J Cancer Prev 2022; 27(3): 147-156
Published online September 30, 2022
© Korean Society of Cancer Prevention
Soo-Young Na1,* , Ki Bae Kim2,* , Yun Jeong Lim3 , Hyun Joo Song4
1Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, 2Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, 3Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, 4Department of Internal Medicine, Jeju National University College of Medicine, Jeju, Korea
Correspondence to :
Yun Jeong Lim, E-mail: firstname.lastname@example.org, https://orcid.org/0000-0002-3279-332X
Hyun Joo Song, E-mail: email@example.com, https://orcid.org/0000-0002-2561-555X
*These authors contributed equally to this work as co-first authors.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Vitamin D is considered to be the main mediator of the beneficial effects of sun exposure. In humans, highest expression of Vitamin D receptors is found in the intestinal tract. In addition, 1α,25-dihydroxyvitamin D3 (or calcitriol), the most active Vitamin D metabolite, plays important homeostatic roles in the intestine, particularly calcium absorption. Vitamin D deficiency is defined as a serum 25-hydroxyvitamin D [25(OH)D] level of < 20 ng/mL. Previous studies show that higher circulating 25(OH)D levels are associated with reduced risk of colorectal cancer (CRC) and improved survival. Most research to date has been conducted in animals, specifically mice. Although human studies have a limited number of participants, one study recruiting a large cohort of patients with advanced or metastatic CRC revealed that higher plasma 25(OH)D levels are associated with improved overall and progression-free survival. However, the effects of Vitamin D supplementation on incidence and mortality of CRC remain inconclusive. Although Vitamin D may help to prevent cancer, there is a paucity of research demonstrating conclusively that Vitamin D alters prognosis after chemotherapy. Here, we review the mechanisms by which Vitamin D affects CRC, as well as the results of clinical, epidemiological, and human intervention studies. We also discuss current perspectives and future directions regarding Vitamin D and CRC.
Keywords: Vitamin D, 25-Hydroxyvitamin D, Vitamin D deficiency, Colorectal neoplasms
In the past decade, colorectal cancer (CRC) has become the third most common cancer worldwide, and the second leading cause of cancer-associated death [1,2]. In 2020, it was estimated that about 10% of global cancer incidence, and about 9.4% of cancer-related deaths, could be attributed to CRC . Risk factors for CRC include sex, age, race, and genetic factors [2-6]. Exposure to environmental risk factors, such as the shift to a modern lifestyle and a Westernized diet, plays a very important role in the increasing global incidence of CRC . Epidemiological and observational studies have identified CRC as the neoplasm most commonly associated with Vitamin D deficiency . However, design, data analysis and interpretation of some epidemiological and prospective interventional clinical studies are controversial.
Vitamin D is the principal mediator of the beneficial effects of sun exposure . The human body manufactures 80%–90% of its Vitamin D via UV exposure, and 10%–20% is from nutrients absorbed in the small intestine. Food sources include salmon, mackerel, eel, tuna, eggs, milk, yogurt, and mushrooms . Vitamin D is metabolized in the liver as Vitamin D3 (cholecalciferol), with 25-hydroxyvitamin D [25(OH)D] excreted by the kidney . The small intestine is the organ showing highest expression of Vitamin D receptors (VDR). Furthermore, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] (also called calcitriol), the most active Vitamin D metabolite, has many important homeostatic actions. Serum levels of 25(OH)D formed upon exposure to sunlight never exceed 60 ng/mL . According to the Mayo Clinic reference ranges, total serum 25(OH)D levels range from 30–80 ng/mL. Vitamin D insufficiency is defined as a 25(OH)D level of < 30 ng/mL, whereas deficiency is defined as < 20 ng/mL (values < 10 ng/mL are considered extremely low). By contrast, a 25(OH)D level of ≥ 80 ng/mL is defined as possible toxicity .
Vitamin D deficiency is pandemic and currently one of the major global health issues. Vitamin D deficiency affects. more than 1 billion children and adults worldwide. Pregnant women, people of color (Black, Hispanic, and anyone with increased skin melanin pigmentation), obese people, and people who avoid direct sun exposure are at high risk . Vitamin D deficiency is prevalent in Europe, China, India, the Middle East, Southeast Asia, Central and South America, and Africa, where foods are not fortified with Vitamin D. It is estimated that approximately 30% of children and 60% of adults worldwide are either Vitamin D deficient or insufficient . The major cause of deficiency is lack of sufficient sun exposure. Skin coloration and aging are two primary physiological factors underlying low levels of Vitamin D production. Very few foods contain Vitamin D as natural ingredient [16,17].
In the remainder of this article, we review the role of Vitamin D in CRC, as well as the results of clinical studies. We also discuss epidemiological and human intervention studies, and possible reasons why evidence for an effect of Vitamin D supplementation remains inconclusive.
Calcitriol has many important homeostatic actions in the small intestine. Of the four forms of Vitamin D (Vitamin D3, Vitamin D2 [ergocalciferol], calcidiol, and calcitriol), Vitamin D3 is almost exclusively produced after exposure to sunlight, while Vitamin D2 is obtained from plants. They are transported to the liver and converted to calcidiol, the active form of Vitamin D in the body. Calcidiol is converted to calcitriol mainly in the kidney (Fig. 1).
The three cytochrome P450s (CYPs) involved in Vitamin D metabolism are
The physiological role of Vitamin D is regulation of calcium and phosphate metabolism, which accounts for its broader range of biological functions, including potential anti-neoplastic effects. Calcitriol, a biologically active form of Vitamin D, plays an important role in calcium metabolism and bone mineralization . VDRs are highly expressed in the gut, mediate the biological actions of the calcitriol, and play a crucial role in immune regulation, proliferation, and intestinal homeostasis.
Calcitriol promotes differentiation of epithelial cells to maintain the intestinal epithelial barrier . It also contributes to intestinal homeostasis by exerting complex effects on immune cells, inducing expression of xenobiotic detoxifying enzymes, and regulating the gut microbiota. In CRC, calcitriol inhibits angiogenesis as well as proliferation, and invasion of carcinoma cells, and sensitizes them to apoptosis.
The composition of the gut microbiome of colorectal cancer patients and healthy people is different. The human colon microbiota has many
Calcitriol interferes with the growth and invasiveness of carcinoma cells by promoting differentiation of epithelial cells; these cells act as a barrier, interfere with migration of carcinoma cells through the extracellular matrix, maintain homeostasis by facilitating normal immune responses, and regulate the composition of the microbiota. Calcitriol promotes apoptosis by regulating the expression of genes related to apoptosis . Calcitriol also upregulated the differentiation of colon carcinoma cells by inducing E-cadherin and the inhibition of β-catenin signaling . Calcitriol acts by binding to the high-affinity VDR, expression of which is increased in hyperplastic polyps during the early stages of tumorigenesis, but falls at the later stages of neoplasia .
Many mechanistic studies demonstrate that calcitriol inhibits proliferation and promotes epithelial differentiation of VDR-expressing human colonic carcinoma cell lines. A key action underlining this effect is multilevel inhibition of Wnt/β-catenin signaling, abnormal activation of which in colon epithelial cells triggers and promotes CRC .
Calcitriol inhibits proliferation of carcinoma cells by inducing G1 cell cycle arrest which is attributable to upregulation of the cell cycle inhibitors
The Wnt/β-catenin pathway is activated primarily during embryonic development; however, it also contributes to homeostasis of other tissues. The pathway is activated aberrantly in several carcinomas, including CRC, and is implicated in expression of several genes that contribute development and progression carcinogenesis. Active Vitamin D inhibits Wnt/β-catenin signaling via multiple pathways. CRC contains approximately 4.5 times more Wnt/β-catenin-stained cells than normal colon cells. Activation of Wnt/β-catenin occurs early in CRC, and in most cases of CRC, one to two genes in this pathway harbor mutations. The pathway is activated by mutation of genes encoding
VEGF is required for formation of the new blood vessels necessary for growth and dissemination of solid tumors. Calcitriol inhibits transcription and expression of Hypoxia-inducible factor-1 (HIF-1), and decreases expression of VEGF. Calcitriol triggers antiangiogenic effects through NF-κB signaling, and the nuclear proteins fork into headbox M1 (FOXM1) and Dickkopf 4 (DKK4). It also inhibits interleukin-8 (IL-8), an important angiogenic factor .
Vitamin D affects apoptosis of CRC cells. Calcitriol suppresses expression of anti-apoptotic proteins such as BCL-2, BAG1, and BCL-XL, and induces expression of pro-apoptotic proteins BAX, BAK, and BAD. Calcitriol facilitates the release of cytochrome
Vitamin D plays role chemoprevention of CRC . It exerts anti-proliferative effects in human colon cells by inducing cell cycle arrest through
The numerous antitumor effects of Vitamin D suggest that supplementation would be effective in reducing the occurrence, size, or recurrence of tumors. However, many studies show that supplementation with Vitamin D does not in itself have a statistically significant clinical effect. The VITamin D and OmegA-3 TriaL (VITAL) study showed no association between Vitamin D supplementation and reduced risk of colorectal adenoma (CRA) or serrated polyps . However, the COLON (COlorectal cancer: Longitudinal, Observational study on Nutritional and lifestyle factors that may influence colorectal tumor recurrence, survival and quality of life) study showed that supplementation with ≥ 50 nmol/L, coupled with a high magnesium intake (median split) (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.31–0.89), lowered the mortality in CRC patients . MDL-811, a small-molecule activating sirtuin 6 (SIRT6) synergically enhances the anti-CRC effect of Vitamin D both in vitro and in vivo . Promoter methylation of secreted frizzled-related protein, an Wnt antagonist was decreased in patients who had higher levels of Vitamin D. Maintaining a high concentration of Vitamin D, therefore, may increase the response to neoadjuvant treatment .
The hypothesis that Vitamin D protects against colon cancer arose from a study on the geographic distribution of colon cancer mortality in the US. The study by Garland  showed an inverse association between annual mean daily solar radiation and age-adjusted rates of colon cancer-related. The result of study is considered to support the hypothesis that there is a relationship between Vitamin D and CRC.
It is generally accepted that 25(OH)D levels of > 30 ng/mL (75 nmol/L [1 ng/mL = 2.5 nmol/L]) are sufficient, with 20–29 ng/mL regarded as insufficiency and < 20 ng/mL (50 nmol/L) defined as Vitamin D deficiency [49,50]. Ng et al.  measured serum 25(OH)D levels prospectively in 515 patients with stage IV CRC, all of whom were enrolled in a randomized controlled trial (RCT) of chemotherapy (the N9741 trial). Subgroup analysis revealed that Vitamin D deficiency (50% had < 20 ng/mL; 82% had < 30 ng/mL) was highly prevalent in all patients with stage IV CRC
Many observational studies have examined the association between serum 25(OH)D levels and the incidence of CRC; the evidence for inverse association between serum 25(OH)D levels and CRC incidence seems relatively strong. A nested case-control study from the Women’s Health Study based on 274 CRC cases and 274 controls revealed that the mean serum 25(OH)D level was lower in cases than in controls (21.9 vs. 23.9 ng/mL,
A recent meta-analysis of 17 cohorts comprising 5,706 CRC cases and 7,107 controls with a wide range of serum 25(OH)D levels shows that deficiency of 25(OH)D (< 20 ng/mL) is associated with a 31% higher CRC risk (relative risk [RR], 1.31; 95% CI, 1.05–1.62), and that sufficiency (30–35 or 35–40 ng/mL) is associated with 19% (RR, 0.81; 95% CI, 0.67–0.99) and 27% (RR, 0.73; 95% CI, 0.59–0.91) lower risk . In this analysis, higher serum 25(OH)D levels showed a significant association with female, but not male, sex for lowering the risk of CRC . Another meta-analysis of 30 studies from 1989 to 2019 also indicates a negative association between serum 25(OH)D levels and CRC risk (RR, 0.68; 95% CI, 0.60–0.78); a subgroup analysis showed that this difference was significant in females (RR, 0.57; 95% CI, 0.43–0.75) but not in males (RR, 0.91; 95% CI, 0.75–1.11). One interesting subgroup analysis in this study revealed that higher serum 25(OH)D levels are significantly related to a lower incidence of CRC in European and American (RR, 0.67; 95% CI, 0.58–0.76), but not in Asian, populations (RR, 0.84; 95% CI, 0.58–1.22) . However, a meta-analysis of eight case-control studies from Asian countries (a total of 2,916 cases and 6,678 controls; mean serum 25(OH)D level = 20.21 ± 7.92 ng/mL [3.65–36.5 ng/mL]) revealed that the incidence of CRC was lower in the highest category than in the lowest (OR, 0.75; 95% CI, 0.58–0.97), although this meta-analysis identified heterogeneity among the studies (I2 = 53.9%;
With respect to the association between serum 25(OH)D levels and colorectal polyps, several meta-analyses of observational studies show an inverse association between serum 25(OH)D levels and CRA in both Western and Asian populations [57,59-62]. A recently published meta-analysis of 23 studies showed that the incidence of CRA correlated inversely with serum 25(OH)D levels (RR, 0.80; 95% CI, 0.71–0.89) . This inverse association was significant in females (RR, 0.63; 95% CI, 0.45–0.89) but not in males (RR, 0.89; 95% CI, 0.68–1.16), and in European and American (RR, 0.82; 95% CI: 0.75–0.91), but not Asian (RR, 0.67; 95% CI, 0.40–1.14), populations .
Previous observational studies suggest that higher serum 25(OH)D levels are associated with reduced risk of CRC. However, the effect and role of Vitamin D on disease progression and outcome remain unknown. A meta-analysis that included five notable prospective cohort studies from 2008–2012 (a total of 2,330 CRC patients with a follow-up of 2.7–24 years) estimated the association between serum 25(OH)D levels and survival . The analysis included patients from four Western studies and one Asian study [51,64-67]. The highest category was associated with much lower overall (HR, 0.71; 95% CI, 0.55–0.91) and disease-specific (HR, 0.65; 95% CI, 0.49–0.86) mortality of patients than the lowest category despite the heterogeneous 25(OH)D categorization among individual studies .
A concentration-response sub-analysis revealed that an increase in the serum 25(OH)D level by 8 ng/mL was associated with reduced overall (HR, 0.91; 95% CI, 0.81–1.01) and disease-specific (HR, 0.90; 95% CI, 0.84–0.97) mortality .
Yuan et al.  measured serum 25(OH)D levels prospectively in 1,041 patients with previously untreated advanced or metastatic CRC; all patients were participating in a phase 3 RCT (CALGB/SWOG 80405) of chemotherapy. They showed that the highest quintile (≥ 24.1 ng/mL) was associated with improved overall (HR, 0.66; 95% CI, 0.53–0.83) and progression-free (HR, 0.81; 95% CI, 0.66–1.00) survival when compared with the lowest quintile (≤ 10.8 ng/mL) . This finding was consistent regardless of prognostic factors. Two recent meta-analyses by Wu et al.  and Huang et al.  have been published. The former analyzed 17,770 CRC patients from 17 studies and showed inverse association between high versus low 25(OH)D levels and overall (HR, 0.64; 95% CI, 0.55–0.72) and CRC-specific (HR, 0.65; 0.56–0.73) survival. A pooled concentration-response analysis revealed a 7% reduction (HR, 0.93; 95% CI, 0.90–0.95) in all-cause mortality and a 12% reduction (HR, 0.88; 95% CI: 0.84, 0.93) in CRC-specific mortality per 8 ng/mL increment in the serum 25(OH)D level . The latter, which included 12 studies, also demonstrated that higher serum 25(OH)D levels lead to more favorable results regarding overall (HR, 0.69; 95% CI, 0.61–0.78) and CRC-specific survival (HR, 0.64; 95% CI, 0.56–0.73) .
Vitamin D supplements comprise either Vitamin D3 or Vitamin D2. Vitamin D2 has less than one-third the potency and a shorter duration of action than Vitamin D3 with respect to increasing serum 25(OH)D levels . Previous studies suggest that Vitamin D3 is better than Vitamin D2 for patients who require Vitamin D supplementation [69-71]. A Cochrane review showed that Vitamin D2 did not confer a mortality benefit . Vitamin D supplements vary in concentration from 400 international units (IU) (low dose) to 5,000 IU (high dose). To prevent Vitamin D deficiency, the Institute of Medicine recommends a daily intake of 600 IU per day, with a maximum recommended intake of 4,000 IU per day . For those aged over 70 years, 800 IU is recommended. The Endocrine Society’s recommendation is a daily allowance of 1,500–2,000 IU, with an upper limit of 10,000 IU for adults .
Previous observational studies show that higher serum 25(OH)D levels are associated with CRC incidence and survival rates; however, observational studies cannot address whether higher 25(OH)D levels cause a reduction in CRC incidence and/or improve outcomes. Animal studies show that Vitamin D analogs (BGP-13 and BGP-15) inhibit growth and induce apoptosis of human HT-29 tumor xenografts . Also, adjuvant treatment using Vitamin D analogs PRI-2191 and PRI-2205 plus chemotherapy shows stronger antitumor effects than chemotherapy alone (5-fluorouracil, irinotecan, or oxaliplatin) [75,76].
From 1996–1997, Trivedi et al.  conducted an RCT of 2,686 participants (2,037 males and 649 females) over the age of 65 years to determine the effect of Vitamin D on fractures and mortality; patients took one capsule (100,000 IU) of Vitamin D3 or placebo every 4 months for 5 years. After 5 years, the mean 25(OH)D levels in the treatment and placebo groups were 29.7 ng/mL (± 8.3) and 21.4 ng/mL (± 8.4), with 28 and 27 cases of CRC, respectively (adjusted RR, 1.02; 95% CI, 0.60–1.74;
Post-hoc analysis of the 15,646 females (43%) who were not taking calcium or Vitamin D supplements outside of the study revealed that the risk of CRC in the intervention group fell by 17% when compared with that in the placebo group (HR, 0.83; 95% CI, 0.60–1.15;
A 4-year population-based RCT (CAPS) of 2,303 elderly females was conducted to determine whether supplementation with Vitamin D3 plus calcium reduced the risk of cancer among post-menopausal females . The intervention group received 2,000 IU/d of Vitamin D3 and 1,500 mg/d of calcium; the mean 25(OH)D level (42.5 ng/mL [95% CI, 41.7–43.3]) in the intervention group did not result in a significantly lower risk of cancer of any type (3.89% vs. 5.58%; 95% CI, –0.06% to 3.46%;
A study of whether Vitamin D prevents CRA examined 2,259 participants recently diagnosed with adenoma within the previous 4 months; patients were randomly assigned to receive daily calcium (1,200 mg) and Vitamin D3 (1,000 IU) or placebo A follow-up colonoscopy was performed 3 or 5 years after the index colonoscopy . Overall, 43% of participants had metachronous adenoma at follow-up; neither Vitamin D alone (adjusted risk ratio, 0.99; 95% CI, 0.89–1.09) nor Vitamin D plus calcium (adjusted RR, 0.93; 95% CI, 0.80–1.08) showed significant efficacy for preventing colorectal polyps, regardless of the degree of change in serum 25(OH)D levels .
Thus, trials published to date show that Vitamin D supplementation does not prevent CRC or CRA (Table 1). However, the study by Trivedi had a small sample size, the WHI study used a dosage that was too low for significance and reported poor compliance, and the primary objective of the VITAL and CAPS trials was not the incidence of CRC. Therefore, further research is necessary to assess the possible roles of Vitamin D in preventing CRC.
Clinical trials assessing the benefits of Vitamin D supplementation in patients with CRC are warranted. An RCT by Trivedi et al.  showed that subgroup mortality was not different between the intervention and placebo groups (7/28 vs. 11/27; RR. 0.62, 95% CI, 0.24–1.60;
The AMATERASU trial enrolled patients with gastrointestinal cancer (stages I to III) at a single center in Japan; the aim was to determine whether post-operative Vitamin D3 supplementation improves survival .A total of 417 patients (48% of whom also had CRC) were assigned randomly to Vitamin D (2,000 IU/day) or placebo groups during a median follow-up of 3.5 years. The 5-year relapse-free survival was not different in overall gastrointestinal cancers (77% vs. 69%; HR, 0.76; 95% CI, 0.50–1.14;
The intestinal tract shows highest expression of VDR. In addition, calcitriol, the most active Vitamin D metabolite, has many important homeostatic actions in the intestine. Various Vitamin D signaling pathways may elicit chemopreventive and therapeutic effects against CRC. Epidemiological studies suggest that Vitamin D deficiency increases the incidence of CRC, and that it has a negative impact on survival of CRC patients. However, clinical trials assessing the benefits of Vitamin D supplementation in CRC are inconclusive; thus, further studies are needed to clarify the role of Vitamin D in CRC. Future studies should also examine potential genetic influences on the effects of Vitamin D supplementation (including Vitamin D metabolism, expression of the Vitamin D receptor and/or proteins that bind Vitamin D); such studies may help to identify patients most likely to benefit from supplements.
This work is supproted by Dongguk University research fund and grant (2022R1F1A1066166) from Ministry of science and ICT (national research foundation of Korea).
No potential conflicts of interest were disclosed.
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