【Nature】Three heavy articles in a row: Cancer stem cells in the intestine have adverse effects on neighboring cells

This article is original by Translational Medicine.
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Author: Yun Introduction: Malignant stem cells in the intestine secrete factors that promote the differentiation of neighboring stem cells, thereby helping those with cancer-promoting mutations to replace normal stem cells
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Decades of research have revealed how mutations promote the evolution of malignant cells and the ultimate characteristics of specific tumors
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It is increasingly recognized that the surrounding tissue environment will affect the natural selection of these mutation-driven characteristics
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However, little is known about the effects of interactions between malignant cells and their neighboring wild-type cells and how malignant cells shape their surroundings through these interactions
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Recently, researchers published an article titled "Cancer stem cells in the gut have a bad influence on neighbouring cells" in the journal Nature, providing important insights into the dynamics of competition between cancer cells and their neighboring cells in the intestine
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To study the interaction between cells with cancer-promoting mutations and neighboring cells in their natural environment, the researchers developed a microscope-based method that uses a multicolor system to monitor the cell lineage (cloning) of mice
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It can track intestinal stem cells expressing cancer-related mutations in two key genes Kras and Pik3ca, and evaluate their wild-type neighboring cells
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The study found that intestinal stem cells carrying these mutant genes increased the differentiation rate of surrounding wild-type cells
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This result is driven by mutant stem cells that secrete specific factors (below)
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In addition, the researchers found that the structural cells surrounding stem cells (called stromal cells) generally promote stem cell maintenance—if mutant stem cells are present, they will increase the secretion of their differentiation-promoting factors
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This leads to poor support of the environment for maintaining intestinal stem cells
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Regardless of whether the stem cells have cancer-promoting mutations or not, these secreted factors will promote differentiation
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Crucially, cells with mutations are less affected than cells without mutations, which gives mutant stem cells a competitive advantage
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The area of ​​the intestine adjacent to the cell clone created by the mutation (a unit called a crypt) shows an increase in cell turnover, which further promotes the establishment of the mutant cell clone
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The adenomatous polyposis colon (APC) disease gene in stem cells, as a tumor suppressor gene for colorectal cancer, is the most common site of germline and somatic mutations
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When this gene is mutated, it will induce the phosphorylation and degradation of β-catenin, negatively regulate the WNT pathway, and induce colon cancer
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To this end, scientists have been committed to eradicating cancer stem cells
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In Drosophila experiments, cells with Apc mutations can defeat the wild-type cells around them by inducing the death of these cells
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In contrast, none of the three papers highlighted here report increased cell death in wild-type cells adjacent to cells with Apc, Kras, or Pik3ca mutations
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These three studies jointly revealed how malignant intestinal stem cells can win intestinal competition by promoting the differentiation of neighboring stem cells into less specialized and proliferating cell types
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Other studies using leukemia formation models also show that the secretion of factors by malignant cells, such as pro-inflammatory cytokine molecules, can impair the adaptability of normal cells and enhance the adaptability of malignant cells
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Although cell competition is a process that obviously participates in the progression of malignant tumors, it is also a quality control mechanism for maintaining tissue health
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For example, during embryonic development, normal cells secrete factors to eliminate defective cells to ensure healthy growth; this phenomenon echoes the mechanisms described in these three studies
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There are many other examples of cell competition processes that affect health and disease
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A study reported that the expression of the protein COL17A1 regulates the division of basal (stem) cells in the skin
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Cell damage can lead to down-regulation of COL17A1 expression, which promotes the differentiation of these stem cells into mature cells in the outer cortex
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This causes healthy basal cells to replace damaged basal cells
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In addition, normal cells can "drive out" mutant cells: for example, normal epithelial cells will force cells with cancer-promoting mutations to squeeze out of the skin layer, thereby preventing the occurrence of cancer
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In addition to tumor suppression, the effective identification and elimination of "loser" cells during cell competition is also critical to the lifespan of Drosophila melanogaster
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The incidence of colon cancer increases exponentially with age
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This raises the question: Are the processes reported in these studies created by aging to promote cancer? A large number of studies in the past decade have described how as we age, how can cells with cancer-promoting mutations in our tissues become more and more abundant? Studies have shown that such cells can impair the maintenance of neighboring stem cells.
It is hypothesized that such precancerous clones may cause tissue aging (by reducing tissue maintenance) and aging-related cancers (by selecting cancer-promoting mutations that may resist, perhaps even strengthening and promoting differentiation.
power)
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Cancer treatment usually focuses on using our own natural defense system to fight off
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So far, the focus has been on promoting defenses mediated by the immune system
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However, as we become more and more aware of the importance of stem cells and various aspects of the tissue environment to tumor progression, interventions may be developed to promote stem cells and tissue environments that are not conducive to the development of malignant tumors
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In view of the ability of healthy tissues to eliminate dysfunction or malignant cells, these three studies should further encourage the development of therapeutic strategies to prevent cancer by counteracting the pro-differentiation effects of malignant cells, thereby improving the adaptability of competing normal cells
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 Reference materials: https:// Note: This article aims to introduce the progress of medical research and cannot be used as a reference for treatment options
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If you need health guidance, please go to a regular hospital
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