Inhibiting the GAS6/AXL axis suppresses tumor progression by blocking the interaction between cancer-associated fibroblasts and cancer cells in gastric carcinoma

Abstract

Background The effects of cancer-associated fibroblasts (CAF) on the progression of gastric carcinoma (GC) has recently been demonstrated. However, agents targeting the interaction between CAF and GC cells have not been applied in a clinical setting. Here, we examined if inhibition for Axl receptor tyrosine kinase (AXL) can suppress CAF-induced aggressive phenotype in GC. Methods We investigated the function of CAF-derived growth arrest-specific 6 (GAS6), a major ligand of AXL, on the migration and proliferation of GC cells. The effect of the AXL inhibitor, BGB324, on the CAF-induced aggressive phenotype of GC cells was also investigated. In addition, we performed immunohistochemistry to examine the expression of phosphorylated AXL protein in 175 GC tissues and evaluated its correlation with the prognosis. Results The qPCR and western blot analysis showed that GAS6 expression was higher in CAF relative to other cells. We found that co-culture with CAF increased the phosphorylation of AXL (P-AXL), differentiation into a mesenchymal-like phenotype, and cell survival in GC cell lines. When the expression of AXL was genetically inhibited in GC cells, the effect of CAF was reduced. BGB324, a small molecule inhibitor of AXL, suppressed the effects of CAF on GC cell lines. In GC tissues, high levels of P-AXL were significantly associated with poor overall survival (P = 0.022). Conclusions We concluded that CAF are a major source of GAS6 and that GAS6 promotes an aggressiveness through AXL activation in GC. We suggested that an AXL inhibitor may be a novel agent for GC treatment.

Regulation of ARL2 in colorectal cancer cell proliferation and tumorigenicity, and its negative association with AXL

“…For example, AXL induced the activation of downstream AKT, and inhibited the proliferation and migration of pancreatic cancer cells in vitro (29). In addition, GAS6 promoted gastric cancer invasiveness by activating AXL (30). Previous studies have demonstrated the role of AXL in regulating cell growth, migration and tumorigenesis of CRC cells (29,30).…”

“…IHC analysis of ARL2 was performed on 19 colon cancer and 3 healthy colorectal tissues. The samples were fixed in 10% neutral buffered formalin for ~3-24 h at room temperature, dehydrated in gradient alcohol solution (30,50,70,80,90,95, 100, 100% alcohol each for 30 min) and paraffin-embedded. Paraffin-embedded tissues were cut into ~3-µm thick continuous sections.…”

Qigesan inhibits esophageal cancer cell invasion and migration by inhibiting Gas6/Axl-induced epithelial-mesenchymal transition

“…Tumor metastasis is mainly caused by tumor cell migration and invasion [25][26][27]. Studies have shown that Gas6 and Axl are highly expressed in gastric, ovarian, and liver cancers, among many others, and patient prognosis is negatively correlated with Gas6/Axl complex levels [10,28,29]. Gas6/Axl can promote bone marrow and lung cancer metastasis and invasion as well as prostate cancer cell survival [30,31].…”

Gas6/Axl Signaling Pathway in the Tumor Immune Microenvironment

“…In the tumor microenvironment, cancer-associated fibroblasts (CAFs) and CD45 + -expressing tumor-infiltrating leukocytes (TILs) also express Gas6 [ 69 , 70 , 71 , 72 ]. Among the TILs, macrophages and dendritic cells express high levels of Gas6 [ 71 , 72 ], which can be further promoted in these cell types by IL-10, M-CSF, and IFN⍺ [ 6 , 72 ].…”

“…Although the mechanisms underlying Gas6 upregulation in TILs is not fully understood, in vitro studies demonstrate that tumor cells or tumor cell conditioned media induce Gas6 expression and secretion in macrophages [ 71 , 73 ]. Gomes and colleagues showed that stromal cell-derived Gas6 promotes tumor cell migration, invasion, survival, and proliferation [ 70 , 71 ]. Potential downstream effectors of the Gas6/Axl signaling through macrophage-derived Gas6 include pAkt and pStat3 [ 64 , 71 ].…”