Secretory leukocyte protease inhibitor promotes dysregulated angiogenesis
Caoifa M. Dougan1, Sinead Weldon1, Clifford C. Taggart1, Donna M. Small1*
1Airway Innate Immunity Research (AiiR) Group. Centre of Experimental Medicine (CEM), Wellcome – Wolfson Building, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland
Secretory leukocyte protease inhibitor (SLPI) is a member of the whey acidic protein (WAP) four-disulfide-core (WFDC) protein family. Within the lung environment, SLPI can inhibit proteases such as neutrophil elastase and modulate inflammation thereby protecting the lung epithelium from damage during pulmonary disease processes. Recently however, SLPI overexpression in non-small cell lung carcinoma (NSCLC) is postulated to mediate an environment more suited to pro-tumour progression, i.e. enhanced neo-angiogenesis and prolonged inflammation.
Recent findings from our laboratory examining clinical biopsies have observed that SLPI is elevated in both tumour and immune cells in NSCLC cases when compared to normal lung tissue. Furthermore, we have studied the development of xenograft tumours in wild type and SLPI null (-/-) C57BL/6 mice using the syngeneic Lewis Lung Carcinoma (LLC) cell line to clarify the contribution of SLPI in the promotion of various hallmarks of tumourigenesis. We have noted a significant decrease in both tumour volume and the number and size of CD31+ functional vessels in tumours from the SLPI-/- mice compared to WT mice. Moreover, in preliminary experiments, we have observed that SLPI is involved in the dysregulation of interleukin-17 (IL-17), an inflammatory cytokine produced by the CD4+ T helper Th17 cells, which are reported to be negatively correlated to prognosis in patients with NSCLC.
These early studies have shown a role for SLPI in LLC tumour development and angiogenesis with current investigations considering the effect SLPI may have on apoptosis, tumour proliferation and immune cell infiltration. The above findings may highlight SLPI as a potential therapeutic target in cancer.