Leukemia inhibitory factor (LIF), and its receptor (LIFR), are commonly over-expressed in many solid cancers and recent studies have implicated LIF/LIFR axis as a promising clinical target for cancer therapy. LIF/LIFR...Leukemia inhibitory factor (LIF), and its receptor (LIFR), are commonly over-expressed in many solid cancers and recent studies have implicated LIF/LIFR axis as a promising clinical target for cancer therapy. LIF/LIFR activate oncogenic signaling pathways including JAK/STAT3 as immediate effectors and MAPK, AKT, mTOR further downstream. LIF/LIFR signaling plays a key role in tumor growth, progression, metastasis, stemness and therapy resistance. Many solid cancers show overexpression of LIF and autocrine stimulation of the LIF/LIFR axis;these are associated with a poorer relapse-free survival. LIF/LIFR signaling also plays a role in modulating multiple immune cell types present in tumor micro environment (TME). Recently, two targeted agents that target LIF (humanized anti-LIF antibody, MSC-1) and LIFR inhibitor (EC359) were under development. Both agents showed effectivity in preclinical models and clinical trials using MSC-1 antibody are in progress. This article reviews the significance of LIF/LIFR pathways and inhibitors that disrupt this process for the treatment of cancer.展开更多
Dear Editor,LIF,a multi-functional cytokine,is frequently overexpressed in many human cancers,including breast,colorectal,and pancreatic cancers(Liu et al.,2013;Li et al.,2014;Yu et al.,2014;Pascual-Garcia et al.,2019...Dear Editor,LIF,a multi-functional cytokine,is frequently overexpressed in many human cancers,including breast,colorectal,and pancreatic cancers(Liu et al.,2013;Li et al.,2014;Yu et al.,2014;Pascual-Garcia et al.,2019;Shi et al.,2019;Wang et al.,2019).LIF overexpression is frequently associated with poor prognosis in human cancers(Liu et al.,2013;Li et al.,2014;Yu et al.,2014).LIF functions through binding to LIF receptor complex composed of LIF receptor(LIF-R)and glycoprotein gp130(Taga and Kishimoto,1997;Heinrich et al.,2003;Watanabe et al.,2006).LIF overexpression induces activation of several oncogenic signaling pathways in a cell/tissue type-specific manner,including STAT3,PI3K/AKT,and mTOR,which in turn promotes proliferation,metastasis,and therapeutic resistance of cancer cells(Liu et al.,2013;Li et al.,2014;Yu et al.,2014;Shi et al.,2019).Recent studies have suggested that LIF is a potential important target for cancer therapy,especially for cancers with LIF overexpression.LIF neutralization antibodies(LIF neu Abs)have been reported to block LIF signaling and largely abolish the promoting effect of LIF on cancer progression(Li et al.,2014;Yue et al.,2016;Shi et al.,2019).展开更多
基金This work was supported by the DOD BCRP (No. W81XWH-18-1-0016 (R.K.V)W81XWH-18-1-0015 (H.B.N)+2 种基金NCI R44CA235991 (H.B.N))NCI Cancer Center Support (No. P30CA054174-17)Elsa U. Pardee foundation (No. 166675-44096 (S.V), NIH (No. 1R01CA179120-01 (R.K.V)).Acknow。
文摘Leukemia inhibitory factor (LIF), and its receptor (LIFR), are commonly over-expressed in many solid cancers and recent studies have implicated LIF/LIFR axis as a promising clinical target for cancer therapy. LIF/LIFR activate oncogenic signaling pathways including JAK/STAT3 as immediate effectors and MAPK, AKT, mTOR further downstream. LIF/LIFR signaling plays a key role in tumor growth, progression, metastasis, stemness and therapy resistance. Many solid cancers show overexpression of LIF and autocrine stimulation of the LIF/LIFR axis;these are associated with a poorer relapse-free survival. LIF/LIFR signaling also plays a role in modulating multiple immune cell types present in tumor micro environment (TME). Recently, two targeted agents that target LIF (humanized anti-LIF antibody, MSC-1) and LIFR inhibitor (EC359) were under development. Both agents showed effectivity in preclinical models and clinical trials using MSC-1 antibody are in progress. This article reviews the significance of LIF/LIFR pathways and inhibitors that disrupt this process for the treatment of cancer.
文摘Dear Editor,LIF,a multi-functional cytokine,is frequently overexpressed in many human cancers,including breast,colorectal,and pancreatic cancers(Liu et al.,2013;Li et al.,2014;Yu et al.,2014;Pascual-Garcia et al.,2019;Shi et al.,2019;Wang et al.,2019).LIF overexpression is frequently associated with poor prognosis in human cancers(Liu et al.,2013;Li et al.,2014;Yu et al.,2014).LIF functions through binding to LIF receptor complex composed of LIF receptor(LIF-R)and glycoprotein gp130(Taga and Kishimoto,1997;Heinrich et al.,2003;Watanabe et al.,2006).LIF overexpression induces activation of several oncogenic signaling pathways in a cell/tissue type-specific manner,including STAT3,PI3K/AKT,and mTOR,which in turn promotes proliferation,metastasis,and therapeutic resistance of cancer cells(Liu et al.,2013;Li et al.,2014;Yu et al.,2014;Shi et al.,2019).Recent studies have suggested that LIF is a potential important target for cancer therapy,especially for cancers with LIF overexpression.LIF neutralization antibodies(LIF neu Abs)have been reported to block LIF signaling and largely abolish the promoting effect of LIF on cancer progression(Li et al.,2014;Yue et al.,2016;Shi et al.,2019).
