The molecular pathogenesis of craniopharyngiomas

Abstract

Research from the last 20 years has provided important insights into the molecular pathogenesis of craniopharyngiomas (CPs). Besides the well-known clinical and histological differences between the subtypes of CPs, adamantinomatous (ACP) and papillary (PCP) craniopharyngiomas, other molecular differences have been identified, further elucidating pathways related to the origin and development of such tumors. The present minireview assesses current knowledge on embryogenesis and the genetic, epigenetic, transcriptomic, and signaling pathways involved in the ACP and PCP subtypes, revealing the similarities and differences in their profiles. ACP and PCP subtypes can be identified by the presence of mutations in CTNNB1 and BRAF genes, with prevalence around 60% and 90%, respectively. Therefore, β-catenin accumulates in the nucleus-cytoplasm of cell clusters in ACPs and, in PCPs, cell immunostaining with specific antibody against the V600E-mutated protein can be seen. Distinct patterns of DNA methylation further differentiate ACPs and PCPs. In addition, research on genetic and epigenetic changes and tumor microenvironment specificities have further clarified the development and progression of the disease. No relevant transcriptional differences in ACPs have emerged between children and adults. In conclusion, ACPs and PCPs present diverse genetic signatures and each subtype is associated with specific signaling pathways. A better understanding of the pathways related to the growth of such tumors is paramount for the development of novel targeted therapeutic agents.

Keywords: BRAF V600E; CTNNB1; Craniopharyngioma; adamantinomatous; molecular pathogenesis; papillary.

Figure 1. Schematic representation of the main molecular events underlying the tumorigenesis of papillary craniopharyngiomas (PCPs).

Figure 2. Schematic representation of the canonical Wnt/β-catenin-signaling pathway. (A) In the absence of a Wnt ligand, β-catenin binds to the destruction complex (APC, AXIN, CK1 and GSK3β) and is phosphorylated by CK1 and GSK3β, then ubiquitinated and degraded by the proteasome, preventing the transcription of β-catenin target genes. (B) In the presence of a Wnt ligand, the ligand binds to its cellular receptors (Frizzled and LRP5/6), resulting in the recruitment of DVL to the membrane, which inactivates the β-catenin destruction complex, leading to accumulation of β-catenin. β-catenin translocates into the nucleus and activates target gene transcription by interacting with TCF/LEF transcription factors. (C) In the presence of CTNNB1 exon 3 mutation, β-catenin becomes resistant to degradation and accumulates, activating the Wnt pathway even in the absence of a Wnt ligand.

Figure 3. Schematic representation of the cellular compartments of the adamantonomatous craniopharyngioma (ACP) and the tumor microenvironment. The ACPs are composed of β-catenin positive cell clusters, adjacent to stellate cells known as reticulum stellate, surrounded by a palisaded basal layer of cells and intense gliosis and inflammatory reaction in the adjacent brain. These clusters could act as a paracrine tumor-signaling center by activating cells with a secretory phenotype, which may then secrete growth factors, cytokines, chemokines, and proteases, thereby changing the tumor microenvironment. Besides Wnt-pathway activation driven by the CTNNB1 mutations, different pathways and proteins have been shown to be overexpressed in ACPs as Sonic Hedgehog (SHH), epidermal growth factor (EGF), fibroblast growth factor (FGF), bone morphogenetic protein (BMP), matrix-metallopeptidases (MMP), pro-inflammatory factors as interleukins and chemokines and their receptors (IL6R, IL2RB, PTGS2, CKCR4, CXCL12), while adhesion molecules seem to be underexpressed (CD44, claudin-1).