Abstract
Here we found that levels of cathelicidin, an antimicrobial peptide, were increased in colon cancer tissues compared to noncancerous tissues. Importantly, cathelicidin was mainly expressed in immune cells. Contact with tumor cells caused macrophages to secrete cathelicidin. Neutralization of cathelicidin, in vivo, significantly reduced the engraftment of macrophages into colon tumors, as well as proliferation of tumor cells, resulting in an inhibition of tumor growth. Furthermore, treatment with cathelicidin neutralizing antibody de-activated the Wnt/β-catenin signaling pathway in tumor cells both in vivo and in vitro. Cathelicidin activated Wnt/β-catenin signaling by inducing phosphorylation of PTEN, leading to activation of PI3K/Akt signaling and subsequent phosphorylation of GSK3β, resulting in stabilization and nuclear translocation of β-catenin. These data indicate that cathelicidin, expressed by immune cells in the tumor microenvironment, promotes colon cancer growth through activation of the PTEN/PI3K/Akt and Wnt/β-catenin signaling pathways.
Highlights
Clinical evidence indicates that chronic inflammation is linked with cancer development [1]
There were few macrophages that were positive for CD68 in noncancerous colonic mucosa; there was a large number of CD68-positive macrophages in tumor regions (Fig. 1A, e–h)
These data indicate that human cationic antimicrobial peptide-18 (hCAP-18)/LL37 is highly expressed in human colon cancer and that infiltrating inflammatory immune cells are the main source of hCAP-18/LL-37 in tumor tissue
Summary
Clinical evidence indicates that chronic inflammation is linked with cancer development [1]. Emerging evidence indicates that numerous soluble factors secreted by infiltrating immune cells contribute to cancer growth, including the growth and progression of CRC [1, 3,4,5]; the actual role of these molecules in tumor promotion is poorly understood. The human cathelicidin gene, CAMP, is isolated from human cells and codes for human cationic antimicrobial peptide-18 (hCAP-18) [6]. The Camp gene codes for the cathelicidin-related AMP (CRAMP) peptide in mice, which is similar to the LL-37 peptide in humans. Both have α-helical structures, antimicrobial functions and analogous tissue distribution [6, 7]. In addition to combating microorganisms, cathelicidin plays a role in various immune functions, including immune modulation, inflammatory reactions, cell proliferation, angiogenesis and inhibition of apoptosis [8, 10]
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