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Updated: Jun 3, 2026
Macrophage Differentiation and Polarization into an M2-Like Phenotype using a Human Monocyte-Like THP-1 Leukemia Cell Line
Published on: August 2, 2021
Macrophages induce neuroendocrine differentiation of prostate cancer cells via BMP6-IL6 Loop
Geun Taek Lee1, Seok Joo Kwon, Jae-Ho Lee
1Section of Urologic Oncology, Dean and Betty Gallo Prostate Cancer Center, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey.
Background:
Frequently associated with hormone refractory prostate cancer are neuroendocrine cells. Because these cells do not express androgen receptors and are castration-resistant, further understanding the mechanism of neuroendocrine differentiation (NED) of prostate cancer cells may yield novel intervention methods in hormone refractory prostate cancer. In this regard, the present study investigated the effect of macrophages on prostate cancer NED.
Methods:
THP-1 and LNCaP or RAW264.7 and TRAMP-C2 cell line co-cultures were used to investigate NED-macrophage interactions. Also interleukin-6 (IL-6) knockout mice and macrophage-depleted mice were used to test NED in vivo.
Results:
We found that co-culturing with THP-1 human monocytic cell line and RAW 264.7 murine macrophage cell line led to the NED of LNCaP and TRAMP-C2 prostate cancer cells, respectively. Specifically, the conditioned media of activated macrophages stimulated the expression of parathyroid hormone-related peptide (PTHrP), a marker of NED, in both LNCaP and TRAMP-C2 cells. Mechanistically, bone morphogenetic protein-6 (BMP-6) derived from prostate cancer cells increased the expression of IL-6 in macrophages. Subsequently, IL-6 induced the NED of prostate cancer cells. When this feedback loop was disrupted with neutralizing antibodies to either BMP-6 or IL-6, NED was no longer observed. In human prostate cancer tissues, neuroendocrine cells frequently co-localized with macrophages and BMP-6. In mice, the removal of IL-6 or macrophages blocked the BMP-6-induced NED of prostate cancer cells.
Conclusions:
Therefore, we propose that BMP-6 secreted by prostate cancer cells induces IL-6 expression in macrophages; IL-6, in turn, stimulates the NED of prostate cancer cells.
Insights
Macrophages promote prostate cancer neuroendocrine differentiation (NED) via a BMP-6/IL-6 pathway. Blocking this interaction inhibits NED, offering potential therapeutic targets for hormone-refractory prostate cancer.
Area of Science:
- Oncology
- Cell Biology
- Immunology
Background:
- Neuroendocrine cells are linked to hormone-refractory prostate cancer and lack androgen receptors.
- Understanding neuroendocrine differentiation (NED) is crucial for developing new treatments for castration-resistant prostate cancer.
Purpose of the Study:
- To investigate the role of macrophages in prostate cancer neuroendocrine differentiation (NED).
Main Methods:
- Co-culture systems using human (THP-1, LNCaP) and murine (RAW264.7, TRAMP-C2) cell lines.
- In vivo studies using interleukin-6 (IL-6) knockout and macrophage-depleted mice.
Main Results:
- Macrophage co-culture induced NED in prostate cancer cells, marked by increased parathyroid hormone-related peptide (PTHrP) expression.
- A feedback loop was identified: prostate cancer cell-derived bone morphogenetic protein-6 (BMP-6) induced IL-6 in macrophages, which in turn promoted NED.
- Disruption of the BMP-6/IL-6 pathway using neutralizing antibodies blocked NED in vitro and in vivo.
Conclusions:
- Prostate cancer cell-secreted BMP-6 stimulates IL-6 production in macrophages.
- Macrophage-derived IL-6 drives neuroendocrine differentiation in prostate cancer cells.
- This BMP-6/IL-6 signaling axis represents a potential therapeutic target for hormone-refractory prostate cancer.
