Leukemia inhibitory factor (LIF) is a member of the interleukin-6 (IL-6) family of cytokines, which performs a variety of biological functions in living organisms. In-depth studies on the role of LIF in cancer cells have revealed that it plays an important role in tumor growth, migration, invasion, maintenance of stem cell stemness and immune evasion. LIF affect cells through various signaling pathways by binding to their receptors. Common signaling transduction mechanisms include janus kinase/signal transducers and activators of transcription (JAK/STAT), phosphoinositide 3-kinase/protein kinase B (PI3K-AKT) etc, of which JAK/STAT is the main signaling transduction mechanism. Different drugs and therapies have been developed to target the signaling pathways. This article reviews the expression, functions, mechanism of action and therapeutic methods of LIF in cancer cells, which can provide reference for the treatment of cancer.

1.Nicola NA, Babon JJ. Leukemia inhibitory factor (LIF)[J]. Cytokine Growth Factor Rev, 2015, 26(5): 533-544. DOI: 10.1016/j.cytogfr.2015.07.001.

2.Humbert L, Ghozlan M, Canaff L, et al. The leukemia inhibitory factor (LIF) and p21 mediate the TGFβ tumor suppressive effects in human cutaneous melanoma[J]. BMC Cancer, 2015, 15: 200. DOI: 10.1186/s12885-015-1177-1.

3.Gearing DP, Thut CJ, Vandebos T, et al. Leukemia inhibitory factor receptor is structurally related to the IL-6 signal transducer, gp130[J]. EMBO J, 1991, 10(10): 2839-2348. DOI: 10.1002/j.1460-2075.1991.tb07833.x.

4.Metcalf D. The unsolved enigmas of leukemia inhibitory factor[J]. Stem Cells, 2003, 21(1): 5-14. DOI: 10.1634/stemcells.21-1-5.

5.Uhlén M, Fagerberg L, Hallström BM, et al. Proteomics. Tissue-based map of the human proteome[J]. Science, 2015, 347(6220): 1260419. DOI: 10.1126/science.1260419.

6.Liu J, Yu H, Hu W. LIF is a new p53 negative regulator[J]. J Nat Sci, 2015, 1(7): e131. https://pubmed.ncbi.nlm.nih.gov/26161442/.

7.Xu G, Wang H, Li W, et al. Leukemia inhibitory factor inhibits the proliferation of gastric cancer by inducing G1-phase arrest[J]. J Cell Physiol, 2019, 234(4): 3613-3620. DOI: 10.1002/jcp.27083.

8.Rose-John S, Scheller J, Schaper F. "Family reunion"--A structured view on the composition of the receptor complexes of interleukin-6-type and interleukin-12-type cytokines[J]. Cytokine Growth Factor Rev, 2015, 26(5): 471-474. DOI: 10.1016/j.cytogfr.2015.07.011.

9.Xu Y, Kershaw NJ, Luo CS, et al. Crystal structure of the entire ectodomain of gp130: insights into the molecular assembly of the tall cytokine receptor complexes[J]. J Biol Chem, 2010, 285(28): 21214-21218. DOI: 10.1074/jbc.C110.129502.

10.Betzel C, Visanji M, Dauter Z, et al. Crystallization and preliminary X-ray analysis of leukemia inhibitory factor[J]. FEBS Lett, 1993, 336(2): 236-238. DOI: 10.1016/0014-5793(93)80810-h.

11.Fitzgerald KA, O'neill LAJ, Gearing AJH, et al. The cytokine factsbook and webfacts (second edition)[M/OL]. London: Academic Press, 2001: 346-350. [2023-10-25]. https://www.sciencedirect.com/science/article/abs/pii/B9780121551421500749.

12.Smith AG, Heath JK, Donaldson DD, et al. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides[J]. Nature, 1988, 336(6200): 688-690. DOI: 10.1038/336688a0.

13.Weivoda MM, Chew CK, Monroe DG, et al. Identification of osteoclast-osteoblast coupling factors in humans reveals links between bone and energy metabolism[J]. Nat Commun, 2020, 11(1): 87. DOI: 10.1038/s41467-019-14003-6.

14.Sims NA, Johnson RW. Leukemia inhibitory factor: a paracrine mediator of bone metabolism[J]. Growth Factors, 2012, 30(2): 76-87. DOI: 10.3109/08977194.2012.656760.

15.Moon C, Yoo JY, Matarazzo V, et al. Leukemia inhibitory factor inhibits neuronal terminal differentiation through STAT3 activation[J]. Proc Natl Acad Sci USA, 2002, 99(13): 9015-9020. DOI: 10.1073/pnas.132131699.

16.Yaftiyan A, Eskandarian M, Jahangiri AH, et al. Leukemia inhibitory factor (LIF) modulates the development of dendritic cells in a dual manner[J]. Immunopharmacol Immunotoxicol, 2019, 41(3): 455-462. DOI: 10.1080/08923973.2019.1619761.

17.Zhou C, He X, Tong C, et al. Cancer-associated adipocytes promote the invasion and metastasis in breast cancer through LIF/CXCLs positive feedback loop[J]. Int J Biol Sci, 2022, 18(4): 1363-1380. DOI: 10.7150/ijbs.65227.

18.Ohata Y, Tsuchiya M, Hirai H, et al. Leukemia inhibitory factor produced by fibroblasts within tumor stroma participates in invasion of oral squamous cell carcinoma[J]. PLoS One, 2018, 13(2): e0191865. DOI: 10.1371/journal.pone.0191865.

19.Wang H, Si S, Jiang M, et al. Leukemia inhibitory factor is involved in the pathogenesis of NSCLC through activation of the STAT3 signaling pathway[J]. Oncol Lett, 2021, 22(3): 663. DOI: 10.3892/ol.2021.12924.

20.Gulluoglu S, Sahin M, Tuysuz EC, et al. Leukemia inhibitory factor promotes aggressiveness of chordoma[J]. Oncol Res, 2017, 25(7): 1177-1188. DOI: 10.3727/096504017X14874349473815.

21.Zhong W, Liu H, Li F, et al. Elevated expression of LIF predicts a poor prognosis and promotes cell migration and invasion of clear cell renal cell carcinoma[J]. Front Oncol, 2022, 12: 934128. DOI: 10.3389/fonc.2022.934128.

22.Wang J, Xie C, Pan S, et al. N-myc downstream-regulated gene 2 inhibits human cholangiocarcinoma progression and is regulated by leukemia inhibitory factor/microRNA-181c negative feedback pathway[J]. Hepatology, 2016, 64(5): 1606-1622. DOI: 10.1002/hep.28781.

23.Li X, Yang Q, Yu H, et al. LIF promotes tumorigenesis and metastasis of breast cancer through the AKT-mTOR pathway[J]. Oncotarget, 2014, 5(3): 788-801. DOI: 10.18632/oncotarget.1772.

24.Bay JM, Patterson BK, Teng NN. Leukemia inhibitory factor downregulates human papillomavirus-16 oncogene expression and inhibits the proliferation of cervical carcinoma cells[J]. Infect Dis Obstet Gynecol, 2011, 2011: 463081. DOI: 10.1155/2011/463081.

25.Li W, Soufiany I, Lyu X, et al. SP1-upregulated LBX2-AS1 promotes the progression of glioma by targeting the miR-491-5p/LIF axis[J]. J Cancer, 2021, 12(23): 6989-7002. DOI: 10.7150/jca.63289.

26.McLean K, Tan L, Bolland DE, et al. Leukemia inhibitory factor functions in parallel with interleukin-6 to promote ovarian cancer growth[J]. Oncogene, 2019, 38(9): 1576-1584. DOI: 10.1038/s41388-018-0523-6.

27.Bagheri V, Esmaeili SA, Gholamin M, et al. Rapid isolation of gastric adenocarcinoma cancer stem cells as a target for autologous dendritic cell-based immunotherapy[J]. Iran J Biotechnol, 2022, 20(2): e3045. DOI: 10.30498/ijb.2021.284841.3045.

28.Watanabe Y, Yoshimura K, Yoshikawa K, et al. A stem cell medium containing neural stimulating factor induces a pancreatic cancer stem-like cell-enriched population[J]. Int J Oncol, 2014, 45(5): 1857-1866. DOI: 10.3892/ijo.2014.2603.

29.Vaziri N, Shariati L, Zarrabi A, et al. Cancer-associated fibroblasts regulate the plasticity of breast cancer stemness through the production of leukemia inhibitory factor[J]. Life (Basel), 2021, 11(12): 1298. DOI: 10.3390/life11121298.

30.Seeneevassen L, Giraud J, Molina-Castro S, et al. Leukaemia inhibitory factor (LIF) inhibits cancer stem cells tumorigenic properties through hippo kinases activation in gastric cancer[J]. Cancers (Basel), 2020, 12(8): 2011. DOI: 10.3390/cancers12082011.

31.Sreenivasan L, Li LV, Leclair P, et al. Targeting the gp130/STAT3 axis attenuates tumor microenvironment mediated chemoresistance in group 3 medulloblastoma cells[J]. Cells, 2022, 11(3): 381. DOI: 10.3390/cells11030381.

32.Pascual-García M, Bonfill-Teixidor E, Planas-Rigol E, et al. LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy[J]. Nat Commun, 2019, 10(1): 2416. DOI: 10.1038/s41467-019-10369-9.

33.Yu S, Li Q, Wang Y, et al. Tumor-derived LIF promotes chemoresistance via activating tumor-associated macrophages in gastric cancers[J]. Exp Cell Res, 2021, 406(1): 112734. DOI: 10.1016/j.yexcr.2021.112734.

34.Rashidfarrokhi A, Pillai R, Hao Y, et al. Tumor-intrinsic LKB1-LIF signaling axis establishes a myeloid niche to promote immune evasion and tumor growth[J]. bioRxiv, 2023, 2023.07.15.549147. DOI: 10.1101/2023.07.15.549147.

35.Hirai H, Karian P, Kikyo N. Regulation of embryonic stem cell self-renewal and pluripotency by leukaemia inhibitory factor[J]. Biochem J, 2011, 438(1): 11-23. DOI: 10.1042/BJ20102152.

36.Zhang W, Shi X, Chen R, et al. Novel long non-coding RNA lncAMPC promotes metastasis and immunosuppression in prostate cancer by stimulating LIF/LIFR expression[J] Mol Ther, 2020, 28(11): 2473-2487. DOI: 10.1016/j.ymthe.2020.06.013.

37.Luo H, Yang Z, Zhang Q, et al. LIF inhibits proliferation of esophageal squamous carcinoma cells by radiation mediated through JAK-STAT signaling pathway[J]. J Cancer, 2023, 14(4): 532-543. DOI: 10.7150/jca.81222.

38.Biffi G, Oni TE, Spielman B, et al. IL-1-induced JAK/STAT signaling is antagonized by TGF-β to shape CAF heterogeneity in pancreatic ductal adenocarcinoma[J]. Cancer Discov, 2019, 9(2): 282-301. DOI: 10.1158/2159-8290.CD-18-0710.

39.Starenki D, Singh NK, Jensen DR, et al. Recombinant leukemia inhibitory factor suppresses human medullary thyroid carcinoma cell line xenografts in mice[J]. Cancer Lett, 2013, 339(1): 144-151. DOI: 10.1016/j.canlet.2013.07.006.

40.Liang Y, Zhou R, Liu X, et al. Leukemia inhibitory factor facilitates self-renewal and differentiation and attenuates oxidative stress of BMSCs by activating PI3K/AKT signaling[J]. Oxid Med Cell Longev, 2022, 2022: 5772509. DOI: 10.1155/2022/5772509.

41.Ke M, He Q, Hong D, et al. Leukemia inhibitory factor regulates marmoset induced pluripotent stem cell proliferation via a PI3K/Aktdependent Tbx3 activation pathway[J]. Int J Mol Med, 2018, 42(1): 131-140. DOI: 10.3892/ijmm.2018.3610.

42.Morton SD, Cadamuro M, Brivio S, et al. Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation[J]. Oncotarget, 2015, 6(28): 26052-26064. DOI: 10.18632/oncotarget.4482.

43.Yin S, Jin W, Qiu Y, et al. Solamargine induces hepatocellular carcinoma cell apoptosis and autophagy via inhibiting LIF/miR-192-5p/CYR61/Akt signaling pathways and eliciting immunostimulatory tumor microenvironment[J]. J Hematol Oncol, 2022, 15(1): 32. DOI: 10.1186/s13045-022-01248-w.

44.Shi Y, Gao W, Lytle NK, et al. Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring[J]. Nature, 2019, 569(7754): 131-135. DOI: 10.1038/s41586-019-1130-6.

45.Bressy C, Lac S, Nigri J, et al. LIF drives neural remodeling in pancreatic cancer and offers a new candidate biomarker[J]. Cancer Res, 2018, 78(4): 909-921. DOI: 10.1158/0008-5472.CAN-15-2790.

46.Wang MT, Fer N, Galeas J, et al. Blockade of leukemia inhibitory factor as a therapeutic approach to KRAS driven pancreatic cancer[J]. Nat Commun, 2019, 10(1): 3055. DOI: 10.1038/s41467-019-11044-9.

47.Di Giorgio C, Bellini R, Lupia A, et al. Discovery of BAR502, as potent steroidal antagonist of leukemia inhibitory factor receptor for the treatment of pancreatic adenocarcinoma[J]. Front Oncol, 2023, 13: 1140730. DOI: 10.3389/fonc.2023.1140730.

48.Di Giorgio C, Lupia A, Marchianò S, et al. Repositioning mifepristone as a leukaemia inhibitory factor receptor antagonist for the treatment of pancreatic adenocarcinoma[J]. Cells, 2022, 11(21): 3482. DOI: 10.3390/cells11213482.

49.Astrazeneca. A phase 1 multicenter, open-label, dose-escalation and dose-expansion study to evaluate the safety, pharmacokinetics, pharmacodynamics, immunogenicity and antitumor activity of MSC-1 in patients with advanced solid tumors[R/OL]. clinicaltrials.gov, 2023. [2023-09-05]. https://clinicaltrials.gov/study/NCT03490669.

50.Ghanei Z, Mehri N, Jamshidizad A, et al. Immunization against leukemia inhibitory factor and its receptor suppresses tumor formation of breast cancer initiating cells in BALB/c mouse[J]. Sci Rep, 2020, 10(1): 11465. DOI: 10.1038/s41598-020-68158-0.

51.Yue X, Wu F, Wang J, et al. EC330, a small-molecule compound, is a potential novel inhibitor of LIF signaling[J]. J Mol Cell Biol, 2020, 12(6): 477-480. DOI: 10.1093/jmcb/mjaa008.

52.Hall BR, Cannon A, Thompson C, et al. Utilizing cell line-derived organoids to evaluate the efficacy of a novel LIFR-inhibitor, EC359 in targeting pancreatic tumor stroma[J]. Genes Cancer, 2019, 10(1-2): 1-10. DOI: 10.18632/genesandcancer.184.

53.Loriot Y, Marabelle A, Guégan JP, et al. Plasma proteomics identifies leukemia inhibitory factor (LIF) as a novel predictive biomarker of immune-checkpoint blockade resistance[J]. Ann Oncol, 2021, 32(11): 1381-1390. DOI: 10.1016/j.annonc.2021.08.1748.

54.Zhang X, Hu B, Sun YF, et al. Arsenic trioxide induces differentiation of cancer stem cells in hepatocellular carcinoma through inhibition of LIF/JAK1/STAT3 and NF-kB signaling pathways synergistically[J]. Clin Transl Med, 2021, 11(2): e335. DOI: 10.1002/ctm2.335.