Adipocyte-derived IL-6 and leptin promote breast Cancer metastasis via upregulation of Lysyl Hydroxylase-2 expression

Jin-Yong He,Xin Shi,Li Sun,Hao-Lin Hu,Yang Liu,Sheng-Tao Yuan,Xiao-Hui Wei,Xin-Hong Kuang,Si-Jing Li,Lai Wang,Zheng-Zheng Li

doi:10.1186/s12964-018-0309-z

Abstract

BackgroundAdipocytes make up the major component of breast tissue, accounting for 90% of stromal tissue. Thus, the crosstalk between adipocytes and breast cancer cells may play a critical role in cancer progression. Adipocyte-breast cancer interactions have been considered important for the promotion of breast cancer metastasis. However, the specific mechanisms underlying these interactions are unclear. In this study, we investigated the mechanisms of adipocyte-mediated breast cancer metastasis.MethodsBreast cancer cells were cocultured with mature adipocytes for migration and 3D matrix invasion assays. Next, lentivirus-mediated loss-of-function experiments were used to explore the function of lysyl hydroxylase (PLOD2) in breast cancer migration and adipocyte-dependent migration of breast cancer cells. The role of PLOD2 in breast cancer metastasis was further confirmed using orthotopic mammary fat pad xenografts in vivo. Clinical samples were used to confirm that PLOD2 expression is increased in tumor tissue and is associated with poor prognosis of breast cancer patients. Cells were treated with cytokines and pharmacological inhibitors in order to verify which adipokines were responsible for activation of PLOD2 expression and which signaling pathways were activated in vitro.ResultsGene expression profiling and Western blotting analyses revealed that PLOD2 was upregulated in breast cancer cells following coculture with adipocytes; this process was accompanied by enhanced breast cancer cell migration and invasion. Loss-of-function studies indicated that PLOD2 knockdown suppressed cell migration and disrupted the formation of actin stress fibers in breast cancer cells and abrogated the migration induced by following coculture with adipocytes. Moreover, experiments performed in orthotopic mammary fat pad xenografts showed that PLOD2 knockdown could reduce metastasis to the lung and liver. Further, high PLOD2 expression correlated with poor prognosis of breast cancer patients. Mechanistically, adipocyte-derived interleukin-6 (IL-6) and leptin may facilitate PLOD2 upregulation in breast cancer cells and promote breast cancer metastasis in tail vein metastasis assays. Further investigation revealed that adipocyte-derived IL-6 and leptin promoted PLOD2 expression through activation of the JAK/STAT3 and PI3K/AKT signaling pathways.ConclusionsOur study reveals that adipocyte-derived IL-6 and leptin promote PLOD2 expression by activating the JAK/STAT3 and PI3K/AKT signaling pathways, thus promoting breast cancer metastasis.

Highlights

Adipocytes make up the major component of breast tissue, accounting for 90% of stromal tissue
Lysyl hydroxylase 2 (PLOD2) is upregulated during adipocyte-stimulated migration and invasion We first established an adipocyte-breast cancer cell coculture system, shown in Fig. 1a, where adipocytes were seeded in the bottom layer and breast cancer cells were seeded in the upper layer of a Transwell culture system
To further verify that adipokines contribute to adipocyte-mediated effects, we investigated the expression of PLOD2 in breast cancer cells cultured in conditioned medium (CM) obtained from preadipocytes, adipocytes, or adipocytes previously grown in the presence of cancer cells

Summary

Introduction

Adipocytes make up the major component of breast tissue, accounting for 90% of stromal tissue. The crosstalk between adipocytes and breast cancer cells may play a critical role in cancer progression. Adipocyte-derived factors, such as leptin, interleukin-6 (IL-6), adiponectin, tumor necrosis factor (TNF-α), monocyte chemotactic protein-1 (MCP-1) and endotrophin (ETP), function within the tumor microenvironment to promote tumor progression [4,5,6]. These adipokines activate several signaling networks associated with migration, proliferation, angiogenesis, fibrosis and apoptosis, including the JAK/STAT, AKT and ERK1/2 signaling pathways, which are frequently activated in tumor tissues [7, 8]

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Discussion

Conclusion