní proteiny B-Raf antagonisté a inhibitory   genetika   MeSH
• senioři MeSH
• transkriptom MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• protoonkogenní proteiny B-Raf MeSH

Clinical evidence suggests that healing is faster and almost scarless at an early neonatal age in comparison with that in adults. In this study, the phenotypes of neonatal and adult dermal fibroblasts and keratinocytes (nestin, smooth muscle actin, keratin types 8, 14 and 19, and fibronectin) were compared. Furthermore, functional assays (proliferation, migration, scratch wound closure) including mutual epithelial‑mesenchymal interactions were also performed to complete the series of experiments. Positivity for nestin and α smooth muscle actin was higher in neonatal fibroblasts (NFs) when compared with their adult counterparts (adult fibroblasts; AFs). Although the proliferation of NFs and AFs was similar, they significantly differed in their migration potential. The keratinocyte experiments revealed small, poorly differentiated cells (positive for keratins 8, 14 and 19) in primary cultures isolated from neonatal tissues. Moreover, the neonatal keratinocytes exhibited significantly faster rates of healing the experimentally induced in vitro defects in comparison with adult cells. Notably, the epithelial/mesenchymal interaction studies showed that NFs in co-culture with adult keratinocytes significantly stimulated the adult epithelial cells to acquire the phenotype of small, non-confluent cells expressing markers of poor differentiation. These results indicate the important differences between neonatal and adult cells that may be associated with improved wound healing during the early neonatal period.

• MeSH
• aktiny metabolismus   MeSH
• buněčná diferenciace MeSH
• crista neuralis cytologie   MeSH
• dárci tkání * MeSH
• dospělí MeSH
• epitelové buňky cytologie   metabolismus   MeSH
• fenotyp MeSH
• fibroblasty cytologie   metabolismus   MeSH
• fibronektiny biosyntéza   MeSH
• imunohistochemie MeSH
• keratinocyty cytologie   metabolismus   MeSH
• kmenové buňky metabolismus   MeSH
• kokultivační techniky MeSH
• lidé MeSH
• mezoderm cytologie   MeSH
• myofibroblasty cytologie   MeSH
• nestin metabolismus   MeSH
• neuroplasticita MeSH
• novorozenec MeSH
• pohyb buněk MeSH
• proliferace buněk MeSH
• stanovení celkové genové exprese MeSH
• stárnutí fyziologie   MeSH
• vývojová regulace genové exprese MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ACTA2 protein, human MeSH Prohlížeč
• aktiny MeSH
• fibronektiny MeSH
• nestin MeSH

Epidermal stem cells (ESCs) are crucial for maintenance and self- renewal of skin epithelium and also for regular hair cycling. Their role in wound healing is also indispensable. ESCs reside in a defined outer root sheath portion of hair follicle-also known as the bulge region. ECS are also found between basal cells of the interfollicular epidermis or mucous membranes. The non-epithelial elements such as mesenchymal stem cell-like elements of dermis or surrounding adipose tissue can also contribute to this niche formation. Cancer stem cells (CSCs) participate in formation of common epithelial malignant diseases such as basal cell or squamous cell carcinoma. In this review article, we focus on the role of cancer microenvironment with emphasis on the effect of cancer-associated fibroblasts (CAFs). This model reflects various biological aspects of interaction between cancer cell and CAFs with multiple parallels to interaction of normal epidermal stem cells and their niche. The complexity of intercellular interactions within tumor stroma is depicted on example of malignant melanoma, where keratinocytes also contribute the microenvironmental landscape during early phase of tumor progression. Interactions seen in normal bulge region can therefore be an important source of information for proper understanding to melanoma. The therapeutic consequences of targeting of microenvironment in anticancer therapy and for improved wound healing are included to article.

• Klíčová slova
• cancer microenvironment, cancer-associated fibroblast, niche, stem cell, wound healing,
• MeSH
• epidermální buňky MeSH
• epitelové buňky patologie   MeSH
• fibroblasty patologie   MeSH
• hojení ran fyziologie   MeSH
• keratinocyty patologie   MeSH
• lidé MeSH
• melanom patologie   MeSH
• mezenchymální kmenové buňky patologie   MeSH
• nádorové kmenové buňky patologie   MeSH
• nádorové mikroprostředí fyziologie   MeSH
• nádory kůže patologie   MeSH
• nika kmenových buněk fyziologie   MeSH
• vlasový folikul cytologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Malignant melanoma is a highly aggressive tumor with increasing incidence and high mortality. The importance of immunohistochemistry in diagnosis of the primary tumor and in early identification of metastases in lymphatic nodes is enormous; however melanoma phenotype is frequently variable and thus several markers must be employed simultaneously. The purposes of this study are to describe changes of phenotype of malignant melanoma in vitro and in vivo and to investigate whether changes of environmental factors mimicking natural conditions affect the phenotype of melanoma cells and can revert the typical in vitro loss of diagnostic markers. The influence of microenvironment was studied by means of immunocytochemistry on co-cultures of melanoma cells with melanoma-associated fibroblast and/or in conditioned media. The markers typical for melanoma (HMB45, Melan-A, Tyrosinase) were lost in malignant cells isolated from malignant effusion; however, tumor metastases shared identical phenotype with primary tumor (all markers positive). The melanoma cell lines also exerted reduced phenotype in vitro. The only constantly present diagnostic marker observed in our experiment was S100 protein and, in lesser extent, also Nestin. The phenotype loss was reverted under the influence of melanoma-associated fibroblast and/or both types of conditioned media. Loss of some markers of melanoma cell phenotype is not only of diagnostic significance, but it can presumably also contribute to biological behavior of melanoma. The presented study shows how the conditions of cultivation of melanoma cells can influence their phenotype. This observation can have some impact on considerations about the role of microenvironment in tumor biology.

• MeSH
• biologické modely MeSH
• buněčné kultury MeSH
• fibroblasty cytologie   účinky léků   metabolismus   MeSH
• imunofenotypizace MeSH
• imunohistochemie MeSH
• kokultivační techniky MeSH
• kultivační média speciální farmakologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• MART-1 antigen metabolismus   MeSH
• melanom metabolismus   patologie   MeSH
• melanomové antigeny metabolismus   MeSH
• melanomový antigen gp100 MeSH
• nádorové biomarkery metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádorové buňky kultivované MeSH
• nádorové mikroprostředí účinky léků   MeSH
• nádory kůže metabolismus   patologie   MeSH
• nestin metabolismus   MeSH
• proteiny S100 metabolismus   MeSH
• tyrosinasa metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kultivační média speciální MeSH
• MART-1 antigen MeSH
• melanomové antigeny MeSH
• melanomový antigen gp100 MeSH
• nádorové biomarkery MeSH
• nestin MeSH
• PMEL protein, human MeSH Prohlížeč
• proteiny S100 MeSH
• tyrosinasa MeSH

It is widely recognized that stromal fibroblasts significantly influence biological properties of multiple tumors including breast cancer. However, these epithelial-mesenchymal interactions seem to be essential in tumor biology and it is not fully clear whether this interaction is tumor type-specific or has a more general non-specific character. To elucidate this question, we tested the effect of cancer-associated fibroblasts (CAFs) isolated from different types of tumors (breast cancer skin metastasis, cutaneous basal cell carcinoma and melanoma, squamous cell carcinoma arising from oral cavity mucous membrane) on the EM-G3 breast cancer cell line. The results were compared with control experiments using normal human dermal fibroblasts, 3T3 mouse fibroblasts, and 3T3 fibroblasts influenced by the fibroblasts prepared from the basal cell carcinoma. Our results demonstrated that expression of luminal marker keratin 8 was influenced only by CAFs prepared from any tested tumors. In contrast, all tested types of fibroblasts showed a strong stimulatory effect on the expression of basal/myoepithelial marker keratin 14. The CAFs also elevated the number of cells with positivity for both keratins 8 and 14 that are similar to ductal originated precursor cells. The expression of proliferation marker Ki67 was not influenced by any of the tested fibroblasts. In conclusion, our data indicate that CAFs are able to influence the phenotype of a breast cancer cell line and this effect is based on a tumor type-unspecific mechanism. Finally, a clear functional difference between normal and CAFs was demonstrated.

• MeSH
• bazocelulární karcinom metabolismus   patologie   MeSH
• buňky 3T3 MeSH
• fibroblasty metabolismus   MeSH
• keratin-8 metabolismus   MeSH
• kokultivační techniky MeSH
• lidé MeSH
• melanom metabolismus   patologie   MeSH
• myši MeSH
• nádorové biomarkery metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory kůže metabolismus   patologie   sekundární   MeSH
• nádory prsu metabolismus   patologie   MeSH
• spinocelulární karcinom metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• keratin-8 MeSH
• KRT8 protein, human MeSH Prohlížeč
• nádorové biomarkery MeSH