Stem cells and cancer of the stomach and intestine

Abstract

Cancer in the 21st century has become the number one cause of death in developed countries. Although much progress has been made in improving patient survival, tumour relapse is one of the important causes of cancer treatment failure. An early observation in the study of cancer was the heterogeneity of tumours. Traditionally, this was explained by a combination of genomic instability of tumours and micro environmental factors leading to diverse phenotypical characteristics. It was assumed that cells in a tumour have an equal capacity to propagate the cancer. This model is currently known as the stochastic model. Recently, the Cancer stem cell model has been proposed to explain the heterogeneity of a tumour and its progression. According to this model, the heterogeneity of tumours is the result of aberrant differentiation of tumour cells into the cells of the tissue the tumour originated from. Tumours were suggested to contain stem cell-like cells, the cancer stem cells or tumour-initiating cells, which are uniquely capable of propagating a tumour much like normal stem cells fuel proliferation and differentiation in normal tissue. In this review we discuss the normal stem cell biology of the stomach and intestine followed by both the stochastic and cancer stem cell models in light of recent findings in the gastric and intestinal systems. The molecular pathways underlying normal and tumourigenic growth have been well studied, and recently the stem cells of the stomach and intestine have been identified. Furthermore, intestinal stem cells were identified as the cells-of-origin of colon cancer upon loss of the tumour suppressor APC. Lastly, several studies have proposed the positive identification of a cancer stem cell of human colon cancer. At the end we compare the cancer stem cell model and the stochastic model. We conclude that clonal evolution of tumour cells resulting from genetic mutations underlies tumour initiation and progression in both cancer models. This implies that at any point during tumour development any tumour cell can revert to a cancer stem cell after having gained a clonal advantage over the original cancer stem cell. Therefore, these models represent two sides of the same coin.

Figure 1

Anatomy of the intestine. A) Schematic representation of the crypt‐villus axis. B) Lineage tracing experiments demonstrating that LGR5 cells are the stem cells of the intestine. Blue ribbons show the expression of LacZ from the Rosa26LacZ locus upon induction of CRE enzyme with tamoxifen, on the LGR5EGFP‐IRES‐CREert/Rosa26R mouse. After one day single CBC cells are induced. Six months later, entire blue ribbons indicate that the CBC cells that had an activated Rosa26LacZ are still producing all the cells of the intestinal epithelium. C) Differentiation hierarchy of the small intestine.

Figure 2

Anatomy of the stomach. A) Schematic representation of a gastric unit. B) Position of the proposed stem cells in a gastric unit. C) Lineage tracing experiments demonstrating that the LGR5 cells are stem cells of the stomach antrum. Blue ribbons show the expression of LacZ from the Rosa26LacZ locus upon induction of CRE enzyme with tamoxifen, on the LGR5EGFP‐IRES‐CREert/Rosa26R mouse. After two days single LGR5 cells are induced. Twenty months later entire blue ribbons are still present, indicating that the LGR5 stem cells are still producing all the cells of the intestinal epithelium. C) Differentiation hierarchy of the small intestine.

Figure 3

Comparison of the stochastic and the cancer stem cell model. In the stochastic model all cells have an equal probability to propagate the tumour. In the cancer stem cell model a unique population of CSC has the potential to propagate the tumour.

Figure 4

Tumour initiation by the cell of origin. Recently, it was shown that adenomas induced by loss of APC originate from the normal stem cells of the intestine, not the progenitors or differentiated cells. LGR5 expressing stem cells are the cells of origin.