Tuesday, February 06, 2007

Killer Symbiosis

Okay, it's now day two of Omics! Omics!'s attempt to contribute to the Just Science Week of Science blog effort; some sort of feed mischief prevented yesterday's original post on cancer cellular ecology & reserve post on re-energizing E.coli from showing up there. Here's a new attempt to get through.

One of the actor's I introduced in the ocancer cellular ecology post is cancer stroma. This is essentially scar tissue built up of fibroblasts which have been recruited to the tumor site. Is this simply a benign bodily response? A border wall being erected by one side to exclude the other? Well, there is evidence that tumor stroma is far from a passive player, but rather an active ally of the tumor.

First though, we need to review some biochemistry. The metabolism of sugar to energy in our cells requires a complex pathway of events. The system can be divided into three basic subsystems: glycolysis, the citric acid (or Krebs) cycle, and the respiratory electron transport chain. The handoff from glycolysis to the citric acid cycle is the molecule pyruvate. However, this three stage system requires oxygen; in the absence of oxygen energy production halts at glycolysis. Which means the cell needs to deal with all that pyruvate, or the system stalls.

The first biotechnologists discovered that yeast has a very interesting solution to this problem: it converts the pyruvate to ethanol. But in animals, the endpoint is instead lactic acid. It is lactic acid buildup that gives you a burning sensation from tired muscles. Obtaining energy solely from glycolysis is far less effective than going the whole scheme (about 6X if I remember correctly), so animals tend to reserve it for special occasions -- such as quick bursts of muscle activity or other occasions when oxygen can't get to the cells fast enough. As my freshman bio prof pointed out, this leads to the white meat vs. dark meat dichotomy of chickens: chickens walk all the time, so the legs operate in the aerobic regime, whereas the wings are for short flights and operate anerobically. The oxygen storage protein myoglobin contains oxygen & gives the dark meat its characteristic color.

A German doctor named Otto Warburg made an interesting observation in the 1920's that tumors routinely rely on glycolysis for their energy production. This Warburg effect, for which he was awarded the Nobel prize, has stood the test of time, though its cause is still debated. Why would tumors choose to rely on an inefficient pathway for energy production? While tumors are often hypoxic, the Warburg effect is not dependent on hypoxia. One interesting possibility was published last year (and may not yet be free): the tumor suppressor protein p53 may be a key regulator of the glycolysis vs. respiration switch. p53 is inactivated through mutation or protein destabilization in many, many tumors, and switching to respiration may be the price to be paid for getting rid of the local cop.

A paper from a year ago (free!) laid out a fascinating story using immunohistochemistry (IHC). This is a technique which uses antibodies as stains for specific proteins on slices of tissue. With IHC, you see the cellular architecture in high resolution, overlaid with the distribution of one protein. Run a bunch of antibodies on closely related samples (such as successive slices from the same biopsy), and you can build up a picture of how multiple proteins are distributed. What this study reveals is a vicious symbiosis between tumor and stroma.

What the paper shows (the key figure summarizes things neatly) is a splitting of the conventional three-step pathway between tumor and stroma. The tumor expresses a key set of genes to optimize glycolysis. This starts with a glucose transporter (GLUT1) to bring the sugar in and upregulation of an enzyme to convert pyruvate to lactate (LDH5) and a transporter capable of exporting the lactate from the cell (MCT1). A key enzyme for funneling pyruvate (PDH1) into the citric acid cycle is shut off, with a key negative regulator of PDH1 (PDK1) upregulated.

The tumor stroma cells have a complementary set of regulations. Their glucose transport system is essentially shut down, but they instead upregulate a protein to import lactate (MCT1 again; it works both ways), another to convert lactate back into pyruvate (LDH5) and again upregulate the PDH1 gateway to the citric acid cycle. The stroma cells are also turning up their carbonic anhydrase genes, which reduce the acidity generated by the tumor cells' glycolysis.

These changes are not observed in normal fibroblasts, nor are most of them present in the normal endothelial cells in the tumor's vicinity (GLUT1 is upregulated in the tumor-associated blood vessel endothelial cells). Clearly what is happening is a division of metabolic labor between tumor and stroma. The stroma is not a passive bystander, but an active quisling.

[forgot to tag this; updating]

1 comment:

hank said...

I think the concise biochem overview is worth a read all by itself.