Glypican-1 as a Therapy Target in Esophageal Squamous Cell Carcinoma

Abstract

I read with interest the article by Li et al. [1] revealing that Glypican-1 (GPC1), a cell-surface heparan sulfate proteoglycan, is upregulated in esophageal squamous cell carcinoma (ESCC) tissues and promotes the aggressive proliferation of ESCC cells. They further show that GPC1 promotes the aggressive proliferation of ESCC cells by regulating the PTEN/Akt/β-catenin pathway, which indicates this pathway is important for the development of ESCC. Although this novel discovery opens the door for new treatment of ESCC, it is not known whether GPC1 deficiency or inhibition suppresses the development of ESCC only through the PTEN/ Akt/β-catenin pathway and whether genetic deletion or pharmaceutical inhibition of GPC1 could produce unwanted side effects. Interestingly, two recent studies demonstrated a similar function of GPC1 in pancreatic carcinoma. They showed that downregulation of GPC1 expression resulted in attenuated TGF-ß1-induced cell growth inhibition and Smad2 phosphorylation but no significant difference in TGF-ß1-induced p21 expression in Colo-357 pancreatic cancer cells was observed,demonstrating that GPC1 is required for efficient TGF-ß signaling in Colo-357 pancreatic cancer cells [2]. They further showed that enhanced GPC1 expression correlates with BMP and activin receptors in pancreatic cancer. GPC1 down-regulation suppresses pancreatic cancer cell growth and slightly modifies signaling of members of the TGF-ß family of growth factors, which indicated GPC1 interfered with TGF-ß, BMP, and activin signaling in pancreatic cancer [3]. Along this line, it would be interesting to find out whether targeting GPC1 suppresses the development of cancer through the TGF-ß, BMP, and activin signaling pathway? Qiao et al observed that moderate GPC1 overexpression stimulates endothelial cells (ECS) growth in cultured mouse brain ECs, but proliferation is significantly suppressed when GPC1 expression is either knocked down or the molecule is highly overexpressed. High or low expression of GPC1 causes cell cycle arrest at mitosis or the G2 phase of the cell cycle, accompanied by endoreduplication and consequently polyploidization [4]. These observations demonstrate that GPC1 has physiological roles in the EC cell cycle progression, and thus its misregulation might lead to disrupting normal endothelial cell cycle progression. Another study showed that appropriate levels of GPC1 are essential for the proper regulation of canonical Wnt signaling during differentiation and organization of trigeminal placodal cells into ganglia [5]. For clinical application, the desired approach is to modulate GPC1 expression to attenuate tumor development without inducing unwanted side effects in other organs. Thus, it would be interesting to know whether the anti-GPC1 approach is safe in treating ESCC. In summary, the work by Li et al. [1] demonstrated that inhibition of GPC1 attenuates the development of ESCC by regulating the PTEN/Akt/β-catenin pathway. Further studies on whether the PTEN/Akt/β-catenin pathway was the only signaling to regulate GPC1 expression and examination of the clinical effects of inhibition of GPC1 in ESCC are certainly warranted. These studies will pave the way to the development of rationalized decision to target this signal against ESCC. It is very important to test the molecular dysregulations, not only the clinical outcome, in other organs and tissues that could occur upon targeting GPC1 via PTEN/ Akt/β-catenin pathway in patients with ESCC. * Qingcui Song [email protected]