The Axl receptor tyrosine kinase confers an adverse prognostic influence in pancreatic cancer and represents a new therapeutic target

Abstract

Background Pancreatic cancer is a near uniformly lethal disease and a better understanding of the molecular basis of this malignancy may lead to improved therapeutics. The Axl receptor tyrosine kinase is implicated in cellular transformation and tumor progression, although its role in pancreatic cancer has not been previously documented. Results Axl labeling was present in 54 of 99 (55%), and was absent in 45 of 99 (45%) cases, respectively. Axl expression in pancreatic cancer was significantly associated with lymph node metastases (p < 0.01), and a shorter median survival (12 versus 18 months, p < 0.01), than in tumors with negative labeling. Stable knockdown of Axl resulted in significant reduction in cell viability (p < 0.001), anchorage independent growth (p = 0.0031), as well as attenuation of migratory (p < 0.001) and invasive properties (p < 0.005), compared to vector-transfected cells. Profound inhibition of p42/p44 MAP kinase and PI-3kinase/Akt effector pathways was observed in MIAPaCa-2 cells with loss of Axl function. The reduction in invasion and migration upon Axl knockdown was mirrored by a decrease in the amounts of activated (GTP-bound) GTPase proteins Rho and Rac, significant downregulation in transcript levels of the epithelial mesenchymal transition (EMT)-associated transcription factors slug, snail and twist, and significant decrease in matrix metalloproteinase MMP-9 mRNA levels. Materials The immunohistochemical expression of Axl protein was assessed in a panel of 99 archival pancreatic cancers. Endogenous Axl expression was stably downregulated by lentiviral short hairpin shRNA directed against AXL mRNA in MIAPaCa-2 cells, and the effects on cell viability, anchorage independent growth, invasion, migration and intracellular effector pathways was assessed, by comparing to lentiviral vector-transfected cells. Conclusion Expression of Axl tyrosine kinase in pancreatic cancers confers an adverse prognostic influence, and represents a new therapeutic target in this malignancy.

Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival

“…Axl, often coexpressed with Gas6, is detected in many metastatic cancers, indicating that autocrine Axl signaling might be a frequent consequence of EMT in many tumor types (12,24). Interestingly, Axl expression is required to maintain Snail, Slug, and Twist expression in pancreatic adenocarcinoma cells (25). This, together with our findings that these EMT transcription factors potently induce Axl expression, suggests that Axl could participate in a positive feedback loop that sustains the malignant mesenchymal phenotype of tumor cells.…”

Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer

“…Gas6-activated Axl signaling marshalls important downstream regulators of cell motility such as Rac and Akt (Allen et al, 2002;Hasanbasic et al, 2004) and regulates haptotaxis toward vitronectin in endothelial cells (Holland et al, 2005). Recent studies support a role for Axl as a regulator of glioma, breast, lung and pancreatic tumor cell migration (Shieh et al, 2005;Vajkoczy et al, 2006;Koorstra et al, 2009) and very recently Axl was identified as an important regulator of breast cancer metastasis and survival of patients (Vajkoczy et al, 2006;Gjerdrum et al, 2010). We found that vimentin regulates Axl expression in breast cancer cell lines.…”

An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies

“…Dysregulation of Axl or its ligand Gas6 is implicated in the pathogenesis of a variety of human cancers. Overexpression of Axl has been reported in a wide array of human cancers (Craven et al, 1995;Ito et al, 1999;Berclaz et al, 2001;Sun et al, 2004;Shieh et al, 2005) and is associated with invasiveness and metastasis in lung (Shieh et al, 2005), prostate (Sainaghi et al, 2005), breast (Meric et al, 2002;Zhang et al, 2008), gastric (Wu et al, 2002) and pancreatic (Koorstra et al, 2009) cancers, renal cell carcinoma (Chung et al, 2003) as well as glioblastoma (Hutterer et al, 2008). Recently, by profiling of phosphotyrosine signaling, activated Axl protein was detected in about 5% primary tumors of non-small-cell lung cancer (NSCLC) (Rikova et al, 2007).…”