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.

Keywords: Invasive cancer; Leptin; Metastasis; Obesity; Prognosis.

Fig. 1. Leptin-associated biomolecules that may promote cancer cell proliferation and migration

EGFR: Epidermal growth factor receptor, ERK: Extracellular signal-regulated kinases, HIF-1α: Hypoxia-inducible factor-1 alpha, ICAM: Intercellular adhesion molecule, JAK: Janus kinase, MMPs: Matrix metalloproteinases, NF-κB: Nuclear factor-kappa B, PI3K: Phosphatidylinositol 3-kinase, STAT: Signal transducer and activator of transcription, TGF-β: Transforming growth factor-beta, VEGF: Vascular endothelial growth factor

Fig. 2. Adipocytes in tumor microenvironment

(a) A schematic diagram to show the influence of adipocytes on the progression of cancer. (b) Immunohistochemical expression of leptin in tumor-adjacent adipose tissue, which was collected from the mammary fat pad of a CD-1 female mouse. In this xenograft model, T47D breast cancer cells were inoculated. The arrows indicate the presence of leptin in the cytoplasm of cells. (↑ - Increase)

Fig. 3

Leptin-related intracellular signaling molecules and their association with survival/anti-apoptotic and proliferative potential of cells.

Fig. 4. Immunohistochemical expression of leptin receptor and relevant effector molecules in tissue sections from mammary tumors of TGFα mice

Expression of (a) Ob-Rb, (b) STAT3, (c) p-STAT3, (d) PI3K, (e) cell proliferation marker proliferating cell nuclear antigen (PCNA), and (f) anti-apoptotic protein Bcl-2. Presence of yellowish- to dark-brown color indicates positive staining.