The potential role of leptin in tumor invasion and metastasis

Abstract

The adipocyte-released hormone-like cytokine/adipokine leptin behaves differently in obesity compared to its functions in the normal healthy state. In obese individuals, elevated leptin levels act as a pro-inflammatory adipokine and are associated with certain types of cancers. Further, a growing body of evidence suggests that higher circulating leptin concentrations and/or elevated expression of leptin receptors (Ob-R) in tumors may be poor prognostic factors. Although the underlying pathological mechanisms of leptin’s association with poor prognosis are not clear, leptin can impact the tumor microenvironment in several ways. For example, leptin is associated with a number of biological components that could lead to tumor cell invasion and distant metastasis. This includes interactions with carcinoma-associated fibroblasts, tumor promoting effects of infiltrating macrophages, activation of matrix metalloproteinases, transforming growth factor-β signaling, etc. Recent studies also have shown that leptin plays a role in the epithelial-mesenchymal transition, an important phenomenon for cancer cell migration and/or metastasis. Furthermore, leptin’s potentiating effects on insulin-like growth factor-I, epidermal growth factor receptor and HER2/neu have been reported. Regarding unfavorable prognosis, leptin has been shown to influence both adenocarcinomas and squamous cell carcinomas. Features of poor prognosis such as tumor invasion, lymph node involvement and distant metastasis have been recorded in several cancer types with higher levels of leptin and/or Ob-R. This review will describe the current scenario in a precise manner. In general, obesity indicates poor prognosis in cancer patients.

The Adipose Stem Cell as a Novel Metabolic Actor in Adrenocortical Carcinoma Progression: Evidence from an In Vitro Tumor Microenvironment Crosstalk Model

“…Circulating leptin is one of the factors involved in the association between obesity and some solid cancers [42]. Leptin, locally secreted in the TME by both adipocytes and cancer-associated fibroblasts (CAFs) [43], has been shown to be involved in various steps of tumor invasion and metastasis through interaction with its Ob-R receptor expressed by cancer cells and activation of the downstream signaling pathway JAK-STAT3, PI3K/AKT and MAPK [29].…”

Underrated enemy – from nonalcoholic fatty liver disease to cancers of the gastrointestinal tract

“…Circulating leptin levels are higher in patients with NAFLD than in controls, and these are associated with increased severity of NAFLD [ 132 , 133 ]. Leptin is associated with increased carcinogenesis, indirectly through regulation of inflammation and oxidative stress or directly through up-regulation of cell proliferation, inhibition of apoptosis, potentiation of angiogenesis and modulation of the immune response [ 134 ]. Its pro-cancerogenic activity takes place through the JAK/STAT (Janus kinase/signal transducer and activator of transcription), PI3K/PTEN/Akt/mTOR (phosphoinositide 3-kinase/phosphatase and tensin homolog/protein kinase B/mammalian target of rapamycin), Raf/MEK/ERK (protooncogene c-RAF/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase) pathways [ 130 , 135 ].…”

Cancer and comorbidity: The role of leptin in breast cancer and associated pathologies

“…Moreover, decreased levels of sex hormone-binding globulins (SHBG) in obese postmenopausal women may increase free/bioavailable estrogens and breast cancer risk. It has also been suggested that an excess of local adipose tissue may play a critical role in disease progression by providing various substances such as fatty acids and pro-inflammatory cytokines[ 3 ].…”

“…Adult obesity is commonly associated with higher blood levels of leptin[ 7 , 8 ]. In regard to carcinogenesis, several studies have indicated that leptin potentiates the growth of breast cancer cells[ 3 , 9 , 10 ].…”