Friday, January 23, 2009

Why do tumor cells glycolyse?

Since Pasteur and Warburg it is known that tissue tends to increase glucose uptake in low oxygen environments and that tumors continue metabolizing glucose anaerobically even in presence of oxygen.
Warburg originally hypothesized that this effect not only was a hallmark of cancer but also that is was its main cause. Warburg believed that all tumor cells had malfunctioning mitochondria and thus were forced to rely on anaerobic energy metabolism.
Gatenby and Gillies recently proposed the acid mediated tumor invasion hypothesis, through which, not only glycolysis was necessary for tumor proliferation and invasion, but also that this phenotype is selected by the micronenvironment were epithelial tumors are formed.
This hypothesis proposes that the use of abundant glucose in serum anaerobically would provide enough energy for tumors to develop and also produce acicity that promotes degradation of extracellular matrix and induces apoptose in normal surrounding tissue.
One interesting point, however is that tumor do not entirely abandon aerobic metabolism. Oxygen is necessary for keeping the basic functioning of TCA cycle that not only produces energy but also is linked to production of fatty acids and and many other metabolic pathways in cells. It has been shown that tumor regions in anoxic conditions become too acid for even tumor cells to survive.
I propose that the reduction of O2 consumption in tumors is an adaptation at population level. The cells that are in tumor rim, closer to oxygen-rich tissue, consume less oxygen which diffuses through them towards the cells in the inner core of tumor, preventing excessive acidosis and allowing tumor growth.
This kind of behavior is not normally proposed in tumors, that are normally considered as a heterogenous disorganized mass, but maybe these systems of cooperation between different subpopulations in a heterogeneous environment are exactly what differentiate malignant tumors from the many neoplasias that are periodically destroyed in our bodies without our knowing.

Democracy and Cancer

For long time it has been known that molecular signaling in cells is done through scale-free networks, both at gene and protein levels.
Such networks possess an architecture that confers resistance to failures but fragility to attacks.
The Internet uses such architecture: every computer is connected to an "internet access provider" which is connected to other servers that are interconnected all over the world. The design of internet addresses is an example of this hierarchical architecture, where each node is directly connected to approximately the same number of nodes (or at least the same order of magnitude).
A failure in a random computer in the network is not likely to affect the network performance since the chances of this computer being in a node in the lowest levels of the network (a user computer) is a lot lower than being one of the servers. Also, the catastrophic consequences of a failure in one main node in the network, associated with the low number of computers in this level, allow spending more money in protecting these high-level nodes with backup systems.
This architecture also allows control of network flux (it is sufficient to control a few high level nodes in order to control most of network flow) but also raise the risk of attacks.
Many examples exist of hacker attacks directed to websites, corporative networks and even entire countries.
How does this links to cancer?
It is widely accepted that cancer is originated from genetic instability. Many other factors, such as population heterogeneity (also born from genetic instability) and environmental conditions (selective forces, inflammation, exposure of body to carcinogens, etc.) are also important and may harness the genetic variability and direct towards malignancy.
Genetic instability can be considered as failures in the regulatory networks of the cell. These failures are most probable to happen in nodes in the lower levels of the network, for these are the most numerous. The mutations can occur in three ways: the first would be either a silent mutation or a mutation that would cause little effect on cell state, the second being a mutation that would alter cell state in a way that it would activate cell programmed death mechanism.
The third and most dangerous way if a mutation that alters cell state but bypasses apoptosis. Such mutations, if accumulated, would allow cell to escape body's control system and start a tumor.

Another point I'd like to point out is that the scale-free architecture from cell networks are optimized for evolutionary purposes: when a node is connected to many different others, and each of these others is connected to many others, it is possible for this system to gradually evolve to selection through increase of weight of influence from one of the 2nd degree nodes but also show more dramatic evolution due to modification of weight of a 1st degree neighbor or of the node itself.

Lastly, this architecture is very similar to a democracy, where most of the people has one low value vote, while fewer have higher level votes (congressmen) and very few have rights to alter the state of entire groups (governors, president). The idea of democracy is not that the majority is smarter than individuals but rather that a great number of people are less likely to take decisions that will harm the entire group. Due to practicity, democracy had to be stratified to allow decisions to be taken more rapidly, and thus appeared the scale free network of decision making known today is most democratic nations.

Most of the efforts today in cancer treatment are focused on finding targets that can be treated by highly specific drugs. It is believed that if these targets, which are often mutated in cancer, are silenced, cancer cells would die or at least lose its advantage over normal cells.
This idea would be correct if the only mutated nodes were the ones selected by the therapy. Unfortunately cancer is not based on attack but rather to failure and thus the probability is that, if a high level node has been mutated, this event was preceded by many more other mutations in intermediate and lower levels nodes all over cell signaling network.

Instead of a corrupt governor or president, cancer is more likely to be the result of a coup d'ĂȘtat that gradually formed from the infiltration of enemies all over the hierarchy of cell network. If one leader is removed from the network, it is likely that many other still exist in a lower level and will eventually replace the lost comrade.

In such a situation, the strategies to be used would be similar to the ones that have had success in fighting corruption in poor countries: the development of education and the increase of level of life of citizens tends to reduce the chances that corrupt leaders will be elected. The same is true for cells: if the micro environment of tumors is changed to endanger the survival of cells, there will be an opportunity for these cells to suffer mutations and diverge towards cancer. Conversely, modification in micro environment may reverse this tendency by preventing new cells from turning into cancer cells and also by reducing the efficiency of the tumor phenotype which is adapted to adverse conditions.

Regulatory network of genes with known role in cancer.
From "A map of human cancer signaling."
Qinghua Cui, Yun Ma, Maria Jaramillo, Hamza Bari, Arif Awan, Song Yang, Simo Zhang, Lixue Liu, Meng Lu, Maureen O'Connor-McCourt, Enrico O Purisima & Edwin Wang doi:10.1038/msb4100200