The emerging role of leukemia inhibitory factor in cancer and therapy

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Abstract

Leukemia inhibitory factor (LIF) is a multi-functional cytokine of the interleukin-6 (IL-6) superfamily. Initially identified as a factor that inhibits the proliferation of murine myeloid leukemia cells, LIF displays a wide variety of important functions in a cell-, tissue- and context-dependent manner in many physiological and pathological processes, including regulating cell proliferation, pluripotent stem cell self-renewal, tissue/organ development and regeneration, neurogenesis and neural regeneration, maternal reproduction, inflammation, infection, immune response, and metabolism. Emerging evidence has shown that LIF plays an important but complex role in human cancers; while LIF displays a tumor suppressive function in some types of cancers, including leukemia, LIF is overexpressed and exerts an oncogenic function in many more types of cancers. Further, targeting LIF has been actively investigated as a novel strategy for cancer therapy. This review summarizes the recent advances in the studies on LIF in human cancers and its potential application in cancer therapy. A better understanding of the role of LIF in different types of cancers and its underlying mechanisms will help to develop more effective strategies for cancer therapy.

Introduction

LIF is a multi-functional cytokine of the IL-6 superfamily. In addition to LIF, this superfamily also includes IL-6, IL-11, Oncostatin M (OSM), cardiotrophin-1 (CT-1), ciliary neurotrophic factor (CNTF), cardiotrophin-like cytokine (CLC), and IL-27 (Murakami, Kamimura, & Hirano, 2019; Rose-John, 2018; Yue, Wu, & Hu, 2015). LIF was initially identified as a factor that inhibits the proliferation of murine myeloid leukemia M1 cells and induces their terminal differentiation (Gearing et al., 1987; Hilton, Nicola, & Metcalf, 1988; Lowe et al., 1989). That is why LIF was named leukemia inhibitory factor. Interestingly, at almost the same time, LIF was also identified as the differentiation-inhibitory factor that maintains the pluripotency of mouse embryonic stem cells and suppresses their differentiation (Smith et al., 1988; Williams et al., 1988), the hepatocyte-stimulating factor III that induces liver cells to produce acute-phase proteins in cultured rat hepatoma cells (Baumann, Onorato, Gauldie, & Jahreis, 1987), the cholinergic neuronal differentiation factor (CNDF) that causes neurotransmitter switching in neurons (Yamamori et al., 1989), and the melanoma-derived lipoprotein lipase inhibitor (MLPLI) that blocks the transportation of lipid to adipocytes (Mori, Yamaguchi, & Abe, 1989). These early studies demonstrated that LIF is a multi-functional cytokine that plays different roles in different cells, tissues and organs.

LIF protein is a monomeric glycoprotein which is often modified by glycosylation. While the molecular weight of the unglycosylated LIF protein is ~20–25 kDa, the molecular weight of the glycosylated LIF is in the range of 37–63 kDa (Metcalfe, 2011; Simpson et al., 1988; Yue et al., 2015). LIF exists as a compact four-helix bundle topology stabilized by three disulfide bridges, which is important for receptor binding (Boulanger, Bankovich, Kortemme, Baker, & Garcia, 2003; Robinson et al., 1994). LIF binds to its heterodimer receptor complex on the cell membrane composed of a LIF receptor (LIFR) and a glycoprotein gp130 (Nicola & Babon, 2015). LIF binds to both gp130 and LIFR with high affinity, and the interaction of LIF with LIFR is ~80-fold tighter than with gp130 (Boulanger et al., 2003; Hilton & Nicola, 1992) (Fig. 1A–C). The gp130/LIFR complex is also the receptor for several other IL-6 family members, including OSM, CNTF, CT-1 and CLC, all of which signal through the gp130/LIFR heterodimer (Boulanger & Garcia, 2004). The gp130/LIFR complex is constitutively associated with members of the JAK family of tyrosine kinases (Stahl et al., 1994). When LIF binds to its receptor, the JAK family kinases are rapidly activated to initiate the tyrosine phosphorylation cascade of three major signaling pathways, including the JAK/STAT pathway (Stahl et al., 1994), the MAPK pathway (Thoma, Bird, Friend, Gearing, & Dower, 1994) and the PI3K pathway (Fahmi et al., 2013; Oh et al., 1998). It has also been reported that LIF can regulate many other signaling pathways, including the mTOR, PTEN, IGF1, TGFβ, FGF, VEGF/HIF-1α, integrin, estrogen receptor, Notch, Toll/NF-κB, Wnt/β-catenin, ephrin and YAP pathways (Chen et al., 2012; Rosario & Stewart, 2016; Wang et al., 2019). Through regulation of these different signaling pathways, LIF is involved in many different physiological and pathological processes, including regulating myeloid leukemia cell differentiation, pluripotent stem cell self-renewal, tissue/organ development and regeneration (e.g. the muscle, kidney, bone, and intestine), neurogenesis and neural regeneration, maternal reproduction, inflammation, infection, immune response, and metabolism (Davis et al., 2019; Nicola & Babon, 2015; Pasquin, Sharma, & Gauchat, 2016; Rosario & Stewart, 2016; West, 2019) (Fig. 1D). Interestingly, a growing body of studies have reported that LIF also plays an important role in initiation and progression of solid tumors in addition to its role in suppression of leukemia. In this review, we summarize recent advances on the functions of LIF in different physiological processes and diseases, especially in cancer, and the potential application of LIF-related therapies in cancer and other diseases.

Section snippets

The multiple functions of LIF in biological processes and diseases

LIF is a multi-functional cytokine that plays a wide variety of important roles in different cells, tissues and organs, including the proliferation and differentiation of leukemia and hemopoietic cells, pluripotent stem cell self-renewal, tissue/organ development and regeneration, neurogenesis and neural regeneration, maternal reproduction, immune response, metabolism, as well as cancer (Fig. 1D).

The role of LIF in cancer

A growing body of studies have shown a complex role of LIF in cancer. Although LIF was initially identified to inhibit the proliferation of leukemia cells, studies have indicated an oncogenic function of LIF in many different types of solid tumors. LIF was found to be frequently overexpressed in many types of solid tumors, including colorectal cancer (Yu et al., 2014), breast cancer (Li et al., 2014; Quaglino, Schere-Levy, Romorini, Meiss, & Kordon, 2007), pancreatic cancer (Peng, Zhou, Sheng,

Neutralizing antibodies

Given the important role of LIF in cancer progression in many solid tumors, LIF has the direct potential to be developed as a therapy target for cancers (Fig. 3A). As a cytokine that functions through binding to the gp130/LIFR on cell membrane, LIF signaling has been shown to be blocked by LIF-neutralizing antibodies that efficiently antagonize many of LIF's functions in many different studies (Chen et al., 2013; Fischer, Wajant, Kontermann, Pfizenmaier, & Maier, 2014; Mao et al., 2016;

Summary and perspectives

As summarized above, LIF displays different functions in different cells, tissues, and organs under different conditions and at different development stages through different mechanisms. While LIF displays an oncogenic effect in many solid tumors, LIF displays a tumor suppressive effect in leukemia and some special types of solid tumors. Further, different signaling pathways are involved in mediating the complex role of LIF in tumorigenesis. The different biological outcomes of LIF might be

Submission declaration

This paper has not been published and is not under consideration for publication elsewhere.

Conflict of interest statement

Authors declare no conflict of interest.

Acknowledgment

This work was supported in part by grants from National Institutes of Health (NIH; R01CA227912 and R01CA214746 to Z.F., and R01CA203965 to W.H.) and Congressionally Directed Medical Research Programs (CDMRP; W81XWH-16-1-0358 to W.H.).

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