The Extracellular Matrix in Soft Tissue Sarcomas: Pathobiology and Cellular Signalling

Soft tissue sarcomas are rare cancers of mesenchymal origin or differentiation comprising over 70 different histological subtypes. Due to their mesenchymal differentiation, sarcomas are thought to produce and deposit large quantities of extracellular matrix (ECM) components. Interactions between ECM ligands and their corresponding adhesion receptors such as the integrins and the discoidin domain receptors play key roles in driving many fundamental oncogenic processes including uncontrolled proliferation, cellular invasion and altered metabolism. In this review, we focus on emerging studies that describe the key ECM components commonly found in soft tissue sarcomas and discuss preclinical and clinical evidence outlining the important role that these proteins and their cognate adhesion receptors play in sarcomagenesis. We conclude by providing a perspective on the need for more comprehensive in-depth analyses of both the ECM and adhesion receptor biology in multiple histological subtypes in order to identify new drug targets and prognostic biomarkers for this group of rare diseases of unmet need.

Oral Mesenchymal Stromal Cells in Systemic Sclerosis: Characterization and Response to a Hyaluronic-Acid-Based Biomaterial

Introduction. As oral mesenchymal stromal cells (MSCs) have not, to date, been isolated from systemic sclerosis (SSc) patients, the aim of this in vitro experiment was to characterize gingival MSCs (SScgMSCs) and granulation tissue MSCs (SScgtMSCs) from SSc and to evaluate their functionality in comparison to healthy MSCs (hMSCs), in normal or hyaluronic acid (HA) culture media. Materials and Methods. Isolated cells were described by immunophenotyping of surface antigen make-up and by trilineage mesenchymal differentiation capacity. Colony-Forming Unit-Fibroblast (CFU-F) test and migration potential evaluated MSC functionality. Results. All types of MSCs displayed positivity for the following surface markers: CD29, CD73, CD90, CD105, CD44, and CD79a. These cells did not express CD34, CD45, HL-DR, and CD14. Isolated MSCs differentiated into osteoblasts, adipocytes, and chondroblasts. The frequency of CFU-F for SScgtMSCs was significantly lower than that of hMSCs (p = 0.05) and SScgMSCs (p = 0.004) in normal medium, and also markedly lower than that of SScgMSCs (p = 0.09) in HA medium. Following HA exposure, both SScgMSCs and SScgtMSCs migrated significantly less (p = 0.033 and p = 0.005, respectively) than hMSCs. Conclusions. A reduced functionality of MSCs derived from SSc as compared to hMSCs was observed. HA in culture medium appeared to significantly stimulate the migration potential of hMSCs.

Molecular Tumor Subtypes of HPV-Positive Head and Neck Cancers: Biological Characteristics and Implications for Clinical Outcomes

Until recently, research on the molecular signatures of Human papillomavirus (HPV)-associated head and neck cancers mainly focused on their differences with respect to HPV-negative head and neck squamous cell carcinomas (HNSCCs). However, given the continuing high incidence level of HPV-related HNSCC, the time is ripe to characterize the heterogeneity that exists within these cancers. Here, we review research thus far on HPV-positive HNSCC molecular subtypes, and their relationship with clinical characteristics and HPV integration into the host genome. Different omics data including host transcriptomics and epigenomics, as well as HPV characteristics, can provide complementary viewpoints. Keratinization, mesenchymal differentiation, immune signatures, stromal cells and oxidoreductive processes all play important roles.

Bone Cells Differentiation: How CFTR Mutations May Rule the Game of Stem Cells Commitment?

Cystic fibrosis (CF)-related bone disease has emerged as a significant comorbidity of CF and is characterized by decreased bone formation and increased bone resorption. Both osteoblast and osteoclast differentiations are impacted by cystic fibrosis transmembrane conductance regulator (CFTR) mutations. The defect of CFTR chloride channel or the loss of CFTR’s ability to interact with other proteins affect several signaling pathways involved in stem cell differentiation and the commitment of these cells toward bone lineages. Specifically, TGF-β, nuclear factor-kappa B (NF-κB), PI3K/AKT, and MAPK/ERK signaling are disturbed by CFTR mutations, thus perturbing stem cell differentiation. High inflammation in patients changes myeloid lineage secretion, affecting both myeloid and mesenchymal differentiation. In osteoblast, Wnt signaling is impacted, resulting in consequences for both bone formation and resorption. Finally, CFTR could also have a direct role in osteoclast’s resorptive function. In this review, we summarize the existing literature on the role of CFTR mutations on the commitment of induced pluripotent stem cells to bone cells.

Selective Proliferation of Highly Functional Adipose-Derived Stem Cells in Microgravity Culture with Stirred Microspheres

Therapeutic effects of adult stem-cell transplantations are limited by poor cell-retention in target organs, and a reduced potential for optimal cell differentiation compared to embryonic stem cells. However, contemporary studies have indicated heterogeneity within adult stem-cell pools, and a novel culturing technique may address these limitations by selecting those for cell proliferation which are highly functional. Here, we report the preservation of stemness in human adipose-derived stem cells (hASCs) by using microgravity conditions combined with microspheres in a stirred suspension. The cells were bound to microspheres (100−300 μm) and cultured using a wave-stirring shaker. One-week cultures using polystyrene and collagen microspheres increased the proportions of SSEA-3(+) hASCs 4.4- and 4.3-fold (2.7- and 2.9-fold increases in their numbers), respectively, compared to normal culture conditions. These cultured hASCs expressed higher levels of pluripotent markers (OCT4, SOX2, NANOG, MYC, and KLF), and had improved abilities for proliferation, colony formation, network formation, and multiple-mesenchymal differentiation. We believe that this novel culturing method may further enhance regenerative therapies using hASCs.

Gliosarcoma in patients under 20 years of age. A clinicopathologic study of 11 cases and detailed review of the literature

Background Gliosarcoma is a rare variant of IDH- wild type glioblastoma with both glial and mesenchymal differentiation. It accounts for approximately 2% of glioblastomas and has a poor prognosis similar to that of classic glioblastoma. It is seen mostly between 40 and 60 years of age with a mean age over 50 years. Pediatric gliosarcoma is even rarer than gliosarcoma in adults. We describe the clinicopathological features of gliosarcoma in patients under 20 years of age and determine whether there are significant differences from gliosarcoma in adults. We also present detailed review of published literature on pediatric gliosarcoma. Methods Slides of gliosarcomas in patients under 20 years of age were reviewed. Clinicopathological features were noted in detail and follow up was obtained. Results Eleven cases of gliosarcoma were reported in patients under 20 years of age. Ages ranged from three to 19 years (mean age 13 years). Frontal, parietal and temporal lobes were the commonest locations. Mean and median tumor size was six and five cm respectively. All 11 cases demonstrated the classic biphasic pattern. In 10 cases, glial component was astrocytic and was highlighted on GFAP. Sarcomatous component in most cases resembled fibrosarcoma and was high grade in 72.7%. Glial areas were reticulin poor while sarcomatous areas were reticulin rich. In over 45% cases, bizarre tumor giant cells were seen in the sarcomatous areas. In 1 case, sarcomatous areas showed extensive bone and cartilage formation. Other histologic features included hyalinized blood vessels, hemorrhage, infarction, gemistocytic cells, rhabdoid cells etc. Follow up was available in nine patients, five received chemoradiation post resection while three received radiotherapy only. Prognosis was dismal and eight patients died within one to 14 months following resection. Conclusions Gliosarcomas in patients under 20 comprised 13% of all gliosarcomas reported during the study period. Frequency and mean age were higher compared to other published reports. Pathological features were similar to those described in literature. Clinicopathological features and prognosis of pediatric gliosarcomas were similar to adult gliosarcomas.

Biological characteristics of stem cells derived from burned skin—a comparative study with umbilical cord stem cells

Introduction Burned human skin, which is routinely excised and discarded, contains viable mesenchymal stromal/stem cells (burn-derived mesenchymal stromal/stem cells; BD-MSCs). These cells show promising potential to enable and aid wound regeneration. However, little is known about their cell characteristics and biological function. Objectives This study had two aims: first, to assess critical and cellular characteristics of BD-MSCs and, second, to compare those results with multipotent well-characterized MSCs from Wharton’s jelly of human umbilical cords (umbilical cord mesenchymal stromal/stem cells, UC-MSCs). Methods BD- and UC-MSCs were compared using immunophenotyping, multi-lineage differentiation, seahorse analysis for glycolytic and mitochondrial function, immune surface markers, and cell secretion profile assays. Results When compared to UC-MSCs, BD-MSCs demonstrated a lower mesenchymal differentiation capacity and altered inflammatory cytokine secretomes at baseline and after stimulation with lipopolysaccharides. No significant differences were found in population doubling time, colony formation, cell proliferation cell cycle, production of reactive oxygen species, glycolytic and mitochondrial function, and in the expression of major histocompatibility complex I and II and toll-like receptor (TLR). Importance, translation This study reveals valuable insights about MSCs obtained from burned skin and show comparable cellular characteristics with UC-MSCs, highlighting their potentials in cell therapy and skin regeneration.