Ovarian cancers overexpress the antimicrobial protein hCAP‐18 and its derivative LL‐37 increases ovarian cancer cell proliferation and invasion

Abstract

The role of the pro-inflammatory peptide, LL-37, and its proform, human cationic antimicrobial protein 18 (hCAP-18), in cancer development and progression is poorly understood. In damaged and inflamed tissue, LL-37 functions as a chemoattractant, mitogen and pro-angiogenic factor suggesting that the peptide may potentiate tumor progression. The aim of this study was to characterize the distribution of hCAP-18/LL-37 in normal and cancerous ovarian tissue and to examine the effects of LL-37 on ovarian cancer cells. Expression of hCAP-18/LL-37 was localized to immune and granulosa cells of normal ovarian tissue. By contrast, ovarian tumors displayed significantly higher levels of hCAP-18/LL-37 where expression was observed in tumor and stromal cells. Protein expression was statistically compared to the degree of immune cell infiltration and microvessel density in epithelial-derived ovarian tumors and a significant correlation was observed for both. It was demonstrated that ovarian tumor tissue lysates and ovarian cancer cell lines express hCAP-18/LL-37. Treatment of ovarian cancer cell lines with recombinant LL-37 stimulated proliferation, chemotaxis, invasion and matrix metalloproteinase expression. These data demonstrate for the first time that hCAP-18/LL-37 is significantly overexpressed in ovarian tumors and suggest LL-37 may contribute to ovarian tumorigenesis through direct stimulation of tumor cells, initiation of angiogenesis and recruitment of immune cells. These data provide further evidence of the existing relationship between pro-inflammatory molecules and ovarian cancer progression. ' 2007 Wiley-Liss, Inc.

Magnetic nanoparticles enhance the anticancer activity of cathelicidin LL-37 peptide against colon cancer cells

“…In vitro studies revealed that ovarian cancer cells treated with LL-37 are activated to proliferate at a rate similar to that for other mitogens, such as epidermal growth factor. 18 Similarly, higher proliferation was observed in breast cancer cells overexpressing LL-37. 19 The mitogenic effects of LL-37 on lung cancer cells and lung cancer xenografts are accompanied by phosphorylation of the epidermal growth factor receptor and subsequent activation of the Ras/mitogen-activated protein kinase cascade.…”

The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells

“…MSC-conditioned medium was analyzed by a luminex-based assay. Zymography assays were performed as before (1). Quantification of band intensity was performed using ImageJ software.…”

“…istological examination of ovarian, breast, and lung tumors has shown that the pro-inf lammatory peptide LL-37 (leucine, leucine-37) is up-regulated in these malignancies (1)(2)(3). LL-37 was originally identified as a component of host defense peptides released by innate immune cells to combat microorganisms (4)(5)(6).…”

Alarmins: awaiting a clinical response

“…Human cationic antimicrobial protein 18 (hCAP-18) is the only known member of the cathelicidin family in humans. The active peptide LL-37 is overexpressed in breast, lung, and ovarian tumors, probably functioning as an autocrine survival factor (91)(92)(93). It may also promote tumor growth through angiogenesis and recruitment of CD45 + cells (69).…”