Abstract
Simple SummaryDespite recent advances in molecular brain tumor therapies, glioblastoma multiforme remains a diagnostic and therapeutic challenge with, in most cases, unfavorable outcome. Leptin and related mediators of immune-metabolic traffic have attracted increased recognition in the past decade in brain tumor biology, in particular potential implications in the diagnosis and treatment of recurrent and newly diagnosed high and low grade gliomas. Randomized controlled trails are on the way to elaborate the role of leptin and its receptor ObR by targeting and using antidiabetic drugs known to interact with distinct pathways associated with leptin signaling. To date, most of the findings in clinical studies remain preliminary and of heterogenous character, although experimental studies have underpinned the relevance of leptin and ObR in the pathophysiology of brain tumors in general.Leptin has been recognized as a potential tumor growth promoter in various cancers including cranial tumor pathologies such as pituitary adenomas, meningiomas and gliomas. Despite recent advances in adjunctive therapy and the established surgical resection, chemo- and radiotherapy regimen, glioblastoma multiforme remains a particular diagnostic and therapeutic challenge among the intracranial tumor pathologies, with a poor long-term prognosis. Systemic inflammation and immune-metabolic signaling through diverse pathways are thought to impact the genesis and recurrence of brain tumors, and glioblastoma multiforme in particular. Among the various circulating mediators, leptin has gained especial diagnostic and therapeutic interest, although the precise relationship between leptin and glioblastoma biology remains largely unknown. In this narrative review (MEDLINE/OVID, SCOPUS, PubMed and manual searches of the bibliographies of known primary and review articles), we discuss the current literature using the following search terms: leptin, glioblastoma multiforme, carcinogenesis, immunometabolism, biomarkers, metformin, antidiabetic medication and metabolic disorders. An increasing body of experimental evidence implicates a relationship between the development and maintenance of gliomas (and brain tumors in general) with a dysregulated central and peripheral immune-metabolic network mediated by circulating adipokines, chemokines and cellular components, and in particular the leptin adipokine. In this review, we summarize the current evidence of the role of leptin in glioblastoma pathophysiology. In addition, we describe the status of alternative diagnostic tools and adjunctive therapeutics targeting leptin, leptin-receptors, antidiabetic drugs and associated pathways. Further experimental and clinical trials are needed to elucidate the mechanism of action and the value of immune-metabolism molecular phenotyping (central and peripheral) in order to develop novel adjunctive diagnostics and therapeutics for newly diagnosed and recurrent glioblastoma patients.
Highlights
In addition to its canonical role in immune-metabolic signaling, leptin is well-known to promote cellular proliferation, survival and migration through its associated receptor (ObR) and related pathways under physiological conditions, as well as during the initiation and progression of cancers of different organ systems
Leptin is encoded by the LEP gene on chromosome 7q31.3 in humans, and its principal site of action is in the brain, where it mainly acts on the hypothalamus to promote the activity of anorexigenic POMC (Pro-opiomelanocortin) neurons and inhibit orexigenic NPY/AgRP (Neuropeptide Y/Agouti-related protein) neurons in the arcuate nucleus [7,8,9]
A subsequent retrospective cohort analysis conducted by Seliger et al observed the opposite effect, as metformin hydrochloride (MFRMN) was significantly associated with increased overall survival (OS) and progression-free survival (PFS) in grade III gliomas (n = 231 subjects), while no improvement was observed for the high-grade glioma (HGG) subgroup (n = 862 subjects), supporting the hypothesis that isocitrate dehydrogenase (IDH) 1/2-MT status and a lower grade may increase the likelihood of response to metabolically active drugs (Table 1) [64]
Summary
In addition to its canonical role in immune-metabolic signaling (satiety and weight loss/gain), leptin is well-known to promote cellular proliferation, survival and migration through its associated receptor (ObR) and related pathways under physiological conditions, as well as during the initiation and progression of cancers of different organ systems (breast, lung, prostate, brain). ObR belongs to the class I cytokine receptor superfamily and has various isoforms, including a long isoform comprised of extensive cytoplasmic domains that is expressed in most tissues and is responsible for most leptin signal transduction [18] Signal transduction through this receptor involves tyrosine kinases of the Janus kinase family (JAKs) and signal transducers and activators of transcription (STATs) [9,18]. We sought to highlight and discuss the relevant literature covering the relationships between and potential diagnostic value of leptin, ObR and the complex biological characteristics of GBM This narrative review will discuss current and future therapeutic considerations targeting leptin’s immune-metabolic activity (antidiabetic drugs)
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