Emerging Perspectives on Leukemia Inhibitory Factor and its Receptor in Cancer

Abstract

Tumorigenesis and metastasis have deep connections to inflammation and inflammatory cytokines, but the mechanisms underlying these relationships are poorly understood. Leukemia Inhibitory Factor (LIF) and its receptor (LIFR), part of the interleukin-6 (IL-6) cytokine family, make up one such ill-defined piece of the puzzle connecting inflammation to cancer. Although other members of the IL-6 family have been shown to be involved in the metastasis of multiple types of cancer, the role of LIF and LIFR has been challenging to determine. Described by others in the past as enigmatic and paradoxical, LIF and LIFR are expressed in a diverse array of cells in the body, and the narrative surrounding them in cancer-related processes has been vague, and at times even contradictory. Despite this, recent insights into their functional roles in cancer have highlighted interesting patterns that may allude to a broader understanding of LIF and LIFR within tumor growth and metastasis. This review will discuss in depth the signaling pathways activated by LIF and LIFR specifically in the context of cancer–the purpose being to summarize recent literature concerning the downstream effects of LIF/LIFR signaling in a variety of cancer-related circumstances in an effort to begin teasing out the intricate web of contradictions that have made this pair so challenging to define.

Pan-cancer analysis identifies LIFR as a prognostic and immunological biomarker for uterine corpus endometrial carcinoma

“…LIF-LIFR signaling is involved in cancer progression and its deregulation occurs in multiple cancers. Studies have confirmed the oncogenic functions of LIF-LIFR in tumor stemness, progression, alterations in the tumor microenvironment and therapy resistance (18,26,28).…”

“…As a pleiotropic glycoprotein, LIF belongs to the IL-6 cytokine family and is highly conserved across species. The interaction of LIF-LIFR triggers multiple signaling pathways, such as AKT, mTOR and STAT3 (9,26), thus providing an impetus to tumor cell EMT, migration and invasion, both in vitro and in vivo. LIF mediates signaling via membrane receptor complex comprised of gp130 and LIFR (27).…”

Small and Large Extracellular Vesicles Derived from Pleural Mesothelioma Cell Lines Offer Biomarker Potential

“…Among these are NADH-ubiquinone oxidoreductase subunit A13 ( NDUFA13 ), which is located in the mitochondrial inner membrane and function as a tumor suppressor [ 77 ]; protein Wnt-10a ( WNT10A ), involved in Wnt signaling and has an established role in mesothelioma [ 78 ]; transcription factor 7-like 2 ( TCF7L2 ), a transcription factor in the Wnt-signaling pathway [ 79 ]; mitotic spindle assembly checkpoint protein MAD1 ( MAD1L1) , a checkpoint gene with its dysfunction associated with chromosol instability [ 80 ]; and Fas cell surface death receptor ( FAS ), a member of the tumor necrosis factor-receptor superfamily with a key role in apoptotic signaling pathways and where mutations can prevent the immune system from attacking tumor cells [ 81 ]. In the 18 K EVs, two cancer-associated proteins were exclusively found: EH domain-binding protein 1 ( EHBP1 ), associated with endocytic trafficking and previously reported in prostate cancer [ 82 , 83 ]; and leukemia inhibitory factor receptor ( LIFR ), involved in the cellular differentiation, proliferation and survival and previously reported in epithelial tumors of the salivary gland [ 84 ]. In the 100 K EVs, among the unique cancer-associated proteins, we found notch receptor 3 ( NOTCH3 ), which plays a key role in the function and survival of vascular smooth muscle cells [ 85 ]; serine/threonine-protein kinase 10 ( STK10 ), which functions as a tumor suppressor [ 86 ]; janus kinase 2 ( JAK2 ), which plays a key role in cytokine and growth factor signaling [ 87 ]; and fanconi anemia group J protein ( FANCJ ), which plays an important role in cell cycle checkpoint control [ 88 ].…”

Transition of amyloid/mutant p53 from tumor suppressor to an oncogene and therapeutic approaches to ameliorate metastasis and cancer stemness

“…Interestingly, it was also found that Leukemia Inhibitory Factor (LIF) was significantly overexpressed in both the T1 (first generation) and T5 generation of MCF-10A cells carrying amyloid p53 [ 13 ]. LIF along with its receptor (LIFR) form a part of the interleukin-6 (IL-6) cytokine family LIF/LIFR signaling pathway, which plays an important role in tumor progression, stemness, and resistance to therapy [ 38 ]. Many solid cancers have been reported to overexpress LIF [ 39 ].…”