AXL is a potential therapeutic target in dedifferentiated and pleomorphic liposarcomas

Abstract

BackgroundAXL is a well-characterized, protumorigenic receptor tyrosine kinase that is highly expressed and activated in numerous human carcinomas and sarcomas, including aggressive subtypes of liposarcoma. However, the role of AXL in the pathogenesis of well-differentiated (WDLPS), dedifferentiated (DDLPS), and pleomorphic liposarcoma (PLS) has not yet been determined.MethodsImmunohistochemical analysis of AXL expression was conducted on two tissue microarrays containing patient WDLPS, DDLPS, and PLS samples. A panel of DDLPS and PLS cell lines were interrogated via western blot for AXL expression and activity and by ELISA for growth arrest-specific 6 (GAS6) production. AXL knockdown was achieved by siRNA or shRNA. The effects of AXL knockdown on cell proliferation, migration, and invasion were measured in vitro. In addition, AXL shRNA-containing DDLPS cells were assessed for their tumor-forming capacity in vivo.ResultsIn this study, we determined that AXL is expressed in a subset of WDLPS, DDLPS, and PLS patient tumor samples. In addition, AXL and its ligand GAS6 are expressed in a panel of DDLPS and PLS cell lines. We show that the in vitro activation of AXL via stimulation with exogenous GAS6 resulted in a significant increase in cell proliferation, migration, and invasion in DDLPS and PLS cell lines. Transient knockdown of AXL resulted in attenuation of these protumorigenic phenotypes in vitro. Stable AXL knockdown not only decreased migratory and invasive characteristics of DDLPS and PLS cells in vitro but also significantly diminished tumorigenicity of two dedifferentiated liposarcoma xenograft models in vivo.ConclusionsOur results suggest that AXL signaling contributes to the aggressiveness of DDLPS and PLS, and that AXL is therefore a potential therapeutic target for treatment of these rare, yet devastating tumors.

Activated tyrosine kinases in gastrointestinal stromal tumor with loss of KIT oncoprotein expression

“…AXL is overexpressed in metastatic colon and prostate cancer, mesothelioma, thyroid carcinoma, breast cancer, and melanoma [29][30][31][32][33][34]. Additionally, Gas6/AXL signaling plays an important role in tumor formation, tumor invasion and metastasis, and tumor cell survival [34][35][36][37]. Although AXL has been identified to play a crucial oncogeneic role in GISTs [16] that have converted, during TKItherapy, to a KIT-independent state, the pathogenic mechanisms of AXL remain unclear.…”

Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models

“… 24 AXL inhibitors based on small non-coding RNAs have also been shown to successfully reduce proliferation and metastasis of various cancer cells. 23 , 32 , 36 , 37 , 38 However, clinical development of RNAi-based therapeutics is hampered by the lack of nanodelivery systems that can efficiently and safely deliver these small molecules into tumors. 39 Aptamers have been shown to provide favorable specificity and stability in in vivo studies.…”

AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications

“…AXL potentially drives cell proliferation through effector molecules in the PI3K/AKT/mTOR, RAS/RAF/MEK/ERK, JAK/STAT, and NF-κB signalling pathways [10, 69]. AXL fosters cell survival by regulating NF-κB nuclear translocation, increasing the expression of anti-apoptotic markers (survivin, BCL-2, and BCL-XL) and reducing the activity of pro-apoptotic proteins (BAD and caspase-3) [45, 52, 70].…”