Colorectal cancer will once again be one of the most commonly diagnosed types of tumour in Spain this year.

According to the Spanish Society of Medical Oncology (SEOM), 44,573 new cases will be detected in Spain this year. Worldwide, the incidence of this disease has doubled in the past 20 years, affecting more and more people under the age of 50. This trend is particularly worrying in some Western countries, where factors such as changes in diet and lifestyle, lack of exercise, alterations in the gut microbiome and exposure to certain adverse environmental factors may be playing a key role. 

What is causing the increase in cases among young people and how can we reduce these numbers? 

In the last CaixaResearch Debate we examined the situation of colon cancer: the challenges presented by its early diagnosis and treatment and the latest advances in this field, with the help of four leading researchers: 

• Eduard Batlle, ICREA researcher, head of the Colorectal Cancer laboratory at IRB Barcelona and group leader at CIBER Cancer (CIBERONC), is working to understand how tumour cells generate metastasis.
• Angélica Figueroa, R4 researcher, leader of the Epithelial Plasticity and Metastasis group at the Institute of Biomedical Research (INBIC) of the University Hospital Complex of A Coruña (CHUAC). With the support of “la Caixa” Foundation’s Innovation programme, she’s developing a drug to stop colon cancer metastasis.
• Toni Gabaldón is an ICREA researcher and leader of the Comparative Genomics lab at IRB Barcelona and the Barcelona Supercomputing Center (BSC). He’s currently working on a project supported by CaixaImpulse to develop a non-invasive early detection system that combines gut microbiota analysis with artificial intelligence algorithms.
• Elena Élez, medical oncologist at the Vall d’Hebron University Hospital in Barcelona (HUVH) and head of the Colorectal Cancer group at the Vall d’Hebron Institute of Oncology (VHIO), where she’s working on developing new therapies to treat metastatic colon cancer.

Below we review the main ideas discussed by the four experts during the debate, chaired by Beatriz Pérez, a health journalist at El Periódico de Catalunya.

 

Understanding colon cancer

 

What is colon cancer?

“The colon is the longest part of the large intestine and is lined internally by a layer of cells called the mucosa. Over the years, this mucosa has a tendency to develop generally benign structures, known as polyps or adenomas. However, certain mutations can alter their behaviour and cause the cells to begin to infiltrate the intestinal wall, giving rise to adenocarcinoma of the colon, the most common type of tumour in this area” – Elena Élez

“The intestinal mucosa is the fastest regenerating tissue in our body. Thanks to stem cells, the entire wall of the intestine regenerates almost every week. When certain mutations occur, this balance between cell death and regeneration breaks down and cells start to accumulate. Initially, they’re benign (half the population over the age of 50 develops some of these benign polyps) but, over time, they can progress and transform into a more aggressive tumour” – Eduard Batlle

 

How prevalent is colon cancer?

“Colon cancer is the third most common cancer worldwide with 1.9 million new cases per year, and it’s the second most deadly. In Spain, it’s the second most common tumour in men after prostate cancer, and in women after breast cancer, with more than 44,500 cases diagnosed each year. It accounts for around 10% of all cancer cases and causes approximately 11,000 deaths per year, being the second most deadly after lung cancer” – Angelica Figueroa

Angelica Figueroa.

“Cases are also on the rise in our country. This trend is mainly due to an increase in the number of cases detected thanks to the population screening programme but also to an increase in risk factors associated with living habits, such as an unhealthy diet, lack of exercise and a sedentary lifestyle. One worrying fact is the increase in cases in people under 50 in some countries, such as the United States and New Zealand. Although this trend has not been confirmed yet in Spain by the data registered, it’s an aspect we’re beginning to notice in consultations and we’re keeping a close eye on it” – Elena Élez

 

Symptoms, screening and early detection

 

What are the symptoms of colon cancer?

“It’s essential to be aware of possible changes in our bowel habits. While constipation alone is not a risk factor, a sustained tendency to suffer from constipation or, conversely, frequent episodes of diarrhoea should be a reason to consult a doctor. There are also more obvious symptoms, such as blood in the stool, persistent fatigue accompanied by anaemia or unexplained weight loss. In general, any prolonged alteration in the usual pattern should be evaluated by a doctor” – Elena Élez

 

Why does it tend to be detected late in young people?

“The delay in diagnosis is due to several factors. Colon cancer in young people is less common, so that it doesn’t tend to be suspected so readily, by doctors or by the patients themselves. What’s more, its symptoms are non-specific, making early detection difficult. In addition, tumours in young people tend to be more aggressive and progress more quickly, so they’re generally at a more advanced stage once they’re diagnosed” – Angélica Figueroa

 

What are two-step screening programmes?

“In Spain, colorectal cancer screening is offered to people aged 50-69, even if they have no symptoms. In a first phase, participants receive a kit to collect a small stool sample, which is then analysed at the hospital for the presence of haemoglobin, an indicator of possible bleeding in the bowel. If the result is positive, a colonoscopy is performed, a more detailed examination using a camera probe to detect any polyps, lesions or tumours” – Toni Gabaldón

Toni Gabaldón.

“This two-step approach combines a simple, inexpensive and non-invasive first test with a second, more accurate but also more costly and invasive test. Thanks to this system, numerous tumours and precancerous lesions have been detected, improving early diagnosis and increasing the likelihood of successful treatment and patient survival” – Toni Gabaldón

 

How could the screening system be improved?

“Screening is a highly valuable tool but it has its limitations. Its high cost and the need for a large number of tests place a considerable burden on the healthcare system. In addition, the false positive rate is high: about 5% of tests detect faecal occult blood but less than 30% of those cases who undergo a colonoscopy have a clinically relevant abnormality. If we could reduce these false positives, we could extend screening to other population groups” – Toni Gabaldón

“New biomarkers that are more specific than haemoglobin are being investigated to improve the efficacy of screening. At IRB Barcelona, we’re studying the gut microbiota to identify bacteria associated with polyps and tumours. Using artificial intelligence, we’re training an algorithm that helps to better select people who really need a colonoscopy, based on their microbial profile. This technique could reduce unnecessary colonoscopies by 30%, easing the burden on the healthcare system” – Toni Gabaldón

 

Should screening be started at an earlier age?

“Medicine should always be applied where it’s the most efficient use of resources. The incidence of colorectal cancer is still much lower among people under 50. If we had more efficient screening systems, we could think about extending the age groups, especially if we end up finding that cases are indeed on the rise among the younger population” – Toni Gabaldón

“Beyond screening at a younger age, it’s also essential to improve the participation rates for the existing programmes. The participation rate for the 50+ population is less than 100%, which limits its effectiveness. If we implement screening in younger people but only a small fraction of them actually come for testing, its real impact would be very small” – Angelica Figueroa

 

What are the causes?

 

How important is the genetic factor in the disease’s development?

“About 10% of colon cancers have some kind of genetic basis. Those who’ve inherited these mutations have a very high probability of developing colon cancer but we’re talking about a very small percentage of the population. Usually these families, because of their history, are already being specifically monitored. In general, the vast majority of colon cancers have a sporadic origin” – Eduard Batlle

Elena Élez.

“We always try to look for a hereditary pattern, for family members who, generation after generation, have had one of these tumours. If this pattern exists, the patient is referred to a high-risk unit. In any case, the best recommendation is always to take part in the screening programme when it’s your turn, because it is not always easy to know your family history” – Elena Élez

 

How does it relate to diseases such as irritable bowel syndrome or Crohn’s disease?

“It has been shown that inflammatory bowel diseases can be a risk factor for developing colorectal cancer. However, these patients are monitored to prevent its development and diagnose it early” – Elena Élez

 

What is the role played by the microbiota?

“The gut and mucosa where colon cancer develops is an ecosystem populated by a wide variety of microorganisms. This is, in fact, the area of the body where the human microbiome is the most diverse and abundant. These microbes are not simply present but also interact constantly with our mucosa. Some of these interactions may encourage the development of a tumour, whilst others turn out to be more beneficial” – Toni Gabaldón

“Although much remains to be understood, we know that certain microorganisms interact more aggressively with our mucous membranes, creating inflammation. If this inflammation becomes chronic and persists over time, it can damage tissues. Moreover, some bacteria release toxins that directly attack mucosal cells, which could lead to mutations and increase the risk of tumours. We also know that this microbiological ecosystem is in a constant process of metabolisation, producing compounds that are sometimes used by tumour cells to accelerate their growth” – Toni Gabaldón

 

The risk of metastasis and possible treatments

 

How does colon cancer spread and metastasise?

“These tumours grow first in the mucosal wall of the colon but some invade adjacent tissue and spread their cells through the bloodstream, eventually colonising other organs. Surgery is an effective treatment for the primary tumour and most patients don’t die from it. However, the big challenge is metastasis, as these cells can settle in vital organs such as the liver or lungs, making them difficult to treat. Even some patients who come with a localised tumour that’s removed end up developing metastases in a few years” – Eduard Batlle

“Essentially, this metastasis is initially invisible in the patient. After removing the primary tumour, we don’t know where these residual cells are or what they look like, and we don’t know how to remove them effectively. Half of all colon cancer metastases occur in the liver, approximately 25% in the lung and the same percentage in the peritoneum, which is the cavity occupied by our entrails” – Eduard Batlle

 

What percentage of patients develop metastases?

“At the time of initial diagnosis, about 30% of patients already have metastasis. In addition, 50% of diagnosed patients develop metastases sooner or later. These are much more difficult to treat and more resistant to conventional therapies, as well as involving vital organs. In fact, 90% of deaths from colorectal cancer are the result of metastasis” – Angelica Figueroa

 

Why does metastasis occur?

“Despite their clinical importance, we know less about metastases than about the primary tumour. Metastases occur when some tumour cells acquire the ability to invade tissues and travel through the blood to other organs, where they manage to establish themselves and form new tumours. However, only a small fraction of these cells survive to metastasise. We’re now at a point where we can begin to develop strategies to prevent or combat metastases more effectively. This is, without doubt, the biggest challenge in colon cancer research” – Eduard Batlle

Eduard Batlle.

“Our research group has focused on understanding the biology of these metastatic cells and the key factors in them spreading. We’ve discovered that their behaviour is different from that of the primary tumour: they have a great plastic capacity that enables them to migrate and adapt to different organs. One crucial finding in this process is the hakai protein, which seems to play a key role in this plasticity” – Angélica Figueroa

“Thanks to funding from “la Caixa” Foundation, we’re developing new compounds aimed at blocking the hakai protein and thereby slowing down metastasis. We’re currently working on optimising these compounds for use in humans, with the hope that, in the next few years, they’ll enter the regulatory phase and, subsequently, clinical trials. These are complex, risky projects but they’re fundamental, as we currently have no specific treatments for metastasis” – Angélica Figueroa.

 

What treatments are available for metastasis?

“The first step in treating metastasis is a thorough understanding of the biology of the tumour. By identifying the mutations and characteristics of each case, we can select the most effective treatments and avoid those that will offer no benefit and only add unnecessary toxicity. This strategy, known as precision medicine, is already being implemented in our healthcare system and it combines chemotherapy (which is still essential in most cases) with targeted therapies such as monoclonal antibodies“.

“In our research, we’ve identified a specific molecular alteration present in 5% of patients with metastatic colorectal cancer: microsatellite instability. These tumours have a high rate of mutations that produce proteins which are detected by the immune system as foreign, facilitating the use of immunotherapy. Our studies have shown that, in these cases, combining immunotherapy with other drugs is more effective than chemotherapy as a first line of treatment.

“However, we’ve observed that patients with liver metastasis respond worse to immunotherapy. We still need to understand why this happens and develop therapeutic strategies to help overcome this resistance. Collaboration between different research groups is key to progress in this field” – Elena Élez

“Tissue biopsy, an invasive and painful procedure, has traditionally been used to determine which patients will respond best to which treatments. We’re therefore exploring alternative methods that allow us to study the tumour and its progression in a less aggressive way. We’ve developed an innovative sample analysis system. Using a liquid biopsy, we extract circulating tumour cells from the blood and implant them on a microchip, known as an organ-on-chip, which faithfully reproduces the characteristics of the tumour. This device provides us with an in vivo model, enabling the disease to be monitored more precisely and helping to predict how it will develop. Thanks to this, we can adjust the treatment in a personalised way as the disease progresses” – Elena Élez

 

Preventing colorectal cancer

 

What behaviours can we adopt to prevent colon cancer?

“The most decisive factor in improving the prognosis of this disease is its prevention. To do so, it’s essential to adopt the habits of a healthy lifestyle, such as a balanced diet that provides all the necessary nutrients and regularly carrying out moderate physical activity” – Elena Élez

 

Is stress linked to colon cancer?

“Although stress per se has not been shown to promote the development of colon cancer, the factors mentioned above are closely related. A person suffering from chronic or emotional stress may alter their diet and degree of physical activity, which could trigger inflammatory processes and facilitate the development of colorectal cancer. This is all related to the microbiome, a complex system that varies from person to person and changes throughout our lives. To prevent colon cancer and its consequences, the key messages are: adopt a healthy lifestyle and carry out early diagnoses” – Elena Élez