Molecular evolution of colorectal cancer: from multistep carcinogenesis to the big bang

What is it about?

One of the central questions in cancer research is how the tumor acquires all the molecular features needed to grow into a clinically overt cancer. There is overwhelming evidence that tumor development is driven by mutations and that more than one mutation is needed to make a tumor. The dominant thinking is that tumor development starts form one cell with a mutation that makes her proliferate in an uncontrolled manner. Then, additional mutations, one at the time occurring in a single cell of the growing tumor, determine other characteristics of a malignant tumor, such as the ability to invade the surrounding tissue or to colonize other organs. This is the multistep carcinogenesis model. But very recent evidence from colorectal cancer tells another story: the cancer cell becomes genetically unstable, most likely due to an initial mutation. Due to the instability, the tumor cells rapidly accumulate many, many mutations, probably so many that many cells die because a vital gene has been hit: a genetically unstable cancer cannot grow indefinitely unless it stabilizes the genome. Molecular analyses of colorectal cancer show that after an initial phase of genetic instability, stable subclones grow out. So, in a way, multistep carcinogenesis is still true, yet it is limited to a short period during which stable clones are selected from a genetically unstable population. Hence, the tumor starts with a great heterogeneity of clones that grow in parallel. But what transforms a genetically unstable tumor cell into a stable one? This is unknown and probably an aspect worth investigating.

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Why is it important?

Tumor heterogeneity is important because it determines drug responses. You analyze a tiny piece of a tumor to detect mutations that drive tumor growth and you use drugs that inactivate the effect of these "driver mutations". But then a small subpopulation with another driver mutation grows even better and the therapy fails. Therefore it is important to understand how heterogeneity is created.

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