Leptin regulation of proangiogenic molecules in benign and cancerous endometrial cells

Abstract

Several proangiogenic/proinflammatory factors involved in endometrial cancer are regulated by leptin, but the signaling mechanisms responsible for these leptin‐induced actions are largely unknown. Here, we report that in benign (primary and HES) and cancerous‐endometrial epithelial cells (EEC) (An3Ca, SK‐UT2 and Ishikawa), leptin in a dose‐dependent manner regulates vascular endothelial growth factor, (VEGF); interleukin‐1 beta, (IL‐1β); leukemia inhibitory factor, (LIF) and their respective receptors, VEGFR2, IL‐1R tI and LIFR. Remarkably, leptin induces a greater increase in VEGF/VEGFR2 and LIF levels in cancer than in benign cells. However, IL‐1β was only increased by leptin in benign primary‐EEC. Cancer‐EEC expressed higher levels of leptin receptor (full‐length OB‐Rb and short isoforms) in contrast to benign primary‐EEC. Leptin‐mediated activation of JAK2 (janus kinase 2) was upstream to the activation of PI‐3K (phosphatidylinositol‐3 kinase) and/or MAPK (mitogen‐activated protein kinase) signaling pathways. Leptin induction of cytokines/receptors generally involved JAK2 and MAPK activation, but PI‐3K phosphorylation was required for leptin increase of LIF, IL‐1/IL‐1R tI. Leptin‐mediated activation of mTOR (mammalian target of Rapamycin), mainly linked to MAPK, played a central role in leptin regulation of all cytokines and receptors. These results suggest that leptin's effects are cell‐specific and could confer a proliferative or cell survival advantage or possibly promote endometrial thickness. Leptin's effects on proangiogenic molecules were more evident in malignant versus benign cells and may imply that there is an underlying shift in leptin‐induced cell signaling pathways in endometrial cancer cells. © 2008 Wiley‐Liss, Inc.

Leptin accelerates enterocyte turnover during methotrexate-induced intestinal mucositis in a rat model

“…Leptin serum levels are about five times higher in obese people than in normal individuals. Leptin has been reported to act as a mitogenic agent and stimulates the growth of several obesity-associated advanced human cancers, including breast cancer, 25 colon cancer, 26 endometrial cancer 27 and renal cancer. 28 The use of leptin in these patients to prevent chemotherapy-induced mucositis should be probably avoided.…”

Regulation of Angiogenesis in Human Cancer via Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2)

“…White adipose tissue is the primary source of leptin in benign tissue but it is also expressed and secreted by cancer cells. Leptin is a known mitogenic, inflammatory and angiogenic factor for many tissues (Sierra-Honigmann et al 1998) and increases the levels of VEGF/VEGFR-2 in cancer cells (Carino et al 2008;Gonzalez et al 2006;Rene Gonzalez et al 2009). Therefore, leptin from corporal, mammary adipose tissue or cancer cells could affect cancer cells through autocrine and paracrine actions.…”

“…Recently, leptin was added to the list of factors that upregulate VEGF-A and VEGFR-2 (Carino et al 2008;Gonzalez et al 2006;Rene Gonzalez et al 2009). Leptin is a small nonglycosilated protein (16 kD) product of the ob gene.…”

“…We have previously found that leptin signaling plays an important role in the growth of breast cancer that is associated with the regulation of prowww.intechopen.com angiogenic, pro-inflammatory and pro-proliferative molecules (Rene Gonzalez et al 2009). Leptin increases VEGFR-2 expression in endometrial cancer cells in vitro (Carino et al 2008) and in breast cancer cells in vitro and in vivo (Gonzalez et al 2006;Rene Gonzalez et al 2009). Leptin upregulation of VEGF-A/VEGFR-2 was partially mediated by IL-1 system.…”

Leptin expression in proliferative, secretory and hyperplastic endometrial tissues

“…Patients with endometrial hyperplasia and endometrial cancer had higher serum leptin levels when compared with controls with adjusted body mass index (BMI) values, and leptin was reported to have a significant effect on endometrial proliferation (11). Leptin's effect on proangiogenic molecules (VEGF, IL-1beta, LIF) and their receptors (VEGFR2, IL-1R, LIFR) was much more prominent in endometrial cancer cells compared with benign endometrial tumors, and leptin and/or a pathogenic pathway stimulated by leptin were postulated to be responsible for this malignant transformation (12). It has been considered that leptin might affect endometrial proliferation and its receptors might be regulated by some proliferative factors.…”