Wednesday, March 11, 2009

Mets are Vets?

The other day I was talking to one of my advisers and he mentioned that a reviewer had just critiques the fact that the Acid Mediated Tumor Invasion does not consider the fact that the aggressive cells selected by tumor microenvironment (hypoxic and acidic) should lose this phenotype once they progress through healthy tumors, since the selective pressure on these cells decreases as they invade further from original tumor.
A metaphor used by that time was that tumor cells are like Navy Seals who, once far from their training environment, relaxing in a paradisaical beach would eventually get soft like other regular people.
The point here, I believe, is that the metaphor is wrong for tumor cells are not trained to be tough, they are selected, they are traumatized like 17-year old boys who are sent to war. Those who are able to adapt, to toughen up, survive and come back home, but many of them cannot adapt back to normal life.
The perfect example is John Rambo. When Rambo, and many other Vietnam war vets, returned to US, he no longer could live in society as we do. He would see threats everywhere, he would trust no one and would not accept the authority of civilians. In the movie Rambo escapes from prison and hides in the woods nearby the city. When the police and National Guard try and capture him he turns back to the Green Beret M.O. and kills them all.
At the end of the movie he destroy much of the city including the Police Station.
I believe that the cells that survived the stress created by tumor development and reached a more healthy environment to live will, in their majority, settle down. The cells that start new metastases however are like John Rambo: they cannot re-adapt to normal environment so they tend to re-create the original environment that traumatized them.
If this is true, there may be ways of acquiring an aggressive phenotype through reversible ways (most of tumor cells) but some of these ways may yield to irreversible conversion and eventually lead to cells that can generate metastases.
A microarray analysis as well as protein expression of cells recovered from metastases compared to the original tumor cells might yield to clues on how this commitment happens.

Monday, March 02, 2009

Substrate-induced starvation in cells?

I was just reading an article sent to me by my PhD adviser about evolution of metabolic networks.
It is impressive how metabolism is structured in a complex network with apparent redundancies, inefficiencies and bottlenecks.
But this post is about something extremely interesting I read in one of the references: apparently some of these metabolic pathways are "boosted up" by an energy-dependent step. These are called "Turbo-designed pathways" and glycolysis is one of them.
In glycolysis, before glucose catabolism can yield 4 molecules of ATP, first it consumes 2 molecules.
When yeast is grown in culture with high glucose concentration, negative feedback mechanisms prevent the cell from wasting too much energy in accumulating substrates intracellularly and at the cost of a lot of energy. Yeast just uptakes enough glucose, phosphorilates it (2 moles of ATP consumed) and then metabolizes it to get enough energy.
However, when yeast is grown in media with high malate (analogous to glucose) concentration, these cells will deplete all their energy uptaking this substrate and before they are able to make out the ATP surplus, they are already dead.
It is like someone spending all their money in seeds and not saving anything for sowing the crops.

The funny thing is that tumor cells are known for increased glucose metabolism, not only increased glucose consumption but anaerobic glucose metabolism, which is much less efficient. So wouldn't these cells just starve to death? I guess they would, if the increase in the metabolic flux where in the ATP consuming steps, what would lead to accumulation of metabolites and energy deprivation. But if the increase is in the ATP generating steps (after glyceraldehyde-3-phosphate dehydrogenase) then it would yield to energy surplus.

This conclusion is very interesting because it suggests that any increase in expression of glycolytic enzymes pre-GAPD should come only after the ATP-surplus enzymes have already been mutated (or its expression increased) to increase its reactions fluxes.

For references:

The danger of metabolic pathways with turbo design. Teusink et al., 1998
Glycolysis, turbo design and the endocrine pancreatic β cell. Iynedjian, 1998