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Research Paper

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

Jan-Bart M. Koorstra, Collins Karikari, Georg Feldmann, Savita Bisht, Pamela Leal Rojas, Johann Offerhaus, Hector Alvarez and Anirban Maitra

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. The immunohistochemical expression of Axl protein was assessed in a panel of 99 archival pancreatic cancers. 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<0.05), than in tumors with negative labeling. Stable knockdown of AXL transcripts was enabled in Axl-overexpressing MIAPaCa-2 cells using lentiviral short hairpin shRNA, and 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. Expression of Axl tyrosine kinase in pancreatic cancers confers an adverse prognostic influence, and represents a new therapeutic target in this malignancy.

Authors

Jan-Bart M. Koorstra

Johns Hopkins University School of Medicine, Baltimore, Maryland/Department of Pathology, Utrecht Medical Center, Utrecht, The NetherlandsJohns Hopkins University School of Medicine, Baltimore, Maryland/Department of Pathology, Utrecht Medical Center, Utrecht, The Netherlands

Collins Karikari

Johns Hopkins University School of Medicine; The Sol Goldman Pancreatic Cancer Research Center; 720 Rutland Ave; Baltimore, MD 21205 United States

Georg Feldmann

Johns Hopkins University School of Medicine 1550 Orleans Street Baltimore, MD 21231 United States

Savita Bisht

Johns Hopkins University School of Medicine; Department of Pathology; CRB II Room 316; 1550 Orleans St.; Baltimore, MD 21231 United States

Pamela Leal Rojas

Johns Hopkins University School of Medicine; Department of Pathology; CRB II Room 316; 1550 Orleans St.; Baltimore, MD 21231 United States

Johann Offerhaus

Utrecht Medical Center; Heidelberglaan 100; Utrecht, 3508 GA 85500 Netherlands

Hector Alvarez

Anirban Maitra Corresponding author: amaitra1@jhmi.edu

Johns Hopkins University School of Medicine; Department of Pathology; CRB II Room 316; 1550 Orleans St.; Baltimore, MD 21231 United States