The future of the treatment of cancer will be, must be, dominated by classes of therapy that can be easily and cost-effective applied to many different types of cancer. Such therapies can only exist as a result of targeting mechanisms that are shared by many or all types of cancer. It must also be challenging or impossible for cancerous cells to do without these mechanisms. The biggest issue in cancer research over the past few decades, in my opinion, is the specificity of therapies, the amount of time and resources poured into efforts to produce treatments that can only work on one type or a few types of cancer, and that often target mechanisms that cancerous cells in any given tumor can lose or replace. Cancers evolve rapidly, frantic growth coupled with a high rate of mutation. Cancer therapies that operate on replaceable mechanisms may just pressure the cancer to evolve in a new direction. There is only so much funding, only so many researchers, and only so much time. The work must be efficient if cancer is to be controlled within our lifetimes.
When it comes to our own personal future engagements with cancer - it will happen, just live long enough - it is reassuring to see the signs of more research programs that are focused on universal or widely applicable approaches to cancer. These are cost-effective ways forward for the research community, and are the only way to gain the necessary efficiency for significant progress in the near future, the next twenty years. Among these technologies, approaches, and promising early stage research: targeted blockade of telomere lengthening, by sabotaging telomerase, and interfering in alternative lengthening of telomeres (ALT); the chimeric antigen receptor immunotherapies that have a comparatively low cost of adaptation to different cancers; restoring circadian mechanisms broken in cancerous cells; using a kill switch in cells that is targeted by huntingtin, explaining why Huntington's disease patients experience very low cancer risk.
The work here is a new addition to this list. This line of research is early stage, but it outlines an area of cellular behavior that appears to be common to many different tissues and thus types of cancer. With further investigation, scientists may find targets that could shut down cancerous tissue if developed into treatments. It is far too early to say how useful this will turn out to be in the fullness of time, when compared with the other options on the table, most of which are still yet to reach the clinic, but it is exactly the sort of fundamental work that we'd all like to see more of from the cancer research community.
Mature cells in the stomach sometimes revert back to behaving like rapidly dividing stem cells. Now, 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 process by which mature cells begin dividing again has been named paligenosis. "When we began the war on cancer in the 1970s, scientists thought all cancers were similar. 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. Paligenosis 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, and that process is the same in every tissue we've studied."
In 1900, it was speculated that a sequence of context-independent energetic and structural changes governed the reversion of differentiated cells to a proliferative, regenerative state. Accordingly, we show here that differentiated cells in diverse organs become proliferative via a shared program. 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.
Our 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. We propose this program, which we term "paligenosis", is a fundamental process, like apoptosis, available to differentiated cells to fuel regeneration following injury.