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

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.

• Keywords
• IL-6, cancer ecosystem, cancer microenvironment, cancer-associated fibroblast, exosome,
• MeSH
• Exosomes metabolism   MeSH
• Cancer-Associated Fibroblasts metabolism   MeSH
• Interleukin-6 metabolism   MeSH
• Humans MeSH
• Tumor Microenvironment MeSH
• Neoplasms metabolism   MeSH
• Paracrine Communication MeSH
• Cell Movement MeSH
• Cell Proliferation MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• IL6 protein, human MeSH Browser
• Interleukin-6 MeSH

BACKGROUND/AIM: Pancreatic ductal adenocarcinoma (PDAC) still represents one of the most aggressive cancers. Understanding of the epithelial-mesenchymal crosstalk as a crucial part of the tumor microenvironment should pave the way for therapies to improve patient survival rates. Well-established cell lines present a useful and reproducible model to study PDAC biology. However, the tumor-stromal interactions between cancer cells and cancer-associated fibroblasts (CAFs) are still poorly understood. MATERIALS AND METHODS: We studied interactions between four PDAC cell lines (Panc-1, CAPAN-2, MIAPaCa-2, and PaTu-8902) and conditioned media derived from primary cultures of normal fibroblasts/PDAC-derived CAFs (PANFs). RESULTS: When the tested PDAC cell lines were stimulated by PANF-derived conditioned media, the most aggressive behavior was acquired by the Panc-1 cell line (increased number and size of colonies, remaining expression of vimentin and keratin 8 as well as increase of epithelial-to-mesenchymal polarization markers), whereas PaTu-8902 cells were rather inhibited. Of note, administration of the conditioned media to MIAPaCa-2 cells resulted in an inverse effect on the size and number of colonies, whereas CAPAN-2 cells were rather stimulated. To explain the heterogeneous pattern of the observed PDAC crosstalk at the in vitro level, we further compared the phenotype of primary cultures of cells derived from ascitic fluid with that of the tested PDAC cell lines, analyzed tumor samples of PDAC patients, and performed gene expression profiling of PANFs. Immuno-cyto/histo-chemical analysis found specific phenotype differences within the group of examined patients and tested PDAC cell lines, whereas the genomic approach in PANFs found the key molecules (IL6, IL8, MFGE8 and periostin) that may contribute to the cancer aggressive behavior. CONCLUSION: The desmoplastic patient-specific regulation of cancer cells by CAFs (also demonstrated by the heterogeneous response of PDAC cell lines to fibroblasts) precludes simple targeting and development of an effective treatment strategy and rather requires establishment of an individualized tumor-specific treatment protocol.

• Keywords
• Epithelial–mesenchymal interaction, cancer stem cell, pancreas, tumor micro - environment, tumor stroma,
• MeSH
• Carcinoma, Pancreatic Ductal metabolism   pathology   MeSH
• Epithelial-Mesenchymal Transition MeSH
• Cancer-Associated Fibroblasts metabolism   pathology   MeSH
• Fibroblasts metabolism   pathology   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Tumor Microenvironment MeSH
• Pancreatic Neoplasms metabolism   pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article 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.

• Keywords
• COVID-19, IL-6, ageing, cancer ecosystem, cancer-associated fibroblasts, cytokine, cytokine storm, tumour microenvironment,
• MeSH
• COVID-19 MeSH
• Interleukin-6 genetics   metabolism   MeSH
• Coronavirus Infections metabolism   pathology   MeSH
• Humans MeSH
• Neoplasms metabolism   pathology   MeSH
• Pandemics MeSH
• Signal Transduction MeSH
• Aging metabolism   pathology   MeSH
• Pneumonia, Viral metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Interleukin-6 MeSH

The incidence of cutaneous malignant melanoma has been steadily increasing worldwide for several decades. This phenomenon seems to follow the trend observed in many types of malignancies caused by multiple significant factors, including ageing. Despite the progress in cutaneous malignant melanoma therapeutic options, the curability of advanced disease after metastasis represents a serious challenge for further research. In this review, we summarise data on the microenvironment of cutaneous malignant melanoma with emphasis on intercellular signalling during the disease progression. Malignant melanocytes with features of neural crest stem cells interact with non‑malignant populations within this microenvironment. We focus on representative bioactive factors regulating this intercellular crosstalk. We describe the possible key factors and signalling cascades responsible for the high complexity of the melanoma microenvironment and its premetastatic niches. Furthermore, we present the concept of melanoma early becoming a systemic disease. This systemic effect is presented as a background for the new horizons in the therapy of cutaneous melanoma.

• Keywords
• melanoma, cancer microenvironment, cancer-associated fibroblast, cytokine, chemokine, growth factor,
• MeSH
• Skin cytology   pathology   MeSH
• Humans MeSH
• Melanocytes pathology   MeSH
• Melanoma secondary   MeSH
• Cell Communication * MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Tumor Microenvironment * MeSH
• Skin Neoplasms pathology   MeSH
• Brain Neoplasms secondary   MeSH
• Lung Neoplasms secondary   MeSH
• Disease Progression MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Similarly to other types of malignant tumours, the incidence of head and neck cancer is increasing globally. It is frequently associated with smoking and alcohol abuse, and in a broader sense also with prolonged exposure to these factors during ageing. A higher incidence of tumours observed in younger populations without a history of alcohol and tobacco abuse may be due to HPV infection. Malignant tumours form an intricate ecosystem of cancer cells, fibroblasts, blood/lymphatic capillaries and infiltrating immune cells. This dynamic system, the tumour microenvironment, has a significant impact on the biological properties of cancer cells. The microenvironment participates in the control of local aggressiveness of cancer cells, their growth, and their consequent migration to lymph nodes and distant organs during metastatic spread. In cancers originating from squamous epithelium, a similarity was demonstrated between the cancer microenvironment and healing wounds. In this review, we focus on the specificity of the microenvironment of head and neck cancer with emphasis on the mechanism of intercellular crosstalk manipulation for potential therapeutic application.

• Keywords
• IL-6, cancer, cancer ecosystem, cancer microenvironment, cancer therapy, cancer-associated fibroblast, cytokine, extracellular matrix, tumour-associated macrophages,
• Publication type
• Journal Article MeSH
• Review 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

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.

• Keywords
• cancer microenvironment, cancer-associated fibroblast, niche, stem cell, wound healing,
• MeSH
• Epidermal Cells MeSH
• Epithelial Cells pathology   MeSH
• Fibroblasts pathology   MeSH
• Wound Healing physiology   MeSH
• Keratinocytes pathology   MeSH
• Humans MeSH
• Melanoma pathology   MeSH
• Mesenchymal Stem Cells pathology   MeSH
• Neoplastic Stem Cells pathology   MeSH
• Tumor Microenvironment physiology   MeSH
• Skin Neoplasms pathology   MeSH
• Stem Cell Niche physiology   MeSH
• Hair Follicle cytology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH