Proietti Francesco
Pizzuto Andrea
INTRODUCTION
Colorectal cancer is a cancer from uncontrolled cell growth in the colon or rectum. Most cases of colon cancer begin as small, noncancerous (benign) clumps of cells called adenomatous polyps.
In the last years the incidence of colorectal cancer has greatly increased in both Europe and US, and now represents the fourth most common cancer and the third most common cause of death from cancer in both men and women. However, fortunately, 5-year surviving has greatly increased, due to the improvement of early diagnosis and therapies. Adenocarcinoma accounting for more than 95% of colorectal cancer is the most common form.
Aside from genetic forms (Lynch syndrome and FAP), results from several epidemiological studies have suggested that there are several risk factors associated with an increased risk, such as high intake of fat, alcohol or red meat, obesity, smoking, a lack of physical exercise, presence of IBD.
VITAMIN D
See also: Vitamin D
Vitamin D is a group of fat-soluble prohormones responsible for enhancing intestinal absorption of calcium, iron, magnesium, phosphate and zinc. In humans, the most important compounds in this group are vitamin D3 (also known as cholecalciferol) and vitamin D2 (ergocalciferol). Cholecalciferol and ergocalciferol can be ingested from the diet and from supplements. The body can also synthesize vitamin D (specifically cholecalciferol) in the skin, from cholesterol, when sun exposure is adequate. Whether it is made in the skin or ingested, cholecalciferol is hydroxylated in the liver at position 25 to form 25-hydroxycholecalciferol. 25OH vitamin D is transported to the proximal tubules of the kidneys, where it is hydroxylated at the 1-α position to form calcitriol (1,25-dihydroxycholecalciferol). This product is a potent ligand of the vitamin D receptor (VDR), which mediates most of the physiological actions of the vitamin. The conversion of vitamin D in the active form is influenced from serum PTH levels.
The active vitamin D has many biological functions:
- maintains skeletal calcium balance by promoting calcium absorption in the intestines and promoting bone resorption
- affects the immune system, and VDRs are expressed in several white blood cells, including monocytes and activated T and B cells
- is involved in the biosynthesis of neurotrophic factors, synthesis of nitric oxide synthase, and increased glutathione levels
- is involved in cell proliferation and differentiation, and there are several evidences of an effect on cell death, tumor invasion, and angiogenesis, which makes it a candidate agent for cancer regulation
Several levels of evidence support the relationship between vitamin D and cancer:
- low circulating levels of vitamin D are associated with increased risk of developing cancer
- a high intake of vitamin D is associated with a reduced risk of cancer,
- the aggressiveness of a cancer is lower in summer when the production of vitamin D is higher
- polymorphisms of genes encoding proteins involved in the signal pathway of vitamin D affect the risk of developing cancer
Vitamin D and Cancer.2012
Through the genomic actions of vitamin D3 via VDR regulation of several genes containing VDREs, 1,25(OH)2 vitamin D3 and its analogues inhibit cell cycle progression and tumor cell growth in several cancer cell lines.
VITAMIN D AND COLORECTAL CANCER
The first study that tried to link vitamin D status and Colorectal Cancer is a study of 1980, which arose from the observation that in US colon cancer mortality rates were highest in places where populations were exposed to the least amounts of natural light
Do sunlight and vitamin D reduce the likelihood of colon cancer? 1980.
Since then, several studies have been conducted to determine the relationship between serum levels of 25(OH)D or vitamin D intake and risk of colorectal cancer. Higher intake of vitamin D and higher circulating 25(OH)D has generally been associated with a lower risk of colorectal cancer. Also, one study indicates that patients who are diagnosed and treated in the sunnier months (where vitamin D levels are much higher), may have a better prognosis from colorectal cancer.
In particular, a cohort study with follow-up times out to 12 years found a significantly reduced risk for higher serum 25(OH)D levels.
An ecological study of cancer incidence and mortality rates in France with respect to latitude, an index for vitamin D production. 2010.
Furthermore, among patients with colorectal cancer, higher prediagnosis plasma 25(OH)D levels were associated with a significant improvement in overall survival
Circulating 25-hydroxyvitamin d levels and survival in patients with colorectal cancer. 2008.
Also, a large metanalysis in 2007 have shown that a low dose of vitamin D did not protect against colorectal cancer (and this is the reason why many previous studies did not show a significant protection), yet a higher dose may reduce its incidence
Optimal vitamin D status for colorectal cancer prevention: a quantitative meta analysis. 2007.
One of the mechanisms that may be involved is the inhibition of Wnt/β-catenin signaling.
The Wnt/β-catenin pathway controls the intracellular levels of β-catenin. In the absence of Wnt signals, free β-catenin is targeted by a cytoplasmic protein complex known as the β-catenin destruction complex, which promotes its phosphorylation, ubiquitination and degradation by the proteasome. Activation of the Wnt/β-catenin pathway is the initial event in a high proportion of colorectal carcinomas and recent massive sequencing has shown that over 94% of colon tumors harbor mutations in one or more genes of the pathway
1,25(OH)2D3 inhibits β-catenin/TCF transcriptional activity in colon carcinoma cells by several mechanisms. It promotes VDR/β-catenin binding, thus reducing the amount of β-catenin bound to TCF (1); it induces the expression of CDH1 gene coding for E-cadherin, which sequesters β-catenin at the plasma membrane adherens junctions (2); and it enhances the expression of the extracellular Wnt inhibitor DKK-1 (3) and of TCF4 (4)
Despite this evidences, the NCI does not recommend for or against the use of vitamin D supplements to reduce the risk of colorectal or any other type of cancer, because there are no randomized trial designed to assess the role of vitamin D in cancer. New randomized trials need to be conducted, including informations on when to start taking vitamin D, for how long and at what dose.
The VITamin D and OmegA-3 TriaL (VITAL) is an ongoing randomized clinical trial investigating whether taking daily dietary supplements of vitamin D3 (2000 IU) or omega-3 fatty acids reduces the risk of developing cancer, heart disease, and stroke in people who do not have a prior history of these illnesses.
