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

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 shown tha t c -Myc pro te in express ion is 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.

ABC-DLBCL subtype represents more than 90% of PCNSLs (Batchelor, 2016) and is the most aggressive subtype with a cure rate of only 40% (G.Lenz et al., 2008).One of the characteristics of ABC-DLBCL subtype is the activation of NF-kappaB pathway whereas GCB-DLBCL presents low levels of this signaling (Pasqualucci and Zhang, 2016).NF-kappaB is a downstream signaling of both B cell receptor (BCR) and CD40 receptors and ABC-DLBCL cells show a "chronic and active" form of BCR signaling (R. Eric Davis et al., 2010).MYD88 mediates the activity of NF-kappaB as well as type I interferon responses (S.-C.Lin, Lo, and Wu, 2010).MYD88 mutations are observed in around 30% to 40% of ABC-DLBCL.MYD88 mutations stimulates STAT3 signaling which is also a phenotypic trait of ABC-DLBCL subtype (Ngo et al., 2011).
c-Myc alterations and protein expression have been shown in aggressive DLBCL (Karube and Campo, 2015).These alterations are frequently associated with oncogenic abnormalities, as B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma 6 (Bcl-6) genes translocation and overexpression (Karube and Campo, 2015).c-Myc rearrangements appear similarly expressed in both GCB and ABC-DLBCL (Johnson et al., 2012).Although mRNA of c-Myc is increased by low levels gains of c-Myc, several studies have shown that c-Myc protein expression is overexpressed without c-Myc abnormalities (Horn et al., 2013;Johnson et al., 2012;Stasik et al., 2010;Valera et al., 2013).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 (Meyer and Penn, 2008).
We focus this review on the hypothesis of an opposite interplay between the canonical WNT/betacatenin pathway and PPAR gamma in regulating the molecular mechanisms underlying the PCNSLs.

Canonical WNT/beta-catenin pathway
Wingless and integration site (named WNT) pathway is a cascade of several signaling which is involved in development, metabolism, cellular growth, and maintain of stem cells (van Amerongen and Nusse, 2009).WNT pathway is composed by secreted lipid-modified glycoproteins (Al-Harthi, 2012).Dysregulation of the WNT pathway is involved in several pathways (Lecarpentier et al., 2014).Aberrant WNT/beta-catenin pathway is observed in cancer development (Sumithra, Saxena, and Das, 2016).WNT extracellular ligands bind Frizzled (FZD) receptors and low density lipoprotein receptor-related protein 5 and 6 (LRP 5/6) and disheveled (DSH), which induce betacatenin accumulation and then beta-catenin nuclear translocation for binding T-cell factor/lymphoid enhancer factor (TCF/LEF).(Logan and Nusse, ! 2004).Nuclear beta-catenin associated with TCF/ LEF activates several target genes expression such as c-Myc, cyclin D1 (Angers and Moon, 2009).D o w n r e g u l a t i o n o f t h e W N T p a t h w a y i s characterized by the absence of binding between WNT extracellular ligands and the complex FZD/ LRP 5/6.Thus, the beta-catenin destruction complex composed by adenomatous polyposis coli (APC), AXIN and glycogen synthase kinase-3 (GSK-3beta) is activated and mediates proteasomal degradation of beta-catenin (Clevers and Nusse, 2012).GSK-3beta inhibits cytosolic beta-catenin accumulation and nuclear translocation (Aberle, Bauer, Stappert, Kispert, and Kemler, 1997;Clevers and Nusse, 2012).

Interactions between c-Myc and NF-kappaB pathway
The proliferative index of B-cell lymphomas is largely due to the activation of NF-kappaB pathway but also due to the dysregulation of c-Myc activity (Ott, Rosenwald, and Campo, 2013).c-Myc participates to the proliferation of NF-kappaB activated B cells (David et al., 2017).The interplay b e t w e e n N F -k a p p a B a n d S TAT p a t h w a y upregulates c-Myc expression in ABC-BLBCLs (Ding et al., 2008).

Conclusion
PCNSLs are angiocentric neoplasia which are infiltrative and extend beyond the primary lesion.ABC-DLBCL subtype represents more than 90% of PCNSLs and is the most aggressive subtype with a cure rate of only 40%.Therefore, it is essential to investigate the mechanisms underlying the development and progression of PCNSLs and to explore more effective therapeutic strategies.
In PCNSLs, the canonical WNT/beta-catenin pathway is upregulated while PPAR gamma is downregulated.These two systems act in an opposite manner.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 (cf. Figure 1).c-Myc is considered as a key prognostic and predictive biomarker for survival in DLBCL, its expression is associated with worst survival rates.
In addition, STAT3 signaling pathway upregulates the expression and transcriptional activity of betacatenin.STAT3 is a tumor aggressiveness factor.MYD88 stimulates inflammation in ABC-DLBCL through the activation of NF-kappaB pathway.NF-kappaB increases STAT3 pathway through the stimulation of IL-6 and/or IL-10 and directly increases WNT/beta-catenin pathway.STAT3 increases PI3K/Akt pathway, which inhibits GSK-3beta to activate WNT/beta-catenin pathway and thus allow beta-catenin accumulation, stabilization and nuclear translocation.Nuclear beta-catenin translocation activates WNT target genes, such as c-Myc.

! 8
Canonical WNT/beta-catenin pathway activation induces inactivation of PPAR gamma leading to a decreased in insulin sensitivity and an increased in neuro-inflammation.PPAR gamma agonists induce the inhibition of several signaling pathways such as the NF-kappaB, STAT, WNT/beta-catenin and PI3K/ Akt pathways through the activation of GSK-3beta.PPAR gamma agonists may have a major negative key role in the regulation of progression of PCNSLs.

Figure 1 .
Figure1.Oncogenic pathways involved in PCNSL.MYD88 mutations stimulate NF-kappaB activity and the neuroinflammation leading to activate IL-6 and/or IL-10.Activation of these interleukin promotes STAT3 signaling to activate PI3K/Akt pathway.PI3K inhibits GSK-3beta, the major WNT inhibitor.In PCNSL, WNT is directly activated by NF-kappaB and PI3K through the inhibition of GSK-3beta.In PCNSL, WNT ligands bind FZD receptors, LRP 5/6 and DSH, which induce beta-catenin accumulation and then beta-catenin nuclear translocation.STAT3 signaling also directly stimulates beta-catenin accumulation and c-Myc activation.In a positive feedback, WNT/beta-catenin pathway stimulates NF-kappaB, PI3K and STAT3.Nuclear beta-catenin activates c-Myc leading to stimulate cell cycle, cell growth, cellular metabolism, protein synthesis and mitochondrial metabolism.

Figure 2 .
Figure2.Actions of PPAR gamma in PCNSL.PPAR gamma agonists directly inhibit MYD88 expression and NF-kappaB activity, leading to reduce neuroinflammation.PPAR gamma agonists also decrease PI3K/Akt pathway whereas they activate GSK-3beta activity to inhibit WNT pathway.PPAR gamma agonists stimulate DKK, which downregulates WNT/beta-catenin pathway.Absence of WNT ligands prevents binding with FZD/LRP 5/6.The betacatenin destruction complex is formed and composed by APC, AXIN and GSK-3beta, which mediates proteasomal degradation of beta-catenin.Thus, c-Myc is not activated.