Page 70 - Vitamin D and Cancer

3 Anti-inflammatory Activity of Calcitriol in Cancer 57

as infiltrating macrophages within the tumors [69, 70]. In other cancers, COX-2
expression has been demonstrated in vascular endothelial cells, fibroblasts, and
smooth muscle cells around the cancer [71, 72]. PGs generated by COX-2 act in an
autocrine and paracrine manner to stimulate cell growth. At the cellular level both
arachidonic acid, the substrate for COX, and the product prostaglandin E (PGE )
2 2
stimulate proliferation by regulating the expression of genes that are involved in
growth regulation including c-fos [73]. Studies in experimental models of cancer
have shown that COX-2 enhances tumor development and progression by promot-
ing resistance to apoptosis and stimulating angiogenesis and tumor invasion, and it
is therefore regarded as an oncogene [14, 39].

3.3.1.2 15-PGDH

15-PGDH is the enzyme that catalyzes the conversion of PGs to their corresponding
15-keto derivatives, which exhibit greatly reduced biological activity. Therefore,
15-PGDH can be regarded as a physiological antagonist of COX-2. 15-PGDH has
been described as an oncogene antagonist in colon cancer by Yan et al. [74]. Their
studies show that 15-PGDH is universally expressed in normal colon but is rou-
tinely absent or severely reduced in cancer specimens. Most importantly, the stable
transfection of a 15-PGDH expression vector into colon cancer cells greatly reduces
the ability of the cells to form tumors and/or slows tumor growth in nude mice
demonstrating that 15-PGDH functions as a tumor suppressor [74]. Another study
in mice also demonstrates that 15-PGDH acts in vivo as a highly potent suppressor
of colon neoplasia development [75]. Low expression of 15-PGDH and methyla-
tion of the 15-PGDH promoter in 30–40% of primary breast tumors has been
reported by Wolf et al. [76]. Their studies in BCa cells also demonstrated a suppres-
sion of cell proliferation in vitro and decreased tumorigenicity in vivo following the
overexpression of 15-PGDH, thus supporting a tumor suppressor role for 15-PGDH
in BCa [76].

3.3.1.3 PG Receptors

PGE and PGF are the major PGs stimulating the proliferation of PCa cells and they
act by binding to G-protein coupled membrane receptors (prostanoid receptors).
There are eight members in the prostanoid receptor subfamily and they are distin-
guished by their ligand-binding profile and the signal transduction pathways that
they activate accounting for some of the diverse and often opposing effects of PGs
[77]. PGE acts through four different receptor subtypes (EP1-EP4), while PGF
acts through the FP receptor. PCa cells express both EP and FP receptors [35, 73].
PG receptors are also expressed in most endothelial cells, macrophages, and
stromal cells found in the tumor microenvironment. PG interaction with its recep-
tors can send positive feedback signals to increase COX-2 mRNA levels [73, 78, 79].
Therefore, irrespective of the initial trigger of COX-2 expression, PGs could