Thursday, April 5, 2012

Cancer: Death by Suicide or Death by Execution?(Rommel's Dilemma)

Apoptosis, programmed cell death, is a central issue in cancers and the failure of apoptosis allows pre-cancerous cells to become very dangerous. As the article notes ...

Cancer cells can die in several ways, Weiner says. One is a natural process called apoptosis, or programmed cell death, which is a way that the body keeps the cells growing within an organ or body in check. "This is a normal process, so the immune system ignores those cells," Weiner says. Manycancer drugs are designed to promote apoptosis.
See the problem? Apoptosis is way of ensuring that the process of cell death does not lead to nearby cells being attacked by the immune system. The failure of apoptosis may enable tumours to grow but that does not mean increasing apoptosis is always the best way to kill the cells. I even vaguely recall studies suggesting apoptosis can lead to humoral factors that limit the immune response.

Apoptosis is even found in bacteria, single celled organisms. I could never understand why the process evolved at that level until I realised that bacteria are preyed upon by bacteriophages, viruses that replicate within them. When a virus infiltrates a cell it does not immediately or even directly kill the cell, it just replicates. It has better replicative potential if it doesn't kill a cell quickly so viral particles can reach very high levels in a cell. So much so that the cell undergoes lysis(breakage) of the cell walls. This enables the viral particles to escape and begin infecting other cells.

So a bacterium that can induce suicide confers a group selection advantage because apoptosis is a very different form of cell death. In that scenario the cell walls do not lysis, preventing the escape of viral particles. Now I know the neoDarwinists hate group selection with a vengeance but you're pushing shit uphill to explain immunology and apoptosis without it!

So apoptosis is not an ideal strategy to instigate tumour cell death. It prevents immunological function and greatly reduces and immune driven response against the tumour. We need necrotic cell death. Death of the slow and painful kind that involves cell lysis. Why? Because the immune system recognises as dangers signals some molecules that are typically confined to the cell. As the article notes .. .
In the Cell study, the French researchers discovered that when cancer cells are dying via autophagy, it is the release of energy in the cancer cell, in the form of the chemical ATP, that alerts immune cells to the existence of a big problem. This ATP activates toll-like immune cell receptors, which are a very primitive group of proteins that play a key role in the innate immune system by acting as alarms. 
 ATP is a classic danger signal. The activation of Toll receptors is very interesting, it reminds me of studies showing how heat shock protein 60, another protein the immune system doesn't like to see "hanging around"(and sometimes implicated in autoimmunity but difficulties there). Stressed cells produce lots of hsp 60, it is a key stress  protein and under some conditions is probably the most abundant protein in a cell(so I have read). It's release into the extra-cellular space is evidence of cell necrosis hence attracts the interest of immune cells. A little appreciated function of immune cells is the vital role they play in cleaning up the extra cellular environment. So certain immune cells, especially dendritic cells, are like watchtower guards, and when they see a possible problem issue commands to get the troops to investigate. With regard to hsp 60, it is endocytosed by immune cells(absorbed into the cell), where it also activates Toll receptors and so driving inflammation.

In this particular news item the bods stress that we need to think about carefully orchestrating the death of cancer cells to maximise the immune response. Their emphasis is on increasing autophagy. Autophagy is a process of intra-cellular "house keeping" where various molecules are degraded into component parts for latter use or excretion. Autophagy literally means "self eating". The cancer cells cannabalise themselves to such an extent they do irreparable damage, possibly because the benefits of de novo lipid synthesis seen in cancer cells is abrogated by continuous autophagy which eventually leads to cell wall leakage of ATP and I suspect other "danger signals".

And finally they do state:

Additionally, drugs could be designed that force cancer cells to produce ATP when they are sick and dying, Weiner says. "That way, the immune system is primed to attack cancer that recurs."

DCA can do that, some studies suggest carnitine derivatives can do that ... .

No comments: