Adipose tissue secretes several adipokines that are supposed to stimulate inflammation, cell proliferation and angiogenesis. One of the most important member of such adipokines family is leptin, which increases cell proliferation in several tumor cell lines, enhances endothelial cell migration in vitro, and has been suggested to be an angiogenic/vasculogenic factor [12–17, 20].
It has been suggested that leptin may contribute to tumor growth. However, a direct cause and effect role of leptin in accelerating tumor growth is uncertain. Besides, most of the data supporting leptin's role in stimulating cell proliferation and angiogenesis have been derived from invitro studies.
In our study, the tumors weight of leptin treated mice were significantly more than tumors from all other groups of mice. Leptin has been identified in several types of human cancers and may also be linked to poor prognosis. In two studies, leptin and leptin receptor expression were significantly increased in primary and metastatic breast cancer relative to noncancerous tissues in women . In a clinical study of colorectal cancer, leptin expression was associated with tumor G2 grade . In renal cell carcinomas leptin and leptin receptor expression was well correlated with progression-free survival, venous invasion and lymph node metastasis . Leptin has also been suggested to have a role in uterine and endometrial cancers . There is very little previous information on the relationship between leptin and melanoma. Just one epidemiological study demonstrated that high serum leptin was positively correlated with melanoma risk .
The limited published animal studies trying to find whether leptin promote tumor growth have reported different results. Some studies support the hypothesis that the absence of leptin signaling diminishes mammary tumor growth in mice [10, 20, 28, 29].
Brandon et al, in their well-designed study have shown that leptin deficiency attenuates but does not abolish melanoma tumor growth .
Furthermore, In mouse model of mammary tumor, using a leptin receptor antagonist revealed that leptin signaling promotes the growth of some types of mammary tumors and increases the expression of proliferating cell nuclear antigen, cyclin D1, vascular endothelial growth factor (VEGF) and its receptor type two (VEGF-R2) [30, 31]. Furthermore Fusco et al have recently shown that inactivation of LepR inhibits proliferation and viability of human breast cancer cell lines . Inconsistent with the results of these studies, obese Zucker rats, which have defective leptin receptor, developed more mammary tumors than lean Zucker rats after exposure to the carcinogen, 7,12-dimethylbenzanthracene .
Leptin administration led to increase plasma NO concentrations as have been reported previously in several other studies [34–37]. It has been shown that the leptin-induced NO production is mediated through protein kinase A and mitogen-activated protein kinase (MAPK) activation. Interestingly antagonism of leptin by 9f8 antibody resulted in significantly lower plasma NO concentrations compare to both leptin and control group. The significant effect of this antibody on NO production despite of non-significant effects on tumor growth and EPC numbers may be because of use of large, pharmacological concentrations of leptin to demonstrate the 2 latter effects in this study.
Leptin receptors are expressed in mouse melanoma cells as well as EPCs .
The results of the present study indicated that leptin enhance the numbers of EPCs in peripheral blood. Recent studies indicated that the EPC derived from bone marrow also contributes to tumor vasculogenesis [3–5, 39]. However the extent of EPCs incorporation into the tumor vasculature has been a subject of controversy [40–42]. To the best of our knowledge, this is the first time that has been shown that leptin increased EPCs in melanoma tumor model. It has been recently reported that leptin increased the adhesion and the homing potential of EPCs and may thus enhance their capacity to promote vascular regeneration in vivo . Leptin induces NO, an important mediator of EPC mobilization. NO may trigger EPC recruitment from bone marrow probably by activating a phosphatidylinositol (PI) 3-kinase-independentAkt-eNOS phosphorylation pathway [42, 43]. So, the mechanism of increased EPCs in the circulation may be due to mobilization of these cells from bone marrow. Furthermore it has been shown that leptin can increase other mediators of vasculogenesis such as VEGF, and intracellular signaling pathways of cell proliferation, including p38 MAPK and ERK1/2 MAPK phosphorylation .