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.

• Keywords
• Cancer-associated fibroblasts, Ectomesenchyme, Expression pattern, Fibroblasts, Homeobox genes, Mesoderm,
• MeSH
• Adult MeSH
• Fibroblasts * metabolism   cytology   MeSH
• Genes, Homeobox * MeSH
• Homeodomain Proteins * genetics   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Mesoderm * metabolism   cytology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Homeodomain Proteins * MeSH

Gliomagenesis induces profound changes in the composition of the extracellular matrix (ECM) of the brain. In this study, we identified a cellular population responsible for the increased deposition of collagen I and fibronectin in glioblastoma. Elevated levels of the fibrillar proteins collagen I and fibronectin were associated with the expression of fibroblast activation protein (FAP), which is predominantly found in pericyte-like cells in glioblastoma. FAP+ pericyte-like cells were present in regions rich in collagen I and fibronectin in biopsy material and produced substantially more collagen I and fibronectin in vitro compared to other cell types found in the GBM microenvironment. Using mass spectrometry, we demonstrated that 3D matrices produced by FAP+ pericyte-like cells are rich in collagen I and fibronectin and contain several basement membrane proteins. This expression pattern differed markedly from glioma cells. Finally, we have shown that ECM produced by FAP+ pericyte-like cells enhances the migration of glioma cells including glioma stem-like cells, promotes their adhesion, and activates focal adhesion kinase (FAK) signaling. Taken together, our findings establish FAP+ pericyte-like cells as crucial producers of a complex ECM rich in collagen I and fibronectin, facilitating the dissemination of glioma cells through FAK activation.

• Keywords
• collagen type I, extracellular matrix proteins, fibronectin, glioblastoma, pericytes, proteomics,
• MeSH
• Endopeptidases MeSH
• Extracellular Matrix * metabolism   pathology   MeSH
• Fibronectins * metabolism   MeSH
• Glioblastoma pathology   metabolism   MeSH
• Glioma * pathology   metabolism   MeSH
• Collagen Type I metabolism   MeSH
• Humans MeSH
• Membrane Proteins metabolism   MeSH
• Cell Line, Tumor MeSH
• Tumor Microenvironment physiology   MeSH
• Brain Neoplasms * pathology   metabolism   MeSH
• Pericytes * metabolism   pathology   MeSH
• Cell Movement physiology   MeSH
• Serine Endopeptidases metabolism   MeSH
• Gelatinases metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Endopeptidases MeSH
• fibroblast activation protein alpha MeSH Browser
• Fibronectins * MeSH
• Collagen Type I MeSH
• Membrane Proteins MeSH
• Serine Endopeptidases MeSH
• Gelatinases MeSH

Fibroblast activation protein (FAP) is a membrane-bound protease that is upregulated in a wide range of tumours and viewed as a marker of tumour-promoting stroma. Previously, we demonstrated increased FAP expression in glioblastomas and described its localisation in cancer and stromal cells. In this study, we show that FAP+ stromal cells are mostly localised in the vicinity of activated CD105+ endothelial cells and their quantity positively correlates with glioblastoma vascularisation. FAP+ mesenchymal cells derived from human glioblastomas are non-tumorigenic and mostly lack the cytogenetic aberrations characteristic of glioblastomas. Conditioned media from these cells induce angiogenic sprouting and chemotaxis of endothelial cells and promote migration and growth of glioma cells. In a chorioallantoic membrane assay, co-application of FAP+ mesenchymal cells with glioma cells was associated with enhanced abnormal angiogenesis, as evidenced by an increased number of erythrocytes in vessel-like structures and higher occurrence of haemorrhages. FAP+ mesenchymal cells express proangiogenic factors, but in comparison to normal pericytes exhibit decreased levels of antiangiogenic molecules and an increased Angiopoietin 2/1 ratio. Our results show that FAP+ mesenchymal cells promote angiogenesis and glioma cell migration and growth by paracrine communication and in this manner, they may thus contribute to glioblastoma progression.

• Keywords
• angiogenesis, angiopoietin, fibroblast activation protein, glioblastoma, microenvironment, seprase, vessel destabilisation,
• Publication type
• Journal Article MeSH

The proline-specific serine protease fibroblast activation protein (FAP) can participate in the progression of malignant tumors and represents a potential diagnostic and therapeutic target. Recently, we demonstrated an increased expression of FAP in glioblastomas, particularly those of the mesenchymal subtype. Factors controlling FAP expression in glioblastomas are unknown, but evidence suggests that transforming growth factor beta (TGFbeta) can trigger mesenchymal changes in these tumors. Here, we investigated whether TGFbeta promotes FAP expression in transformed and stromal cells constituting the glioblastoma microenvironment. We found that both FAP and TGFbeta-1 are upregulated in glioblastomas and display a significant positive correlation. We detected TGFbeta-1 immunopositivity broadly in glioblastoma tissues, including tumor parenchyma regions in the immediate vicinity of FAP-immunopositive perivascular stromal cells. Wedemonstrate for the first time that TGFbeta-1 induces expression of FAP in non-stem glioma cells, pericytes, and glioblastoma-derived endothelial and FAP+ mesenchymal cells, but not in glioma stem-like cells. In glioma cells, this effect is mediated by the TGFbeta type I receptor and canonical Smad signaling and involves activation of FAP gene transcription. We further present evidence of FAP regulation by TGFbeta-1 secreted by glioma cells. Our results provide insight into the previously unrecognized regulation of FAP expression by autocrine and paracrine TGFbeta-1 signaling in a broad spectrum of cell types present in the glioblastoma microenvironment.

• Keywords
• Smad2, fibroblast activation protein, glioblastoma, regulation of expression, seprase, signaling, transforming growth factor beta, tumor microenvironment,
• MeSH
• Endopeptidases genetics   metabolism   MeSH
• Fluorescent Antibody Technique MeSH
• Phosphorylation MeSH
• Glioblastoma etiology   metabolism   pathology   MeSH
• Immunohistochemistry MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Membrane Proteins genetics   metabolism   MeSH
• Cell Line, Tumor MeSH
• Tumor Microenvironment drug effects   genetics   MeSH
• Gene Expression Regulation, Neoplastic * drug effects   MeSH
• Transforming Growth Factor beta1 metabolism   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Endopeptidases MeSH
• fibroblast activation protein alpha MeSH Browser
• Membrane Proteins MeSH
• TGFB1 protein, human MeSH Browser
• Transforming Growth Factor beta1 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