Interleukin‐6 induces VEGF secretion from prostate cancer cells in a manner independent of androgen receptor activation

Ishii, Kenichiro; Sasaki, Takeshi; Iguchi, Kazuhiro; Kajiwara, Shinya; Kato, Manabu; Kanda, Hideki; Hirokawa, Yoshifumi; Arima, Kiminobu; Mizokami, Atsushi; Sugimura, Yoshiki

doi:10.1002/pros.23643

Cited by 24 publications

(28 citation statements)

References 32 publications

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“…At the time of PSA progression, relative elevations (as compared with the 3‐month time point) were noted in IL‐6, VEGF, and IL‐27. These data are consistent with copious literature implicating IL‐6 as a pro‐inflammatory driver of PCa progression . However, these data show an association and do not prove causality.…”

Section: Discussionsupporting

confidence: 85%

Association between immunosuppressive cytokines and PSA progression in biochemically recurrent prostate cancer treated with intermittent hormonal therapy

et al. 2020

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Background: Immunosuppressive cytokines have the potential to promote prostate cancer progression. Assessing their longitudinal changes may implicate mechanisms of progression, treatment resistance, and suggest new therapeutic targets.Methods: Thirty-seven men with biochemically recurrent (BCR) prostate cancer who received 6 months of androgen deprivation therapy (ADT) and were monitored until the time to prostate-specific antigen progression (TTPP) were identified from a completed phase III trial (NCT00020085). Serum samples were archived at baseline, 3 months after ADT, and at TTPP. Cytokine concentrations were quantified using a 36-parameter electrochemiluminescence assay. The Wilcoxon signed-rank sum test was used to compare observations between time points. Kaplan-Meier analysis was used to calculate TTPP dichotomized by cytokine values above or below the median.Pearson's rank correlation coefficient was used to compare continuous variables.Results: Median TTPP was 399 days (range, 114-1641). Median prostate-specific antigen (PSA) at baseline and progression were 8.5 and 5.3 ng/mL, respectively.Twenty-three patients (62%) achieved undetectable PSA with ADT. Castrate levels of testosterone (<50 ng/dL) after 3 months of ADT occurred in 35 patients (95%). TNF-α (P = .002), IL-23 (P = .002), and CXCL10 (P = .001) significantly increased from baseline to post ADT. Certain cytokines correlated longitudinally: TNF-α correlated with IL-23 (r = .72; P < .001) and IL-8 (r = .59; P < .001) from baseline to post ADT and to PSA progression. Neutrophil-to-lymphocyte ratio correlated with IL-27 (r = .57; P < .001) and MIP-3α (r = .56; P < .001). Patients with a detectable PSA after ADT had elevated levels of IL-6 (P = .049) and IL-8 (P = .013) at PSA progression as compared with those with an undetectable PSA. There was a trend toward shorter TTPP in patients with TNF-α levels above the median (P = .042).Conclusions: Several innate cytokines were associated with biochemically recurrent prostate cancer. K E Y W O R D S biochemical recurrence, IL-8, IL-23, TNF-α

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Section: Discussionsupporting

confidence: 85%

Association between immunosuppressive cytokines and PSA progression in biochemically recurrent prostate cancer treated with intermittent hormonal therapy

et al. 2020

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“…With respect to its requirement for cell viability and growth, most tellingly, one group studying astrocytes (Quintana et al, 2013;Quintana et al, 2008) found that while global IL-6R knockout (which leads to compensations) had a small effect, conditional knockout in astrocytes led to their apoptosis. In support of the involvement of IL-6R in cell growth, other papers have linked IL-6 to intestinal epithelial cell and fibroblast growth, VEGF-A secretion from prostate cancer cells (Ishii et al, 2018), bone metastases in breast cancer (Wakabayashi et al, 2018) and hepatocyte proliferation. Additionally, IL-6R has been linked to increased gp130 expression and upregulation of leukemia inhibitory factor (LIF), an alternative gp-130 signaling system able to compensate for IL-6R deficiency Liu et al, 2000).…”

Section: Discussionmentioning

confidence: 95%

VEGFR2 survival and mitotic signaling depends on joint activation of associated C3ar1/C5ar1 and IL-6R–gp130

Hwang

Strainic

Pohlmann

et al. 2019

Journal of Cell Science

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Purified vascular endothelial cell (EC) growth factor receptor-2 (VEGFR2) auto-phosphorylates upon VEGF-A occupation in vitro, arguing that VEGR2 confers its mitotic and viability signaling in and of itself. Herein, we show that, in ECs, VEGFR2 function requires concurrent C3a/C5a receptor (C3ar1/C5ar1) and IL-6 receptor (IL-6R)-gp130 co-signaling. C3ar1/C5ar1 or IL-6R blockade totally abolished VEGFR2 auto-phosphorylation, downstream Src, ERK, AKT, mTOR and STAT3 activation, and EC cell cycle entry.

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“…IL-6, which is produced by both PCa and stromal cells, is another fundamental player within the PCa microenvironment that influences many aspects of prostate tumorigenesis, including proliferation, angiogenesis, and insensitivity to androgens [40,125,126]. For example, CAF-secreted IL-6 induces VEGF secretion from PCa cells, stimulating tumor angiogenesis ( Figure 1) [40]. Due to its multiple effects on prostate TME, the clinical use of inhibitors of IL-6 or its related transcription factor STAT3 is under investigation [126].…”

Section: Caf-tumor Signaling: Paracrine Systemic Cell-cell Direct mentioning

confidence: 99%

“…Several studies indicate that CAFs also actively promote PCa resistance to anti-androgen therapies, thus inducing CRPC. CAF-derived IL-6 is involved in this process, with evidence suggesting that it could enable AR transcriptional activity in PCa cells in the absence of androgens by modulating MAPK, STAT3, and PI3K/AKT signaling [40,125]. In 3D co-culture models of CAFs/PCa cell lines, CAFs decrease the sensitivity to the anti-androgens bicalutamide and enzalutamide in a PI3K/Akt signaling-dependent manner [14].…”

Section: Caf-mediated Resistance To Androgen Deprivation and Chemothementioning

confidence: 99%

The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis

Bonollo

Thalmann

Julio

et al. 2020

Cancers

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Tumors strongly depend on their surrounding tumor microenvironment (TME) for growth and progression, since stromal elements are required to generate the optimal conditions for cancer cell proliferation, invasion, and possibly metastasis. Prostate cancer (PCa), though easily curable during primary stages, represents a clinical challenge in advanced stages because of the acquisition of resistance to anti-cancer treatments, especially androgen-deprivation therapies (ADT), which possibly lead to uncurable metastases such as those affecting the bone. An increasing number of studies is giving evidence that prostate TME components, especially cancer-associated fibroblasts (CAFs), which are the most abundant cell type, play a causal role in PCa since the very early disease stages, influencing therapy resistance and metastatic progression. This is highlighted by the prognostic value of the analysis of stromal markers, which may predict disease recurrence and metastasis. However, further investigations on the molecular mechanisms of tumor–stroma interactions are still needed to develop novel therapeutic approaches targeting stromal components. In this review, we report the current knowledge of the characteristics and functions of the stroma in prostate tumorigenesis, including relevant discussion of normal prostate homeostasis, chronic inflammatory conditions, pre-neoplastic lesions, and primary and metastatic tumors. Specifically, we focus on the role of CAFs, to point out their prognostic and therapeutic potential in PCa.

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Interleukin‐6 induces VEGF secretion from prostate cancer cells in a manner independent of androgen receptor activation

Abstract: Our results suggest that IL-6 might induce VEGF secretion from PCa cells in a manner independent of AR activation. To prevent IL-6-induced VEGF secretion, inhibition of the PI3K/AKT signaling pathway could be an important pharmacological goal regardless of ADT.

Cited by 24 publications

References 32 publications

Association between immunosuppressive cytokines and PSA progression in biochemically recurrent prostate cancer treated with intermittent hormonal therapy

Association between immunosuppressive cytokines and PSA progression in biochemically recurrent prostate cancer treated with intermittent hormonal therapy

VEGFR2 survival and mitotic signaling depends on joint activation of associated C3ar1/C5ar1 and IL-6R–gp130

The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis

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