Page 158 - Vitamin D and Cancer

7 Induction of Differentiation in Cancer Cells by Vitamin D 145

SCC Squamous cell carcinoma
Sp-1 Specificity protein 1
TCF4 T-cell transcription factor 4
Wnt Wingless-related MMTV integration site
VDR Vitamin D receptor
VDRE Vitamin D response element
3

7.1 Introduction

In general, differentiation is a term that signifies the structural and functional
changes that lead to maturation of cells during development of various lineages.
Cancer cells are unable, in varying degrees, to achieve such maturation, and thus
malignant neoplastic cells show a lack of, or only partial, evidence of differentia-
tion, known as anaplasia. Since the basic underlying cause for the failure to dif-
ferentiate can be attributed to structural changes in the cell’s DNA, i.e., mutations,
which are essentially irreversible, it is remarkable that some compounds can induce
several types of malignant cells to undergo differentiation toward the more mature
phenotypes. The physiological form of vitamin D, 1a,25-dihydroxyvitamin D (1,25D),
3
is one such compound, and the importance of this finding is that it offers the poten-
tial to be an alternative to, or to provide an adjunctive intervention to the therapy,
as well as the prevention of neoplastic diseases.
The feasibility of differentiation therapy of cancer is supported by the early
observations that some cases of neuroblastoma, a childhood malignancy, can spon-
taneously differentiate into tumors that are composed of normal-appearing neuronal
cells, and the child’s life is spared [1, 2]. The reasons for this conversion have not
been elucidated, but it seems reasonable to assume that as the child matures, the
endocrine and the immune systems become more efficient, and one or more of such
factors are able to induce differentiation of neural precursor cells to the more
mature, noninvasive forms.
An example of an already successful interventional approach to differentiation
therapy of a neoplastic disease is the use of all-trans retinoic acid (ATRA) for the
treatment of acute promyelocytic leukemia (APL) and perhaps other leukemias
[3–5]. Additionally, a synthetic analog of ATRA, Fenretinide, can potentially serve
as an agent which can prevent breast cancer in women [6], illustrating the fact that
a demonstration of a clear clinical therapeutic effect of a differentiation agent opens
up the possibility that it may also serve as a cancer chemopreventive compound.
While the role of 1,25D in cancer chemotherapy and cancer chemoprevention is
only beginning to be established, there are several reasons to believe that its promise
will be fulfilled. These reasons include the fact that 1,25D is a naturally occurring
physiological substance, and thus unlikely to cause the adverse reactions which occur
when xenobiotics are administered to patients, unless given in very high concentrations.
Second, the issue of hypercalcemia, which occurs when the concentrations of 1,25D
greatly exceed the physiological range, and has previously limited its clinical appli-
cations [7, 8], can be addressed by the dual strategy of developing analogs of 1,25D