Colorectal cancer (CRC) and cardiovascular disease (CVD) stand as global leading causes of morbidity and mortality. Additionally, prevalent treatments for CRC may induce cardiotoxic effects, consequently elevating the risk of CVD [1].
A growing concern is the unexpected surge in young-onset colorectal cancer (yoCRC), typically diagnosed in individuals under 50 years, with its incidence and mortality rates rising annually by 1.5% and 1.2%, respectively. Should this trend persist, estimates suggest a doubling in colon cancer incidence and a quadrupling in rectal cancer rates within this age group by 2030 [2] [3].
Risk factors for colorectal cancer (CRC) include both inherited and environmental influences. Although a greater proportion of yoCRC cases is associated with hereditary syndromes, the evidence points to the majority being sporadic. Additionally, epidemiological data strongly suggest an increase in the incidence of yoCRC among successive birth cohorts since 1960 [4], suggesting that generational exposure to shared environmental risk factors might play a significant role in its pathogenesis [2].
While cancer and cardiovascular disease (CVD) are traditionally viewed as distinct health conditions, the evident pathophysiological connections and shared risk factors highlight an opportunity for oncologists and cardiologists to engage in synergistic collaborative efforts [1].
Specifically, chronic inflammation emerges as a likely common denominator among the shared risk factors for colorectal cancer and cardiovascular disease (CVD), influencing most, if not all, other individual risk factors through pathways typically associated with inflammation. These shared risk factors often encompass environmental or lifestyle elements, including a Western diet, sedentary behavior, smoking, alcohol consumption, obesity, and other inflammatory environmental triggers [5].
A recent study supports the assessment of environmental and lifestyle risk factors potentially contributing to the development of yoCRC through microbial dysbiosis [2].
Study methodology
This retrospective study used 16S rRNA sequencing on tumor and adjacent non-malignant tissues from 276 cases to compare microbial profiles of yoCRC and average-onset CRC (aoCRC), assessing their link with clinical factors. It involved patients diagnosed with CRC before 50 (yoCRC, n=136) and those 60 or older (aoCRC, n=140) [2].
The study analyzed tumor microbial diversity in yoCRC and aoCRC patients, concentrating on both alpha (α) diversity, which evaluates microbial variety within a sample based on taxa richness and evenness, and beta (β) diversity, which examines variations in microbial composition (identity of taxa) across samples [2].
Furthermore, differential abundance analysis explored differences in tumor bacterial populations between yoCRC and aoCRC patients, identifying bacterial taxa significantly enriched in each group. Concurrently, network analysis revealed correlations among microbial genera within yoCRC and aoCRC tumors [2].
The authors also conducted a comprehensive analysis of the microbiome profiles of yoCRC and aoCRC tumors, examining them against a range of clinicopathological variables including tumor location, body mass index (BMI), tumor lateralization (left vs. right), and cancer stage, among others. Following this, they performed a correlation analysis to identify associations between specific microbes and the clinical characteristics of both patient groups [2].
Distinct intratumoral microbiome of young-onset colorectal cancer
The study’s results indicate that both yoCRC and aoCRC tumor specimens showed reduced alpha diversity when compared to adjacent non-malignant tissue. Moreover, microbial diversity was generally higher in both tumor and adjacent non-malignant tissues in younger patients than in older ones. These findings collectively suggest a reduction in microbial richness and diversity associated with both aging and the progression from healthy to cancerous tissue [2].
CRC tumors across both age groups exhibited a broadly similar bacterial genera composition, yet they varied significantly in relative abundance. Specifically, Akkermansia and Bacteroides were identified as predominant microbes enriched in yoCRC tumors. Notably, the relative abundance of Akkermansia was associated with an extended overall survival (OS), while Bacteroides were more prevalent in early-stage (stages I–III) tumors compared to stage IV primary tumors in younger patients [2].
Some studies indicate that Akkermansia, a mucin-degrading bacterium, enhances mucus thickness and gut barrier integrity [6], whereas Bacteroides, in the absence of dietary carbohydrates and fibers, may switch to digesting mucin glycans, thereby boosting mucosal barrier function and preventing pathogen invasion [7].
The breakdown of the intestinal mucosal barrier facilitates the entry of pathogenic bacteria and their interaction with immune cells in the colonic microenvironment, causing inflammation and DNA damage, which are recognized precursors of oncogenesis [8].
Consequently, the presence of Akkermansia and Bacteroides in yoCRC tumors might reflect the tumor microenvironment’s activity in fostering the growth of protective bacterial species to circumvent the immune response and support self-tolerance, or on the other hand, it might represent a natural mechanism to reduce inflammation and enhance the function of the gut epithelium in younger patients with CRC [2]. Overall, however, these distinct behaviors of the two genera in yoCRC dysbiosis suggest important directions for future studies and support the hypothesis that lifestyle factors can play a critical role in yoCRC pathogenesis [2].
Moreover, aoCRC tumors, especially in patients with metastatic disease, showed a higher enrichment of Fusobacterium, which positively correlated with tumor size in aoCRC patients. Although Fusobacterium’s relative abundance was low in yoCRC tumors, its presence was significantly linked to decreased OS [2]. Furthermore, network analysis demonstrated negative correlations between Akkermansia and Fusobacterium in tumors from both cohorts, suggesting that Fusobacterium may have a consistent role in promoting carcinogenesis in CRC across all ages [2].
In addition, in aoCRC tumors, Akkermansia was found to be more abundant in primary tumors of patients at earlier stages of the disease compared to those with metastatic disease, and its abundance was inversely correlated with tumor size [2].
Conclusions
The study revealed that the microbiome of yoCRC tumors is significantly more diverse and unique than that of aoCRC, uncovering intricate correlations within tumor microbial communities that shed light on the unique yoCRC tumor environment. It identified distinct microbial patterns between yoCRC and aoCRC that correlate with clinical features and outcomes, challenging the conventional view that yoCRC is simply an early manifestation of aoCRC. This suggests that external, environmental, or lifestyle factors influencing microbial balance play a crucial role in yoCRC development. Future research should focus on microbiota like Akkermansia and Bacteroides as potential targets for prevention, diagnosis, prognosis, and treatment in yoCRC [2].
References
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