Lipoprotein(a): 7-ketocholesterol and cancer

This group did lots and lots and lots and lots of very, very, very clever things. So many, so complex and so clever that I'm not going to try and discuss them all. I was stuck with having to read them all because of the big lump of truth that they tripped over without apparently commenting and I had to look for any justification of the actual conclusions they came to! It's one of those papers where you can't tie the discussion to the results...

This is the executive summary to let me get to the holes in the study.

They found that oxLDL acts on cancer cells in tissue culture to induce two specific changes. The first was the induction of autophagy. This is the housekeeping process of clearing out the odds and sods of damaged and non functional proteins which accumulate with aging. This is a Good Thing, classically induced by ketosis. Good old beta hydroxybutyrate is the classic trigger. So, apparently, is oxLDL!

Obviously, if you are certain that oxLDL causes cancer, you have to consider that any Good Thing happening in bad cancer cells is a Bad Thing for the organism in general. There is no doubt that oxLDL does induce autophagy in cancer cells. This is purported to encourage super cancer cells to develop. These are what I was looking for in the results.

The second thing which oxLDL does is to induce apoptosis in cancer cells. Generally, death is considered to be a Bad Thing from a cancer's perspective. For the organism affected by cancer cells, apoptosis of those cancer cells might be considered a Good Thing.

I dunno.

Perhaps you could say that oxLDL is really Good all round, the cancer cells can die with the happy satisfaction that they had dusted the cupboard under the stairs and emptied the rubbish bins before they committed suicide and the organism is happy to lose the cancer?

There is an unspeakable amount of detail about cell pathways involved but the bottom line is free radicals, ROS. Some ROS equals autophagy, lots equals apoptosis.

OxLDL causes lots of ROS.

Now, if you ignore the discussion and introduction, both of which are exercises in cognitive dissonance, and go to the results you can play hunt the super squeaky clean autophagic cancer cells. Until you are blue in the face. They're not there because they are all either dead or looking VERY sick. No one mentioned finding sleek autophagous cancer cells. Just dead ones.

The action of oxLDL on cancer cells is to kill them. There was no other finding noted on the cellular level, using a microscope. OxLDL, especially the 7-ketocholesterol component, is a potent apoptosis inducer in cancer cells. Quite how this can be a Bad Thing, as expressed throughout this paper, is beyond me.

But there are a series of snags.

OxLDL also induces apoptosis in cultured human umbilical vein endothelial cells. This is undoubtedly a Bad Thing from the CVD point of view. Like Really Bad.

So perhaps oxLDL is really the cause of arteriosclerosis?

It's a nice idea but there really isn't a lot of oxLDL in the blood of any species. In humans it's bound to Lp(a) and in all other species it is present at the lower limits of detectbility. Let's just go back to the Bergman/Krauss/Tsimikas paper and recap:

"In individuals with low Lp[a] levels, there is a corresponding low level of OxPL/apoB, suggesting that in the absence of Lp[a], these OxPLs do not accumulate on plasma apoB-containing lipoproteins other than to a minor degree. A similar situation exists with most animals that we have studied (32, 33). For example, in mice with marked hypercholesterolemia, a situation in which OxPLs recognized by E06 are abundant in the arterial tissues (and probably elsewhere as well), the levels of OxPL/apoB in plasma are very low, and often just at the level of detection of our assay (33). In contrast, Lp[a]-transgenic mice have very high OxPL/apoB levels, even in a C57BL/6 background without obvious atherosclerosis (34). Presumably, this reflects the generation of such OxPLs as a component of normal physiological processes. Lp[a]-transgenic mice express both human apoB-100 and apo[a] and thus can form a true covalent Lp[a] similar to that found in humans (34). Mice expressing high levels of human apoB-100 alone, or apo[a] alone, nevertheless have very low levels of OxPL/apoB (34), suggesting the need for an intact Lp[a] to enable preferential binding of OxPL."

So when you take some native LDL, cook it with copper sulphate and then pour the resulting mess of goo on to cultured cells on a petridish you are really getting a handle on what is happening in the real world of human cardiovascular disease aren't you? Like yeah.

In the real world the oxidised lipids of oxLDL rapidly transfer to Lp(a) (in humans, apes and transgenic Lp[a] mice) or (in all other species) they are excreted, presumably by the liver. Either way, they don't hang around.


Lp(a) has a large sticky moiety which binds to fibrin and proteoglycans. It's not going to see either of these in healthy vascular tissue. Delivering 7-ketcholesterol to the damaged tissue around a cancer cell might be a bit of a magic bullet. It's hardly surprising the body makes lots of apo(a) when the liver picks up markers that you have cancer.

Delivering it to damaged vascular tissue, where fibrin or proteoglycans are exposed, might be good or bad. Probably good in view of a number of other oxidised lipid products present in Lp(a). But if the damage is on going and severe it seems a little unfair to blame the sticking plaster for the damage.

But I would maintain that circulating Lp(a) through healthy tissue has NOTHING in common with pouring copper-oxidised LDL on to cultured vascular smooth muscle cells or endothelial cells.

I suppose at some stage we have to talk about the natural arteriosclerosis which occurs in aged rats and rabbits, but there is so much more of interest about Lp(a) and so little research published to work from...

Peter

BTW Barry Groves has an interesting article by Wayne Martin on the role of Dipyridamole in cancer management. It has a nice description of cancers and fibrin which fits neatly with Lp(a) being a potential anticancer stratagem based on targeting blood clot with an apoptosis inducing agent.