Page 159 - Vitamin D and Cancer

146 E. Gocek and G.P. Studzinski

with reduced calcium-mobilizing properties [9–12], and combining these with other
compounds which enhance the differentiation-inducing actions of 1,25D or its analogs
[13–15]. Also, progress is being made in understanding the mechanisms responsible
for 1,25D-induced differentiation, summarized later in this review, and although
this understanding is by no means complete, it is likely that insights will be obtained
that can be translated to clinical applications.
Differentiation of neoplastic cells induced by 1,25D and other agents rarely, if
ever, results in the generation of completely normal, functioning cells. Indeed, the
appearance of cells resulting from induced progenitors has been aptly described as
resembling “caricatures” rather than normal cells. Such cells may exhibit, and are
recognized by, some features of the normal, mature cells of the particular develop-
mental lineage, but seldom function like the mature normal cells. However, this is
not the major objective of differentiation therapy of neoplastic diseases; the real
benefits are due to the cessation of the proliferation of these cells, which is a con-
sequence of cell cycle arrest associated with differentiation [16–19], and in some
cases to the reduced survival of the differentiated cells. For instance, 1,25D-induced
monocytic differentiation of myeloid leukemia cells can result in the G1 phase cell
cycle block, resulting in cessation of cell proliferation [19], while 1,25D treatment
of breast or prostate cancer cells can induce cell death by apoptosis as well as dif-
ferentiation [20–22].
An important consideration in the area of 1,25D-induced differentiation is cell-
type and cell-context specificity. For instance, in contrast to breast and prostate cancer
cells which are induced to undergo apoptosis, in myeloid leukemia cells 1,25D-induced
differentiation is accompanied by increased cell survival [23, 24]. The pathways
which are known to signal 1,25D-induced differentiation and the associated cell cycle
and survival effects also differ, though they may overlap, in different cell types. This
may further be complicated by the type of mutations that are responsible for the block
of differentiation, and the resulting uncontrolled proliferation of the neoplastic cells.
We therefore discuss separately the principal cancer cell types known to be candidates
for differentiation therapy or chemoprevention by 1,25D.

7.2 Solid Tumors

7.2.1 Colon Cancer

It is well established that colon cancer cells in culture can undergo differentiation to
a more mature phenotype, and the inducing agents include the short-chain fatty acid
butyrate and 1,25D. The evidence for differentiation has traditionally been the
expression of the hydrolytic enzyme alkaline phosphatase (Alk Pase), which can be
demonstrated on the microvilli and tubulovacuolar system of the surface “principal
cells” of the colon mucosa [25, 26], but is poorly expressed in proliferating colon cancer
cells [27]. More recently, other markers of colonic epithelial cell differentiation