*(L4-5):
4. Laymen with a strong science foundation (read popular science magazines like Scientific American)
5. Enjoyed and did well in science courses in college but took a degree in another field (Enjoy Steven J. Gould, read books about science)
When I was growing up almost all cancers were difficult if not impossible to control, relapses were common, and complete cures very rare. To come down with cancer was the kiss of death. Finding effective drugs in the battle against the disease was largely a trial and error procedure. At best doctors hoped to keep in check or delay the relentless scourge. Most of the effective cancer treatments were very toxic to the body, and for many, the cure was worse than the disease.
Today, therapy is rapidly entering a new phase, as scientists are beginning to provide the blueprint for a new molecular arsenal – deadly, precise, and frequently non-toxic to normal cells. Several promising drugs are already in clinical testing, and many more are undergoing tests in laboratory animals. In a great tribute to the importance of basic research, the new molecular approach is founded solidly on studies which focus on a very fundamental issue: the interplay of forces that govern the life and death of every cell.
We have been taught that our bodies are composed of cells that seamlessly integrate into the organs and tissues that make up our bodies. Yet, in many ways, these cells are by nature far from subordinate. They are dynamic entities which have not entirely forgotten the ancient ancestral imperative to divide and multiply at every opportunity. In order for multi-cellular organisms to arise, a 3-billion year old history of acting as autonomous agents had to come to an end. Played out in a microcosm is the age-old conflict between the individual and society. The rules of cellular society are relatively rigidly enforced, but at times they do break down. Sometimes the consequences are relatively localized and have minor effects. Other times they are deadly. Such is the case of cancer - the number two killer of Americans.
But this ancient enemy may be on the verge of being conquered, as scientists are on the threshold of demystifying the nature of the cancer cell. The progress made in this area in the last two decades has been astounding. Those who do research on the basic mechanisms that control cell survival and those who treat cancer patients are at last approaching common ground on a molecular playing field.
The roots of cancer are to be found at the time when the first multi-cellular organisms arose. Used to an independent life, single cells were now being asked to cooperate, and coordinate their activities with other cells in order to achieve effective integration in the new multi-cellular entities they formed. So ancient was this challenge that the basic mechanisms to achieve this integration were worked out at least 700 million years ago, in organisms as simple and primitive as jelly fish.
These new multi-cellular alliances were so fragile that the penalties for insubordination needed to be draconian. Uncooperative cells were put to death. But the system of controls went even one step further. In a form of social control that goes well beyond anything we see in human society, cells were often persuaded to commit suicide. And to add insult to injury, they were further asked to police themselves. If they found anything seriously wrong with their own internal dynamics that could not be fixed, and this problem threatened the well-being of the whole, they were supposed to take their own life without being asked. So great is the concern that renegade cells will be a harm to the whole organism, that cells are poised at all times to kill themselves, and only the assurances of neighboring cells that they are okay prevents them from the act. These reassuring signals from outside the cell are transmitted to the nucleus by another very ancient metabolic pathway.
Thus, within our cells every day a battle is raging between their life-affirming circuitry and their suicide circuitry. But the war analogy shortchanges this relationship, which is more properly reflected in the concept of yin-yang. As in most things, life at the cellular level is all about achieving a balance.
We know all this because we have discovered components of these ancient antagonistic pathways pitting cell survival and cell proliferation against cell suicide in every organism observed from the Hydra (a jelly fish relative), to the roundworm C. elegans, to the fruit fly, all the way to humans. The phenomenon of cell suicide was named apoptosis, Greek for the falling of dead leaves in autumn. The life-affirming pathways are generally known as the survival and growth pathways.
Given the momentous importance of these pathways, it is perhaps a bit surprising that at the core of these different pathways are relatively simple circuits. The apoptosis circuit was first worked out in a simple roundworm called C. elegans. So important was this work that it earned the 2002 Nobel Prize in Physiology and Medicine for John Sulston and Robert Horvitz.
To accommodate the greater sophistication of higher organisms, this core circuit has been elaborated considerably in higher organisms, which permits much more regulatory ability, while retaining the essential core system and the outcome of the execution. During the course of this elaboration, many subtleties have been introduced that make precise prediction of interactions still difficult to make. The increased intricacy can be thought of as reflecting an ongoing arms race between the preservers of organism integrity and the cell's selfish desire to procreate.
Opposing this cell death circuit are circuits which promote survival and proliferation, both of which are ancient in their own right. The keystone molecule of the survival circuitry is known as AKT (alias PKB), an enzyme that attaches high energy phosphates to selected proteins. Phosphates are the energy currency of the cell. Adding them to other molecules, termed phosphorylation, "charges" them, making them more likely to react with other molecules. In the case of proteins it often leads them to change shape and be in a position more favorable for interaction with other molecules.
When the survival receptor is stimulated by a survival factor coming from outside the cell it changes shape and incestuously phosphorylates itself. In its self-charged state it directly or indirectly causes phosphates to be added to a phosphokinase termed PI3K (for phosphoinositol-3-kinase). Phosphokinases are energizers which attach high-energy phosphate groups to other molecules. They are very common second messengers in cells. Second messengers are typically found in the cytoplasm, and carry messages from the receptors in the membrane to the nucleus or other parts of the cytoplasm. In the cell survival pathway, PI3K helps activate AKT by phophorylating it. Our little exercise in tracing this chain of molecules which depend on phosphates for their activation quite well captures the major way in which signals are passed between and within cells.
AKT promotes cell survival in at least three main ways. First, it inhibits apoptosis by directly blocking some components of the apoptosis pathway, stimulating the production of apoptosis inhibitors, and indirectly by blocking proteins which stimulate the production of new components of the apoptosis pathway from DNA. Second, it promotes cell growth by releasing growth promoting molecules from inhibition. Finally, it promotes cell division by counteracting the inhibitors of cell division. Akt has been implicated in the growth and survival of tumors and the spreading of cancer cells from these tumors to other parts of the body, a phenomenon termed metastasis.
At the heart of the proliferation circuitry is RAS, a very important and widespread second messenger. About 20% of all human cancers have a mutated RAS gene, and 40-50% have a mutation somewhere in the RAS pathway. RAS is activated by external growth factors such as epidermal growth factor (EGF) which bind to a receptor in the cell membrane (in this case RTK).
In this case the same stimulus, EGF, activates a receptor which then triggers both the proliferation and survival pathways (via RAS and AKT, respectively). This is quite common but not universal.
For the newbies to things molecular, this may seem like a lot of terminology to be introduced to. But much has already been achieved in understanding cell signaling in health and disease. These two pathways are found in (dare I say?) every living cell in the body. By tweaking the system so that the receptor has a slightly different specificity in each cell type, albeit heart, liver, brain, etc., the organism has the ability to trigger specific reactions in only those cell types.
It is hard to imagine ourselves as a churning cauldron of continual cell proliferation and compensatory cell death, but it has been estimated that every second 1 million cells are born and 1 million die in the healthy adult. The bulk of the new cells are skin cells, cells lining the gut and lungs, red and white blood cells, and immune system cells, although new cells can be produced even in muscle and nervous system.
In healthy cells, a balance is maintained between the three circuits, permitting the processes of cell survival and proliferation and cell death where appropriate. As we shall see in the next episode, these three pathways are in a high percentage of cancers that arise. In part #2 - Renegade Cells and Cancer - we will see that while each cancer has a unique manifestation, the basic underlying causes are the same. This permitted Hanahan and Weinberg (2000) to identify the hallmarks of cancer.
