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Abstract
Tumor-associated macrophages have been shown to promote tumor growth. They may have an obligatory function in angiogenesis, invasion, and metastasis through release of inflammatory mediators. Their presence in ovarian cancer has been correlated with poor prognosis in these patients. The human cationic antimicrobial protein-18 (hCAP18)/LL-37 was originally identified as an effector molecule of the innate immune system. It is released by innate immune cells, such as macrophages, to combat microorganisms. Previous studies have characterized the hCAP18/LL-37 as a growth factor that has been shown to promote ovarian tumor progression. However, the role hCAP18/LL-37 has in macrophage-promoted ovarian tumor development and how its expression is controlled in this context remains poorly understood. Here, we demonstrate in co-culture experiments of macrophages and ovarian cancer cells a significant increase in the in vitro proliferation and invasiveness of the tumor cells is observed. These enhanced growth and invasion properties correlated with hCAP18/LL-37 induction. HCAP18/LL-37 expression was diminished by addition of two neutralizing antibodies, TLR2 or TLR6, as well as Cyp27B1 or VDR inhibitors. Furthermore, either the TLR2 or TLR6 antibody reduced vitamin D3 signaling and tumor cell progression in vitro. Addition of Cyp27B1 or VDR inhibitors abrogated TLR2/6 activation-induced expression of hCAP18/LL-37 in macrophages. Knockdown of tumor-produced versican V1 by RNAi in these tumor cells led to a decreased induction of hCAP18/LL-37 in macrophages. Versican V1 knockdown also inhibited TLR2 and vitamin D3 signaling, as well as growth and invasiveness of these tumor cells in the in vitro co-culture. In summary, we have found that versican V1 enhances hCAP18/LL-37 expression in macrophages through activation of TLR2 and subsequent vitamin D-dependent mechanisms which promote ovarian tumor progression in vitro.
Highlights
A tumor microenvironment plays a critical role in tumor initiation and promotion
Tumor-associated macrophages (TAMs) replaced with peripheral blood monocyte-derived macrophages for in vitro co-culture experiment had been reported by various groups
Human peripheral blood monocyte-derived macrophages were placed in transwell inserts and various ovarian cancer cell lines were seeded on the bottom of 24-well plates
Summary
A tumor microenvironment plays a critical role in tumor initiation and promotion. This unique microenvironment contains innate immune cells, lymphocytes and connective tissue as well as malignant cells [1]. Innate immune cells ( known as myeloid cells), include macrophages, release cytokines and chemokines as well as influence tumorigenesis [1,2,3]. Tumor-associated macrophages (TAMs) are an important component of inflammatory infiltrates in tumors. There is a growing body of evidence that several pro-inflammatory factors produced by macrophages, promote tumor growth, angiogenesis, invasion, and metastases [1,5,9]. The actual role a number of key pro-inflammatory molecules have in tumor promotion and their mechanisms of expression and function remains poorly understood
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