Cancer Evo: An introduction to cancer biology

In February I announced the Cancer Evolution series. Finally, here is part one of the two part introduction!

"Evolution", as applied to cancer, is not just a metaphor standing for "change" or "development". Cancers really do evolve: tumours are populations of individuals which reproduce and show variation, leading to evolution by natural selection. In our picture of evolution, cells -- specifically somatic cells, the dead-end cells of the body (as supposed to sperm and eggs) -- play the role of individuals within populations. To understand how and why they evolve, we must therefore look inside the cells, and find out how they work. This post serves as an introduction to cell and molecular biology, which I hope, together with the forthcoming introduction to evolutionary biology, will be enough to allow non-biologists to follow the details in the rest of the series.

Cancers are diseases of genes and genomes

Our cells are capable of performing thousands of different process. They must, for example, grow and divide; respond to external stimuli, like hormones or environmental change; store and retrieve nutrients; make products to release from the cell; and eventually die gracefully. These processes, and many more besides, take the form of chemical reactions -- lots of very complicated interacting chemical reactions that add up to the events listed. Cells are full of molecular tools which encourage these chemical reactions to occur, and which make sure that they are finely controlled. These tools are typically enzymes, a class of protein. They are chains of different building blocks: several types of "amino acid" arranged in a specific pattern -- a pattern which determines the protein's shape, and therefore its properties, such as function and efficiency.

The sequence of amino acids in a protein, and therefore the protein's properties, are represented in turn by genes. Genes are themselves sequences of a different building block -- nucleotides -- and their sequences correspond to the protein sequences. Indeed, one group of enzymes is dedicated to the task of translating those gene sequences into the sequences of new enzymes during gene expression. A small change in a gene sequence (an inherited or acquired mutation), though, can have a range of effects on the enzyme that it encodes, and some of those effects can be catastrophic. Many mutations will go entirely unnoticed, and others are negligible. But if a mutation hits the code for a crucial location in an important enzyme, that tiny change in sequence might knock out (or switch permanently on) a whole cellular system.

This is how cancers tend to get started: a mutation affects the function of an enzyme, changing that enzyme's ability to control chemical reactions, and thus a key system in the cell goes unregulated and that cell starts behaving badly. As cancers progress, they pick up further mutations, disrupting more and more cellular systems, including, as we will see in a future post, the (imperfect) systems that are in place for detecting and correcting mutations. Once those systems have been damaged, there follows major deterioration of the genome, and the ability of the cell to function. This progressive deterioration of the genome, and the variety of associated cellular systems, are what we will explore in this series of posts.

Cancers are diseases of cell growth, division, and death

Cancers can also be described as diseases of the cell cycle. Tumours are, after all, groups of cell clones proliferating beyond control. The life of a healthy cell is highly regulated: new cells are created by cell division ("mitosis"); cells differentiate into specialised occupations in the body; and when they grow old, they undergo a process of programmed cell death ("apoptosis"). These events, like any other in the cell, are regulated by enzymes, and it is disruption to these processes which causes cancers.

Cell division requires the activation of a number of cellular systems, to perform tasks such as the duplication of the cell's genome and the production of many cell components, such as its enzymes and membranes. It can be divided into a number of discrete stages. At rest, the cell is in the first "gap phase", G1. During G1, the cell is just waiting for the right moment to start division. It monitors the conditions of its external and internal environments, and awaits the "proceed" signal. The cell runs its "restriction checkpoint": a system for testing the integrity of its genome, to ensure that it is in good condition. If the cell passes the checkpoint, it is ready to divide; if it fails, it will refuse to divide (becoming "quiescent" in the "G0 phase") and may even activate a system of controlled self-destruction called "apoptosis".

The first sign of cell division activity is when the cell is prompted into the "synthesis phase", when the cell's complement of chromosomes -- its genome -- is duplicated. Synthesis is followed by another gap phase, G2, during which the "G2 checkpoint" must be passed. This "checkpoint", like the restriction checkpoint, is a system for testing genome integrity, and specifically whether genome duplication has been successful. Very small "typos" are to be expected during genome duplication, and the checkpoint activates DNA repair mechanisms to correct these. If the cell passes the checkpoint, it is ready for the big event, mitosis: the carefully choreographed series of processes by which the cell divides. If it fails, the cell will activate apoptosis.

The system of checkpoints and DNA repair are imperfect, and at every cell division, the genome inevitably picks up some (mostly harmless) mutations. As a precaution against cells picking up too many small mutations, which together might add up to produce harmful effects -- including cancers and the effects of aging -- cells have another control system: programmed replicative senescence. This system counts the number of divisions that a cell has been through, and when the number grows too high, the cell will fail the restriction checkpoint, growth and division will be halted, and the cell will become senescent or die.

Synthesis: social control genes

Cancers occur when mutations cause cells to grow and divide beyond their normal limits, and to outlive their programmed senescence. The common factor between cancer as a genetic disease and cancer as a cell lifecycle disease is the genes whose protein products are part of, or influence, the systems of cell growth, division, and death. These genes are oncogenes (or more properly, proto-oncogenes) and tumour suppressor genes. The products of oncogenes typically act, within strict limits, to cause the cell to proceed through the cell cycle and to divide. The products of tumour suppressor genes typically act as a check on cell division. When these genes are mutated such that they can not perform their function correctly, or when regulation of the expression of these genes is lost such that too much or too little of the enzyme is produced, the cell cycle becomes dysregulated, and a cancer can form. We will meet some specific oncogenes and tumour suppressor genes when we look at the cellular systems and events involved in cancer.

Oncogenes and tumour suppressor genes can be directly involved in the mechanisms of the cell cycle and the systems of checkpoints, repair, and programmed cell death. But just as often they are part of the complicated network of interacting signals that tell the cell what is happening in the body around it, and what its various systems should be doing. Cell division does not occur spontaneously, but when the cell detects that conditions are right for proliferation. Thousands of varieties of "receptors" sit on the surface of the cell. These proteins contain docking sites for specific molecules, known as the receptor's "ligand", found in the cell's environment -- nutrients in the blood, and hormones released by other cells, for example. When a receptor detects its ligand, it sends a message inside the cell, typically by activating a "cascade" of intracellular signalling molecules -- the receptor activates messenger i, which activates several of messenger ii, which together activate many of messenger iii. Messenger iii might then, for example, tell the cell to change its pattern of gene expression so as to push it into the synthesis phase of the cell cycle. There may also be cleanup-enzymes i-iii which go around switching the messengers off at a constant rate, such that the signal ceases when its activation by the receptor ceases.

Cell signalling networks are very complicated, with different systems interacting, and many messengers carrying subtly different messages depending on the context and concentration in which they are active. It does not require much to change in order for a messenger to go off message. Messengers i-iii are therefore potential oncogenes: if they were to be mutated so as to be always on, the cell would constantly think that it is receiving the command to divide. Cleanup-enzymes i-iii would be tumour suppressor genes, producing a similar state were they to be mutated to an always-off state. The quirks and complexities of cell signalling in cancer evolution will be explored in several of the forthcoming posts of the series.

Recapitulation

Cells grow and divide to build and maintain our bodies. Our bodies functions arise largely out of the events and complicated and carefully regulated systems within our cells, which are mostly carried out by molecular machines called enzymes. These enzymes are produced by the genome, a set of instructions which is inherited during cell division. Mistakes in genome duplication -- mutations -- can cause the production of malformed enzymes, or incorrect concentrations of enzymes, and thus cause the disruption of cellular systems. When this happens the cell behaves badly, and might become cancerous. These enzymes are known as "oncogenes" and "tumour suppressor genes" according to their activities, and they are typically involved in the systems of cell growth, division, and death, or genome auditing and repair, either directly or as part of cell signalling networks.

The next post in the series will be an introduction to the basic biology of evolution, and after this the series will move on to looking in greater depth at the cellular systems involved in cancer, and how tumours evolve.