The migrating cancer stem cells model--a conceptual explanation of malignant tumour progression

Human colorectal cancer is one of the best, if not the best, understood tumour diseases. These tumours develop stepwise via an adenoma-carcinoma sequence. The steps in this process can easily be discriminated with light microscopy. The breakthrough in understanding carcinogenesis was the finding that mutations in tumour suppressor genes and oncogenes accumulate in parallel with these steps. This accumulation is the cause for the malignant progression of colorectal cancers, leading to highly invasive and migrating tumour cells. This concept is known as the multistep carcinogenesis model and has become the paradigm of tumour progression in general. But this model does not explain the complex, heterogeneous histology of colorectal tumours or the good differentiation of metastases, which are expected to have lost their differentiation because of the accumulation of mutations. Here, we present the model of migrating tumour stem cells, which explains these contradictions in the context of the histology of colorectal tumours. Thus colorectal tumours consist of tumour stem cells, which have recently been defined as a small CD133-positive population of tumour cells. These cells trans-differentiate into epithelial cells, which represent the main mass of the colorectal tumours. Moreover, the tumour stem cells are the active component of migration and invasion, thus conferring the malignant phenotype. Taken together, mutations confer to the tumour cells the capability to live outside of their stem cell niche and intestinal compartment. In addition, the trans-differentiation potential of the tumour cell confers plasticity to the tumour and thus contributes to the heterogeneity of colorectal cancers.