Increased expression of both FGF proteins and their receptors observed in many cancers is often associated with the development of chemoresistance, limiting the effectiveness of currently used anti-cancer therapies. Malfunctioning of the FGF/FGFR axis in cancer cells generates a number of molecular mechanisms that may affect the sensitivity of tumors to the applied drugs. Of key importance is the deregulation of cell signaling, which can lead to increased cell proliferation, survival, and motility, and ultimately to malignancy. Signaling pathways activated by FGFRs inhibit apoptosis, reducing the cytotoxic effect of some anti-cancer drugs. FGFRs-dependent signaling may also initiate angiogenesis and EMT, which facilitates metastasis and also correlates with drug resistance. Therefore, treatment strategies based on FGF/FGFR inhibition (using receptor inhibitors, ligand traps, monoclonal antibodies, or microRNAs) appear to be extremely promising. However, this approach may lead to further development of resistance through acquisition of specific mutations, metabolism switching, and molecular cross-talks. This review brings together information on the mechanisms underlying the involvement of the FGF/FGFR axis in the generation of drug resistance in cancer and highlights the need for further research to overcome this serious problem with novel therapeutic strategies.

Neutrophils play a critical role in the first-line of defense against circulating pathogens and contain a wide array of granules that store antimicrobial proteins, with neutrophil serine proteases (NSPs) and defensins serving as crucial components. NSPs such as neutrophil elastase (NE), proteinase 3 (PR3), cathepsin G (CatG) and neutrophil serine protease 4 (NSP4) exhibit distinct substrate specificities that underpin their critical roles in immune defense and inflammation [1]. After neutrophils are activated, they form and release neutrophil extracellular traps (NETs) consisting of decondensed chromatin and intracellular proteins through a process called NETosis, which leads to neutrophil death. Although NETosis is predominantly categorized as a suicidal process, several studies have suggested that neutrophils remain viable after NETosis under certain circumstances. To date, research has focused on the mechanisms underlying NETosis and roles of various factors such as reactive oxygen species (ROS), nicotinamide adenine dinucleotide phosphate (NADPH), myeloperoxidase (MPO), and peptidyl arginine deiminase 4 (PAD4). Metabolic pathways such as glycolysis are critical for NET formation, with exogenous glucose and glutamine enhancing NET release. Neutrophils cultured in glucose-free conditions fail to undergo NETosis upon phorbol-12-myristate-13-acetate (PMA) stimulation. ROS-mediated signaling promotes NE release from the azurosome, F-actin degradation, and NE translocation to the nucleus, facilitating chromatin decondensation. Notably, rapid F-actin disassembly has similarly been observed during NETosis induced by PMA and ionomycin. Recently, the role of NSPs during NET formation and their extracellular functions have received increased attention from researchers. The exact mechanism of NET formation remains unknown, and the process itself still raises controversies regarding its overlapping aspects with other forms of cell death, the role of NSPs, the nature of scaffolding DNA, and the possible involvement of other factors. Here, we discuss the intricate pathways governing NET formation, outline the diverse enzymes and proteins crucial for NET assembly, and highlight potential mechanisms controlling NET release. We pay particular attention to the regulation of NSP proteolytic activity and the nuanced role of NSPs during processes such as degranulation, which can be classified as extracellular mechanisms associated with NET formation. Dysregulated NETosis and NSP activity have been implicated in pathological states and diseases. Therefore, understanding the functions of NSPs and their role in NET formation might facilitate the development of new diagnostic and therapeutic strategies.

Elevated levels of growth factors and phospholipids (PLs) have been found in osteoarthritic synovial fluid (SF), although the metabolic regulation of PLs is currently unknown. This study aimed to determine the effects of growth factors on the biosynthesis of PLs by fibroblast-like synoviocytes (FLS) obtained from human osteoarthritic knee joints. Electrospray ionization tandem mass spectrometry was applied to analyse the newly synthesized PLs. In the presence of stable isotope-labelled PL precursors, cultured FLS were treated with either transforming growth factor-β1 (TGF-β1), bone morphogenetic protein (BMP)-2, BMP-4, BMP-7 or insulin-like growth factor-1 (IGF-1) alone or in combination with specific inhibitors of cell signalling pathways. TGF-β1 and IGF-1 markedly stimulated the biosynthesis of phosphatidylcholine (PC) before sphingomyelin (SM) and lysophosphatidylcholine (LPC) species were stimulated. BMPs elaborated less pronounced effects. The BMPs tested have different potentials to induce the biosynthesis of phosphatidylethanolamine (PE) and PE-based plasmalogens. Our study shows for the first time that TGF-β1 and IGF-1 substantially regulate the biosynthesis of PC, SM and LPC in human FLS. The functional consequences of elevated levels of PLs require additional study. The BMPs tested may be joint protective in that they upregulate PE-based plasmalogens that function as endogenous antioxidants against reactive oxygen species.