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Published on: December 14, 2019
Macrophages of M1 phenotype have properties that influence lung cancer cell progression
Alexander Hedbrant1, Jonny Wijkander1, Tomas Seidal1
1Department of Health Sciences, Karlstad University, 651 88, Karlstad, Sweden.
Abstract:
Stromal macrophages of different phenotypes can contribute to the expression of proteins that affects metastasis such as urokinase-type plasminogen activator (uPA), its receptor uPAR, and plasminogen activator inhibitor-1 (PAI-1), but knowledge of how essential their contribution is in comparison to the cancer cells in small cell lung cancer (SCLC) and lung squamous cell carcinoma (SCC) is lacking. The expression of uPA, uPAR, and PAI-1 and of the matrix metalloproteinases (MMP)-2 and MMP-9 were studied in human macrophages of M1 and M2 phenotype and compared to a lung SCC (NCI-H520) and a SCLC (NCI-H69) cell line. Effects of treatment with conditioned media (CM) from M1 and M2 macrophages on the expression of these genes in H520 and H69 cells as well as effects on the cell growth were investigated. In addition, data on the stromal macrophages immunoreactivity of uPAR, MMP-2, and MMP-9 in a few SCC and SCLC biopsies was included. uPAR, MMP-2, and MMP-9 were confirmed in stromal cells including macrophages in the SCC and SCLC biopsies. In vitro, both macrophage phenotypes expressed considerably higher mRNA levels of uPA, uPAR, PAI-1, and MMP-9 compared to the cancer cell lines, and regarding uPAR, the highest level was found in the M1 macrophage phenotype. Furthermore, M1 CM treatment not only induced an upregulation of PAI-1 in both H520 and H69 cells but also inhibited cell growth in both cell lines, giving M1 macrophages both tumor-promoting and tumor-killing potential.
Insights
Stromal macrophages, particularly M1 phenotype, significantly influence metastasis-related proteins like urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMP) in lung cancers. M1 macrophages exhibit dual roles, promoting and inhibiting tumor growth.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Stromal macrophages are implicated in cancer metastasis through protein expression, but their comparative role versus cancer cells in lung cancers remains unclear.
- Key proteins involved in metastasis include urokinase-type plasminogen activator (uPA), its receptor uPAR, plasminogen activator inhibitor-1 (PAI-1), and matrix metalloproteinases (MMP-2, MMP-9).
Purpose of the Study:
- To compare the expression of metastasis-associated genes (uPA, uPAR, PAI-1, MMP-2, MMP-9) in M1 and M2 macrophages versus small cell lung cancer (SCLC) and lung squamous cell carcinoma (SCC) cell lines.
- To investigate the effects of macrophage-conditioned media on cancer cell gene expression and growth.
- To analyze the in-situ presence of uPAR, MMP-2, and MMP-9 in lung cancer biopsies.
Main Methods:
- Quantitative analysis of mRNA expression in M1/M2 macrophages and NCI-H520 (SCC) / NCI-H69 (SCLC) cell lines.
- Treatment of cancer cell lines with conditioned media (CM) from M1 and M2 macrophages.
- Immunohistochemical analysis of tumor biopsies for uPAR, MMP-2, and MMP-9 expression in stromal cells.
Main Results:
- Macrophages, especially M1 phenotype, expressed significantly higher levels of uPA, uPAR, PAI-1, and MMP-9 mRNA compared to cancer cell lines.
- M1 macrophage-conditioned media upregulated PAI-1 in both SCC and SCLC cells and inhibited their growth.
- uPAR, MMP-2, and MMP-9 were detected in stromal cells, including macrophages, within SCC and SCLC biopsies.
Conclusions:
- Stromal macrophages, particularly M1 phenotype, play a substantial role in expressing key proteins affecting metastasis in lung cancer.
- M1 macrophages demonstrate a dual role, potentially promoting metastasis via PAI-1 upregulation and inhibiting tumor growth simultaneously.
- These findings highlight the complex interplay between macrophages and cancer cells in SCLC and SCC progression.
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