Recent research demonstrated that mature cells in the stomach sometimes revert back to behaving like rapidly dividing stem cells. Now, the researchers have found that this process may be universal; no matter the organ, when tissue responds to certain types of injury, mature cells seem to get younger and begin dividing rapidly, creating scenarios that can lead to cancer.
Older cells may be dangerous because when they revert to stem cell-like behavior, they carry with them all of the potential cancer-causing mutations that have accumulated during their lifespans. However, because mature cells in the stomach, pancreas, liver and kidney all activate the same genes and go through the same process when they begin to divide again, the findings could mean that cancer initiation is much more similar across organs than scientists have thought. That could support using the same strategies to treat or prevent cancer in a variety of different organs.
The findings about how mature cells begin dividing again -- a process the researchers have named paligenosis -- are reported in The EMBO Journal.
"When we began the war on cancer in the 1970s, scientists thought all cancers were similar," said senior investigator. "It turned out cancers are very different from one organ to another and from person to person. But if, as this study suggests, the way that cells become proliferative again is similar across many different organs, we can imagine therapies that interfere with cancer initiation in a more global way, regardless of where that cancer may appear in the body."
Studying cells from the stomach and pancreas in humans and mice, as well as mouse kidney and liver cells, and cells from more than 800 tumor and precancerous lesions in people, the researchers found when tissue is injured by infections or trauma, mature cells can revert back to a stem-cell state in which they divide repeatedly. And along the way, those cells all activate the same genes to break down the mature cells and help them begin to divide again.
Authors show that metaplasia‐inducing injury caused both gastric chief and pancreatic acinar cells to decrease mTORC1 activity and massively upregulate lysosomes/autophagosomes; then increase damage associated metaplastic genes such as Sox9; and finally reactivate mTORC1 and re‐enter the cell cycle.
Blocking mTORC1 permitted autophagy and metaplastic gene induction but blocked cell cycle re‐entry at S‐phase. In kidney and liver regeneration and in human gastric metaplasia, mTORC1 also correlated with proliferation. In lysosome‐defective Gnptab−/− mice, both metaplasia‐associated gene expression changes and mTORC1‐mediated proliferation were deficient in pancreas and stomach.
These findings indicate differentiated cells become proliferative using a sequential program with intervening checkpoints: (i) differentiated cell structure degradation; (ii) metaplasia‐ or progenitor‐associated gene induction; (iii) cell cycle re‐entry. Authors propose this program, which they term “paligenosis”, is a fundamental process, like apoptosis, available to differentiated cells to fuel regeneration following injury.
"First, we saw a massive increase in the activity of genes associated with cell degradation," said first author. "Then, the cell's growth pathway senses that degradation and releases nutrients that then activate cell growth pathways and allow the mature cells we studied to proliferate."
The author explained, appears similar to apoptosis -- the programmed death of cells as a normal part of an organism's growth and development -- in that it seems to happen the same way in every cell, regardless of its location in the body.
"Nature has provided a way for mature cells to begin dividing again," author said, "and that process is the same in every tissue we've studied."
Researchers believe the discovery that cells in different organs go through the same process to become proliferative could lead to new potential targets for cancer treatment because the factors that initiate tumors could be the same in multiple organs.
"If you were to compare this reprogramming of cells to tearing down a building and putting something new in its place, the slow way to go would be to remove and then replace each brick, one at a time," author said. "What we're seeing is that nature is smarter than just running the building program in reverse. Instead, there is a wrecking ball program: When an old cell begins to divide again, a program runs to clear things out and then rebuild, and the same program runs in every tissue we've analyzed."
Similarities found in cancer initiation in kidney, liver, stomach, pancreas
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