The emerging role of leukemia inhibitory factor in cancer and 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.).
References (179)
- et al.
LIF mediates proinvasive activation of stromal fibroblasts in cancer
Cell Reports
(2014) - et al.
Leukemia inhibitory factor can mediate Ras/Raf/MEK/ERK-induced growth inhibitory signaling in medullary thyroid cancer cells
Cancer Letters
(2010) - et al.
Leukemia inhibitory factor and its receptor promote adipocyte differentiation via the mitogen-activated protein kinase cascade
The Journal of Biological Chemistry
(1999) - et al.
Stimulation of myoblast proliferation in culture by leukaemia inhibitory factor and other cytokines
Journal of the Neurological Sciences
(1991) - et al.
Mesenchymal to epithelial conversion in rat metanephros is induced by LIF
Cell
(1999) - et al.
Leukemia inhibitory factor (LIF) infusion stimulates skeletal muscle regeneration after injury: Injured muscle expresses lif mRNA
Journal of the Neurological Sciences
(1994) - et al.
Distinct sets of acute phase plasma proteins are stimulated by separate human hepatocyte-stimulating factors and monokines in rat hepatoma cells
The Journal of Biological Chemistry
(1987) - et al.
Convergent mechanisms for recognition of divergent cytokines by the shared signaling receptor gp130
Molecular Cell
(2003) - et al.
Shared cytokine signaling receptors: Structural insights from the gp130 system
Advances in Protein Chemistry
(2004) - et al.
Retrograde axonal transport of LIF is increased by peripheral nerve injury: Correlation with increased LIF expression in distal nerve
Neuron
(1994)
Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells
Blood
p42/p44-MAPK and PI3K are sufficient for IL-6 family cytokines/gp130 to signal to hypertrophy and survival in cardiomyocytes in the absence of JAK/STAT activation
Cellular Signalling
Leukemia inhibitory factor triggers activation of signal transducer and activator of transcription 3, proliferation, invasiveness, and altered protease expression in choriocarcinoma cells
The International Journal of Biochemistry & Cell Biology
Leukemia inhibitory factor regulates the activation of inflammatory signals in macrophages and trophoblast cells
Molecular Immunology
MicroRNAs in cancer: Biomarkers, functions and therapy
Trends in Molecular Medicine
Kinetic analyses of the binding of leukemia inhibitory factor to receptor on cells and membranes and in detergent solution
The Journal of Biological Chemistry
Purification of a murine leukemia inhibitory factor from Krebs ascites cells
Analytical Biochemistry
Multiple sclerosis gene therapy with recombinant viral vectors: Overexpression of IL-4, leukemia inhibitory factor, and IL-10 in Wharton’s jelly stem cells used in EAE mice model
Cell Journal
Impact of LIF (leukemia inhibitory factor) expression in malignant melanoma
Experimental and Molecular Pathology
Leukemia inhibitory factor differentiation-inhibiting activity/human interleukin for DA cells augments proliferation of human hematopoietic stem cells
Blood
Tumor suppressor p53 and its mutants in cancer metabolism
Cancer Letters
Recombinant human leukemia inhibitory factor induces acute phase proteins and raises the blood platelet counts in nonhuman primates
Blood
Leukemia inhibitory factor can potentiate murine megakaryocyte production in vitro
Blood
Effects of injected leukemia inhibitory factor on hematopoietic and other tissues in mice
Blood
The mouse mammary tumor cell line, MMT060562, produces prostaglandin E2 and leukemia inhibitory factor and supports osteoclast formation in vitro via a stromal cell-dependent pathway
Journal of Bone and Mineral Research
Cachexia-associated adipose loss induced by tumor-secreted leukemia inhibitory factor is counterbalanced by decreased leptin
JCI Insight
Induction of endogenous neural precursors in mouse models of spinal cord injury and disease
European Journal of Neurology
Cancer-associated cachexia
Nature Reviews. Disease Primers
Common genetic variants in the TP53 pathway and their impact on cancer
Journal of Molecular Cell Biology
Leukemia inhibitory factor promotes neural stem cell self-renewal in the adult brain
The Journal of Neuroscience
p53 regulates LIF expression in human medulloblastoma cells
Journal of Neuro-Oncology
Leukemia inhibitory factor downregulates human papillomavirus-16 oncogene expression and inhibits the proliferation of cervical carcinoma cells
Infectious Diseases in Obstetrics and Gynecology
Leukemia inhibitory factor promotes gastric cancer cell proliferation, migration, and invasion via the LIFR-Hippo-YAP pathway
Annals of the New York Academy of Sciences
Leukemia inhibitory factor increases glucose uptake in mouse skeletal muscle
American Journal of Physiology. Endocrinology and Metabolism
LIF drives neural remodeling in pancreatic cancer and offers a new candidate biomarker
Cancer Research
Leukemia inhibitory factor is essential for subventricular zone neural stem cell and progenitor homeostasis as revealed by a novel flow cytometric analysis
Developmental Neuroscience
Production of multiple cytokines and induction of cachexia in athymic nude mice by a new anaplastic thyroid carcinoma cell line
The Journal of Endocrinology
Leukaemia inhibitory factor mRNA concentration peaks in human endometrium at the time of implantation and the blastocyst contains mRNA for the receptor at this time
Journal of Reproduction and Fertility
LIFR is a breast cancer metastasis suppressor upstream of the hippo-YAP pathway and a prognostic marker
Nature Medicine
Protein kinase inhibitor gamma reciprocally regulates osteoblast and adipocyte differentiation by downregulating leukemia inhibitory factor
Stem Cells
Gprc5a deletion enhances the transformed phenotype in normal and malignant lung epithelial cells by eliciting persistent Stat3 signaling induced by autocrine leukemia inhibitory factor
Cancer Research
Uterine Msx-1 and Wnt4 signaling becomes aberrant in mice with the loss of leukemia inhibitory factor or Hoxa-10: Evidence for a novel cytokine-homeobox-Wnt signaling in implantation
Molecular Endocrinology
Neuroprotective activity of leukemia inhibitory factor is relayed through myeloid zinc finger-1 in a rat model of stroke
Metabolic Brain Disease
Leukemia inhibitory factor modulates the peripheral immune response in a rat model of emergent large vessel occlusion
Journal of Neuroinflammation
Leukemia inhibitory factor enhances bone formation in calvarial bone defect
The Journal of Craniofacial Surgery
Exogenous leukemia inhibitory factor stimulates oligodendrocyte progenitor cell proliferation and enhances hippocampal remyelination
The Journal of Neuroscience
ZEB1: A critical regulator of cell plasticity, DNA damage response, and therapy resistance
Frontiers in Molecular Biosciences
ZEB1 regulates glioma stemness through LIF repression
Scientific Reports
Leukaemia inhibitory factor is necessary for maintenance of haematopoietic stem cells and thymocyte stimulation
Nature
Astrocyte-produced leukemia inhibitory factor expands the neural stem/progenitor pool following perinatal hypoxia-ischemia
Journal of Neuroscience Research
Cited by (36)
MDM2-p53 mediate a miR-181c-3p/LIF axis to regulate low dose-rate radiation-induced DNA damage in human B lymphocytes
2024, Ecotoxicology and Environmental SafetyLeukemia inhibitory factor protects against graft-versus-host disease while preserving graft-versus-leukemia activity
2022, BloodCitation Excerpt :This finding is consistent with the results from our in vivo experiments showing that rLIF decreased IL-12–p40 production from DCs after TBI (Figure 5A-B and supplemental Figure 8B-D). LIF exerts its function through selectively activating its downstream pathways in a highly tissue- and cell type–specific manner.7 We examined a panel of well-known LIF downstream pathways, including the STATs, AKT, ERK, and MAPK pathways,7 in BMDCs derived from C57BL/6 and B6C3F1 upon IFNγ and LPS stimulation.
The Pleiotropic role, functions and targeted therapies of LIF/LIFR axis in cancer: Old spectacles with new insights
2022, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :LIFR is overexpressed and associated with cancer progression, angiogenesis, regulation of stem cells, and developmental systems [1–4]. Among LIFR ligands, LIF is overexpressed and demonstrated to exert a tumor-promoting role and functions in multiple solid cancers, including breast, prostate, endometrial, nasopharyngeal, gastric, colorectal, osteosarcoma, melanoma, pancreatic, and lung cancer [2,6–14]. Recently, the context and cancer type-specific role of LIFR has been explored in multiple cancers, including prostate, gastric, colorectal, breast, endometrial, pancreatic, and lung cancers [1,2,12,13,15–20].
Leukemia inhibitory factor protects against liver steatosis in nonalcoholic fatty liver disease patients and obese mice
2022, Journal of Biological ChemistryLeukemia inhibitory factor suppresses hepatic de novo lipogenesis and induces cachexia in mice
2024, Nature Communications
- 1
Co-first authors.