Interleukin-1β Promotes Skeletal Colonization and Progression of Metastatic Prostate Cancer Cells with Neuroendocrine Features

Abstract

Despite the progress made in the early detection and treatment of prostate adenocarcinoma, the metastatic lesions from this tumor are incurable. We used genome-wide expression analysis of human prostate cancer cells with different metastatic behavior in animal models to reveal that bone-tropic phenotypes upregulate three genes encoding for the cytokine interleukin-1b (IL-1b), the chemokine CXCL6 (GCP-2), and the protease inhibitor elafin (PI3). The Oncomine database revealed that these three genes are significantly upregulated in human prostate cancer versus normal tissue and correlate with Gleason scores !7. This correlation was further validated for IL-1b by immunodetection in prostate tissue arrays. Our study also shows that the exogenous overexpression of IL-1b in nonmetastatic cancer cells promotes their growth into large skeletal lesions in mice, whereas its knockdown significantly impairs the bone progression of highly metastatic cells. In addition, IL-1b secreted by metastatic cells induced the overexpression of COX-2 (PTGS2) in human bone mesenchymal cells treated with conditioned media from bone metastatic prostate cancer cells. Finally, we inspected human tissue specimens from skeletal metastases and detected prostate cancer cells positive for both IL-1b and synaptophysin while concurrently lacking prostate-specific antigen (PSA, KLK3) expression. Collectively, these findings indicate that IL-1b supports the skeletal colonization and metastatic progression of prostate cancer cells with an acquired neuroendocrine phenotype. Cancer Res; 73(11); 3297-305. Ó2013 AACR.

Bioengineered Implantable Scaffolds as a Tool to Study Stromal-Derived Factors in Metastatic Cancer Models

“…The elevation in IL-1β expression may therefore be even greater in a pure stromal cell population. These clinical correlations are consistent with previous reports of IL-1 expression in several invasive tumor types (33, 36, 37). …”

“…In our experiments, IL-1β expression was detected within stromal cells of tumor-bearing but not tumor-free scaffolds, and its role in enhancing metastatic seeding of the bioengineered scaffold by prostate PC-3 cancer cells was supported by the effectiveness of a receptor antagonist administered systemically. Our observations are consistent with a recent report of increased bone metastases following intracardiac injection of IL-1β-transduced prostate cancer cells in the mouse (37). In these experiments, knockdown of endogenous IL-1β within injected tumor cells had no effect in reducing the frequency of metastatic lesions, supporting our observation that stromal cell expression may be the more physiological source of this cytokine, rather than tumor cells.…”

Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone

“…In mice, CXCL5 exhibits a predominant role in the neutrophil influx to the lung as a result of inflammation induced by LPS inhalation, which aligns with its role in human inflammatory diseases as a neutrophil chemoattractant (38). The expression of CXCL6, a human homolog of mouse CXCL5 (60), was significantly upregulated in prostate cancer tissues and correlated with high Gleason scores (≥7) (61). However, analysis of blood serum from prostate cancer bone-metastatic patients revealed differences in CXCL5 when comparing with normal or high-risk localized cancer, while no significant differences were observed for CXCL6.…”

Hydrogel dual delivered celecoxib and anti-PD-1 synergistically improve antitumor immunity

“…14,15 The combinatorial use of celecoxib with PD-1 mAb completely suppresses the upregulation of the inflammatory genes, including IL-1b and IL-6, both of which play critical roles in promoting tumor progression. 48,49 This observation provides the additional justification for the combined utilization of these two drugs for treating tumors. Further, celecoxib coordinated with anti-PD-1 mAb promotes the expression of two anti-angiogenic chemokines, CXCL9 and CXCL10.…”