Research Article: Nur77 deficiency in mice accelerates tumor invasion and metastasis by facilitating TNFα secretion and lowering CSF-1R expression

Date Published: February 7, 2017

Publisher: Public Library of Science

Author(s): Xiu-Ming Li, Jing-Ru Wang, Tong Shen, Shang-Shang Gao, Xiao-Shun He, Jiang-Nan Li, Tian-Yu Yang, Shen Zhang, Wen-Juan Gan, Jian-Ming Li, Hua Wu, Aamir Ahmad.

http://doi.org/10.1371/journal.pone.0171347

Abstract

Nur77, an orphan member of the nuclear receptor superfamily, plays critical roles in inflammation and immunity. However, the role of Nur77 in tumor microenvironment remains elusive. Results showed that deletion of Nur77 strikingly enhanced tumor metastasis compared to WT mice. Additionally, compared to the conditioned media derived from Nur77+/+ peritoneal macrophages (CM1), the conditioned media derived from Nur77-/- peritoneal macrophages (CM2) significantly promoted the EMT of cancer cells, and greatly enhanced the migratory and invasive abilities of cancer cells. Moreover, studies using TNF-α blocking antibody demonstrated that pro-inflammatory cytokine TNF-α was indispensable in supporting CM2-induced EMT to drive cancer cells migration and invasion. Furthermore, we found that Nur77 promoted the expression of CSF-1R, a novel downstream target gene of Nur77, and subsequently enhanced the migration of inflammatory cells. Notably, infiltration of inflammatory cells in the tumors of Nur77-/- mice was markedly abrogated compared to Nur77+/+ mice. Collectively, these results revealed that host Nur77 expression was pivotal in antitumor immune response, and in inhibiting tumor metastasis.

Partial Text

Tumor microenvironment (TME) comprises an abundance of inflammatory and immune cells, and inflammatory mediators, all of which collaborate in the development and progression of cancer [1]. Evidence increasingly suggests that aberrant inflammation mediated by inflammatory and immune cells, such as macrophages, dendritic cells, and lymphocytes, is associated with an increased risk of human diseases including cancer [2, 3]. Inflammatory and immune cells in TME can lead to an antitumor response or pro-tumor support of growth, survival, invasion, and metastasis through secretion of several cytokines, including tumor necrosis factor-alpha (TNF-α) [1, 4–7]. Increased TNF-α levels have been observed in patients with ovarian and breast cancer [8, 9], and is important in promoting tumorigenesis and metastasis. These studies indicate that inflammatory and immune cells in the TME have a vital role in cancer development and progression. However, the underlying regulatory mechanism of inflammatory and immune cells in tumor development and progression remains unclear.

Tumor metastasis is the major cause of human cancer death, and involves the detachment and exudation of cancer cells from the primary tumor, dissemination to distant organ sites and adaptation to foreign environments [29]. Each of these processes is dictated by the cooperation between tumors and their microenvironment. Although various inflammatory and immune cells are enriched in the TME, they fail to exercise anti-tumor effector functions, and thus promote tumor growth and metastasis [1, 2, 30]. The underlying mechanisms of the inflammatory and immune cells in TME that drive tumor development and progression are important issues that need to be further examined. In this study, we investigated the role of host Nur77 in antitumor response. Our results revealed that the expression of host Nur77 is required for its antitumor response. Host genetic deletion of Nur77 in mice significantly enhanced B16 melanoma cells metastasis to the lung and liver, which was consistent with a recent report that Nur77-deficient mice that specifically lacked “patrolling” monocytes” (PMo) showed increased cancer lung metastasis in vivo [31].

 

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http://doi.org/10.1371/journal.pone.0171347

 

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