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.

• Keywords
• breast cancer, cell differentiation, epithelial‑mesenchymal interaction, neutralizing antibody, tumor microenvironment,
• MeSH
• Antigens, Surface MeSH
• Cancer-Associated Fibroblasts * metabolism   MeSH
• Fibroblasts metabolism   MeSH
• Keratins genetics   metabolism   MeSH
• Humans MeSH
• Melanoma, Cutaneous Malignant MeSH
• MCF-7 Cells MeSH
• Milk Proteins genetics   metabolism   MeSH
• Cell Line, Tumor MeSH
• Tumor Microenvironment genetics   MeSH
• Breast Neoplasms * drug therapy   genetics   metabolism   MeSH
• Prognosis MeSH
• Transcriptome MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antigens, Surface MeSH
• Keratins MeSH
• MFGE8 protein, human MeSH Browser
• Milk Proteins 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

Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inhibition of the TET1 protein (ten-eleven translocation methylcytosine dioxygenase 1) by specific iron chelators. Therefore, in the present work, we prepared a series of pyrrolopyrrole derivatives with hydrazide (1) or hydrazone (2-6) iron-binding groups. As a result, we determined that the basic pyrrolo[3,2-b]pyrrole derivative 1 was a strong inhibitor of the TET1 protein (IC50 = 1.33 μM), supported by microscale thermophoresis and molecular docking. Pyrrolo[3,2-b]pyrroles 2-6, bearing substituted 2-hydroxybenzylidene moieties, displayed no significant inhibitory activity. In addition, in vitro studies demonstrated that derivative 1 exhibits potent anticancer activity and an exclusive mitochondrial localization, confirmed by Pearson's correlation coefficient of 0.92.

• Keywords
• TET1 protein inhibitor, hydrazone, mitochondria, pyrrolo[3,2-b]pyrrole,
• MeSH
• Iron Chelating Agents MeSH
• Dioxygenases * metabolism   MeSH
• DNA MeSH
• Hydrazones chemistry   MeSH
• Mitochondrial Proteins MeSH
• Pyrroles * chemistry   pharmacology   MeSH
• Molecular Docking Simulation MeSH
• Iron MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Iron Chelating Agents MeSH
• Dioxygenases * MeSH
• DNA MeSH
• Hydrazones MeSH
• Mitochondrial Proteins MeSH
• Pyrroles * MeSH
• Iron 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 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.

• Keywords
• IL-6, cancer microenvironment, head and neck cancer, targeted therapy,
• MeSH
• Interleukin-6 immunology   metabolism   MeSH
• Humans MeSH
• Tumor Microenvironment * MeSH
• Head and Neck Neoplasms immunology   therapy   MeSH
• Signal Transduction MeSH
• Inflammation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Interleukin-6 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

Aberrant regulation of the cell cycle is a typical feature of all forms of cancer. In head and neck squamous cell carcinoma (HNSCC), it is often associated with the overexpression of cyclin D1 (CCND1). However, it remains unclear how CCND1 expression changes between tumor and normal tissues and whether human papillomavirus (HPV) affects differential CCND1 expression. Here, we evaluated the expression of D-type cyclins in a cohort of 94 HNSCC patients of which 82 were subjected to whole genome expression profiling of primary tumors and paired normal mucosa. Comparative analysis of paired samples showed that CCND1 was upregulated in 18% of HNSCC tumors. Counterintuitively, CCND1 was downregulated in 23% of carcinomas, more frequently in HPV-positive samples. There was no correlation between the change in D-type cyclin expression and patient survival. Intriguingly, among the tumors with downregulated CCND1, one-third showed an increase in cyclin D2 (CCND2) expression. On the other hand, one-third of tumors with upregulated CCND1 showed a decrease in CCND2. Collectively, we have shown that CCND1 was frequently downregulated in HNSCC tumors. Furthermore, regardless of the HPV status, our data suggested that a change in CCND1 expression was alleviated by a compensatory change in CCND2 expression.

• Keywords
• 11q13 amplification, CCND1, CCND2, CCND3, D-type cyclins, cell cycle, head and neck squamous cell carcinoma, human papillomavirus, paired tumor-normal samples, patient survival,
• Publication type
• Journal Article 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