A gene previously identified as critical for tumor growth in many human cancers also maintains intestinal stem cells and encourages the growth of cells that support them, according to results of a study led by Johns Hopkins researchers.The finding adds to evidence for the intimate link between stem cells and cancer, and advances prospects for regenerative medicine and cancer treatments.
Life it seems, is not without a sense of irony, as a research team led by investigators at the Johns Hopkins University School of Medicine has just reported that a gene previously identified as critical for tumor growth in many human cancers also maintains intestinal stem cells and encourages the growth of cells that support them. The new findings—released today in the latest issue of Nature Communications in an article entitled “HMGA1 Amplifies Wnt Signalling and Expands the Intestinal Stem Cell Compartment and Paneth Cell Niche”—adds to the growing pool of evidence for the intimate link between stem cells and cancer and advances prospects for regenerative medicine and cancer treatments.
The Hopkins team had been studying genes in the high-mobility group (HMG) family for quite some time. Several years ago, while creating a genetically engineered mouse that expresses high levels of the mouse HMGA1 gene to investigate its role in leukemia, the investigators stumbled upon results that suggested the intestines of these animals were much larger and heavier than those of wild-type animals (or control mice that were not genetically modified). The mouse intestines were also riddled with polyps, abnormal growths projecting from the intestinal lining that can be precursors of cancer. In fact, polyps in humans frequently progress to colon cancer, which is why they are removed during screening colonoscopies in people over 50 and others at risk for colon cancer.
In an attempt to better understand how the HMGA1 gene affected the rodents' intestines, the Hopkins researchers examined the transgenic animals' intestinal cells to determine which ones were expressing this gene. Several different experiments localized the active gene and its protein to stem cells buried in the crypts or deep grooves in the intestinal lining.
After isolating these stem cells from both transgenic and wild-type mice, the researchers found that those carrying the HMGA1 transgene multiplied far more rapidly, forming identical daughter cells in a process called self-renewal, which is a defining property of all stem cells. These transgenic stem cells also readily created intestinal tissues called organoids in laboratory dishes. These organoids had more stem cells than those isolated from wild-type mice.
Interestingly, the researchers found that these unusual properties arise from the ability of HMGA1 to turn on several genes involved in the Wnt signaling pathway, a network of proteins necessary for embryonic development and stem cell activity. Moreover, not only was HMGA1 causing the stem cells themselves to self-renew or proliferate more rapidly in the transgenic animals, but it was also increasing the number of Paneth cells—a type of niche cell known to support intestinal stem cells. Additional experiments showed that the protein produced by HMGA1 activates another gene called Sox9, which is directly responsible for turning stem cells into Paneth cells.
“We suspected that HMGA1 might generate new stem cells, but we were extremely surprised that it also helps support these cells by building a niche,” explained senior study investigator Linda Resar, M.D., professor of medicine, oncology, and pathology at the Institute for Cellular Engineering at The Johns Hopkins University School of Medicine. “We believe that our experiments provide the first example of a factor that both expands the intestinal stem cell compartment and builds a niche.”
Many genes that are involved in the growth and development of embryos or adult stem cells also play critical roles in carcinogenesis. After scanning the Cancer Genome Atlas, a database of genes expressed in human cancers, the research team discovered that the activity of the HMGA1 and SOX9 genes is tightly correlated in normal colon tissue, and both genes become highly overexpressed in colon cancer. “This tells us that the pathway turned on by HMGA1 in normal intestinal stem cells becomes disrupted and hyperactive in colon cancer,” Dr. Resar noted.
The research team plans to continue investigating the function of HMGA1 and SOX9 in intestinal and other cancers as well as their role in stem cells. Both avenues of investigation could eventually lead to clinical therapeutic applications. For instance, if scientists can find a way to turn down overexpression of these genes in cancer, we could disrupt cancer growth and prevent tumor progression. On the flip side, turning up expression of these genes or their pathways could help researchers grow new intestinal tissue to replace tissue destroyed by diseases such as inflammatory bowel disease or radiation treatment for cancer
“What we discovered is something referred to as the Goldilocks paradox,” Dr. Resar remarked. “Too little of this protein disrupts normal stem cell function, but too much can promote abnormal growth and lead to cancer. For our work to help patients, we will need to find ways to get the amount just right and in the appropriate cell context.”