Primary cilia in gastric Gastrointestinal Stromal Tumours (GISTs): an ultrastructural study

Abstract

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal (non-epithelial) neoplasms of the human gastrointestinal (GI) tract. They are thought to derive from interstitial cells of Cajal (ICCs) or an ICC progenitor based on immunophenotypical and ultrastructural similarities. Because ICCs show primary cilium, our hypothesis is based on the possibility that some of these neoplastic cells could also present it. To determine this, an exhaustive ultrastructural study has been developed on four gastric GISTs. Previous studies had demonstrated considerable variability in tumour cells with two dominating phenotypes, spindly and epithelioid. In addition to these two types, we have found another cell type reminiscent of adult ICCs with a voluminous nucleus surrounded by narrow perinuclear cytoplasm with long slender cytoplasmic processes. We have also noted the presence of small undifferentiated cells. In this study, we report for the first time the presence of primary cilia (PCs) in spindle and epithelioid tumour cells, an ultrastructural feature we consider of special interest that has hitherto been ignored in the literature dealing with the ultrastructure of GISTs. We also point out the frequent occurrence of multivesicular bodies (MVBs). The ultrastructural findings described in gastric GISTs in this study appear to be relevant considering the critical roles played by PCs and MVBs recently demonstrated in tumourigenic processes.

Primary cilia in gastrointestinal stromal tumors

“…The median frequency of primary cilia in 4 patients with gastric GISTs in the ultrastructure study with transmission electron microscopy was slightly higher than 5% [14]. The median frequency of primary cilia in 3 patients with gastric GISTs in our immunofluorescent study was 6.54, 1.17 and 7.93%, respectively.…”

“…Primary cilia were observed on the surface of the interstitial cells of Cajal in the rabbit [11], rat duodenum [12] and mouse stomach [13]. The presence of primary cilia in 4 patients with human gastric GIST cells has been already observed in a ultrastructure study [14]. The objective of this study was to investigate the presence and the frequency (quantity) of primary cilia in GISTs in different organs in primary tumors, metastases and recurrent lesions without and with previous treatment with imatinib.…”

Biogenesis of a new type of extracellular vesicles in gastrointestinal stromal tumors: ultrastructural profiles of spheresomes

“…The presence of MVBs has been evidenced in all GISTs included in our previous ultrastructural studies (Castiella et al 2013). In a recent study, GIST cells seem to invade the interstitial stroma through the release of the oncogenic protein tyrosine kinase (KIT)-containing exosomes.…”

PDGFRβ and oncogenic, mutant PDGFRα D842V promote disassembly of primary cilia by a PLCγ and AURKA dependent mechanism

“…Notably, chimeric mice lacking endogenous PDGFRβ display renal cysts and glomerulosclerosis (Klinghoffer et al, 2001), phenotypes associated with defective intracellular Ca 2+ signaling (Kuo et al, 2014) and ciliopathies (Hildebrandt et al, 2011). Because PDGFRα D842V and AURKA expression is linked to GIST (Corless et al, 2011;Yeh et al, 2014), and precursors of GIST cells are ciliated (Castiella et al, 2013), it will be interesting to study whether GIST cells display ciliary defects that are caused by elevated PLCγ and AURKA activity.…”