A gene previously identified as critical for tumor growth in several human cancers also maintains intestinal stem cells plus encourages the growth of cells that support all of them, according to results of a study led by Johns Hopkins scientists. The finding, reported in the Apr. 28 issue associated with Nature Communications , adds to evidence for your intimate link between stem cells and cancer, plus advances prospects for regenerative medicine and cancer remedies.

Study leader Linda Mirielle. S. Resar, M. D., professor of medicine, oncology and pathology at the Institute for Cellular Engineering in the Johns Hopkins University School of Medicine, has been learning genes in the high-mobility group (HMG) family for over 20 years. Several years ago, while creating a genetically engineered mouse that communicates high levels of the mouse HMGA1 gene to investigate its function in leukemia, Resar and her colleagues made the opportunity finding that the intestines of these animals were much larger plus heavier than those of “wild-type” animals (or control rodents that were not genetically modified). The mouse intestines had been also riddled with polyps, abnormal growths projecting from the digestive tract lining that can be precursors of cancer. In fact , polyps within humans frequently progress to colon cancer, which is why these are removed during screening colonoscopies in people over 50 and more at risk for colon cancer.

To better know how HMGA1 affected the rodents’ intestines, Resar and Lingling Xian, M. D., Ph. D., research associate on the Johns Hopkins University School of Medicine, and their own colleagues examined the transgenic animals’ intestinal cells to find out which ones were expressing this gene. Several different experiments local the active gene and its protein to stem tissue buried within the crypts, or deep grooves in the digestive tract lining.

After isolating these stem tissues from both transgenic and wild-type mice, the experts found that those carrying the HMGA1 transgene multiplied much more rapidly, forming identical daughter cells in a process known as self-renewal, which is a defining property of all stem cells. These types of transgenic stem cells also readily created intestinal tissue called “organoids” in laboratory dishes. These organoids acquired more stem cells than those isolated from wild-type rodents.

Further investigation, says Resar, showed these unusual properties arise from the ability of HMGA1 to show on several genes involved in the Wnt pathway, a system of proteins necessary for embryonic development and stem cellular activity.

Stem cells do not function within isolation, explains Resar. They need a “niche” to survive and keep an undifferentiated state. From the French word nicher, meaning to build a nest, a niche is a nest-like compartment composed of cells that secrete growth factors and other proteins that will help stem cells survive. The niche also stops stem cells from morphing into mature intestinal tissues until new intestinal cells are needed. Intestinal stem cellular material are particularly important because a new intestinal lining is usually generated about every 4-5 days.

Searching further into the intestinal crypts of both the transgenic plus wild-type mice, the research team made what they consider an amazing finding: Not only was HMGA1 causing the stem cells them selves to self-renew or proliferate more rapidly in the transgenic pets, but it was also increasing the number of Paneth cells, a type of specific niche market cell known to support intestinal stem cells. Additional tests showed that the protein produced by HMGA1 activates another gene called Sox9, which is directly responsible for turning stem cellular material into Paneth cells.

“We suspected that will HMGA1 might generate new stem cells, but i was extremely surprised that it also helps support these cells because they build a niche, ” Resar says. “We believe that our tests provide the first example of a factor that both expands the particular intestinal stem cell compartment and builds a niche. inch

Many genes that are involved in the growth and development associated with embryos or adult stem cells also play tasks in cancer, Resar adds. After scanning the Malignancy Genome Atlas, a database of genes expressed within human cancers, the research team discovered that the activity of each HMGA1 and SOX9 genes are tightly correlated within normal colon tissue, and both genes become extremely overexpressed in colon cancer. “This tells us that the path turned on by HMGA1 in normal intestinal stem tissue becomes disrupted and hyperactive in colon cancer, inch Resar says.

Resar says the group plans to continue investigating the function of HMGA1 plus SOX9 in intestinal and other cancers as well as their function in stem cells. Both avenues of investigation can eventually lead to clinical applications, she adds. For example , when scientists can find a way to turn down overexpression of these genes within cancer, we could disrupt cancer growth and prevent tumor development. On the flip side, turning up expression of these genes or their paths could help researchers grow new intestinal tissue to replace cells destroyed by diseases such as inflammatory bowel disease or even radiation treatment for cancer. “What we discovered is definitely something referred to as the Goldilocks paradox, ” she states. “Too little of this protein disrupts normal stem cellular function, but too much can promote abnormal growth plus lead to cancer. For our work to help patients, we will have to find ways to get the amount just right and in the appropriate cell framework. ”

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