Abstract
Melanoma is one of the most murderous tumours over the world. The capability of the tumour to invade all tissues in the body and the low-response to chemotherapies lead to a poor prognosis with high mortality rate. The metastatic stage has still no curative treatment and it is the reason why the investigation of new therapies is required. Tumour progression involves the activation of a tumour-promoting chronic inflammation, in part induced by the secretome of tumours cells with, as consequences, changes in the tumour microenvironment. This is one of the hallmarks permitting the tumour to grow, proliferate, survive and migrate.
Unpublished data from the group has shown that the activation of the Peroxisome proliferator-activated receptor gamma (PPARγ) induces a modification of gene expression in metastatic melanoma cells, thereby promoting a pro-inflammatory response with the expression of the cytokines IL6 and IL1β. Based on these data, the idea that PPARγ may be new target to treat metastatic melanoma emerged.
PPARγ is a nuclear receptor regulating transcription, already used as therapeutic target by drugs called Glitazone, used to treat Diabetic mellitus type II by decreasing Insulin resistance. However, the effect on tumours of PPARγ activation is still unclear, as well as the toxic side effect on cardiovascular system, causing the withdrawal of many of these drugs. Although some epidemiologic studies have reported a probable tumour protector effect of PPARγ activity by reducing inflammation on some types of cancer in human, a significant increase of bladder cancer after treatment with Pioglitazone (a Glitazone still used in our country) has been reported.
In this work, PPARγ was activated with the agonist Glitazone in melanoma cell lines that were in different stages of progression of the disease. The cell lines tested were in a non-metastatic stage of progression of the disease and they did not change their pro-inflammatory gene expression in the presence of PPARγ agonist.
Nevertheless, it has been demonstrated in the lab that metastatic melanoma cells respond to PPARγ agonist, changing the secretome of the tumour. In order to create an experimental model, this work analysed the effect of the secretome of human metastatic melanoma cells treated with PPARγ agonist on mouse fibroblasts. No change of gene expression was observed in normal mouse fibroblasts when they were directly treated with PPARγ ligands. However, the interesting results showed that murine fibroblasts increased the expression of pro-inflammatory markers after incubation with the secretome of melanoma cells treated with agonists of PPARγ.
Accordingly, PPARγ activation may have an effect on modifying the secretome of the tumour, inducing the microenvironment to change into a pro-inflammatory state. However, the recruitment of inflammatory cells can also have an anti-tumoral effect, the in vivo model may show if this inflammation may be deleterious or may be beneficial for the tumour growth and proliferation.