Vitamin D, inflammation and their interplay in colorectal cancer prognosis

Colorectal cancer (CRC) accounts for one in ten cancer cases and deaths worldwide, and the incidence of CRC is still increasing. The number of CRC survivors is further increasing due to population screening programs and better treatments, which have increased cancer survival rates. Cancer recurrence is a major concern for CRC survivors and an important contributor to mortality in this growing population. Therefore, it is necessary to optimize long-term survival in CRC patients. Vitamin D is a potentially interesting compound in this respect, as high compared to low concentrations of vitamin D at diagnosis are associated with higher survival rates in CRC survivors. It is hypothesized that vitamin D exerts its beneficial effect on CRC survival due to its anti-inflammatory potential. Nevertheless, many questions remain unanswered regarding the “black box” between vitamin D and CRC survival. Therefore, the aim of this study was to investigate the relationship between vitamin D, inflammation and their interplay in relation to CRC recurrence and all-cause mortality in two prospective cohort studies in CRC patients in the Netherlands; the COLON study and the EnCoRe study.

We evaluated which clinical characteristics in conjunction with demographic and lifestyle factors are associated with serum 25-hydroxyvitamin D3 (25(OH)D3) concentrations at diagnosis and six months later in chapter 2. The main determinants of vitamin D status as well as changes in concentrations over time were the use of vitamin D supplementations and receiving chemotherapy. Receiving chemotherapy was associated with lower 25(OH)D3 concentrations and a steeper decrease in 25(OH)D3 concentrations in the first six months after diagnosis.

Higher concentrations of 25(OH)D3 at diagnosis were previously associated with a lower all-cause mortality risk in CRC patients. However, in these previous studies the interaction with nutrients involved in vitamin D metabolism (i.e. magnesium en calcium) were not taken into account. Therefore, vitamin D, magnesium and calcium in relation to CRC outcomes was investigated in chapter 3. Moreover, the interaction between vitamin D, magnesium and calcium in relation to CRC was examined. Lower concentrations of vitamin D (severe deficient < 30nmol/L vs sufficient (50-75 nmol/L) seemed to be associated with a higher risk of all-cause mortality. Furthermore, an inverse association between magnesium intake, but not calcium intake, and all-cause mortality was observed. The lowest risk of all-cause mortality was observed in patients with sufficient vitamin D levels as well as a high magnesium intake, suggesting a synergistic interaction between vitamin D and magnesium. No interaction between vitamin D and calcium was observed.

In addition, 25(OH)D3 concentrations are likely to change over time, which could also affect health outcomes in CRC patients. In chapter 4 of this thesis the association between trajectories of vitamin D concentrations over time and CRC outcomes was assessed. Patients characterized by one of the three trajectories with sufficient levels of vitamin D 2 years after diagnosis had a lower risk of all-cause mortality compared to patients with consistent deficient levels. No associations for recurrence were observed.

One of the potential mechanisms by which vitamin D exerts beneficial effects in cancer is by its anti-inflammatory properties. Therefore, we investigated the association between vitamin D concentrations and concentrations of inflammatory markers over time in chapter 5. Higher serum 25(OH)D3 levels at diagnosis, six months and two year after diagnosis as well as over time were associated with lower interleukin 6 (IL6) levels and a combined inflammatory z-score. Serum 25(OH)D3 levels were not associated with C-reactive protein, IL8, IL10 and Tumour Necrosis Factor α (TNFα) levels in plasma. These results indicate that vitamin D could potentially lower inflammation marker levels, however, further intervention studies, investigating the effect of increasing vitamin D levels on inflammatory mediators in CRC patients are needed.

The association between pre-operative and post-operative concentrations of inflammation markers and CRC outcomes, while taking into account lifestyle factors, was investigated in chapter 6. Higher pre-operative as well as post-operative CRP levels were associated with a higher risk of recurrence. Higher pre-operative as well as post-operative IL8 and a combined  inflammatory z-score  were associated with a higher risk of all-cause mortality.

Diet has an effect on inflammation and subsequent health status. We investigated the association between the inflammatory potential of the diet and CRC outcomes in chapter 7. The inflammatory potential of the diet was assessed using the Adapted Dietary Inflammatory Index (ADII). Higher ADII scores were associated with higher levels of TNFα, CRP and the inflammatory z-score at diagnosis and six months after diagnosis, but not with recurrence and all-cause mortality.

An important question to answer is whether vitamin D is causally related to CRC outcomes. Higher 25(OH)D3 concentrations were moderately strong and consistently associated with a lower risk of mortality in CRC patients in epidemiological studies. In addition, a dose-response relationship was observed and a plausible biological pathway was described. Although the afore mentioned evidence provides a good indication for a causal relationship between vitamin D and all-cause mortality, before conclusions can be drawn about causality 1) underlying mechanisms should be further clarified and 2) intervention studies investigating the effect of increasing 25(OH)D3 concentrations in relation to CRC outcomes should be conducted. In addition, while inflammatory cytokines are the most reliable markers of inflammation  and serum 25(OH)D3 concentrations the most reliable marker of vitamin D status in the setting of a large prospective cohort study, circulating concentrations of vitamin D and inflammation may not exclusively reflect processes within the tumour and the tumour microenvironment. Measuring vitamin D status and inflammation in the tumour itself may provide a better understanding of the interaction between vitamin D and inflammation in CRC prognosis.

To conclude, results of this thesis provide a foundation for a causal relationship between higher 25(OH)D3 concentrations and all-cause mortality in CRC patients. However, the role of vitamin D in cancer recurrence is still unclear. The anti-inflammatory effects of vitamin D as one of the potential underlying mechanisms for its association with CRC outcomes should be further explored using a molecular pathological epidemiological research approach.