Metastatic Melanoma: The Enemy of my Enemy is my Friend

-From 2016, articles commented in the Journal and Focus will be posted here (selection by Prof. JH Saurat M.D.)

Metastatic Melanoma: The Enemy of my Enemy is my Friend

Postby CFH » Fri Jan 01, 2016 1:34 pm

Oxidative stress inhibits distant metastasis by human melanoma cells.
Piskounova E, Agathocleous M, Murphy MM, Hu Z, Huddlestun SE, Zhao Z, Leitch AM, Johnson TM, DeBerardinis RJ, Morrison SJ.
Nature. 2015 Nov 12;527(7577):186-91. doi: 10.1038/nature15726. Epub 2015 Oct 14.

Malignant Melanoma is a neoplastic transformation of melanocytes (Reactive Oxygen Species (ROS) play an important pro-carcinogenic role)
Initially the cells are localized to the skin but in later stages, the cells invade the dermis, enter blood vessels and disseminate to the body in a process called metastasis.
This ability is directly correlated to the thickness of the melanoma: Breslow score.

When detected early, it carries an excellent prognosis after surgical excision but the 5 year survival is very low when it metastasizes and (systemic treatments need to be added)

Oxidative stress is normally a destructive process, which increases carcinogenic ability as well as aging through the generation of ROS. ROS are molecules which contain Oxygen with singlet electrons. Examples include superoxide radicals (O2., H2O2)
ROS can be neutralized with antioxidants, but in practice multicentre trials showed ineffectiveness of this strategy and there was a increased incidence of cancer incidence (a protumorigenic effect confirmed in mice)

This article (published in Nature) shows that melanoma cells can effectively nest away from the primary location (metastasis) if they can overcome the cellular stress induced by Reactive Oxygen Species (ROS).
-Indeed elevated ROS levels are found in melanoma cells which detach from the primary tumor, again in the bloodstream and at metastatic sites (transplant of human melanomas in mice)
-At the same time, there is an increase in the production of NADPH (an antioxidant cofactor), which implied an increase in the activity of the folate pathway. Methotrexate (MTX) is a folate antagonist and it's use sharply stopped melanoma metastasis (also in mice) (This was also demonstrated when the folate pathway is blocked by reducing expression of involved protein components)

All in all, this implies an adaptative change of metastatic melanoma cells to buffer the oxidative stress.

To conclude, oxidative stress is the enemy of metastatis melanoma cells (the other enemy). As the editorial comment in "Nature" puts it so well: The Enemy of my Enemy is my Friend !
-There is increased understanding in the process of melanoma metastasis; this could lead to the wider use of low-dose MTX and the development of a new therapeutical arsenal (although it does not appear to be straightforward)
-Of course, further studies are required for this and they need to be done in humans.

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Adaptation to Oxidative Stress enables Melanoma Cells to Metastasize
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