The intestine has a reservoir of stem cells that are resistant to chemotherapy

These comprise a small group of passive stem cells -quiescent- that are activated when needed and have the capacity to produce any kind of intestinal cell. Quiescent cells are relevant for tissue regeneration and for participation in tumor development.

After Chemotherapy, these cells change their behaviour, become active and regenerate all cell types in the intestine (in green). CREDIT Franscisco Barriga, IRB Barcelona

The intestine has a high rate of cellular regeneration due to the wear and tear originated by its function degrading and absorbing nutrients and eliminating waste. The entire cell wall is renewed once a week approximately. This explains why the intestine holds a large number of stem cells in constant division, thereby producing new cell populations of the various types present in this organ.

Researchers at the Institute for Research in Biomedicine (IRB Barcelona) headed by ICREA investigator Eduard Batlle, head of the Colorectal Cancer Laboratory, have discovered a new group of intestinal stem cells with very different characteristics to those of the abundant and active stem cells already known in this organ. Performed in collaboration with the Centro Nacional de Análisis Genómico (CNAG-CRG), the study has been published in Cell Stem Cell. These new group of stem cells are quiescent, that is to say, they do not proliferate and are apparently dormant.

The researchers describe them as a reservoir of stem cells–it is estimated that there is one quiescent cell for every 10 active intestinal stem cells. In healthy conditions, these cells have no apparent relevant function. However, they are important in situations of stress, for example, after chemotherapy, in inflammatory processes, and in tissue infections–all conditions in which the population of “normal/active” stem cells is depleted. These quiescent cells would serve to regenerate the organ by giving rise to the various types of cells present in the intestine, renewing the population of “normal/active” stem cells, and restoring balance to the tissue.

Eduard Batlle explains that the discovery of quiescent stem cells in the intestine reveals that stem cell biology is more complex that previously appreciated and that it does not follow ahierarchical model of cell organisation. “In intestinal cell hierarchy, there are no cells above others, so the two populations are in a continual balance to ensure the proper function of the organ“.

Most drugs against cancer have a secondary effect on the cells that are dividing in our tissues. “Because quiescent stem cells divide infrequently, they are resistant to many types of chemotherapy and they regenerate the tissue that this treatment has damaged,” explains Eduard Batlle, head of one of the labs of international prestige in research into intestinal stem cells and their involvement in colorectal cancer.

Quiescent cells are present in many kinds of tissue. However, in spite of their relevance in tissue regeneration, increasing evidence points to their involvement in tumour development. “It is difficult to study these cells, mainly because they are scarce and there are technical limitations with respect to monitoring, straining and distinguishing them from the others,” explains Francisco Barriga, first author of the study and current postdoctoral fellow at the Memorial Sloan Kettering Cancer Center in New York.

Using advanced techniques, such as genetic tracing of cell lineages and transcriptomic analysis of individual cells, performed by CNAG-CRG and the Bioinformatics and Biostatistics Unit at IRB Barcelona, the group has identified the distinct genetic programme used by quiescent stem cells with respect to normal intestinal ones. This work has been done over six years.

The researchers have labelled this cell population with a specific marker, the Mex3a protein, which has allowed them to track it over time. “We intend to continue studying quiescent stem cells in health and disease and to discover the function of the genes that distinguish them in the colon and in other organs,” says Batlle.

Barriga et al. Mex3a marks a slowly dividing subpopulation of Lgr5+ intestinal stem cells. Cell Stem Cell (2017). doi: 10.1016/j.stem.2017.02.007 [Abstract]


Longer colonoscopies linked to lower cancer rate

If a colonoscopy seems like the type of thing you’d like to get done with quickly, think again.

Research by a Veterans Affairs team has confirmed that longer-lasting colonoscopies are associated with lower cancer rates.The findings appear online in the journal Gastroenterology. They were based on nearly 77,000 screening colonoscopies.

Experts already know about the link between colonoscopy withdrawal time and patient outcomes, but the new study provides some of the strongest evidence yet to back clinical guidelines covering this aspect of the procedure.

Our results support the use of withdrawal time as a quality indicator, as recommended by current guidelines,” said lead author Dr. Aasma Shaukat, with the Minneapolis VA Health Care System and the University of Minnesota.

In a colonoscopy, a doctor inserts a long, thin tube with a tiny camera fitted to the end into the patient’s colon. After the tube is fully inserted, it is then slowly withdrawn. It is during this “withdrawal time” that the doctor carefully examines the lining of the colon, looking at a view of the colon on a monitor in the exam room. Any small growths, or polyps, are removed with the scope’s snipping tool and sent for biopsy. These growths may grow into cancer within a few years.

According to current guidelines, a “normal” colonoscopy – one in which there is no finding of cancer or pre-cancerous growths, and the doctor does not remove any snippets of tissue to be biopsied–should have a withdrawal time of at least six minutes.

Shaukat’s team looked at data on colonoscopies performed over six years by 51 gastroenterologists in a large community practice in Minnesota. The team calculated average withdrawal times for each doctor. The average for the practice on the whole was 8.6 minutes–well within guidelines. But about 10 percent of the doctors had individual averages of under six minutes.

The researchers then checked the state’s cancer registry to look for cases of colorectal cancer among patients who had been screened at the same practice during the study period.

Patients who had been examined by doctors with shorter withdrawal times, on average, were more likely to have cancer. The rate was more than twice as high for patients whose doctors had average withdrawal times of under six minutes, compared with those whose physicians’ average times were over six minutes.

Withdrawal times of longer than eight minutes didn’t seem to afford any extra reduction of risk. As such, the researchers say focusing quality-improvement efforts on withdrawal times of under six minutes would likely have the most impact.

The study included cancers that occurred within about five years of the patient’s last colonoscopy. The assumption is that such “interval cancers” might have grown from polyps that were present during the colonoscopy but not detected, or not fully removed.

Shaukat says the reasons for sub-standard withdrawal times may vary, but “generally, every physician aims to do a complete inspection of the colon lining, regardless of their withdrawal time.”

Even the American College of Gastroenterology acknowledges that not every colonoscopy withdrawal must take at least six minutes, as some colons can be examined effectively in under six minutes.

Just the same, Shaukat says that withdrawal time appears to be a “robust indicator” of interval cancer risk. She urges more research on the topic, and on related quality measures for colonoscopies.

We need to understand the quality indicators better, define thresholds, and be able to adjust them to the particular patient population and underlying risk. Until there are uniform methods for data collection, adjustment, and collection, the numbers don’t mean much. We might be comparing apples to oranges.”

Shaukat says it’s appropriate for patients to ask their gastroenterologists if they collect and review quality metrics for their colonoscopies. At the same time, though, she points out that most patients won’t be in a position to properly make sense of the actual data.

The exact metrics and their cut-offs are debatable, but a commitment to quality needs to be there for every practice.”

Shaukat et al. Longer Withdrawal Time Is Associated With a Reduced Incidence of Interval Cancer After Screening Colonoscopy. Gastroenterology. 2015; S0016-5085(15)00934-8. doi: 10.1053/j.gastro.2015.06.044. [Abstract]

Toxic mushroom-based drug may help battle colorectal cancer

For some time, cancer scientists have considered the toxin, alpha-amanatin derived from “death cap” mushrooms, as a possible cancer treatment. However, due to its penchant for causing liver toxicity, its potential as an effective therapy has been limited.

Researchers at The University of Texas MD Anderson Cancer Center looked at antibody drug conjugates (ADCs) based on alpha-amanatin as one solution. They found that ADCs, when aimed at a gene called POLR2A, are highly effective in mouse studies in treating colorectal cancer. The drug caused complete tumor regression and greatly reduced toxicity. ADCs allow for improved targeting of cancer cells, resulting in less impact on healthy cells.

Xiongbin Lu, Ph.D., associate professor of Cancer Biology, observed that when the common tumor suppressor gene, TP53 is deleted resulting in cancer growth, another nearby gene, POLR2A is also deleted. Normal cells have two copies of POLR2A and TP53 genes. Lu’s study targeted cancers that had a single copy of both genes, representing 53 percent of colorectal cancers, 62 percent of breast cancers and 75 percent of ovarian cancers.

POLR2A is an essential gene for cell survival, including cancer cells,” said Lu. “Because there is only one copy, the cancer cells are more susceptible to suppression of this gene.”

Lu’s study was published in the April 22, 2015 issue of Nature.

Discovering that POLR2A is deleted at the same time as TP53 means that therapies can more narrowly target the genetic processes allowing cancer cells to thrive. Understanding that one copy of POLR2A can allow cancer to grow gives researchers a new target to hit. As it turns out, it can be suppressed by an ADC based on the mushroom toxin. Lu’s team tested the drug, alpha-amanatin as it was believed that it specifically inhibited POLR2A.

A tremendous effort has been made to restore TP53 activity in cancer therapies,” said Lu. “However, no TP53-based therapy has been successfully translated into clinical cancer treatment due to the complexity of TP53 signaling. POLR2A encodes an enzyme that is inhibited by alpha-amanatin. We found that suppression of POLR2A with low-dose alpha-amanatin stopped cancer cell growth and reduced toxicity.”

We anticipate that inhibiting POLR2A will be a novel therapeutic approach for human cancers harboring such common genomic alterations,” said Lu

Liu et al. TP53 loss creates therapeutic vulnerability in colorectal cancer. Nature. 2015; doi:10.1038/nature14418 [Abstract]

Grape seed promise in fight against bowel cancer

University of Adelaide research has shown for the first time that grape seed can aid the effectiveness of chemotherapy in killing colon cancer cells as well as reducing the chemotherapy’s side effects.

Published in the prestigious journal PLOS ONE, the researchers say that combining grape seed extracts with chemotherapy has potential as a new approach for bowel cancer treatment – to both reduce intestinal damage commonly caused by cancer chemotherapy and to enhance its effect.

Lead author Dr Amy Cheah says there is a growing body of evidence about the antioxidant health benefits of grape seed tannins or polyphenols as anti-inflammatory agents and, more recently, for their anti-cancer properties.

This is the first study showing that grape seed can enhance the potency of one of the major chemotherapy drugs in its action against colon cancer cells,” says Dr Cheah, researcher in the School of Agriculture, Food and Wine.

Our research also showed that in laboratory studies grape seed taken orally significantly reduced inflammation and tissue damage caused by chemotherapy in the small intestine, and had no harmful effects on non-cancerous cells. Unlike chemotherapy, grape seed appears to selectively act on cancer cells and leave healthy cells almost unaffected.”

The researchers used commercially available grape seed extract, a by-product of winemaking. Tannins extracted from the grape seed were freeze-dried and powdered. The extract was tested in laboratory studies using colon cancer cells grown in culture.

The research showed grape seed extract:

    • showed no side effects on the healthy intestine at concentrations of up to 1000mg/kg;
    • significantly decreased intestinal damage compared to the chemotherapy control;
    • decreased chemotherapy-induced inflammation by up to 55%
    • increased growth-inhibitory effects of chemotherapy on colon cancer cells in culture by 26%

Our experimental studies have shown that grape seed extract reduced chemotherapy-induced inflammation and damage and helped protect healthy cells in the gastrointestinal tract,” says Dr Cheah. “While this effect is very promising, we were initially concerned that grape seed could reduce the effectiveness of the chemotherapy.”

In contrast, we found that grape seed extract not only aided the ability of chemotherapy to kill cancer cells, but was also more potent than the chemotherapy we tested at one concentration.”

Co-author and project leader Professor Gordon Howarth says: “Grape seed is showing great potential as an anti-inflammatory treatment for a range of bowel diseases and now as a possible anti-cancer treatment. These first anti-cancer results are from cell culture and the next step will be to investigate more widely.”

Fellow co-author and joint lead researcher Dr Sue Bastian, Senior Lecturer in Oenology, says: “These findings could be a boost to the wine grape industry as it value adds to what is essentially a by-product of the winemaking process.

Cheah et al., (2014). Grape seed extract dose-responsively decreases disease severity in a rat model of mucositis; Concomitantly enhancing chemotherapeutic effectiveness in colon cancer cells. PLOS One, DOI: 10.1371/journal.pone.0085184 [Article]