transforming-growth-factor-beta and Lymphoma--Follicular

Distinguishing gastrointestinal involvement in classic follicular lymphoma (CFL) and duodenal-type follicular lymphoma (DFL) is crucial for proper treatment. This study aimed to describe an integrated diagnostic re-classification of gastrointestinal follicular lymphoma (GIFL) and identify useful features for its differential diagnosis.. We reviewed radiological and endoscopic images and pathology slides of 22 GIFL cases, not otherwise specified.. Thirteen cases of duodenal grade 1 FL without nodal disease were re-classified as DFL. Five cases of non-duodenal grade 3 FL accompanied by nodal enlargement were re-classified as CFL. The DFL showed peripherally accentuated CD21 immunoreactivity, whereas the CFL showed strong homogeneous CD21 expression. Four atypical cases were re-classified as DFL and CFL in one and three cases, respectively.. Our findings support the notion that DFL differs from CFL. In cases of GIFL with atypical features, the possibility of gastrointestinal involvement by CFL should be considered. CD21 expression patterns can assist in the differential diagnosis of CFL and DFL.

Topics: Diagnosis, Differential; Duodenum; Gastrointestinal Neoplasms; Humans; Lymphoma, Follicular; Transforming Growth Factor beta

Follicular lymphoma (FL) is the most common low-grade lymphoma, and although nodal FL is highly responsive to treatment, the majority of patients relapse repeatedly, and the disease has been incurable with a poor prognosis. However, primary FL of the gastrointestinal tract has been increasingly detected in Japan, especially due to recent advances in small bowel endoscopy and increased opportunities for endoscopic examinations and endoscopic diagnosis. However, many cases are detected at an early stage, and the prognosis is good in many cases. In contrast, in Europe and the United States, gastrointestinal FL has long been considered to be present in 12%-24% of Stage-IV patients, and the number of advanced gastrointestinal cases is expected to increase. This editorial provides an overview of the recent therapeutic advances in nodal FL, including antibody-targeted therapy, bispecific antibody therapy, epigenetic modulation, and chimeric antigen receptor T-cell therapy, and reviews the latest therapeutic manuscripts published in the past year. Based on an understanding of the therapeutic advances in nodal FL, we also discuss future possibilities for gastroenterologists to treat gastrointestinal FL, especially in advanced cases.

Topics: Gastrointestinal Neoplasms; Humans; Lymphoma, Follicular; Neoplasm Recurrence, Local; Prognosis; Transforming Growth Factor beta

CXCR5 mediates homing of both B and follicular helper T (T

Topics: Adoptive Transfer; Animals; B-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Differentiation; Coculture Techniques; Female; Germinal Center; Humans; Leukocytes, Mononuclear; Lymphocyte Activation; Lymphoma, Follicular; Male; Mice; Mice, Knockout; Mice, Transgenic; Palatine Tonsil; Receptors, Antigen, T-Cell; Receptors, CXCR5; T-Lymphocyte Subsets; Transcription, Genetic; Transforming Growth Factor beta

FOX genes encode transcription factors which regulate basic developmental processes during embryogenesis and in the adult. Several FOX genes show deregulated expression in particular malignancies, representing oncogenes or tumor suppressors. Here, we screened six Hodgkin lymphoma (HL) cell lines for FOX gene activity by comparative microarray profiling, revealing overexpression of FOXC1 and FOXD1, and reduced transcription of FOXN3, FOXO1, and FOXP1. In silico expression analyses of these FOX gene candidates in HL patient samples supported the cell line data. Chromosomal analyses demonstrated an amplification of the FOXC1 locus at 6p25 and a gain of the FOXR2 locus at Xp11, indicting genomic aberrations for their upregulation. Comparative expression profiling and ensuing stimulation experiments revealed implementation of the TGFβ- and WNT-signaling pathways in deregulation of FOXD1 and FOXN3. Functional analysis of FOXP1 implicated miR9 and miR34a as upstream regulators and PAX5, TCF3, and RAG2 as downstream targets. A similar exercise for FOXC1 revealed repression of MSX1 and activation of IPO7, both mediating inhibition of the B-cell specific homeobox gene ZHX2. Taken together, our data show that aberrantly expressed FOX genes and their downstream targets are involved in the pathogenesis of HL via deregulation of B-cell differentiation and may represent useful diagnostic markers and/or therapeutic targets.

Topics: Burkitt Lymphoma; Cell Line, Tumor; Chromosomes, Human; Forkhead Transcription Factors; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genetic Loci; Hodgkin Disease; Homeodomain Proteins; Humans; Karyopherins; Lymphoma, B-Cell; Lymphoma, Follicular; MicroRNAs; MSX1 Transcription Factor; Receptors, Cytoplasmic and Nuclear; Transcription Factors; Transforming Growth Factor beta; Wnt Signaling Pathway

The prognosis of follicular lymphoma could vary with the tumor immune microenvironment. We evaluated the prognostic value of serum levels of ten cytokines. Our study cohort included 60 follicular lymphoma patients and 20 controls. Serum was available at diagnosis in 31 patients, at first relapse in 18, and complete remission in 11. Bioplex technology was used for determination of nine cytokines [interleukin (IL)-1Ra, IL-6, IL-7, IL-10, IL-13, tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (b-FGF)]. Transforming growth factor beta (TGF-β) was measured by sandwich enzyme-linked immunosorbent assay. IL-1Ra, IL-6, IL-7, IL-10, IL-13, TNF-α, VEGF, and PDGF levels were found increased in follicular lymphoma patients compared to controls. Multivariate analysis identified early stage and high TGF-β levels as independent predictors of overall survival associated with improved outcome. High lactate dehydrogenase and VEGF levels were independently associated with poorer progression-free survival. These results show the prognostic value of TGF-β and VEGF in follicular lymphoma and suggest their contribution to tumor microenvironment alterations.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Disease Progression; Female; Humans; Lymphoma, Follicular; Male; Middle Aged; Prospective Studies; Survival Rate; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Regulatory T cells (T(R)) play a critical role in the inhibition of self-reactive immune responses and as such have been implicated in the suppression of tumor-reactive effector T cells. In this study, we demonstrate that follicular lymphoma (FL)-infiltrating CD8+ and CD4+ T cells are hyporesponsive to CD3/CD28 costimulation. We further identify a population of FL-infiltrating CD4+CD25+GITR+ T(R) that are significantly overrepresented within FL nodes (FLN) compared with that seen in normal (nonmalignant, nonlymphoid hyperplastic) or reactive (nonmalignant, lymphoid hyperplastic) nodes. These T(R) actively suppress both the proliferation of autologous nodal CD8+CD25- and CD4+CD25- T cells, as well as cytokine production (IFN-gamma, TNF-alpha and IL-2), after CD3/CD28 costimulation. Removal of these cells in vitro by CD25+ magnetic bead depletion restores both the proliferation and cytokine production of the remaining T cells, demonstrating that FLN T cell hyporesponsiveness is reversible. In addition to suppressing autologous nodal T cells, these T(R) are also capable of suppressing the proliferation of allogeneic CD8+CD25- and CD4+CD25- T cells from normal lymph nodes as well as normal donor PBL, regardless of very robust stimulation of the target cells with plate-bound anti-CD3 and anti-CD28 Abs. The allogeneic suppression is not reciprocal, as equivalent numbers of CD25+FOXP3+ cells derived from either normal lymph nodes or PBL are not capable of suppressing allogeneic CD8+CD25- and CD4+CD25- T cells, suggesting that FLN T(R) are more suppressive than those derived from nonmalignant sources. Lastly, we demonstrate that inhibition of TGF-beta signaling partially restores FLN T cell proliferation suggesting a mechanistic role for TGF-beta in FLN T(R)-mediated suppression.

Topics: CD28 Antigens; CD3 Complex; CD4 Antigens; Cell Separation; Cytokines; Glucocorticoid-Induced TNFR-Related Protein; Humans; Immune Tolerance; Immunosuppression Therapy; Interleukin-2 Receptor alpha Subunit; Lymph Nodes; Lymphocytes, Tumor-Infiltrating; Lymphoma, Follicular; Receptors, Antigen, T-Cell; Receptors, Nerve Growth Factor; Receptors, Tumor Necrosis Factor; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

We have previously reported an overexpression of Smad1 in follicular lymphoma (FL) cells, which are characterized by the t(14;18) bcl2/IgH translocation. Smad1 is commonly involved in bone morphogenetic protein but not in tumor-transforming growth factor beta (TGFbeta) signaling pathways. This study focuses on Smad1 signaling pathway in non-Hodgkin lymphoma cells including follicular or large-cell lymphoma cells. Our results support the notion that phosphorylation of Smad1 is mediated by TGFbeta present in the microenvironment and occurs in FL in vivo. Using an in vitro coculture system mimicking interactions between stroma cells and FL cells, we found that both the cell partners release TGFbeta at a sufficient concentration to activate Smad pathways in the malignant cells. This Smad1 activation involves TGFbetaRII but not ALK-1 receptors, and does not compete with the Smad2 pathway. Moreover, proliferation assays performed on lymphoma cells expressing wild-type or mutated Smad1, or in which endogenous Smad1 level was decreased by gene silencing, strongly supported that overexpression and activation of Smad1 modifies the biological response of lymphoma B cells to TGFbeta family members. This work opens new insights into aberrant Smad pathways and their pathophysiological role in FL and in other non-Hodgkin lymphomas.

Topics: Activin Receptors, Type I; Activin Receptors, Type II; B-Lymphocytes; Cell Proliferation; DNA-Binding Proteins; Gene Silencing; Humans; Lymphoma, B-Cell; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Mutation; Palatine Tonsil; Phosphorylation; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad Proteins; Smad1 Protein; Smad2 Protein; Stromal Cells; Trans-Activators; Transforming Growth Factor beta; Tumor Cells, Cultured

Transforming growth factor beta1 (TGFbeta1) induces growth arrest in many cell types, including B lymphocytes. The inhibitory action of TGFbeta1 is mediated by the deactivation of kinase complexes. The cell-cycle engine is tightly controlled by cyclin-dependent kinase (cdk) inhibitors, which mediate extracellular negative signals, resulting in cell-cycle arrest at different G1 points.. Our experimental DoHH2 cell line model was derived from a patient with malignant non-Hodgkin's lymphoma (NHL) of follicular origin. We examined the effect of TGFbeta1 on the expression and phosphorylation of key cell-cycle regulators by immunoprecipitation and immunoblotting.. After 48 hours of TGFbeta1 (10 ng/ml) treatment, a significantly increased number of DoHH2 cells was retained in G0/G1 phase. Our results showed the inhibitory action was associated with hypophosphorylation of pRb on serine 795 (S795) and threonine 373 (T373). We examined the composition of the cdk complexes and the level of cdk inhibitors to explain the inhibitory action of TGFbeta1 on cdk activity. Western blotting showed that the total level of the kinase inhibitor p21 (WAF1) increased after TGFbetal treatment. Our results indicate that a notably high level of p21(WAF1) was bound to cdk4/6 due to the treatment and that the binding of p21(WAF1) was associated with cyclin D-cdk4/6 complex decomposition.. Our investigation of the effect of TGFbetal on cell-cycle progression of a non-Hodgkin's lymphoma cell line of follicular lymphoma subtype showed that the TGFbeta1-induced growth arrest of malignant B cells was associated with the activation of CIP/KIP family members of cdk inhibitors.

Topics: Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Humans; Lymphoma, B-Cell; Lymphoma, Follicular; Male; Middle Aged; Phosphorylation; Transforming Growth Factor beta; Transforming Growth Factor beta1

Transforming growth factor beta1 (TGFbeta1) induces growth arrest in many cell types, including B lymphocytes. We examined the effect of TGF on cell cycle progression of a non-Hodgkin lymphoma cell line of follicular lymphoma subtype (FL). After 48 h of TGFbeta1 (10 ng/ml) treatment, a significantly increased number of DoHH2 cells was retained in G(0)/G(1) phase. We examined the level of cell cycle components, cyclins, cyclin-dependent kinases (cdk), and their inhibitors. We found that the expression of cyclin A and p21(WAF1) molecules was primarily modulated by TGFbeta1 treatment while the expression of other regulatory components, like cyclins D, cyclin E, cdk2, cdk4, and cdk6 or p15(INK4B), p16(INK4A), and p27(KIP1) was not significantly affected. We further examined expression and activity of CREB/ATF family members to examine their roles in cyclin A inhibition. The binding activity of CREB-1 and ATF-2 to the CRE region of the cyclin A promoter was almost completely abolished due to the treatment. The total level of CREB-1, ATF-2, and ATF-3 was notably reduced. Moreover, CREB-1 was dephosphorylated due to the treatment as revealed by immunoblotting. We assume that down-regulation of cyclin A was mediated by the absence of CREB/ATF activation dimers. The profound effect on the ATF family of transcription factors indicates the complexity of TGFbeta1 action on FL B malignant cells.

Topics: Cell Cycle; Cell Division; Cyclin A; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinases; Cyclins; DNA-Binding Proteins; G1 Phase; Gene Expression Regulation, Neoplastic; Humans; Kinetics; Lymphoma, B-Cell; Lymphoma, Follicular; Resting Phase, Cell Cycle; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta; Tumor Cells, Cultured