The Molecular Basis and Therapeutic Potential of Leukemia Inhibitory Factor in Cancer Cachexia

Abstract

Cachexia is a chronic metabolic syndrome that is characterized by sustained weight and muscle mass loss and anorexia. Cachexia can be secondary to a variety of diseases and affects the prognosis of patients significantly. The increase in inflammatory cytokines in plasma is deeply related to the occurrence of cachexia. As a member of the IL-6 cytokine family, leukemia inhibitory factor (LIF) exerts multiple biological functions. LIF is over-expressed in the cancer cells and stromal cells of various tumors, promoting the malignant development of tumors via the autocrine and paracrine systems. Intriguingly, increasing studies have confirmed that LIF contributes to the progression of cachexia, especially in patients with metastatic tumors. This review combines all of the evidence to summarize the mechanism of LIF-induced cachexia from the following four aspects: (i) LIF and cancer-associated cachexia, (ii) LIF and alterations of adipose tissue in cachexia, (iii) LIF and anorexia nervosa in cachexia, and (iv) LIF and muscle atrophy in cachexia. Considering the complex mechanisms in cachexia, we also focus on the interactions between LIF and other key cytokines in cachexia and existing therapeutics targeting LIF.

Development and Characterization of a Cancer Cachexia Rat Model Transplanted with Cells of the Rat Lung Adenocarcinoma Cell Line Sato Lung Cancer (SLC)

“…In our study, LIF was detected in culture supernatants of SLC cells and tumor extracts of SLC-transplanted rats, and in the rats' sera at low levels. LIF is a member of the IL-6 superfamily and is characterized by the use of the common receptor chain glycoprotein 130 and activates the Janus kinase-signal transducer and activator of transcription signaling pathway [38]. A recent study showed that mice transplanted with colon 26 cells exhibited LIF-dependent muscle atrophy, despite having a substantially low blood concentration of LIF (approximately 10 pg/mL) [39].…”

Molecular Mechanisms of Cachexia: A Review

“…Interleukin-6 (IL-6) has also been identified as a potential factor that interacts with TNF-α or acts independently to induce systemic inflammation in the context of cancer cachexia [76,77]. Multiple types of cancer have been associated with this particular interleukin, and proinflammatory cytokines that originate from the host, such as IL-1, have the potential to amplify its effects [9].…”

New insights into Chlamydia pathogenesis: Role of leukemia inhibitory factor

“…While these pathways collectively contribute to cellular differentiation, survival and self-renewal, the qualitative and quantitative contributions of individual pathways are cell-type specific, leading to the pleiotropic effects of LIF ( Nicola and Babon, 2015 ). Although named for its ability to inhibit proliferation of a myeloid leukemia cell line by inducing its terminal differentiation into macrophages ( Gearing et al., 1987 ), LIF also regulates the growth and differentiation of embryonic stem cells ( Smith et al., 1988 ; Williams et al., 1988 ), peripheral neurons ( Murphy et al., 1991 ; Li et al., 1995 ; Cheng and Patterson, 1997 ), osteoblasts ( Matsushita et al., 2014 ; Sims, 2020 ), adipocytes ( Guo et al., 2021 ; Zeng et al., 2022 ), hepatocytes ( Baumann and Wong, 1989 ), and endothelial cells ( Ferrara et al., 1992 ; Li et al., 2022 ). This multifarious property of LIF has led to several rediscoveries of the protein and a variety of synonyms have been used in the older literature ( Alexander et al., 1994 ; Nicola and Babon, 2015 ) ( Table 1 ).…”