Cancer Stem Cells in the Gut Influence on Neighbor Cells

Malignant stem cells in the gut secrete factors that promote the differentiation of neighboring stem cells, thereby aiding the replacement of normal stem cells by those with cancer-promoting mutations.

In recent years there has been growing recognition that the surrounding tissue environment affects the natural selection of these mutation-driven characteristics. The effects of interactions between malignant cells and their neighboring cells and how through these interactions, malignant cells shape the surrounding environment to their advantage has been recently studied by Yum et al. 

Yum et al. developed an approach that uses a multicolor system to monitor cellular lineages (clones) in mice and track intestinal stem cells that express cancer-associated mutations in two genes, Kras and Pik3ca, and also to assess their wild-type neighboring cells. 

They reported that the presence of intestinal stem cells harboring these mutated genes increased the rate of differentiation of the surrounding wild-type cells and that these changes were driven by mutant stem cells secreting specific factors. They also found that structural cells (stromal cells) that surround stem cells that normally promote their maintenance, enhanced their secretion of pro-differentiation factors if mutant stem cells were present, which results in a less supportive environment for the maintenance of intestinal stem cells. These secreted factors promote differentiation regardless of whether the stem cells have cancer promoting mutations. 

This study and others have shown how malignant intestinal stem cells can win competitive battles in the gut by promoting neighboring stem cells to differentiate into specialized and less-proliferative cell types. 

The incidence of colon cancer rises exponentially in old age, and the expression of NOTUM (Protein Coding gene) increases with aging too. This raises the question of whether the processes reported in these studies might be some of the ways in which ageing creates an environment that promotes cancer initiation. 

The studies indicate that such cells can impair the maintenance of neighboring stem cells, such pre-malignant clones could hypothetically contribute to both tissue aging (by reducing tissue maintenance) and aging-associated cancers (through selection for cancer-promoting mutations that might resist, and perhaps even reinforce, pro-differentiation forces).

Current treatments for cancer focus on promoting our immune system as a defense against the disease. However, with the new appreciation of how stem cells and their tissue environment are important in tumor progression might change the approach to one that counteracts the pro-differentiative influences of malignant cells in their microenvironment.

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