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Monocyte-Induced Prostate Cancer Cell Invasion is Mediated by Chemokine ligand 2 and Nuclear Factor-κB Activity.

Lindholm PF, Sivapurapu N, Jovanovic B, Kajdacsy-Balla A - J Clin Cell Immunol (2015)

Bottom Line: 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.CCL2 and NF-κB may be useful therapeutic targets to interfere with inflammation-induced prostate cancer invasion.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, Northwestern University, The Feinberg School of Medicine, Chicago, USA.

ABSTRACT

Study background: The 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.

Methods: We 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.

Results: In 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.

Conclusions: Co-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.

No MeSH data available.


Related in: MedlinePlus

CCL2 levels from prostate cancer cells cultured alone or co-cultured with U-937 cells. (A) The PC-3 High Invasion prostate cancer cells cultured alone expressed very low supernatant levels of CCL2 compared with U-937 cells and PC-3 High Invasion/U-937 co-culture supernatants. Also, significantly increased CCL2 levels were detected in the supernatants of U-937 cells co-cultured with DU145 and LNCaP prostate cancer cells. Data are expressed as the mean ± SD of 4 independent experiments. **P<0.001. (B) Increased CCL2 levels (>30 pg/100 μg extract) were detected in the adherent cell extracts from co-cultures of PC-3 High Invasive, DU145 and LNCaP with U-937 cells when compared with the cancer cells alone. The non-adherent cell extracts from PC-3 High Invasive/U-937 and LNCaP/U-937 co-cultures showed similar CCL2 levels as the U-937 cell extracts. Non-adherent cell extracts from DU145/LNCaP co-cultures were increased above U-937 cell extracts. The data are representative of 4 independent experiments.
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Figure 4: CCL2 levels from prostate cancer cells cultured alone or co-cultured with U-937 cells. (A) The PC-3 High Invasion prostate cancer cells cultured alone expressed very low supernatant levels of CCL2 compared with U-937 cells and PC-3 High Invasion/U-937 co-culture supernatants. Also, significantly increased CCL2 levels were detected in the supernatants of U-937 cells co-cultured with DU145 and LNCaP prostate cancer cells. Data are expressed as the mean ± SD of 4 independent experiments. **P<0.001. (B) Increased CCL2 levels (>30 pg/100 μg extract) were detected in the adherent cell extracts from co-cultures of PC-3 High Invasive, DU145 and LNCaP with U-937 cells when compared with the cancer cells alone. The non-adherent cell extracts from PC-3 High Invasive/U-937 and LNCaP/U-937 co-cultures showed similar CCL2 levels as the U-937 cell extracts. Non-adherent cell extracts from DU145/LNCaP co-cultures were increased above U-937 cell extracts. The data are representative of 4 independent experiments.

Mentions: CCL2 was measured at very low levels (<10 pg/mL) by enzyme-linked immunosorbent assays (ELISA) in prostate cancer cell supernatants and U-937 supernatants (147.5 ± 24 pg/mL)(Figure 3A). In the PC-3 High Invasive/U-937 and DU145/U-937 co-culture supernatants, CCL2 increased to 638 ± 17 pg/mL and 600 ± 45 pg/mL, respectively (Figure 3A). Similarly, in LNCaP/U-937 co-culture supernatants, CCL2 was increased from less than 10 pg/mL to 358 pg/mL (Figure 4A).


Monocyte-Induced Prostate Cancer Cell Invasion is Mediated by Chemokine ligand 2 and Nuclear Factor-κB Activity.

Lindholm PF, Sivapurapu N, Jovanovic B, Kajdacsy-Balla A - J Clin Cell Immunol (2015)

CCL2 levels from prostate cancer cells cultured alone or co-cultured with U-937 cells. (A) The PC-3 High Invasion prostate cancer cells cultured alone expressed very low supernatant levels of CCL2 compared with U-937 cells and PC-3 High Invasion/U-937 co-culture supernatants. Also, significantly increased CCL2 levels were detected in the supernatants of U-937 cells co-cultured with DU145 and LNCaP prostate cancer cells. Data are expressed as the mean ± SD of 4 independent experiments. **P<0.001. (B) Increased CCL2 levels (>30 pg/100 μg extract) were detected in the adherent cell extracts from co-cultures of PC-3 High Invasive, DU145 and LNCaP with U-937 cells when compared with the cancer cells alone. The non-adherent cell extracts from PC-3 High Invasive/U-937 and LNCaP/U-937 co-cultures showed similar CCL2 levels as the U-937 cell extracts. Non-adherent cell extracts from DU145/LNCaP co-cultures were increased above U-937 cell extracts. The data are representative of 4 independent experiments.
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Figure 4: CCL2 levels from prostate cancer cells cultured alone or co-cultured with U-937 cells. (A) The PC-3 High Invasion prostate cancer cells cultured alone expressed very low supernatant levels of CCL2 compared with U-937 cells and PC-3 High Invasion/U-937 co-culture supernatants. Also, significantly increased CCL2 levels were detected in the supernatants of U-937 cells co-cultured with DU145 and LNCaP prostate cancer cells. Data are expressed as the mean ± SD of 4 independent experiments. **P<0.001. (B) Increased CCL2 levels (>30 pg/100 μg extract) were detected in the adherent cell extracts from co-cultures of PC-3 High Invasive, DU145 and LNCaP with U-937 cells when compared with the cancer cells alone. The non-adherent cell extracts from PC-3 High Invasive/U-937 and LNCaP/U-937 co-cultures showed similar CCL2 levels as the U-937 cell extracts. Non-adherent cell extracts from DU145/LNCaP co-cultures were increased above U-937 cell extracts. The data are representative of 4 independent experiments.
Mentions: CCL2 was measured at very low levels (<10 pg/mL) by enzyme-linked immunosorbent assays (ELISA) in prostate cancer cell supernatants and U-937 supernatants (147.5 ± 24 pg/mL)(Figure 3A). In the PC-3 High Invasive/U-937 and DU145/U-937 co-culture supernatants, CCL2 increased to 638 ± 17 pg/mL and 600 ± 45 pg/mL, respectively (Figure 3A). Similarly, in LNCaP/U-937 co-culture supernatants, CCL2 was increased from less than 10 pg/mL to 358 pg/mL (Figure 4A).

Bottom Line: 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.CCL2 and NF-κB may be useful therapeutic targets to interfere with inflammation-induced prostate cancer invasion.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, Northwestern University, The Feinberg School of Medicine, Chicago, USA.

ABSTRACT

Study background: The 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.

Methods: We 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.

Results: In 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.

Conclusions: Co-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.

No MeSH data available.


Related in: MedlinePlus