Leukemia Inhibitory Factor Signaling in Cancer Biology
Summary
Leukemia Inhibitory Factor (LIF) is a multifunctional cytokine of the interleukin-6 family that orchestrates key cellular processes including proliferation, differentiation, survival and inflammatory responses. In the context of cancer biology, LIF binds to its cognate receptor (LIFR) and the co-receptor gp130, activating downstream cascades such as JAK/STAT, PI3K/AKT, MAPK and Hippo pathways. Through autocrine and paracrine loops, aberrant LIF/LIFR signalling supports tumour cell proliferation, stemness, metastasis and therapy resistance, while also modulating the tumour microenvironment and immune infiltration. Context-dependent functions of LIF have been reported: in some tumours it promotes angiogenesis and chemoresistance, whereas in others it may exert suppressive effects on metastasis initiation. The dual nature of LIF signalling underscores its global significance as both a biomarker of disease progression and a target for therapeutic intervention. Recent advances in small-molecule LIFR inhibitors, neutralising antibodies and modulation of ferroptotic pathways offer promising avenues for precision oncology applications.
Research from Nature Portfolio
Recent studies have demonstrated that LIF is mechanistically linked to KRAS-driven malignancy in pancreatic ductal adenocarcinoma. Oncogenic KRAS upregulates LIF expression, and genetic ablation or neutralisation of LIF impairs tumour engraftment and progression in murine models. Moreover, LIF-neutralising antibodies synergise with gemcitabine to eradicate established tumours, acting through inhibition of YAP-dependent Hippo signalling rather than canonical STAT pathways. This work establishes LIF as a non-redundant mediator of KRAS-driven oncogenesis and highlights LIF blockade as a promising therapeutic strategy.
Leukemia Inhibitory Factor Signaling in Cancer Biology publication trend
The graph below shows the total number of articles in leukemia inhibitory factor signaling in cancer biology across all publications each year (not limited to Nature Index journals).
Technical terms
LIF: cytokine of the interleukin-6 family involved in cell differentiation, survival and inflammation.
LIFR: the cell-surface receptor that binds LIF and initiates intracellular signalling cascades.
JAK/STAT pathway: signalling axis where Janus kinases phosphorylate STAT transcription factors to regulate gene expression.
Hippo pathway: kinase cascade that controls cell proliferation and apoptosis through regulation of YAP/TAZ transcription co-activators.
Autocrine signalling: a mode of cell communication in which cells respond to substances they themselves secrete.
Ferroptosis: an iron-dependent form of programmed cell death characterised by lipid peroxidation.
References
- Pharmacological inhibition of the LIF/LIFR autocrine loop reveals vulnerability of ovarian cancer cells to ferroptosis. npj Precision Oncology (2024).
- Targeting metastasis-initiating cancer stem cells in gastric cancer with leukaemia inhibitory factor. Cell Death Discovery (2024).
- The LIFR Inhibitor EC359 Effectively Targets Type II Endometrial Cancer by Blocking LIF/LIFR Oncogenic Signaling. International Journal of Molecular Sciences (2023).
- Blockade of leukemia inhibitory factor as a therapeutic approach to KRAS driven pancreatic cancer. Nature Communications (2019).
- Leukemia Inhibitory Factor: An Important Cytokine in Pathologies and Cancer. Biomolecules (2022).
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