Macrophages induce neuroendocrine differentiation of prostate cancer cells via BMP6-IL6 Loop

Geun Taek Lee, Seok Joo Kwon, Jae Ho Lee, Seong Soo Jeon, Kee Taek Jang, Han Yong Choi, Hyun Moo Lee, Wun Jae Kim, Dong Hyeon Lee, Isaac Kim

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1525-1537
Number of pages13
JournalProstate
Volume71
Issue number14
DOIs
StatePublished - Oct 1 2011

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Interleukin-6
Prostatic Neoplasms
Macrophages
Bone Morphogenetic Protein 6
Neuroendocrine Cells
Hormones
Parathyroid Hormone-Related Protein
Cell Line
Castration
Differentiation Antigens
Androgen Receptors
Conditioned Culture Medium
Coculture Techniques
Neutralizing Antibodies
Knockout Mice

All Science Journal Classification (ASJC) codes

  • Oncology
  • Urology

Keywords

  • IL-6
  • bone morphogenetic protein-6
  • cytokines
  • macrophages
  • neuroendocrine-like prostate cancer cell
  • transdifferentiation

Cite this

Lee, G. T., Kwon, S. J., Lee, J. H., Jeon, S. S., Jang, K. T., Choi, H. Y., ... Kim, I. (2011). Macrophages induce neuroendocrine differentiation of prostate cancer cells via BMP6-IL6 Loop. Prostate, 71(14), 1525-1537. https://doi.org/10.1002/pros.21369
Lee, Geun Taek ; Kwon, Seok Joo ; Lee, Jae Ho ; Jeon, Seong Soo ; Jang, Kee Taek ; Choi, Han Yong ; Lee, Hyun Moo ; Kim, Wun Jae ; Lee, Dong Hyeon ; Kim, Isaac. / Macrophages induce neuroendocrine differentiation of prostate cancer cells via BMP6-IL6 Loop. In: Prostate. 2011 ; Vol. 71, No. 14. pp. 1525-1537.
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abstract = "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.",
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Lee, GT, Kwon, SJ, Lee, JH, Jeon, SS, Jang, KT, Choi, HY, Lee, HM, Kim, WJ, Lee, DH & Kim, I 2011, 'Macrophages induce neuroendocrine differentiation of prostate cancer cells via BMP6-IL6 Loop', Prostate, vol. 71, no. 14, pp. 1525-1537. https://doi.org/10.1002/pros.21369

Macrophages induce neuroendocrine differentiation of prostate cancer cells via BMP6-IL6 Loop. / Lee, Geun Taek; Kwon, Seok Joo; Lee, Jae Ho; Jeon, Seong Soo; Jang, Kee Taek; Choi, Han Yong; Lee, Hyun Moo; Kim, Wun Jae; Lee, Dong Hyeon; Kim, Isaac.

In: Prostate, Vol. 71, No. 14, 01.10.2011, p. 1525-1537.

Research output: Contribution to journalArticle

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T1 - Macrophages induce neuroendocrine differentiation of prostate cancer cells via BMP6-IL6 Loop

AU - Lee, Geun Taek

AU - Kwon, Seok Joo

AU - Lee, Jae Ho

AU - Jeon, Seong Soo

AU - Jang, Kee Taek

AU - Choi, Han Yong

AU - Lee, Hyun Moo

AU - Kim, Wun Jae

AU - Lee, Dong Hyeon

AU - Kim, Isaac

PY - 2011/10/1

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N2 - 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.

AB - 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.

KW - IL-6

KW - bone morphogenetic protein-6

KW - cytokines

KW - macrophages

KW - neuroendocrine-like prostate cancer cell

KW - transdifferentiation

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Lee GT, Kwon SJ, Lee JH, Jeon SS, Jang KT, Choi HY et al. Macrophages induce neuroendocrine differentiation of prostate cancer cells via BMP6-IL6 Loop. Prostate. 2011 Oct 1;71(14):1525-1537. https://doi.org/10.1002/pros.21369