From Metabolism to Oncogenes and Back - Part I

One of the biggest stories over the last decade was how metabolism taught researchers new lessons on cancer.

Say what?

Here is a brief history lesson on how cancer was viewed by cell biologists over the last hundred years. Today I'll talk about how our views changed from metabolism to oncogenes, tomorrow (or the day after) I'll close the loop by explaining how metabolism came back into the picture.

About 100 years ago the famous German biochemist, Otto Warburg, thought that the way to understand cancer was through metabolism. Unlike normal cells, which broke down sugar using oxidative pathways (or the Krebs cycle), tumor cells used non-oxidative pathways (glycolysis) to generate energy from sugar. This idea, known as the Warburg hypothesis, inspired many researchers to study metabolism and its regulation. Our understanding of how the cell made and consumed sugars, amino acids, nucleotides, lipids and other biomolecules became all the rage. From these studies we learned quite a bit about topics such as how sugar metabolism was regulated, but not all that much about cancer itself. Just like his mentor Emil Fisher, Warburg won the Nobel prize for Medicine in 1931 for his work on various metabolic pathways. One of his most famous students, Hans Adolf Krebs, also won the Nobel for figuring out how sugar is broken down (hence the Krebs Cycle).

Meanwhile others were taking a different approach to understanding oncogenesis. These researchers played with viruses that were known to promote tumors. One such virus was the Rous Sarcoma Virus (RSV), discovered by Peyton Rous at Rockefeller University in 1916. This virus had the particular ability to trigger neoplasms in chickens. Many decades past without much progress until 1977 when, the Bishop lab discovered that the ability of the RSV to transform normal cells to cancerous cells was due to a single gene in the virus' genome. The gene was named src.

And what was this gene encoding? Through the work of Harold Varmus, a postdoc in the Bishop lab, we found out that the viral src was a mutant version of a gene normally found in the chicken and human genome. The mutant viral gene was dubbed v-src, and the normal chicken version c-src. The genes encoded what is known as a kinase, or an enzyme capable of adding phosphates to tyrosines found on other proteins. Growth factors and extracellular matrix fibers such as collagen act on cell recptors. The receptors then stimulate the activity of this tyrosine kinase which in turn added phosphates to other proteins, many of which were also kinases. Phosphorylation either stimulated or inhibited the next enzyme in these long chains of events. Like a big waterfall, whole groups of proteins became altered in a characteristic sequence called a signaling cascade. At the end of the cascade were DNA binding proteins. Here phosphorylation altered whether these factors bound to specific regions in the genome and affected the activation of a critical set of genes. The changes in gene expression had profound effects on cellular behavior. In the case of src, the activated signal cascade made cells divide faster and prevented the cells from turning on cell-death programs. You can see why an overactive mutant form of this gene would cause cancer.

Src was called a proto-oncogene: normally, this gene plays an essential role in cells by activating cell division, but if it became overactive due to a mutation, it could turn a normal cell tumorogenic. The act of acquiring mutations that led to an increase in cell reproduction and a decrease in cell death was called "transformation".

Cancer research had an Aha moment. The whole field was changed overnight. People realized that cancer can be caused by mutations in the genome. In other words these signaling molecules were prime causes of tumorogenesis. From Michael Bishop's autobiography (from the Nobel site):

In the years that followed, we consolidated our evidence for retroviral transduction, generalized the finding to retroviral oncogenes other than src, helped elucidate the sorts of genetic damage that convert normal cellular genes into cancer genes, explored the contributions of proto-oncogenes to the genesis of human cancer, added to the repertoire of proto-oncogenes by several experimental strategies, pursued the physiological functions of proto-oncogenes in normal organisms, and shared in the discovery of the protein kinase encoded by src.

Many such genes were eventually found. Some of the more famous ones are ras, myc and MAP kinase. Most had something to do with intra-cellular signaling. Some such as the Epithelial Growth Factor Receptor initiated these signaling cascades while other genes such as src, conveyed the signal. Usually they were activated by being phosphorylated and then phosphorylating other signaling molecules. Many such genes had chunks that resembled src. These chunks, or domains, were called SH1 (src homology domain 1, or the part of src that acts as a kinase), SH2 (a phospho-tyrosine binding domain) and SH3 (a poly-proline binding domain).

Eventually other genes were discovered whose normal activity was to suppress cell growth or activate cell death in case the cell went bonkers. If the activity of these "tumor suppressor genes" was abolished by mutation then the cells would become more transformed. One of the most famous of these genes is p53 which is mutated in over 50% of all cancers.

So we now had "proto-oncogenes" and "tumour suppressor genes". These all fit within the concept that cell communication played a big role in cancer. Cells normally gave and received signals from neighboring cells and from the extracellular environment. These signals told the cells when to grow, when to be quiescent, when to move, when to stay put, when to live and when to die. If key signaling enzymes became corrupted, due to mutations or other genetic defects, transformation could occur.

But what about metabolism? Well a simplistic answer would be that tumors are large collections of cells that are poorly vascularized, that is, not many blood vessels grow into and out of the tumors. Since these cells have little access to oxygen, they use non-oxidative metabolic pathways to turn sugar into energy. A key step in the progression of tumorogenesis is that the tumor must acquire this vasculature to gain access to the oxygen and nutrients carried in blood. This was the key insight given to us by Judah Folkman.

But in the next post I'll describe how new research has led to a new appreciation of how metabolism does play a role in cancer. The answer is very surprising and has led to the discovery of an ancient cell signaling pathway. And to give another twist to the tale, ribosomes have a lot to do with this new insight.