Leptin, the product of the obesity gene (ob), controls energy homeostasis through its action on the central nervous system and plays an important role in control of body weight and sexual maturation. This low molecular weight protein (16 kD) is mainly produced by adipocytes in white adipose tissue, and expression has also been demonstrated in placenta and mammary epithelium. In recent years, leptin has emerged as a cytokine of diverse function that plays a role in multiple pathologies including those involving inflammation, angiogenesis, and tumorigenesis. The gene is transcriptionally up-regulated by hypoxia and mediates angiogenesis which is essential for tumor growth and progression. Additional roles for leptin in malignancy include cellular proliferation and migration and various studies have described the association of enhanced leptin levels with malignant progression in tumors of the breast, prostate, endometrium, colon, and gallbladder. expression of leptin is also regulated by insulin through the action of myristolated AKT. Thus, like insulin, leptin stimulates phosphorylation of different potent signal transducers including STAT3, STAT1, MAPK, and the alpha 1 subunit of the plasma membrane Na-K pump. Transcripts induced through leptin via activation of leptin receptor also include components of important cellular pathways including JAK2, STAT3, PI3, SOC 3, MTII, FNK, MRF1, VEGF, TGF beta1, bFGF, EGF, and KGF. Since all leptin receptor isoforms are expressed in fibroblasts (which can also secrete leptin on stimulation with insulin), we have investigated the expression of this tumorigenic cytokine in fibrosarcoma at the level of transcription and protein expression with real time PCR and immunofluorescence based techniques, respectively. Using a series of tissue samples and cell lines from a well-characterized feline model of fibrosarcoma progression as well as matched malignant and non-malignant tissues from human fibrosarcoma patients, our investigations show the progressive expression of leptin concomitant with advancement of the malignant phenotype. Furthermore, leptin producing fibrosarcoma cells showed increased growth and migration in vitro as well as significantly higher rates of metastasis in vivo on injection in nude mice. Thus, our investigations implicate leptin as a component of the molecular pathways involved in the progression of fibrosarcoma. Ongoing analysis of upstream and downstream aspects of the pathway would enable the development of specific intervention targets for these highly invasive and difficult to manage tumors of mesenchymal origin.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]