Hypothesis of Opposite Interplay Between the Canonical WNT/beta-catenin Pathway and PPAR Gamma in Primary Central Nervous System Lymphomas

Abstract

Primary central nervous system lymphomas (PCNSLs) are angiocentric neoplasia which present dense monoclonal lymphocyte proliferation, and occur in brain parenchyma in 90% of the cases. Activated B-cell like Diffuse Large B-cell Lymphoma (ABC-DLBCL) subtype represents more than 90% of PCNSLs and is the most aggressive subtype with a cure rate of only 40%. One of the characteristics of ABC-DLBCL subtype is neuroinflammation through the activation of NF-kappaB pathway. c-Myc alterations and protein expression have been shown in aggressive DLBCL. c-Myc is considered as a key prognostic and predictive biomarker for survival in DLBCL, its expression is associated with worst survival rates. Although mRNA of c-Myc is increased by low levels gains of c-Myc, several studies have s h o w n t h a t cM y c p r o t e i n e x p r e s s i o n i s overexpressed without c-Myc abnormalities. These high levels of c-Myc protein in DLBCL without genetic abnormalities suggest that c-Myc protein expression may be also increased by other mechanisms or signaling pathways which regulate its expression. In PCNSLs, the canonical WNT/betacatenin pathway is upregulated while PPAR gamma is downregulated. The opposite interplay between WNT/beta-catenin pathway and PPAR gamma is reviewed here. Activation of WNT/beta-catenin pathway leads to the transcription of genes involved in cell proliferation, mitochondrial metabolism, protein synthesis, and tumor growth, such as c-Myc. PPAR gamma agonists induce the inhibition of several signaling pathways such as NF-kappaB, STAT, PI3K/Akt and WNT/beta-catenin pathway. Activation of PPAR gamma agonists may have a major negative key role in the regulation of PCNSLs progression.

Large-Scale Proteomic Analysis of Follicular Lymphoma Reveals Extensive Remodeling of Cell Adhesion Pathway and Identifies Hub Proteins Related to the Lymphomagenesis

“…Consistent with this notion, the protein products of all the above genes were found to be significantly down-regulated in our work. Regarding B-cell lymphoma, the PPAR gamma pathway was found to be down-regulated in primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL) [85].…”

TGF-β in fibrosis by acting as a conductor for contractile properties of myofibroblasts

“…These two signaling systems act in an opposite manner in several pathological conditions [4–12]. Thus, when the expression of PPARγ is increased, WNT/β-catenin signaling is decreased, while when WNT/β-catenin signaling is increased, PPARγ expression is decreased [11, 13]. Myofibroblast differentiation is controlled by TGF-β1, which activates canonical WNT signaling and decreases PPARγ expression [14].…”

Distinct microRNA expression signatures of primary and secondary central nervous system lymphomas

“…Pathway enrichment analysis shows similar pattern in this small distinct set of samples to PCNSL, with even more pronounced changes compared to the SCNSL vs PCNSL analysis. The WNT/beta-catenin pathway activated here, was described as activated in PCNSL [86], and the small set of samples defined here might be a distinct PCNSL subgroup where the pathway can be efficiently targeted with Wnt inhibitors [87]. Based on these results, this is a well-defined sample group within the PCNSL cases contributing significantly to the distinct expression patterns between PCNSL and SCNSL.…”