Contents - IARC

Vitamin D and Cancer
Chapter 2 – Objectives and format of the report
2.1 Background
In all vertebrates, the ionised calcium is implicated in mechanisms such as muscular contraction,
cell adhesion, or bone formation. Calcium is an important cellular messenger and is involved in cellular
growth and in cell cycle.
Since animals left calcium rich oceans some 350 millions year ago to evolve on earth’s crust,
vitamin D has always played a vital role for maintaining adequate calcium concentration in the blood
and building and maintaining a robust skeleton through intestinal extraction of calcium from foodstuffs
and bone metabolism.
Exposure of the skin to ultraviolet B radiation (UVB; 280-315 nm) induces not only the
synthesis of vitamin D3 from 7-dehydrocholesterol (7-DHC) but also formation of the physiologically
active metabolites of vitamin D, the 1α,25-dihydroxyvitamin D which mainly acts through binding to the
vitamin D receptor (VDR). Also, vitamin D a “secosteroid”, i.e., a molecule that are very similar in
structure to steroids by one of the four steroid rings is broken and B-ring carbons atoms are not joined.
Thus vitamin D is more like a hormone and not strictly a vitamin according to the classical criteria that
an essential nutrient is a substance the body cannot synthesise in sufficient quantities itself. Also,
vitamins are usually involved in biochemical reactions, while 1α,25-dihydroxyvitamin D exerts its action
via VDR.
As humans moved from UVB rich equatorial areas to more northern areas, natural selection
favoured steadily lighter skins, so that less and less UVB was necessary to synthesise the vitamin D
required for optimal skeleton robustness and muscle functioning (Loomis, 1967). Landmark works by
Jablonski and Chaplin (2000) have shown that skin reflectance is strongly correlated with absolute
latitude and UV radiation levels, suggesting that the main role of melanin pigmentation in humans is
the regulation of the effects of UV radiation on the contents of blood vessels located in the dermis.
This regulation is deemed to protect against the UV induced degradation of folic acid, a member of the
vitamin B family that is essential for numerous vital metabolic and reproductive functions. Folic acid
has, among other functions, involvement in the development of the neural tube 1 , spermatogenesis,
and DNA replication.
Evolutionary pressure led to the lightning of skin of Homo sapiens migrating further away from
the equator that represents a compromise solution to the conflicting physiological requirements of
photo protection for folic acid preservation and endogenous UVB induced vitamin D3 synthesis.
Female skin is generally lighter than that of the male, and this may be required to permit synthesis of
the relatively higher amounts of vitamin D3 necessary during pregnancy and lactation.
When rural populations of Europe and North America started to migrate to smog filled
industrialised cities in the nineteenth century, the lack of sufficient sunlight and food rich in vitamin D
precipitated a clinical expression of severe vitamin D deficiency which manifested as rickets in children
and osteomalacia in women of childbearing age. A causal relationship exists between the
physiologically active form of vitamin D and innate and adaptive immunity to infections: recurrent
infections are commonly associated with rickets, and overall mortality is high in deprived children.
It was only at the beginning of the twentieth century that supplementation with cod liver oil (a rich
dietary source of vitamin D3) and later sun exposure were used to cure rickets and osteomalacia.
Interested readers may consult excellent historical reviews of vitamin D deficiency diseases
(Rajakumar et al.,2003, 2005, 2007).
In 1941, Apperley described for the first time an association between cancer mortality rates and
latitudinal location of states in the USA and of provinces in Canada. Laboratory experiments have
shown that in addition to its action on calcium and bone metabolism, the physiologically active form of
vitamin D, the 1α,25-dihydroxyvitamin D, inhibits cellular proliferation, and promotes differentiation and
apoptosis, all properties compatible with antineoplastic action. But the serum concentration of 1α,25dihydroxyvitamin
D is very stable and very similar between subjects, and thus, its involvement in
cancerous processes was not seen as a valid hypothesis. This view changed with the discovery of
extra-renal production of 1α,25-dihydroxyvitamin D coupled with existence of vitamin D receptors
(VDR) in various organs. Local production of 1α,25-dihydroxyvitamin D is likely to depend more on
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