Decoding Colorectal Cancer: Genetics and Environment

Introduction

Colorectal cancer (CRC), is one of the most common types of cancer that affects people worldwide.

It’s a significant health concern on a global scale.

To put it in perspective, CRC ranks third in terms of how often it occurs and second in terms of how deadly it can be.

In 2018 alone, there were 1.8 million new cases of CRC and sadly, it led to 881,000 deaths. ¹

Experts predict that by 2030, the number of new cases will increase to 2.2 million, and the number of deaths will reach 1.1 million worldwide. ²

In China, over 376,000 new cases and 191,000 deaths are estimated to happen each year . ³

Now, something interesting is happening.

CRC has been decreasing in older adults (those aged 65 and above) because more people are getting colonoscopies, a test that can find CRC early.

But, and this is concerning, the opposite is happening in younger adults, those under 50. ⁴

In the United States, from the mid-1980s to 2013, the number of colon cancer cases increased every year by 2.4% in people aged 20-29, by 1.0% in people aged 30-39, by 1.3% in people aged 40-49, and by 0.5% in people aged 50-54. ^{5 6}

This is a worrying trend, and we need new ways to find and prevent CRC early.

CRC is a tricky disease because it’s caused by a mix of things, some that you inherit from your family and others that come from your environment. ⁷

Only a small number of CRC cases are due to things you inherit, like familial adenomatous polyposis (FAP) and Lynch syndrome. ^{8 9 10}

Most CRCs just happen, they’re not inherited ¹¹

The things in the environment, like the food you eat, whether you smoke, your weight, and alcohol, play a big role in causing non-inherited CRC.

One interesting thing is that the bacteria in your gut, called the intestinal microbiota, also have something to say about CRC. ^{12 13 14 15}

There are trillions of these tiny bacteria in your gut, way more than human cells in your body, and they have lots of genes. ^{16 17}

These bacteria do some important things like helping you digest food, keeping your gut healthy, and fighting off bad germs. ^{18 19 20 21}

But if they get out of balance, it can lead to health problems (24).

But if they get out of balance, it can lead to health problems. ²²

Scientists are now looking at how these gut bacteria are connected to CRC.

They’ve found differences in the types of bacteria in people with CRC and those without.

It’s interesting that these differences start even before CRC does, in the early stage called colorectal adenoma.

So, they might be able to use these changes in the bacteria as signs to find CRC early.

Another interesting idea is that maybe we can change the bacteria in your gut to help prevent or treat CRC.

The process of how CRC develops is very complicated and involves a mix of genetics and environment.

Recent studies suggest that things like inflammation, bad bacteria, harmful substances, and more are connected to how gut bacteria affect CRC.

This article reviews what we know so far about these connections.

Key Points

1. Complex Colorectal Carcinogenesis: Colorectal cancer is a highly complex disease influenced by a combination of genetic and environmental factors.
2. Microbiota-Associated Mechanisms: Emerging studies highlight the critical role of intestinal microbiota in colorectal cancer development, involving inflammation, pathogenic bacteria, genotoxins, oxidative stress, and metabolites.
3. Chronic Inflammation: Chronic inflammation is a significant risk factor for colorectal cancer, particularly in patients with inflammatory bowel diseases like ulcerative colitis and Crohn’s disease.
4. Bacterial Impact: Specific pathogenic bacteria, including Fusobacterium nucleatum, Enterotoxigenic Bacteroides fragilis (ETBF), Porphyromonas anaerobius, and Salmonella bovis, contribute to colorectal cancer progression through various mechanisms.
5. Diet and Microbiota: Dietary choices significantly influence colorectal cancer risk by shaping the gut microbiota composition and the production of metabolites, with butyrate being a notable protective factor.

Mechanism of Colorectal Cancer

Colorectal carcinogenesis is highly complex and involves genetic and environmental factors.

Emerging studies suggest that several mechanisms, including inflammation, pathogenic bacteria, genotoxins, oxidative stress, metabolites, and biofilm, are closely linked to the intestinal microbiota.

Here, we review the known microbiota-associated mechanisms in CRC carcinogenesis

Inflammation and Cancer

Understanding the Connection

The link between inflammation and cancer was first observed by Rudolf Virchow in 1863 when he noted the presence of leukocytes in tumors. ²³

However, it’s only in the past decade that clear evidence has emerged showing that inflammation plays a critical role in the development of cancer.

Chronic Inflammation and CRC

Chronic inflammation is widely recognized as a significant risk factor for colorectal cancer (CRC). ^{24 25 26}

Patients with inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), face a higher risk of developing CRC.

Previous studies have shown that the risk of CRC can increase significantly, up to 18.4% in UC patients and 8.3% in CD patients. ^{27 28}

The Microbiota and Immune System

The intestinal microbiota, the community of bacteria in our gut, has a close relationship with our immune system.

When bacteria stimulate immune responses, it can lead to continuous low-grade inflammation, which can contribute to tumorigenesis.

Importantly, inflammation alone cannot induce CRC without the presence of the microbiota or bacteria-derived compounds. ²⁹

The Role of the Intestinal Mucosal Barrier

Maintaining Gut Health

The intestinal mucosal barrier serves as a protective shield, separating the intestinal microbiota from our immune cells.

This barrier consists of a single layer of intestinal epithelial cells (IECs) connected by tight junctions. ³⁰

However, in both human and CRC mouse models, this barrier can become highly permeable. ³¹

Disruption and Vulnerability

Disrupting the function of the intestinal mucosal barrier, often induced experimentally by substances like dextran sodium sulfate (DSS), can lead to increased susceptibility to CRC. ³²

Specific factors like matriptase, a membrane-anchored serine protease, play a role in maintaining the barrier’s integrity.

When matriptase is absent, it can lead to the development of CRC. ³³

Microbiota Invasion

Transformed IECs, which are cells in the intestinal lining that have become cancerous, often fail to create an effective surface barrier.

This allows commensal bacteria and their degradation products to invade the tumor stoma.

Our bodies recognize these bacteria through pattern recognition receptors (PRRs), like Toll-like receptors (TLRs).

These receptors control the inflammatory response to bacterial molecules, such as lipopolysaccharide. ³⁴

The Inflammatory Response

Cytokines and Signaling

When invading commensal bacteria and their components engage TLRs on tumor-infiltrating myeloid cells, it triggers the production of inflammatory cytokines, including interleukin (IL)-23.

IL-23 then leads to the production of other cytokines like IL-17A, IL-6, and IL-22. ^{35 36}

These cytokines ultimately promote the proliferation of tumor cells by activating signaling pathways like nuclear factor-kB (NF-kB) and STAT3. ^{37 38}

Microbiota-Induced Survival

Commensal bacteria and their components can also upregulate IL-17C in transformed IECs.

This activation, driven by TLRs and MyD88 signaling, induces the expression of genes like B-cell lymphoma-2 (Bcl-2) and Bcl-xL within IECs.

These genes support tumor cell survival and tumorigenesis. ³⁹

Specific Microbes and CRC

F. nucleatum and CRC

Fusobacterium nucleatum (F. nucleatum) contributes to CRC progression by creating a pro-inflammatory environment.

It activates the NF-kB pathway and recruits immune cells when enriched in CRC. ⁴⁰

ETBF and Its Impact

Enterotoxigenic Bacteroides fragilis (ETBF) promotes colonic cancer through various mechanisms. It secretes a toxin that disrupts the colonic barrier and activates STAT3, leading to CRC characterized by Th17 responses. ⁴¹

Additionally, ETBF generates particles that stimulate IECs to produce chemokines required for Th17 cell recruitment and the proliferation of IL-17 signals, supporting tumor growth. ⁴²

P. anaerobius and Tumorigenesis

Porphyromonas anaerobius (P. anaerobius) provokes a pro-inflammatory immune microenvironment that promotes tumorigenesis.

In ApcMin/+ mice, P. anaerobius broadly induces pro-inflammatory cytokine expression, recruiting tumor-infiltrating immune cells and supporting tumor progression. ⁴³

Pathogenic Bacteria in Colorectal Cancer

The Role of Bacterial Adherence

In the world of colorectal cancer, certain pesky bacteria have been identified as troublemakers.

They make themselves at home on the mucosal surface of the colon, and their attachment is often the first step towards causing trouble.

F. nucleatum: An Early Culprit

One such troublemaker is Fusobacterium nucleatum, which is usually found in our mouths.

It starts causing problems early in the development of colorectal cancer. Scientists discovered that F. nucleatum sticks to the colon lining and triggers cancer through a special protein called Fusobacterium adhesin A (FadA).

FadA likes to bind to a protein called E-cadherin and activates a pathway called beta-catenin signaling.

This pathway encourages cancerous and inflammatory responses. ⁴⁴

F. nucleatum: The Immune System’s Nemesis

But that’s not all. F. nucleatum also dampens our immune system’s abilities.

It has another protein on its surface called Fap2, which likes to stick to a part of our immune cells.

This slows down our T cells and natural killer cells, which are important in fighting off diseases.

Fap2 can even lead to the production of inflammatory proteins like IL-8 and CXCL1, which help cancer cells move around. ^{45 46}

F. nucleatum: Playing with Autophagy

F. nucleatum doesn’t stop there; it also tinkers with a process called autophagy in the cells lining our colon.

This happens through tiny molecules called microRNAs. ^{47 48}

P. anaerobius: Another Accomplice

There’s another bacterial troublemaker named Porphyromonas anaerobius, which normally hangs out in our mouths and gut.

It promotes the growth of colorectal cancer in a unique way.

It has a protein called putative cell wall binding repeat 2 (PCWBR2) that likes to stick to the cells lining our intestines.

When it does this, it kicks off a chain reaction that encourages the rapid growth of cancer cells through a pathway called PI3K-Akt signaling. ⁴⁹

S. bovis: The Inflammation Link

Salmonella bovis occasionally shows up in our gut, and it’s more common in people with colorectal cancer.

It seems to contribute to cancer by causing inflammation.

It’s thought to do this by triggering the production of inflammatory substances like IL1, cyclooxygenase-2 (COX-2), and IL-8. ^{50 51}

Salmonella’s Chronic Trouble

Speaking of Salmonella, its infection in humans can become a long-term issue, increasing the risk of cancer.

Salmonella seems to promote colon cancer by using a protein called AvrA.

This sneaky protein activates two important pathways, Wnt/beta-catenin and STAT3, in colon tumor cells. ^{52 53 54}

Genotoxins: The DNA Damage Agents

Bacterial Origins of Genotoxins

Let’s talk about genotoxins – these are substances produced by certain bacteria that can seriously damage our DNA, which is like the instruction manual for our cells.

Some of these bacteria are connected to the development of colorectal cancer.

E. coli and Colibactin

One troublemaker is E. coli, a common bacteria found in our gut.

Some strains of E. coli have a special part of their DNA called a genomic island.

This island contains the code for making a genotoxin called colibactin. ^{55 56}

When cultured mammalian cells are exposed to E. coli carrying this island, it can cause temporary but harmful damage to their DNA. ⁵⁷

In studies using mice, researchers found that colibactin can make cells become old and stop working correctly.

This leads to the production of a growth factor called hepatocyte growth factor, which, in turn, boosts the growth of tumor cells. ⁵⁸

Campylobacter jejuni and Cytolethal Distending Toxin

Another troublemaker is Campylobacter jejuni.

It produces a genotoxin called cytolethal distending toxin, which can cause breaks in the double-stranded DNA in our cells.

This damage promotes the development of colorectal tumors. ⁵⁹

Salmonella and Typhoid Toxin

Even Salmonella, the bacteria famous for causing food poisoning, has its own genotoxin called typhoid toxin.

This toxin can harm DNA by affecting a pathway in the cells lining our colon called the PI3K pathway. ⁶⁰

Oxidative Stress: The Balancing Act

What is Oxidative Stress?

Let’s talk about oxidative stress – it’s like a seesaw in your body.

On one side, you have molecules called prooxidants, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS).

On the other side, you have defenders called antioxidants.

When the seesaw tips too much towards the prooxidants, that’s when you get oxidative stress.

Oxidative Stress in Chronic Inflammation

Oxidative stress is often seen when your body is dealing with long-term inflammation, like the kind caused by the intestinal microbiota – those tiny organisms living in your gut.

Inflammation can rev up your body’s inflammatory cells, and these cells produce a bunch of ROS and RNS.

These troublemakers can harm your DNA and do sneaky things like turning on cancer-causing genes or turning off cancer-fighting ones.

This is why oxidative stress is linked to an increased risk of colorectal cancer.

Microbes and Oxidative Stress

But here’s the twist – it’s not just your body’s cells that can cause oxidative stress.

The bacteria living in your gut can also be culprits.

For example, a bacterium called E. faecalis can cause trouble.

When it infects certain immune cells, it causes them to make a powerful troublemaker called superoxide.

This superoxide then damages the DNA in the cells lining your gut – it’s like a domino effect. ^{61 62}

The Role of Hydroxyl Radicals

Another sneaky move comes from a bacterium called E. faecalis.

It can produce hydroxyl radicals, which are like DNA wrecking balls.

They cause breaks in your DNA, change the DNA code, and even stick proteins to your DNA – it’s a recipe for instability in your chromosomes and an increased risk of colorectal cancer. ^{63 64 65}

More Bacteria, More Trouble

Even bacteria like E. coli and a toxin from Enterotoxigenic Bacteroides fragilis (ETBF) can join the oxidative stress party.

They encourage the cells lining your colon to produce more ROS.

It’s like they’re turning up the heat, and that’s not good news for your gut. ^{66 67}

HIGHLIGHT

Oxidative stress is like a seesaw that should be in balance, but when it tips too far, it can lead to DNA damage and increase the risk of colorectal cancer. Those little microbes in your gut can sometimes play a big role in this tricky balancing act.

Diet and Bacteria Metabolites: Impact on Colorectal Cancer

The Link Between Diet and CRC

Did you know that your diet can significantly influence your risk of developing colorectal cancer (CRC)?

A recent study found that poor diets, characterized by low consumption of whole grains and dairy products and high intake of red and processed meats, were responsible for 38.3% of CRC cases. ⁶⁸

Obesity and being overweight are also significant risk factors for CRC, increasing the risk by 19%. ⁶⁹

The Role of Microbiota in Diet-CRC Connection

Your gut is home to a vast community of microorganisms known as the microbiota, and it plays a crucial role in the relationship between diet and CRC.

It acts as a mediator between the food you eat and its impact on your health.

Microbiota and Diet Diversity

Different diets can shape the composition of your intestinal microbiota.

For instance, diets high in animal protein and fat tend to favor the growth of bacteria like Bacteroides, while diets rich in carbohydrates encourage the dominance of bacteria like Prevotella. ^{70 71}

The Power of Microbial Metabolism

The microbiota also plays a role in breaking down undigested dietary components, such as fructo-oligosaccharides.

As a result, it generates various metabolic products, including short-chain fatty acids (SCFAs) like acetate, butyrate, and propionate.

Butyrate: A Cancer Fighter

Among these SCFAs, butyrate stands out as a potent protector against cancer.

It’s primarily produced by Firmicutes when they ferment dietary fiber and resistant starches.

Butyrate serves as the primary energy source for the cells lining your colon, and it helps regulate their growth.

Importantly, butyrate can inhibit harmful processes in colon cells, such as inflammation and uncontrolled cell growth. ^{72 73}

SCFAs and a Healthy Gut

SCFAs, especially butyrate, also have the power to lower the pH in your colon, making it less hospitable for harmful bacteria.

This helps prevent DNA damage and encourages cell apoptosis (cell death), which is essential for cancer prevention. ⁷⁴

Bile Acids and Dietary Influence

Bile acids, which play a role in fat digestion, are another aspect of microbial metabolism influenced by diet.

High-fat diets can lead to an increase in secondary bile acids in your gut, and this is associated with a higher CRC risk. ^{75 76}

Fat and Bile Acid Connection

Research has shown that diets high in fat can lead to an increase in secondary bile acids in the colon, contributing to a higher risk of CRC.

Studies in mice have linked a Western-style high-fat diet to an increased risk of colon tumors, highlighting the impact of dietary choices. ⁷⁷

Nitroso Compounds and Hydrogen Sulfide

Diets rich in protein can lead to the production of harmful compounds like N-nitroso compounds (NOCs) and hydrogen sulfide (H2S).

These compounds have been associated with an increased risk of CRC.

NOCs can damage DNA through alkylation, while H2S can stimulate CRC progression by disrupting the gut barrier and causing DNA damage. ^{78 79 80 81}

HIGHLIGHT

Your diet can have a significant impact on your CRC risk by influencing the composition of your gut microbiota and the production of metabolites that either protect against or promote cancer development. Making informed dietary choices can play a crucial role in preventing this type of cancer.

The Secret World of Biofilm

What is Biofilm?

Biofilm is a relatively new concept in the study of the relationship between gut microbiota and colorectal cancer (CRC).

Imagine biofilm as a hidden world made up of communities of tiny microbes sticking together in a slimy, protective matrix.

These biofilms can infiltrate the protective layer of the colon and get up close and personal with the cells lining it.

Biofilm’s Role in CRC

Researchers have found that these invasive, multi-microbial bacterial biofilms tend to hang out more on the right side of the colon (about 89% of right-sided tumors) compared to the left side (only 12% of left-sided tumors).

When they set up shop, they bring some trouble with them.

They weaken the connections between intestinal epithelial cells, making the barrier-less sturdy.

This allows bacteria to slip through and come into direct contact with the cells (IECs) lining the colon.

The Trouble with Weakened Barriers

When these bacterial biofilms make contact with IECs, they start to shake things up.

They trigger the activation of a molecule called STAT3 and its partner in crime, IL-6.

Together, they encourage the cells to divide more rapidly and avoid cell death.

This can ultimately promote the development of colorectal cancer.

Biofilm’s Sneaky Strategy

So, the biofilm’s sneaky strategy seems to involve weakening the colon’s protective barrier.

This makes it easier for bacterial antigens (like tiny pieces of bacteria) to sneak through and stir up trouble, leading to inflammation that can increase the risk of cancer. ^{82 83}

HIGHLIGHT

Biofilms are like hidden communities of bacteria that infiltrate the colon’s protective layer, weakening it and allowing bacteria to cause trouble, potentially increasing the risk of colorectal cancer.

Discussion

• Colorectal carcinogenesis is a complex process influenced by both genetic and environmental factors.
• Emerging studies have highlighted several mechanisms associated with the intestinal microbiota that play a role in colorectal cancer (CRC) development, including inflammation, pathogenic bacteria, genotoxins, oxidative stress, metabolites, and biofilm.
• Chronic inflammation is a significant risk factor for CRC, especially in patients with inflammatory bowel diseases like ulcerative colitis and Crohn’s disease.
• The intestinal microbiota has a close relationship with the immune system, and dysregulation of this relationship can contribute to tumorigenesis.
• Disruption of the intestinal mucosal barrier can increase susceptibility to CRC, and factors like matriptase play a role in maintaining its integrity.
• Transformed intestinal epithelial cells (IECs) in CRC often fail to create an effective surface barrier, allowing commensal bacteria and their products to invade the tumor stroma.
• The inflammatory response triggered by invading bacteria can lead to the production of cytokines, such as IL-23, IL-17A, IL-6, and IL-22, which promote tumor cell proliferation.
• Commensal bacteria and their components can upregulate survival genes in IECs, supporting tumor cell survival and tumorigenesis.
• Specific pathogenic bacteria like Fusobacterium nucleatum, Enterotoxigenic Bacteroides fragilis (ETBF), Porphyromonas anaerobius, and Salmonella bovis have been implicated in CRC progression through various mechanisms.
• Genotoxins produced by certain bacteria, such as E. coli, Campylobacter jejuni, and Salmonella, can damage DNA and contribute to colorectal tumor development.
• Oxidative stress, resulting from an imbalance between prooxidants and antioxidants, is linked to CRC, and both host cells and gut bacteria can contribute to oxidative stress.
• Microbes like E. faecalis can produce harmful molecules like superoxide and hydroxyl radicals, causing DNA damage.
• Dietary choices significantly influence CRC risk by shaping the composition of the gut microbiota and the production of metabolites, including short-chain fatty acids (SCFAs), bile acids, nitroso compounds (NOCs), and hydrogen sulfide (H2S).
• Butyrate, a product of microbial fermentation, can protect against CRC by inhibiting inflammation and uncontrolled cell growth.
• Biofilm, composed of communities of microbes, tends to be associated with right-sided colon tumors and can weaken the colon’s protective barrier, promoting inflammation and tumor development.

Conclusion

Understanding the mechanisms of colorectal cancer development is critical for early detection and prevention.

The interplay between genetic factors, environmental influences, and the intestinal microbiota plays a significant role in CRC carcinogenesis.

Chronic inflammation, disruption of the intestinal mucosal barrier, bacterial invasion, genotoxins, oxidative stress, and dietary factors all contribute to the complex process of CRC development.

Targeting these mechanisms through preventative measures, early screening, and potential therapeutic interventions could help reduce the incidence and impact of colorectal cancer.