Researchers at Karolinska Institutet have found a molecule that can both help the intestines to heal after damage and suppress tumour growth in colorectal cancer. The discovery could lead to new treatments for inflammatory bowel disease (IBD) and cancer. The results are published in the journal Nature.
Many patients with inflammatory bowel disease (IBD) such as Crohn’s disease or ulcerative colitis do not respond to available treatments, highlighting the need to identify novel therapeutic strategies. In this study, researchers propose that promoting mucosal healing through tissue regeneration could be a valid alternative to immunosuppressive drugs.
“However, it’s virtually impossible to promote tissue regeneration without the risk of inducing tumour growth, as cancer cells can hijack the body’s natural healing processes and start to grow uncontrollably,” says lead author Srustidhar Das, research specialist in Eduardo Villablanca’s research group at Karolinska Institutet. “We’ve now identified a molecule that can help the intestines to heal after damage while suppressing tumour growth in colorectal cancer.”
New drug candidates
In their search for new ways to treat IBD, the researchers have identified a handful of molecules with drug-candidate potential. They found that activation of a protein called the Liver X receptor (LXR) can promote regeneration and suppress tumour growth in colorectal cancer.
“The discovery of both these functions was astonishing,” says last author Eduardo J. Villablanca, docent at Karolinska Institutet. “We now need to study how LXR controls tumour formation more closely.”
The researchers used a collection of advanced technologies to conduct their study, which included mapping the transcriptome of intestinal cells. The researchers also cultivated what are known as 3D organoids: small, three-dimensional cell structures that mimic the function and structure of the body’s own organs, albeit in miniature format.
They then used spatial transcriptomics to map the gene expression in the different tissues, a technique that has been developed at SciLifeLab by scientists from the Royal Institute of Technology (KTH) and Karolinska Institutet in Sweden.
Third most common cancer
Patients, the third most common type in Sweden, are often treated with chemotherapy and radiotherapy, but this can cause irritation and swelling of the bowel mucosa with subsequent chronic intestinal inflammation.
“Thus, this new therapeutic molecule has the potential to treat not only IBD patients but also cancer patients to prevent chronic bowel disorders after radiotherapy and/or chemotherapy,” says Eduardo J. Villablanca.
Plant fungus provides new drug with a new cellular target
Human colon cancer cells. Credit: National Cancer Institute
Novel chemical compounds from a fungus could provide new perspectives for treating colorectal cancer, one of the most common and deadliest cancers worldwide. The fungus, Bipolaris victoriae, is otherwise known as a fungal plant pathogen which in the 1940s caused the “Victoria blight”, decimating oats and similar grains in the US.
In the journal Angewandte Chemie, researchers reported on the isolation and characterisation of a previously unknown class of metabolites (terpene-nonadride heterodimers). One of these compounds effectively kills colorectal cancer cells by attacking the enzyme DCTPP1, which thus may serve as a potential biomarker for colorectal cancer and a therapeutic target.
Rather than using conventional cytostatic drugs, which have many side effects, modern cancer treatment frequently involves targeted tumour therapies directed at specific target molecules in the tumour cells. The prognosis for colorectal cancer patients remains grim however, demanding new targets and novel drugs.
Targeted tumour therapies are mostly based on small molecules from plants, fungi, bacteria, and marine organisms. About half of current cancer medications were developed from natural substances. A team led by Ninghua Tan, Yi Ma, and Zhe Wang at the China Pharmaceutical University (Nanjing, China) chose to use Bipolaris victoriae S27, a fungus that lives on plants, as the starting point in their search for new drugs.
The team first analysed metabolic products by cultivating the fungus under many different conditions (OSMAC method, one strain, many compounds). They discovered twelve unusual chemical structures belonging to a previously unknown class of compounds: terpene-nonadride heterodimers, molecules made from one terpene and one nonadride unit. Widely found in nature, terpenes are a large group of compounds with very varied carbon frameworks based on isoprene units. Nonadrides are nine-membered carbon rings with maleic anhydride groups. The monomers making up this class of dimers termed “bipoterprides” were also identified and were found to contain additional structural novelties (bicyclic 5/6-nonadrides with carbon rearrangements).
Nine of the bipoterprides were effective against colorectal cancer cells. The most effective was bipoterpride No. 2, which killed tumour cells as effectively as the classic cytostatic drug Cisplatin. In mouse models, it caused tumours to shrink with no toxic side effects.
The team used a variety of methods to analyse the drug’s mechanism: bipoterpride 2 inhibits dCTP-pyrophosphatase 1 (DCTPP1), an enzyme that regulates the cellular nucleotide pool. The heterodimer binds significantly more tightly than each of its individual monomers. The activity of DCTPP1 is elevated in certain types of tumours, promoting the invasion, migration, and proliferation of the cancer cells while also inhibiting programmed cell death. It can also help cancer cells to resist treatment. Bipoterpride 2 inhibits this enzymatic activity and disrupts the now pathologically altered amino acid metabolism in the tumour cells.
The team was thus able to identify DCTPP1 as a new target for the treatment of colorectal cancer and bipoterprides as new potential drug candidates.
A new Cleveland Clinic study has identified diet-derived molecules called metabolites as main drivers of young-onset colorectal cancer risk, especially those associated with red and processed meat. The NPJ Precision Oncologyreport, which analysed metabolite and microbiome datasets, highlighted that one of the best ways a younger ( < 60 years) adult can prevent colorectal cancer is to discuss their diet with their doctor.
Increased monitoring and screening for colorectal cancer is an extremely helpful tool. Despite the success of these methods, these data indicate physicians can take a different approach with their younger patients, says senior author and gastrointestinal oncologist Suneel Kamath,MD.
“At the end of the day, it’s impractical to apply our care models for those over 60 to younger adults simply because we cannot give everyone in the system yearly colonoscopies,” he explains. “What is much more feasible is to give everyone in the system a simple test to measure a biomarker that determines their colorectal cancer risk. Then we can give the most at-risk individuals appropriate screening.”
Former clinical fellow Thejus Jayakrishnan, MD, and Naseer Sangwan, PhD, director of the Microbial Sequencing & Analytics Resource Core co-led the work. Researchers in Cleveland Clinic’s Center for Young-Onset Colorectal Cancer provided large-scale analyses of patient data from individuals who received care for either young- or average-onset colorectal cancer at Cleveland Clinic.
One previous study from this team identified differences in the metabolites (diet-derived molecules) of young – versus average-onset colorectal cancer, while another identified differences in gut microbiome between younger and older adults with colorectal cancer. These studies provided many potential directions for studying young-onset CRC. However, when more factors are involved in cancer risk, it becomes more complicated to understand what’s going on and plan future research, Dr Sangwan says. Interactions between these factors, like when our gut bacteria consume our metabolites and produce their own, make it even more complex.
Dr Sangwan and his team then developed an AI algorithm to combine and analyse the existing studies’ datasets and clarify what factors are most relevant for future study. Surprisingly, Dr Sangwan’s analysis revealed that differences in diet (identified through analysing metabolites) accounted for a significant proportion of the differences observed between the young-onset and older-onset patients.
“Researchers – ourselves included – have begun to focus on the gut microbiome as a primary contributor to colon cancer risk. But our data clearly shows that the main driver is diet,” Dr Sangwan says. “We already know the main metabolites associated with young-onset risk, so we can now move our research forward in the correct direction.”
The team was excited to see diet play such a large role in cancer risk, because it is much easier to identify at-risk patients by counting the metabolites in their blood than it is to sequence the bacterial DNA in their stool for different microbes.
“It can actually be very complicated and difficult to change your microbiome,” explains Dr Kamath. “While it’s not always easy, it is much simpler to change your diet to prevent colon cancer.”
Addressing factors in our diet to prevent colon cancer
Younger colon cancer patients had higher levels of metabolites associated with the production and metabolism of an amino acid called arginine, and with the urea cycle compared to their older peers. These differences may be tied to long-term consumption of red meat and processed meat. The team is now analyzing national datasets to validate their Cleveland Clinic-specific findings in patients across the country.
After they show that arginine and urea cycle metabolites (and, by proxy, red and processed meat overconsumption) are elevated across younger adults with colon cancer nationwide, they plan to test whether certain diets or commercially available drugs that regulate arginine production and the urea cycle can help prevent or even treat young-onset colorectal cancer.
Dr Kamath says that even though more research is needed to understand exactly how dietary factors cause colon cancer, his current findings have already changed the way he delivers patient care.
“Even though I knew before this study that diet is an important factor in colon cancer risk, I didn’t always discuss it with my patients during their first visit. There is so much going on, it can already be so overwhelming,” says Dr Kamath. “Now, I always make sure to bring it up to my patients, and to any healthy friends or family members they may come in with, to try and equip them with the tools they need to make informed choices about their lifestyle.”
Human colon cancer cells. Credit: National Cancer Institute
Colorectal cancer often metastasises to the liver, and for some patients, surgical removal of their liver tumours is not an option. A new study led by researchers at the Wilmot Cancer Institute and University of Rochester Medical Center (URMC) shows that a select group of patients with colorectal cancer that has spread to the liver tend to fare better if they receive a liver transplant as opposed to other common therapies.
In the study, published in JAMA Surgery, patients who had liver transplants tended to live longer without cancer progression than patients who opted for other treatments. While previous studies have shown the benefits of liver transplants for these patients, this is the first study to compare liver transplants to other treatment options.
“In any cancer treatment, it’s very easy to describe the outcomes of the patients who received the intervention, but similar patients that did not undergo the intervention can serve as a good comparison,” said Matthew Byrne, MD, a surgery resident at URMC and author of the study. “Without randomised, controlled trial data, this study offers the best evidence that is available to understand whether liver transplant provides better outcomes over other treatments.”
The study followed 33 patients whose colorectal cancer was under control, but who had liver tumours that could not be surgically removed. All 33 patients were eligible for liver transplantation, but only 20 chose to have a transplant, while 13 opted for other classical therapies, like removal of part of the liver, chemotherapy, or liver-directed therapies.
Compared to the classical therapy group, the liver transplant group had significantly higher progression-free survival rates across three years of follow-up. One year after liver transplant, 90% of patients showed no signs of cancer progression. That number dropped to 73% after two years and to 36% at three years. On the other hand, only 42% of patients who opted for other therapies were cancer-progression-free after one year, which dropped to roughly 10% after two and three years.
The transplant group also had higher overall survival rates than the standard therapy group, though the difference wasn’t statistically significant. At the three-year follow-up, 90% of transplant patients had survived, compared to 73% of patients who received other therapies.
Though this study provides solid evidence, larger clinical trials will be needed to fully understand the added benefit of liver transplant compared to other treatments for these patients, and to better refine which patients benefit most.
Dr Tim Forgan at the surgeon’s console of the da Vinci robotic system. (Photo: Biénne Huisman/Spotlight)
By Biénne Huisman
Within South Africa’s beleaguered public health sector – unsettled by budget cuts, understaffing, and divisive NHI legislation – cutting edge surgical robots that have been used to perform more than 600 surgeries at two Cape Town public hospitals are beacons of excellence that offer a glimmer of hope. Spotlight’s Biénne Huisman visited Dr Tim Forgan at Tygerberg Hospital to learn more.
Cutting edge robotic surgery might not immediately come to mind when one thinks of public hospitals, but in a first for public healthcare in South Africa, such systems are being used at two hospitals in the Western Cape.
The da Vinci Xi systems enable surgeons to control operations from a console – steering three arms with steel “hands” equipped with tiny surgical instruments; plus a fourth arm bearing a video camera (the laparoscope). The system translates a surgeon’s hand movements in real time, with enhanced precision, range and visuals, compared to manual surgery.
“It really is next level, it feels like you’re inside the patient,” says colorectal specialist Dr Tim Forgan, Tygerberg Hospital’s da Vinci robotics coordinator. “With this technology we can operate so much finer. You can see ten times better with this robot than with the naked eye; you can see tiny, tiny nerves you wouldn’t normally see. And you can manoeuvre surgical instruments so much better. Because of that, people have way better function after the procedure.”
He explains that the technology allows major surgery to be completed through small incisions – instead of larger cuts made by a doctor’s hand – leading to less bleeding and a faster recovery time.
Over 600 surgeries in two years
Lorraine Gys from Phillipstown in the Northern Cape can attest. On 22 February 2022, the 65-year-old pensioner became the first patient to undergo da Vinci robotic surgery in South Africa’s public sector. Forgan was behind the console, at Tygerberg Hospital.
Gys tells Spotlight: “The next day the sisters offered to wash me, I said to them ‘no, I’m not helpless.’ My recovery was very quick. I was up and about in no time, while the other patients had to be assisted. I was discharged on day four, and back at home I could even continue doing my own chores.”
Two years later, Gys is cancer free. The mother of three, who now lives in Eerste River, recalls how she made news headlines: “Before the operation, Dr Forgan explained everything to me. They asked my permission, saying that media will be there and the [provincial health] minister.”
Indeed, on the day Forgan operated on Gys, removing a cancerous rectal tumour, he was joined in theatre by several onlookers including former Western Cape MEC of Health and Wellness Nomafrench Mbombo.
“Yes it was a circus,” says Forgan, laughing. “A whole bunch of people watching me operate, quite bloody nerve-wracking. Fortunately I’m experienced at having lots of students around watching; plus performing surgery is just so immersive, everything else fades out.”
On that day, also in the operating room was colorectal surgeon Dr Roger Gerjy, keeping an eye. “He’s a very well-known robotic surgeon; a Swedish surgeon who works in Dubai,” says Forgan. “And if there was a problem, Roger would’ve taken over. He was also there to impart tips and tricks: move the instrument like this, shape it like a hockey stick; because with the robot it’s like having your whole arm inside [the body]. He’d give me advice on what to do with my extra floating arm – where to place it and how to manipulate it – because remember you’re controlling three arms at a time.”
Since 2022, the da Vinci robots installed at Cape Town’s two tertiary hospitals: Groote Schuur and Tygerberg, have enabled over 600 minimally invasive surgeries – including colorectal operations, prostatectomies, cystectomies (bladder removal surgery), and gynaecological procedures to treat endometriosis.
Groote Schuur Hospital has the other da Vinci Xi system run by Western Cape public healthcare
A spokesperson for the Western Cape Ministry of Health and Wellness, under former MEC Mbombo, Luke Albert explains: “We can see the immense impact it has for patients and the health system. For example, a traditional open cystectomy patient would require three days of ICU stay, as well as two weeks of hospital stay to recuperate. During this time, on average, 42% of patients require blood transfusions and almost 20% need total parenteral nutrition (when a patient is fed intravenously). A patient undergoing robotic surgery for a cystectomy requires no ICU stay and goes straight to a general ward for no more than six days on average, with no blood transfusions needed.”
Where the money came from
Asked how the department was able to afford R40 million per system for these machines in the context of severe budget cuts, Albert says: “The purchase was applicable to 2021/22 and not the current financial year; with all provincial health departments currently managing the effects of budget cuts.”
Asked the same question, Forgan explains the investment derived from surplus budget discovered within the throes of the COVID-19 pandemic: “There was a surplus because certain services just couldn’t be done. I mean, for us, we couldn’t do elective surgery. And how state funding works; if you don’t spend your [provincial] budget within the financial year, it goes back to central government.”
What it looks like
On a Friday afternoon at Tygerberg Hospital, Forgan is guiding Spotlight along corridors and up grey linoleum stairs, to the theatre where the da Vinci system is used. Dressed in black surgical scrubs bearing his name and a cap; on his feet Forgan is wearing bright pink crocs. In passing, he waves hello to fellow healthcare staff.
Inside the small blindingly white room, Forgan points out the three core components of the da Vinci system. There is a console with two control levers similar to refined joysticks – he demonstrates how to delicately hold them between forefingers and thumbs – a patient-side cart with four interactive metal arms (they are disposable; each arm can be used on twelve patients), and another trolley with a television screen. All connected by blue fibre optic cables.
As we speak, nurses arrive in the theatre, preparing it for upcoming gynaecology procedures scheduled for Monday. Forgan greets them, then continues to expand on his passion for colorectal surgery.
“With colorectal surgery, there’s a high rate of complications, but I really enjoy it, I really enjoy my job. When you have a successful outcome, saving a person from their cancer and prolonging their life through your intervention, that is the reward. Colorectal cancer is a very unpleasant disease, and operating like this can make one hell of a difference in a patient’s life.”
Colorectal cancer on the increase
Forgan adds that colorectal cancer is on the increase: “There aren’t many colorectal surgeons in South Africa, with a dire need for people to operate in this subspecialty. I mean, there are so few of us, we’re all on a WhatsApp group.”
Colorectal or colon cancer is the second most common cancer in South African men (following prostate cancer), and the third most common cancer in women (following breast and cervical cancer), according to the Cancer Association of South Africa.
Originally from Johannesburg, Forgan attended medical school at the University of the Witwatersrand. He qualified as a general surgeon at Stellenbosch University, sub-specialising in colorectal surgery at the University of Cape Town, before studying minimally invasive colorectal surgery at the Academic Medical Centre in Amsterdam.
He is also president of the South African Colorectal Society and runs a part-time private practise with his Tygerberg colleague, Dr Imraan Mia, at Cape Town’s Christiaan Barnard Hospital, where he has 32 all five-star Google reviews.
‘Early adopter’
Forgan considers himself an early adopter. But learning to use the da Vinci system did not happen overnight.
“We trained for ages,” he says. “On the surgical console there’s a simulator, so you spend hours and days and days doing procedures, over and over and over again. You have to get over 95% for each one of the procedures, before you can move on to the next skill.
“Then it’s how to use the machine, how to put it together, what to do if there’s an emergency; what if there’s a power failure and the machine stops working? How to safely remove it from the person. Then we went to the University of Lyon [in France] for two days of hands-on robotics training. And then a proctor – an international expert – comes to your theatre and does the procedures with you. So that was Dr Roger Gerjy, and that’s when we did Lorraine…”
First introduced by American biotechnology company Intuitive Surgical in 1999, the da Vinci Xi systems have sparked some liability lawsuits. An article from the Tampa Bay Times in February cites a lawsuit filed at the United States District Court in West Palm Beach, with a man claiming that a stray electrical arc from a surgical robot burned his wife’s small intestine during a colon cancer procedure, causing her death. The article quotes Intuitive Surgical’s 2023 financial report, which notes 8 606 da Vinci systems in use worldwide, having performed 2 286 000 procedures in 2023. The financial report mentions an undisclosed number of pending lawsuits, which the company disputes.
Nevertheless, Forgan remains an advocate.
Exiting via Tygerberg’s maze of corridors, he continues to reflect on his job. After our meeting, he is set to deliver a talk at the Cape Town International Convention Centre. His manner is earnest. Shrugging, he describes himself as a “glorified plumber”.
Human colon cancer cells. Credit: National Cancer Institute
Results from a new trial indicate that immunotherapy could successfully be used to treat the most common form of colorectal cancer, also known as bowel cancer.
The findings of the new study, a phase 1 trial involving the immunotherapy drugs botensilimab and balstilimab, have been published in the journal Nature Medicine, and it is the first time that consistent and durable responses to immunotherapy have been reported in difficult-to-treat patients.
Co-authored by Professor Justin Stebbing of Anglia Ruskin University (ARU), who describes the results as “potentially game changing”, the study focused on the most common type of colorectal tumours, known as MSS mCRC, or microsatellite stable metastatic colorectal cancer.
Although immunotherapy has previously been shown to work on patients with specific mismatch repair deficient (dMMR) tumours, only a small percentage of colorectal cancer patients have this type of tumour, and immunotherapy has so far been ineffective in patients with more common MSS mCRC tumours.
The new study involved using the immunotherapy drug botensilimab in conjunction with balstilimab on a group of patients in the United States. These drugs are both monoclonal antibodies, which work by triggering the body’s immune system to attack the cancer.
Of the patients in the phase 1 trial, 101 took part in a six-month follow-up and of these, 61% of them saw their tumour shrink or remain stable after receiving a combination of botensilimab (BOT) and balstilimab (BAL). The most common side-effects, or treatment-related adverse events, were diarrhoea and fatigue.
Justin Stebbing, Professor of Biomedical Sciences at Anglia Ruskin University (ARU) and communicating author of the study, said:
“These results are incredibly exciting. Colorectal or bowel cancer is one of the most common forms of cancer worldwide and this is the first time there has been convincing evidence that immunotherapy can work in all forms of colorectal tumours, so this is potentially game changing.
“This is now progressing into later phase clinical trials and we hope the FDA in the United States approve its use very soon. And because this is such an important area, affecting so many people, we hope authorities in the UK are also able to move quickly.” Joint first author Dr Andrea Bullock, Assistant Professor in Medicine at Beth Israel Deaconess Medical Center, said:
“This study sheds light on the potential of the BOT/BAL combination to treat microsatellite stable metastatic colorectal cancer, the most common form of colorectal cancer which has historically not responded to immunotherapy, and we hope our results will offer new hope for those diagnosed.” Joint last author Dr Anthony El-Khoueiry, Associate Director of Clinical Research and Chief of Section of Developmental Therapeutics at the USC Norris Comprehensive Cancer Center, said:
“This phase 1 study of botensilimab highlights its promising anti-tumour activity that encompasses immunologically cold tumours such as MSS colorectal cancer. The efficacy noted highlights the potential of botensilimab through its broader engagement of anti-tumour immunity.”
The full open access paper, published in , is available here
Studies have shown that long-term daily use of aspirin can help to prevent the development and progression of colorectal cancer, but the mechanisms involved have been unclear. New research has revealed that aspirin may exert these protective effects by boosting certain aspects of the body’s immune response against cancer cells. The findings are published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.
To investigate the effects of aspirin (a nonsteroidal anti-inflammatory drug) on colorectal cancer, investigators in Italy obtained tissue samples from 238 patients who underwent surgery for colorectal cancer in 2015–2019, 12% of whom were aspirin users. Patients were enrolled in the METACCRE section of the IMMUNOlogical microenvironment in the REctal Adenocarcinoma Treatment (IMMUNOREACT 8) multicenter observational study. The study was funded by the Associazione Italiana per la Ricerca sul Cancro (AIRC) and was mainly carried out at the University Hospital of Padova.
Compared with tissue samples from patients who did not use aspirin, samples from aspirin users showed less cancer spread to the lymph nodes and higher infiltration of lymphocytes into tumours. In analyses of colorectal cancer cells in the lab, exposing the cells to aspirin caused increased expression of a protein called CD80 on certain immune cells, which enhanced the capacity of the cells to alert other immune cells of the presence of tumour-associated proteins. Supporting this finding, the researchers found that in patients with rectal cancer, aspirin users had higher CD80 expression in healthy rectal tissue, suggesting a pro-immune surveillance effect of aspirin.
“Our study shows a complementary mechanism of cancer prevention or therapy with aspirin besides its classical drug mechanism involving inhibition of inflammation,” said principal investigator Marco Scarpa MD, PhD, of the University of Padova. “Aspirin is absorbed in the colon by passive diffusion to a significant degree. Its absorption is linear and depends on concentration along the bowel, and in the rectum, the concentration of orally administered aspirin can be much lower than in the rest of the colon. Thus, if we want to take advantage of its effects against colorectal cancer, we should think of how to guarantee that aspirin reaches the colorectal tract in adequate doses to be effective.”
Human colon cancer cells. Credit: National Cancer Institute
Researchers at Fred Hutchinson Cancer Center have found that a specific subtype of a microbe commonly found in the mouth is able to travel to the gut and grow within colorectal cancer tumours. This microbe is also a culprit for driving cancer progression and leads to poorer patient outcomes after cancer treatment.
The findings, published in Nature, could help improve therapeutic approaches and early screening methods for colorectal cancer, which is the second most common cause of cancer deaths in adults in the U.S. according to the American Cancer Society.
Examining colorectal cancer tumours removed from 200 patients, the Fred Hutch team measured levels of Fusobacterium nucleatum, a bacterium known to infect tumours. In about 50% of the cases, they found that only a specific subtype of the bacterium was elevated in the tumour tissue compared to healthy tissue.
The researchers also found this microbe in higher numbers within stool samples of colorectal cancer patients compared with stool samples from healthy people.
“We’ve consistently seen that patients with colorectal tumours containing Fusobacterium nucleatum have poor survival and poorer prognosis compared with patients without the microbe,” explained Susan Bullman, PhD, Fred Hutch cancer microbiome researcher and co-corresponding study author. “Now we’re finding that a specific subtype of this microbe is responsible for tumour growth. It suggests therapeutics and screening that target this subgroup within the microbiota would help people who are at a higher risk for more aggressive colorectal cancer.”
In the study, Bullman and co-corresponding author Christopher D. Johnston, PhD, Fred Hutch molecular microbiologist, along with the study’s first author Martha Zepeda-Rivera, PhD, a Washington Research Foundation Fellow and Staff Scientist in the Johnston Lab, wanted to discover how the microbe moves from its typical environment of the mouth to a distant site in the lower gut and how it contributes to cancer growth.
First they found a surprise that could be important for future treatments. The predominant group of Fusobacterium nucleatum in colorectal cancer tumours, thought to be a single subspecies, is actually composed of two distinct lineages known as “clades.”
“This discovery was similar to stumbling upon the Rosetta Stone in terms of genetics,” Johnston explained. “We have bacterial strains that are so phylogenetically close that we thought of them as the same thing, but now we see an enormous difference between their relative abundance in tumours versus the oral cavity.”
By separating out the genetic differences between these clades, the researchers found that the tumour-infiltrating Fna C2 type had acquired distinct genetic traits suggesting it could travel from the mouth through the stomach, withstand stomach acid and then grow in the lower gastrointestinal tract. The analysis revealed 195 genetic differences between the clades.
Then, comparing tumour tissue with healthy tissue from patients with colorectal cancer, the researchers found that only the subtype Fna C2 is significantly enriched in colorectal tumour tissue and is responsible for colorectal cancer growth.
Further molecular analyses of two patient cohorts, including over 200 colorectal tumours, revealed the presence of this Fna C2 lineage in approximately 50% of cases.
The researchers also found in hundreds of stool samples from people with and without colorectal cancer that Fna C2 levels were consistently higher in colorectal cancer.
“We have pinpointed the exact bacterial lineage that is associated with colorectal cancer, and that knowledge is critical for developing effective preventive and treatment methods,” Johnston said.
In an analysis of information on adults with colorectal cancer, patients who also had diabetes, particularly those with diabetic complications, faced a higher risk of early death. The results are published in CANCER, a peer-reviewed journal of the American Cancer Society.
For the study, Kuo‐Liong Chien, MD, PhD, of National Taiwan University, and his colleagues examined data registered between 2007 and 2015 in the Taiwan Cancer Registry Database, which is linked to health insurance and death records. Their analysis included 59 202 individuals with stage I–III colorectal cancer who underwent potentially curative surgery to remove their tumours. Among these patients, 9448 experienced a cancer recurrence and 21 031 died from any cause during the study period.
Compared with individuals without diabetes, those with uncomplicated diabetes were at a minimally or insignificantly higher risk of all‐cause and cancer‐specific death, whereas those with complicated diabetes had 85% higher odds of death from any cause and 41% higher odds of death from cancer. These associations were more pronounced in women and in patients with early‐stage colorectal cancer.
Also, compared to patients without diabetes, patients with uncomplicated or complicated diabetes had a 10–11% higher risk of colorectal cancer recurrence.
The mechanisms behind the relationship between diabetic severity and poor colorectal cancer prognosis could involve various pathways and responses triggered by high insulin and glucose levels in the blood, as well as elevated inflammatory states, which are characteristic of type 2 diabetes.
“While a higher diabetes prevalence was noted in patients with colorectal cancer, the study suggests that coordinated medical care involving multiple specialists can help prevent diabetes complications, potentially improving long-term colorectal cancer oncological outcomes, particularly in women and patients with early-stage cancer,” said Dr Chien.
New research published in eClinicalMedicine suggests that statins might protect patients with ulcerative colitis from developing and dying from colorectal cancer. The study, by Karolinska Insitut researchers, also found that statin treatment was associated with a lower risk of death regardless of cause in patients with ulcerative colitis or Crohn’s disease.
First author Jiangwei Sun notes that previous studies have shown that the risk of colorectal cancer in patients with IBD, such as ulcerative colitis and Crohn’s disease, is 50% higher than in the general population. This is likely to be because of the chronic gut inflammation that these patients have. Researchers have long sought drugs that can reduce the inflammation-related cancer risk.
“Even though more studies are needed to confirm our results, our study suggests that statins can prevent colorectal cancer in patients with inflammatory bowel disease (IBD), which is a high-risk group for this kind of cancer,” says Dr Sun.
The observational study conducted by Dr Sun and his colleagues compared over 10 500 IBD patients from around the country, of whom half were statin users; the other half of the group, who were matched with the first, were not. After a follow-up period of, on average, 5.6 years, 70 of the statin group and 90 of the non-statin group had been diagnosed with colorectal cancer.
The effect increased over time
The protective effect was directly proportional to the length of time the patient had been on statins and could be demonstrated after two years’ treatment.
There were also fewer deaths from colorectal cancer in the statin group (20) than in the non-statin group (37) during the study period, and deaths regardless of cause (529 versus 719).
The study shows that some 200 IBD patients need to be treated with statins to avoid one case of colorectal cancer or death from the cancer within ten years of treatment onset. The protective effect was only statistically valid for patients with ulcerative colitis.
“We think this is because the study contained fewer patients with Crohn’s disease,” explains Dr Sun. “More and larger studies compiling data from patient populations in many countries will probably be needed to achieve statistical significance for Crohn’s disease.”
Significantly fewer deaths
To avoid death regardless of cause during the same ten-year period, the number of treated patients dropped to 20, on account of how statins also protect against more common conditions, such as cardiovascular disease. Statins were linked to fewer deaths in both ulcerative colitis and Crohn’s disease patients.
The study was based on the ESPRESSO-cohort, which is run by its initiative-taker Jonas F Ludvigsson, paediatrician at Örebro University Hospital and professor at Karolinska Institutet, and the study’s last author.
“In that we can combine tissue data from patients with colorectal cancer with data from Swedish health registries, we’re uniquely placed to study the long-term effects of drugs for IBD,” he says. “Our hope is that these studies will improve the care of IBD patients.”
The most solid evidence so far
According to the researchers, the new results provide the most solid evidence so far that statins could be an effective prophylactic for colorectal cancer among people with IBD. However, more knowledge must be gathered before the treatment can be recommended in general guidelines.
“More studies are needed to ascertain if there is a causal relationship, at what point of the pathological process statins should be administered, what a reasonable dose would be and how long treatment needs to last if it’s to be of benefit,” says Dr Sun.
