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 Hoon; Kim, Isaac Yi

doi:10.1002/pros.21369

Cited by 46 publications

(41 citation statements)

References 28 publications

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“…Chung et al showed that IL-6 promoted cell growth of hormone-refractory cells, but had no effect on the growth of hormone-dependent cell lines [113]. Addition of exogenous IL-6 to the culture media of LNCaP cells by several groups has resulted in a dose-dependent inhibition of cell growth with development of a neuroendocrine cell phenotype in some cases; whereas in some instances proliferation is increased [113][114][115][116][117][118][119]. The reasons for these differences have not been clarified to date but it appears that IL-6 is only inhibitory to LNCaP cells, but not other PCa cell lines [120].…”

Section: Interleukin-6mentioning

confidence: 99%

“…Rojas et al demonstrated that IL-6, through activation of signal transducer and activator of transcription 3 (STAT3), stimulated autocrine activation of insulin-like type I growth factor receptor (IGF-IR) to confer tumorigenesis [125]. In addition to tumorigenesis, IL-6 has been suggested to induce neuroendocrine differentiation of PCa tumors [115]. Specifically, it was shown that PCa cellproduced BMP6 induced IL-6 expression from TAMs, Osteoblasts As key mediators of bone mineralization, osteoblasts are the effectors that produce bone mineral in response to PCa metastases resulting in the osteoblastic phenotype.…”

Section: Interleukin-6mentioning

confidence: 99%

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The PCa Tumor Microenvironment

Sottnik

Zhang

Macoska

et al. 2011

Cancer Microenvironment

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The tumor microenvironment (TME) is a very complex niche that consists of multiple cell types, supportive matrix and soluble factors. Cells in the TME consist of both host cells that are present at tumor site at the onset of tumor growth and cells that are recruited in either response to tumor-or host-derived factors. PCa (PCa) thrives on crosstalk between tumor cells and the TME. Crosstalk results in an orchestrated evolution of both the tumor and microenvironment as the tumor progresses. The TME reacts to PCa-produced soluble factors as well as direct interaction with PCa cells. In return, the TME produces soluble factors, structural support and direct contact interactions that influence the establishment and progression of PCa. In this review, we focus on the host side of the equation to provide a foundation for understanding how different aspects of the TME contribute to PCa progression. We discuss immune effector cells, specialized niches, such as the vascular and bone marrow, and several key protein factors that mediate host effects on PCa. This discussion highlights the concept that the TME offers a potentially very fertile target for PCa therapy.

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Section: Interleukin-6mentioning

confidence: 99%

Section: Interleukin-6mentioning

confidence: 99%

The PCa Tumor Microenvironment

Sottnik

Zhang

Macoska

et al. 2011

Cancer Microenvironment

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“…The therapeutic lifespan of these drugs is relatively short, and there is a growing sentiment in the field that the resolution of the problem of resistance does not lie in the development of better AR antagonists/steroid synthesis inhibitors. This position is supported by a large amount of data indicating that the current approaches to achieve androgen ablation can interrupt regulatory feedback loops leading to (a) upregulation of steroidogenesis [6, 7], (b) increased receptor and coregulator expression [8, 9], (c) neuroendocrine differentiation of PCa cells [10, 11], and (d) the selection for gene translocations/RNA splicing events or receptor mutations that result in the production of constitutively active AR variants [12–14]. These activities have been confirmed in human tumors and hence are likely to contribute in a significant manner to treatment failure [15].…”

Section: Introductionmentioning

confidence: 99%

Copper Signaling Axis as a Target for Prostate Cancer Therapeutics

et al. 2014

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Previously published reports indicate that serum copper levels are elevated in prostate cancer (PCa) patients and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for PCa cell function as we observed only modest effects of chelation strategies on the growth of these cells in vitro. With the goal of exploiting PCa cell proclivity for copper uptake, we developed a “conditional lethal” screen to identify compounds whose cytotoxic actions were manifest in a copper-dependent manner. Emerging from this screen were a series of dithiocarbamates, which when complexed with copper, induced Reactive Oxygen Species (ROS)-dependent apoptosis of malignant, but not normal, prostate cells. One of the dithiocarbamates identified, Disulfiram (DSF), is an FDA approved drug that has previously yielded disappointing results in clinical trials in patients with recurrent prostate cancer. Similarly, in our studies DSF alone had a minimal effect on the growth of PCa tumors when propagated as xenografts. However, when DSF was coadministered with copper a very dramatic inhibition of tumor growth in models of hormone sensitive and of castrate resistant disease was observed. Furthermore, we determined that prostate cancer (PCa) cells express high levels of CTR1, the primary copper transporter, and additional chaperones that are required to maintain intracellular copper homeostasis. The expression levels of most of these proteins are increased further upon treatment of AR-positive PCa cell lines with androgens. Not surprisingly robust CTR1-dependent uptake of copper into PCa cells was observed; an activity that was accentuated by activation of androgen receptor (AR). Given these data linking AR to intracellular copper uptake, we believe that dithiocarbamate/copper complexes are likely to be effective for the treatment of PCa patients whose disease is resistant to classical androgen ablation therapies.

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“…More recently, an association between enzalutamide treatment and neuroendocrine (NE) differentiation was reported [59]. The most important feature of NE cells is the insensitivity to androgens due to the absence of nuclear AR [60]. To overcome these limitations of enzalutamide treatment, combination with other agents or sequential therapies should be explored via clinical trials.…”

Section: Expert Opinionmentioning

confidence: 97%

Enzalutamide: looking back at its preclinical discovery

Kim

2014

Expert Opinion on Drug Discovery

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The landscape of CRPC has changed dramatically over the last few years, as new agents with proven benefit in overall survival have been approved. Compared to the average time of 10 - 15 years for a new drug to go from pre-clinical discovery to registration, enzalutamide obtained FDA approval in < 6 years after its initial characterization. Enzalutamide, a targeted agent of the androgen-AR axis, has shown promising results in CRPC and is generally well tolerated. However, drug resistance inevitably emerges is a severe limitation. The authors believe that further clinical studies that look at its use as either a combinational or sequential therapy could help to address these concerns.

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

Abstract: 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.

Cited by 46 publications

References 28 publications

The PCa Tumor Microenvironment

The PCa Tumor Microenvironment

Copper Signaling Axis as a Target for Prostate Cancer Therapeutics

Enzalutamide: looking back at its preclinical discovery

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