Abstract
Study BackgroundThe tumor microenvironment contains inflammatory cells which can influence cancer growth and progression; however the mediators of these effects vary with different cancer types. The mechanisms by which prostate cancer cells communicate with monocytes to promote cancer progression are incompletely understood. This study tested prostate cancer cell and monocyte interactions that lead to increased prostate cancer cell invasion.MethodsWe analyzed the prostate cancer cell invasion and NF-κB activity and cytokine expression during interaction with monocyte-lineage cells in co-cultures. The roles of monocyte chemotactic factor (MCP-1/CCL2) and NF-κB activity for co-culture induced prostate cancer invasion were tested. Clinical prostate cancer NF-κB expression was analyzed by immunohistochemistry.ResultsIn co-cultures of prostate cancer cell lines with monocyte-lineage cells, (C-C motif) ligand 2 (CCL2) levels were significantly increased when compared with monocytes or cancer cells cultured alone. Prostate cancer cell invasion was induced by recombinant CCL2 in a dose dependent manner, similar to co-cultures with monocytes. The monocyte-induced prostate cancer cell invasion was inhibited by CCL2 neutralizing antibodies and by the CCR2 inhibitor, RS102895. Prostate cancer cell invasion and CCL2 expression induced in the co-cultures was inhibited by Lactacystin and Bay11-7082 NF-κB inhibitors. Prostate cancer cell NF-κB DNA binding activity depended on CCL2 dose and was inhibited by CCL2 neutralizing antibodies. Clinical prostate cancer NF-κB expression correlated with tumor grade.ConclusionsCo-cultures with monocyte-lineage cell lines stimulated increased prostate cancer cell invasion through increased CCL2 expression and increased prostate cancer cell NF-κB activity. CCL2 and NF-κB may be useful therapeutic targets to interfere with inflammation-induced prostate cancer invasion.
Highlights
Prostate cancer is the most common malignancy in American men and metastases are responsible for most prostate cancer mortality
CCL2 and NF-κB may be useful therapeutic targets to interfere with inflammationinduced prostate cancer invasion
The data in this study showed that increased prostate cancer cell invasion and NF-κB activation were induced by high CCL2 expression found in the co-cultures
Summary
Prostate cancer is the most common malignancy in American men and metastases are responsible for most prostate cancer mortality. Tumor-associated macrophages (TAM) and stromal cells may support tumor progression by promoting angiogenesis, immune suppression or direct effects on tumor cells. Co-cultures of breast cancer cells and monocytes have been shown to express cell-secreted factors which cause paracrine stimulation of tumor growth and progression [7,8,9,10]. Several tumor specific cell-secreted factors have been identified that mediate interactions between cancer cells and monocytes [8,9,10,11,12,13]. Paracrine stimulation of prostate cancer cells and monocytes has been hypothesized; studies are needed to determine precisely how prostate cancer cells and monocytes cross-communicate to promote prostate cancer growth and progression [14,15]
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