CCBE1 promotes GIST development through enhancing angiogenesis and mediating resistance to imatinib

Abstract

Gastrointestinal stromal tumor (GIST) is the most major mesenchymal neoplasm of the digestive tract. Up to now, imatinib mesylate has been used as a standard first-line treatment for irresectable and metastasized GIST patients or adjuvant treatment for advanced GIST patients who received surgical resection. However, secondary resistance to imatinib usually happens, resulting in a major obstacle in GIST successful therapy. In this study, we first found that collagen and calcium binding EGF domains 1 (CCBE1) expression gradually elevated along with the risk degree of NIH classification, and poor prognosis emerged in the CCBE1-positive patients. In vitro experiments showed that recombinant CCBE1 protein can enhance angiogenesis and neutralize partial effect of imatinib on the GIST-T1 cells. In conclusion, these data indicated that CCBE1 may be served as a new predictor of prognosis in post-operative GIST patients and may play an important role in stimulating GIST progression.

CCBE1 is required for coronary vessel development and proper coronary artery stem formation in the mouse heart

“…Although our expression analysis does not show Ccbe1 expression in the vicinity of the endocardium, we think that epicardial-derived cells (EPDC), which migrate into the myocardium, may be an additional source of CCBE1. In agreement with this, there is evidence that Ccbe1 is expressed in the wall of blood vessels, fibroblasts and ECs (Tian et al, 2016;Jha et al, 2017) and promotes tube formation in vitro (Tian et al, 2016). We think the methods used in this study are not sensitive enough to detect subtle changes in Ccbe1 expression levels.…”

“…However, Ccbe1 expression was confirmed in the septum transversum/proepicardium (Facucho-Oliveira et al, 2011), one of the embryonic sources of coronary endothelium (Katz et al, 2012;Cano et al, 2016), suggesting that CCBE1 may play a role during coronary vasculature development. In accordance with this hypothesis, CCBE1 has been also shown to promote tube formation in vitro (Tian et al, 2016).…”

“…The expression data described earlier show that Ccbe1 is expressed in the epicardium, like Vegf‐c (Chen et al, ), and in the vicinity of the SV endocardium (SV myocardium), two sources of coronary ECs (Katz et al, ; Red‐Horse et al, ; Chen et al, 2014a; Cano et al, 2016), at the stage during which SV endocardium–derived coronary vessels start to form (E11.5–E13.5). These data, together with the ability of CCBE1 to promote tube formation (Tian et al, ), suggest that CCBE1 may play a role during coronary vasculature development. To test this hypothesis, we investigated coronary development in Ccbe1 mutants.…”

Collagen and Calcium Binding EGF Domains 1 (CCBE1) in cancer - a new role past lymphatics?

“…Despite its original description as a gene frequently lost in breast cancer specimens [ 1 ], the earliest studies on the function of CCBE1 showed a role for it in lymphangiogenesis in Zebrafish [ 2 ], and in Hennekam syndrome [ 3 ]. In the last two years, more reports on the role of CCBE1 in cancer have started to emerge [ 4 - 6 ]. In a recent publication, we showed that CCBE1 is targeted by microRNA 330-3p (miR-330-3p), resulting in a more aggressive phenotype in breast cancer [ 4 ].…”

“…Not all studies support a tumour-suppressor role for CCBE1, however. A separate study investigating the clinicopathological correlation of CCBE1 expression in gastrointestinal stromal tumours (GISTs) found that CCBE1 was elevated in higher risk GISTs, and that increased expression of CCBE1 predicted lower DRFS and OS [ 6 ]. Mechanistically, CCBE1 appeared to promote angiogenesis and increased resistance to imatinib in vitro .…”