An obvious idea we’ve all missed

In 3+ decades as a clinical neurologist I saw several hundred unfortunate people with primary brain tumors. Not one of them was made of proliferating neurons. Not a single one. Most were tumors derived from glial cells (gliomas, glioblastomas, astrocytomas, oligodendrogliomas) which make up half the cells in the brain. Some came from the coverings of the brain (meningiomas), or the ventricular lining (ependymomas).

A recent paper in Nature (vol. 543 pp.681 – 686 ’17) decided that it might be worthwhile to figure out why some organs rarely if ever develop cancer (brain, heart, skeletal muscle). Obvious isn’t it? But no one did it until now.

Most of these tissues are terminally differentiated (unlike, skin, lung, breast and gut) and don’t undergo cellular division. This means that they don’t have to copy their DNA over and over to replenish old and dying cells, and so they are much less likely to develop mutation.

They also use oxidative phosphorylation (a mitochondrial function) rather than glycolysis to generate energy. So they looked for genes that were upregulated in terminally differentiated muscle (not brain) cells relative to proliferating muscle cell precursors. Not a complicated idea to test once you think of it (but you and I didn’t). They found 5 such, and tested them for their ability to suppress tumor growth. One such (LACTB) decreased the growth rate of a variety of tumor cells in vitro and in vivo (e.g.– when transplanted into immunodeficient animals). Amazingly it seems to have no effect on normal cells.

Showing how little we understand the goings on inside our cells, why don’t you try to guess what LACTB given your (and our) knowledge of cellular biochemistry and physiology.

LACTB changes mitochondrial lipid metabolism, by reducing the rate of decarboxylation of mitochondrial phosphatidyl serine — say what?

Even when you know what LACTB is doing you’d be hard pressed to figure out how this effect slows cancer cell growth (and possibly prevents it from occuring at all).

So given our knowledge we’d have never found LACTB and having found it we still don’t know how it works.

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Comments

  • Bryan  On April 9, 2017 at 6:10 pm

    Doesn’t glycolysis need to occur for oxidative phosphorylation to happen, especially since neurons use glucose as their main source of energy? Certainly many cancer cells use glycolysis only and turn off oxidative phosphorylation (the Warburg effect), but it shouldn’t be possible to have only oxidative phosphorylation and no glycolysis.

  • Bryan  On April 9, 2017 at 6:27 pm

    Also, researchers have studied the variation in cancer rates among different tissues (e.g. see this paper from 2015 http://science.sciencemag.org/content/347/6217/78, the infamous “cancer is bad luck” paper). Cancer rates in different tissues are largely correlated with the number of stem cell divisions in the tissue type, which makes intuitive sense (more cell division gives more opportunities for mutations to arise during DNA replication). The number of stem cell divisions explains ~66% of the variation in cancer rates among different tissues, however, so there is room for other factors like LACTB to play a role.

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