Leptin and Its Receptor are Overexpressed in Brain Tumors and Correlate with the Degree of Malignancy

Abstract

Although leptin and its receptor (ObR) have emerged as important cancer biomarkers, the role of the leptin system in brain tumor development remains unknown.We screened 87 human brain tumor biopsies using immunohistochemistry and detected leptin and ObR in 55.2% and 60.9% cases, respectively. In contrast, leptin and ObR were absent in 14 samples of normal brain tissue. The presence of leptin correlated with ObR with overall concordance 80.5%. The leptin/ObR system was highly expressed in glioblastomas and anaplastic astrocytomas, while lower expression of both markers was noted in low-grade astrocytomas and gangliogliomas, The association between leptin/ObR and the degree of tumor malignancy was highly significant (p<0.001).Using double immunofluorescence staining of glioblastoma tissues, we found coexpression of leptin with ObR and with the proliferation marker Ki-67 in 87% and 64% of cells, respectively. The leptin/ObR-positive tissues also expressed activated forms of STAT3 and Akt.In line with this finding, ObR-positive glioblastoma cells responded to leptin with cell growth and induction of the STAT3 and Akt pathways as well as inactivation of the cell cycle suppressor Rb.In summary, our data demonstrate that the leptin/ObR system is expressed in malignant brain tumors and might be involved in tumor progression.

Metformin inhibits leptin-induced growth and migration of glioblastoma cells

“…This study confirmed our previous findings that leptin stimulates several growth-related intracellular pathways and acts as a mitogen in GBM cells (20). Furthermore, we demonstrated for the first time that leptin activates migration in human GBM cells, which is consistent with the observation that the hormone induces migration of rat C6 glioma cells (22).…”

“…ObR-positive LN18 and LN229 glioblastoma cell lines were obtained from ATCC (Manassas, VA, USA). Both cell lines were cultured in low-glucose Dulbecco's modified Eagle's medium (DMEM) (Cellgro Mediatech, Manassas, VA, USA) supplemented with 5% fetal bovine serum (Cellgro Mediatech) as described in a previous study (20). The study was approved by the Biosafety Committee at Temple University, PA, USA.…”

“…We previously demonstrated that leptin activates the STAT3 and Akt pathways, and downregulates ERK1/2 signaling in ObR-positive GBM cells (20). In addition, leptin is known to modulate AMPK in a cell context-dependent manner (19,23), although its effects on this enzyme in brain tumor cells have never been studied.…”

“…We reported previously that leptin and its receptor (ObR) are overexpressed in different human brain tumors and that their levels correlate with the degree of malignancy, being the most abundant in GBM (20). In ObR-positive LN18 and LN229 cells, leptin acts as a mitogen/survival factor and its effects coincide with the stimulation of the PI-3K/Akt, signal transducer and activator of transcription 3 (STAT3) pathways as well as the modulation of ERK1/2 signaling and retinoblastoma protein (pRb) phosphorylation (20).…”

High expression of leptin receptor leads to temozolomide resistance with exhibiting stem/progenitor cell features in gliobalastoma

“…13 Diverse cancer cells derived from different tissues, such as brain, breast, colon or prostate, were reported to have ObR expression. [21][22][23][24][25] Furthermore, Ob-R overexpression not only correlated with the degree of malignancy, but also was an independent prognostic variable to predict poor progression-free survival in brain tumor, ovarian cancer, and breast cancer, 24,26,27 which suggested that ObR+ cells might be closely related with tumor initiation and development. In this study, we claimed that ObR+ glioblastoma cells presented chemoresistance, which showed that TMZ could not inhibit cell proliferation and could not induce apoptosis effectively.…”