ID: 48. Issue 1 (November 2015)

• Record Type: Journal Article
• Authors: Poh, Ashleigh Ren-yi; Lessene, Guillaume; Khakham, Yelena; Masson, Frederic; Preaudet, Adele; Putoczki, Tracy; O'Donoghue, Robert; Ernst, Matthias
• Is Part Of: Cytokine. Volume 76:Issue 1(2015)
• Page Start: 73
• Publication Date: 2015-11
• Subjects: Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2015.08.078
• Languages: English
• ISSNs: 1043-4666

Abstract

<abstract xml:lang="en" abstract-type="author" id="ab005"> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <p id="sp005">Colorectal cancer is the second most commonly diagnosed cancer worldwide, and may develop sporadically or due to chronic colitis. Macrophages are a major component of the colorectal tumour microenvironment and may be broadly classified as classically-activated (CAM) 'inflammatory' or alternatively-activated (AAM) 'pro-angiogenic' macrophages. Hematopoietic Cell Kinase (Hck) is a myeloid-specific Src family kinase involved in alternative macrophage polarisation, which correlates with a poor prognosis in human colorectal cancer.</p> <p id="sp010">To investigate the role of Hck in colorectal tumourigenesis, Hck mutant mice that express a constitutively active form of Hck (HckCA) were subjected to models of sporadic and colitis-associated colorectal cancer. In both models, HckCA mice demonstrated increased tumour size and multiplicity compared to wild-type animals. FACS analysis of tumour immune-cell infiltrates did not reveal a difference in the number of tumour-associated macrophages (TAMs) between genotypes; however, CD206+ alternatively-activated TAMs were significantly greater in HckCA mice compared to wild-type. Furthermore, qPCR analysis highlighted a significant increase in genes associated with alternative-macrophage activation in HckCA TAMs.</p> <p id="sp015">To confirm the role of macrophages in HckCA-driven tumourigenesis, wild-type mice were reconstituted with HckCA bone-marrow, and subjected to sporadic or colitis-associated colon cancer induction, after which we observed an increased tumour burden and an AAM phenotype compared to wild-type bone-marrow recipients. Finally, we have shown that the inhibition of Hck using a small molecule inhibitor reduces alternative macrophage polarisation.</p> <p id="sp020">Collectively, our results suggest that excessive Hck activation enhances colorectal tumourigenesis by facilitating alternative macrophage polarisation, which may be alleviated through the therapeutic targeting of this kinase.</p> </sec> </abstract>