Inflammation Modulation by Vitamin D and Calcium in the Morphologically Normal Colorectal Mucosa of Patients with Colorectal Adenoma in a Clinical Trial

Abstract

Increased COX-2 and decreased 15-hydroxyprostaglandin dehydrogenase (15-HPGD) expression promote prostaglandin-mediated inflammation and colorectal carcinogenesis. Experimental studies suggest that vitamin D and calcium may inhibit these pathways, but their effects on colorectal tissue COX-2 and 15-HPGD expression in humans are unknown. We tested the effects of supplemental vitamin D (1,000 IU/day) and/or calcium (1,200 mg/day) on COX-2 and 15-HPGD expression in the morphologically normal rectal mucosa from 62 paients with colorectal adenoma in a placebo-controlled chemoprevention trial. We measured biomarker expression using automated IHC and quantitative image analysis at baseline and 1-year follow-up, and assessed treatment effects using mixed linear models. The primary outcome was the COX-2/15-HPGD expression ratio, because these enzymes function as physiologic antagonists. After 1 year of treatment, the mean COX-2/15-HPGD expression ratio in full-length crypts proportionately decreased 47% in the vitamin D group (P = 0.001), 46% in the calcium group (P = 0.002), and 34% in the calcium + vitamin D group (P = 0.03), relative to the placebo group. Among individuals with the functional vitamin D–binding protein isoform DBP2 (GC rs4588*A), the COX-2/15-HPDG ratio decreased 70% (P = 0.0006), 75% (P = 0.0002), and 60% (P = 0.006) in the vitamin D, calcium, and combined supplementation groups, respectively, relative to placebo. These results show that vitamin D and calcium favorably modulate the balance of expression of COX-2 and 15-HPGD—biomarkers of inflammation that are strongly linked to colorectal carcinogenesis—in the normal-appearing colorectal mucosa of patients with colorectal adenoma (perhaps especially those with the DBP2 isoform). Prevention Relevance: Supplemental calcium and vitamin D reduce indicators of cancer-promoting inflammation in normal colorectal tissue in humans, thus furthering our understanding of how they may help prevent colorectal cancer.

The Link between Prostanoids and Cardiovascular Diseases

“…As yet mentioned, PGE2 is degraded by the 15-PGDH enzyme (encoded by the HPGD gene), and its dysfunction promotes the pathogenesis of several diseases. It plays a critical role in the regulation of inflammation, and a reduction in its expression is associated with the development of this pathological condition [ 226 ]. 15-PGDH activity promotes cardiac fibrosis, even in the infarcted heart, owing to PGE2 degradation; it has been shown that its deletion promotes cardiac recovery and reduces the fibrosis of the heart, too.…”

Vitamin D and Cancer: An Historical Overview of the Epidemiology and Mechanisms

“…1,25(OH) 2 D 3 reduces the protumorigenic effect of PG E 2 in prostate cancer cells by inhibiting COX-2 and so decreasing the levels of PG E 2 and two PG receptors (EP2 and FP) [ 286 ]. Importantly, vitamin D and calcium favorably modulate the balance of expression of COX-2 and 15-hydroxyPG dehydrogenase, its physiological antagonist, in the normal-appearing colorectal mucosa of patients with colorectal adenoma [ 287 ]. Vitamin D enhances the tumoricidal activity of NK cells and macrophages [ 288 , 289 ].…”

Impact of Common Vitamin D–Binding Protein Isoforms on Supplemental Vitamin D3 and/or Calcium Effects on Colorectal Adenoma Recurrence Risk

“…Our findings suggest a similar but weaker pattern of effect modification by DBP2 for calcium supplementation on adenoma risk. In this group’s previous biomarker study, calcium supplementation, relative to placebo, statistically significantly reduced cyclooxygenase-2 colorectal tissue expression but only among individuals with the DBP2 isoform. DBP2 is associated with lower circulating DBP concentrations, which may increase parathyroid hormone secretion and calcium absorption, possibly leading to stronger supplemental calcium effects …”

“…Second, DBP2 is associated with approximately 2- to 4-fold lower 25(OH)D binding affinity, which may increase vitamin D bioavailability, and 2- to 3-fold higher vitamin D target-gene expression induction by 25(OH)D in vitro relative to DBP1s/DBP1f. Third, in a subset of this trial’s participants, vitamin D 3 relative to placebo statistically significantly decreased colorectal tissue expression of cyclooxygenase-2, an inflammation-related biomarker of risk for colorectal cancer, but only among those with the DBP2 isoform …”