Overexpression of receptor tyrosine kinase Axl promotes tumor cell invasion and survival in pancreatic ductal adenocarcinoma

Abstract

BACKGROUND The receptor tyrosine kinase Axl has been reported to be overexpressed in a variety of human cancers. Although previous studies have identified the role of Axl in the transformation, proliferation, survival, and invasion in cancers, the expression and functions of Axl in pancreatic cancer have not been studied in detail. METHODS The expression of Axl protein in 12 pancreatic cancer cell lines and 54 patient samples of stage II pancreatic ductal adenocarcinoma (PDA) and their paired non-neoplastic pancreatic tissue samples were examined. Using univariate and multivariate analysis, Axl expression was correlated with survival and other clinicopathologic features. To examine Axl functions in PDA, the effects of Axl knockdown on the invasion ability and radiation-induced apoptosis in PDA cell lines were measured. RESULTS Axl was overexpressed in 38 of 54 (70%) stage II PDA samples and 9 of 12 (75%) PDA cell lines. Axl overexpression was associated with higher frequencies of distant metastasis and poor overall and recurrence-free survivals (P = .03 and P = .04, respectively) independent of tumor size and stage or lymph node status in patients with stage II PDA. Knockdown of Axl expression in PDA cells abolished Gas6-mediated Akt activation, decreased invasion, and increased radiation-induced PARP cleavage and the percentage of apoptosis. CONCLUSIONS This study showed that Gas6 and Axl are frequently overexpressed in PDA cells and are associated with a poor prognosis in patients with stage II PDA. Axl promotes the invasion and survival of PDA cells. Therefore, targeting the Axl signaling pathway may represent a new approach to the treatment of PDA.

Activation of TYRO3/AXL Tyrosine Kinase Receptors in Thyroid Cancer

“…AXL overexpression has been reported in a variety of human cancers (21,24,(28)(29)(30)(31)(32)(33)(34)(35)(36), and it is associated with negative prognosis (14,24,25,(37)(38)(39). AXL expression confers resistance to different antineoplastic agents (40)(41)(42), can induce angiogenesis (14,43), cancer cell migration and invasion (37,(44)(45)(46).…”

Biology of the TAM Receptors

“…In many settings, however, a definitive demonstration that overexpression is causal for particular features of cancer development or progression has not been made. Elevated expression of TAM signaling components has been reported for leukemias (Graham et al 1994(Graham et al , 2006Hong et al 2008), gliomas (Hutterer et al 2008;Keating et al 2010), colorectal carcinomas (Craven et al 1995), breast cancers (Berclaz et al 2001;Gjerdrum et al 2010), gastrointestinal stromal tumors (Mahadevan et al 2007), hepatocellular carcinoma (He et al 2010), melanoma (Quong et al 1994;Koorstra et al 2009;Zhu et al 2009), pancreatic adenocarcinoma (Song et al 2010), and prostate cancer (Wu et al 2004;Sainaghi et al 2005), among several others.…”

Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer

“…Moreover, ectopic expression of AXL has been shown to confer resistance to EGF receptor therapy in lung cancer (10,11). Multiple studies have demonstrated AXL and MER function in survival, invasion, and metastasis in a variety of tumors (12)(13)(14)(15); thus, attention has focused on the pharmacologic targeting of AXL and MER in cancer. Axl and Mer share structural homology in the kinase domain with other tyrosine kinases, including conserved molecular interactions with ATP; however, several unique features of the active site allow for selective inhibition (16), and small-molecule inhibitors as well as biologics are in preclinical development (6,(16)(17)(18)(19).…”