Interleukin-17 (IL-17) is a pleiotropic cytokine that plays a primary role in triggering epithelial-mesenchymal transition (EMT) in many chronic inflammatory diseases. EMT plays a critical role in ...the progression of salivary gland (SG) fibrosis in primary Sjögren's syndrome (pSS). This study focused on the activation of the canonical TGF-β1/Smad2/3 and noncanonical TGF-β1/Erk1/2 pathways in IL-17-dependent TGFβ1-induced EMT in human SG epithelial cells (SGEC) derived from healthy subjects. The expression of phosphorylated Smad2/3 and Erk1/2 during IL-17 treatment-stimulated EMT was evaluated in healthy SGEC. Cotreatment with IL-17 and specific TGFβ receptor type I kinase inhibitor SB431542, or Erk 1/2 inhibitor U0126, abrogates the corresponding morphological changes and EMT phenotypic markers expression in healthy SGEC. Interestingly, inhibition of canonical TGFβ1/Smad2/3 signal transduction had no effect on activation of the noncanonical TGFβ1/Erk1/2/EMT pathway, suggesting that the two pathways act independently in activating IL-17-dependent EMT in SGEC.
Gastric cancer (GC) is one of the leading types of cancer worldwide, particularly in East Asian populations. Helicobacter pylori (HP) infection has been established as a major risk factor for GC. ...Although more than 50% of the world population is infected with this bacterium, less than 2% develop GC. Therefore, further risk factors (such as host genetic polymorphisms and lifestyle, as well as environmental and epigenetic factors) may also play a role in its occurrence. The correlation between HP infection and GC represents a typical model of a multi‑step process, characterized by some pre-neoplastic lesions with a high risk of progression (atrophic gastritis, intestinal metaplasia and dysplasia). In addition, HP also plays an oncogenic role in the development of mucosa‑associated lymphoid tissue (MALT) lymphoma, that accounts for approximately 3% of all gastric tumors. Hyperplastic polyps often arise in patients with atrophic gastric mucosa and HP‑associated gastritis (25% of cases); however, their malignant transformation is rare (<3% of cases). A number of trials have demonstrated the possibility of cancer prevention through HP screening and eradication, particularly in high‑risk populations, whereas it may not be cost‑effective in areas of low risk. In this review, we discuss i) the complex pathogenetic mechanisms of gastric carcinogenesis in which HP is involved; ii) the main approaches to the diagnosis, prevention, surveillance and treatment of pre-malignant lesions associated with HP infection; iii) the most effective way to detect GC in its earlier stages; and iv) the most important contribution to reducing the burden of GC.
Angiogenesis plays a pivotal role in tumor progression, particularly in melanoma, the deadliest form of skin cancer. This review synthesizes current knowledge on the intricate interplay between ...angiogenesis and tumor microenvironment (TME) in melanoma progression. Pro-angiogenic factors, including VEGF, PlGF, FGF-2, IL-8, Ang, TGF-β, PDGF, integrins, MMPs, and PAF, modulate angiogenesis and contribute to melanoma metastasis. Additionally, cells within the TME, such as cancer-associated fibroblasts, mast cells, and melanoma-associated macrophages, influence tumor angiogenesis and progression. Anti-angiogenic therapies, while showing promise, face challenges such as drug resistance and tumor-induced activation of alternative angiogenic pathways. Rational combinations of anti-angiogenic agents and immunotherapies are being explored to overcome resistance. Biomarker identification for treatment response remains crucial for personalized therapies. This review highlights the complexity of angiogenesis in melanoma and underscores the need for innovative therapeutic approaches tailored to the dynamic TME.
Transforming growth factor β1 (TGF-β1) plays a crucial role in the induction of fibrosis, often associated with chronic phases of inflammatory diseases contributing to marked fibrotic changes that ...compromise normal organ function. The TGF-β1 signal exerts its biological effects via the TGF-β/SMAD/Snail signaling pathway, playing an important pathogenic role in several fibrotic diseases. It has as yet been poorly investigated in the chronic autoimmune disease Sjögren’s syndrome (SS). Here, we firstly tested, by immunohistochemistry, whether the TGF-β1/SMAD/Snail signaling pathway is triggered in human pSS salivary glands (SGs). Next, healthy salivary gland epithelial cell (SGEC) cultures derived from healthy donors were exposed to TGF-β1 treatment, and the relative gene and protein levels of SMAD2/3/4, Snail, E-cadherin, vimentin, and collagen type I were compared by semiquantitative RT-PCR, quantitative real-time PCR, and Western blot analysis. We observed, both at gene and protein levels, higher expression of SMAD2, 3, and 4 and Snail in the SGEC exposed by TGF-β1 compared to untreated healthy SGEC. Additionally, in TGF-β1-treated samples, we found a significant reduction in the epithelial phenotype marker E-cadherin and an increase in the mesenchymal phenotype markers vimentin and collagen type I compared to those in untreated SGEC, indicating that TGF-β1 induces the EMT via the TGF-β1/SMAD/Snail signaling pathway. Therefore, by using the specific TGF-β receptor 1 inhibitor SB-431542 in healthy SGEC treated with TGF-β1, we showed a significant reduction of the fibrosis markers vimentin and collagen type I while the epithelial marker E-cadherin returns to levels similar to untreated healthy SGEC. These data demonstrate that TGF-β1 is an important key factor in the transition phase from SG chronic inflammation to fibrotic disease. Characteristic changes in the morphology and function of TGF-β1-treated healthy SGEC further confirm that TGF-β1 plays a significant role in EMT-dependent fibrosis.
Non-Hodgkin lymphomas (NHLs) encompass a diverse group of malignancies arising from B cells, T cells, and natural killer (NK) cells at various stages of differentiation. Conversely, classical Hodgkin ...lymphomas (cHLs) primarily feature Reed-Sternberg cells (RSCs) amid a background of reactive immune cells. Immunomodulatory pathways, notably the PD-1/PD-L1 axis, play pivotal roles in tumor immune evasion across both NHLs and cHLs. Elevated expression of PD-1 and PD-L1 is observed in a spectrum of lymphomas, influencing prognosis and treatment response. Therapeutically, immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have revolutionized lymphoma management, particularly in relapsed/refractory cases. Nivolumab and pembrolizumab, among others, have demonstrated efficacy in various B-cell lymphomas, with promising outcomes in cHL. Combination strategies incorporating ICIs with conventional chemotherapy or targeted agents show enhanced efficacy and are being explored extensively. In this review we discuss the most important features of the tumor microenvironment of NHLs and cHLs, address the therapeutic approaches with ICIs and try to outline future perspectives.
Nodular fasciitis (NF) and proliferative fasciitis (PF) are benign, reactive mesenchymal neoplasms that can mimic malignancies due to their rapid growth and histological characteristics. NF typically ...affects the subcutaneous tissue, occasionally involving muscles and fascia, predominantly in young adults, and appears frequently in the upper extremities, trunk, and head/neck. PF, a pseudosarcomatous lesion, primarily occurs in the subcutaneous tissue of adults aged 40-70 years and is uncommon in younger populations. This article presents two pediatric cases of NF and PF in unusual locations: a six-year-old girl with a vulvar NF and a 10-year-old girl with a gluteal PF. Both cases demonstrated rapid growth and distinct histological features, confirmed by immunohistochemical analyses and fluorescence in situ hybridization (FISH). These cases underscore the importance of accurate histological recognition to avoid misdiagnosis and ensure appropriate treatment, highlighting the rarity of such occurrences in children and the need for awareness among clinicians and pathologists.
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL), accounting for about 40% of all cases of NHL. Analysis of the tumor microenvironment is an important aspect of the ...assessment of the progression of DLBCL. In this review article, we analyzed the role of different cellular components of the tumor microenvironment, including mast cells, macrophages, and lymphocytes, in the tumor progression of DLBCL. We examined several approaches to confront the available pieces of evidence, whereby three key points emerged. DLBCL is a disease of malignant B cells spreading and accumulating both at nodal and at extranodal sites. In patients with both nodal and extranodal lesions, the subsequent induction of a cancer-friendly environment appears pivotal. The DLBCL cell interaction with mature stromal cells and vessels confers tumor protection and inhibition of immune response while delivering nutrients and oxygen supply. Single cells may also reside and survive in protected niches in the nodal and extranodal sites as a source for residual disease and relapse. This review aims to molecularly and functionally recapitulate the DLBCL-milieu crosstalk, to relate niche and pathological angiogenic constitution and interaction factors to DLBCL progression.
LIGHT/TNFSF14 Affects Adipose Tissue Phenotype Oranger, Angela; Colaianni, Graziana; Ingravallo, Giuseppe ...
International journal of molecular sciences,
01/2024, Letnik:
25, Številka:
2
Journal Article
Recenzirano
Odprti dostop
LIGHT/TNFSF14 is linked to several signaling pathways as a crucial member of a larger immunoregulatory network. It is primarily expressed in inflammatory effector cells, and high levels of LIGHT have ...been reported in obesity. Thus, with the aim of deepening the knowledge of the role of LIGHT on adipose tissue phenotype, we studied wild-type (WT),
,
and
-/
- (DKO) mice fed a normal diet (ND) or high-fat diet (HFD). Our results show that, although there is no significant weight gain between the mice with different genotypes, it is significant within each of them. We also detected an increase in visceral White Adipose Tissue (vWAT) weight in all mice fed HFD, together with the lowest levels of vWAT weight in
and DKO mice fed ND with respect to the other strain. Inguinal WAT (iWAT) weight is significantly affected by genotype and HFD. The least amount of iWAT was detected in DKO mice fed ND. Histological analysis of vWAT showed that both the genotype and the diet significantly affect the adipocyte area, whereas the number is affected only by the genotype. In iWAT, the genotype and the diet significantly affect mean adipocyte area and number; interestingly, the area with the least adipocyte was detected in DKO mice fed ND, suggesting a potential browning effect due to the simultaneous lack of mature lymphocytes and LIGHT. Consistently, Uncoupling Protein 1 (UCP1) staining of iWAT demonstrated that few positive brown adipocytes appeared in DKO mice. Furthermore, LIGHT deficiency is associated with greater levels of UCP1, highlighting the lack of its expression in
mice. Liver examination showed that all mice fed HFD had a steatotic liver, but it was particularly evident for DKO mice. In conclusion, our study demonstrates that the adipose tissue phenotype is affected by LIGHT levels but also much more by mature lymphocytes.
Glioblastoma multiforme (GBM) is characterized by a remarkable cellular and molecular heterogeneity that make the behavior of this tumor highly variable and resistant to therapy. In addition, the ...most serious clinical complication of GBM and other brain tumors is the development of vasogenic edema which dramatically increase the intracranial pressure. In the present study we evaluate the expression, supramolecular organization and spatial distribution of AQP4 and AQP4ex, the new readthrough isoform of AQP4, in relationship with the degree of vasogenic brain edema and tumor progression. To this purpose, tissue samples from regions of tumor core, peritumoral and non-infiltrated tissues of each GBM patient (
n
= 31) were analyzed. Immunofluorescence experiments revealed that the expression of AQP4ex was almost absent in tumoral regions while the canonical AQP4 isoforms appear mostly delocalized. In peritumoral tissues, AQP4 expression was found altered in those perivascular astrocyte processes where AQP4ex appeared reduced and partially delocalized. Protein expression levels measured by immunoblot showed that global AQP4 was reduced mainly in the tumor core. Notably, the relative amount of AQP4ex was more severely reduced starting from the peritumoral region. BN-PAGE experiments showed that the supramolecular organization of AQP4 is only partially affected in GBM. Edema assessment by magnetic resonance imaging revealed that the level of AQP4ex downregulation correlated with edema severity. Finally, the degree of BBB alteration, measured with sodium fluorescein content in GBM biopsies, correlated with the edema index and AQP4ex downregulation. Altogether these data suggest that the AQP4ex isoform is critical in the triggering event of progressive downregulation and mislocalization of AQP4 in GBM, which may affect the integrity of the BBB and contributes to accumulation of edema in the peritumoral tissue. Thus, AQP4ex could be considered as a potential early biomarker of GBM progression.
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