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Src family kinases, HCK and FGR, associate with local inflammation and tumour progression in colorectal cancer

Roseweir, Antonia K., Powell, Arfon G.M.T., Horstman, Sheryl L., Inthagard, Jitwadee, Park, James H., McMillan, Donald C., Horgan, Paul G. and Edwards, Joanne 2019. Src family kinases, HCK and FGR, associate with local inflammation and tumour progression in colorectal cancer. Cellular Signalling 56 , pp. 15-22. 10.1016/j.cellsig.2019.01.007

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Background In colorectal cancer (CRC), inflammatory responses have been reported to associate with patient survival. However, the specific signalling pathways responsible for regulating inflammatory responses are not clear. Src family kinases (SFKs) impact tumourigenic processes, including inflammation. Methods The relationship between SFK expression, inflammatory responses and cancer specific survival (CSS) in stage I-III CRC patients was assessed using immunohistochemistry on a 272 patient discovery cohort and an extended 822 patient validation cohort. Results In the discovery cohort, cytoplasmic FGR associated with improved CSS (P = 0.019), with membrane HCK (p = 0.093) trending towards poorer CSS. In the validation cohort membrane FGR (p = 0.016), membrane HCK (p = 0.019), and cytoplasmic HCK (p = 0.030) all associated with poorer CSS. Both markers also associated with decreased proliferation and cytotoxic T-lymphocytes (all p < 0.05). Furthermore, cytoplasmic HCK was an independent prognostic marker compared to common clinical factors. To assess synergy a combine FGR + HCK score was assessed. The membrane FGR + HCK score strengthened associations with poor prognosis (p = 0.006), decreased proliferation (p < 0.001) and cytotoxic T-lymphocytes (p < 0.001). Conclusions SFKs associate with prognosis and the local inflammatory response in patients with stage I-III CRC. Active membrane FGR and HCK work in parallel to promote tumour progression and down-regulation of the local inflammatory lymphocytic response.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Elsevier
ISSN: 0898-6568
Date of First Compliant Deposit: 28 January 2019
Date of Acceptance: 21 January 2019
Last Modified: 12 Mar 2020 22:27

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