Murine Pancreatic Acinar Cell Carcinoma Growth Kinetics Are Independent of Dietary Vitamin D Deficiency or Supplementation

Abstract

Vitamin D has been proposed as a therapeutic strategy in pancreatic cancer, yet evidence for an effect of dietary vitamin D on pancreatic cancer is ambiguous, with conflicting data from human epidemiological and intervention studies. Here, we tested the role of dietary vitamin D in the in vivo context of the well-characterized Ela1-TAg transgenic mouse model of pancreatic acinar cell carcinoma. Through longitudinal magnetic resonance imaging of mice under conditions of either dietary vitamin D deficiency (<5 IU/kg vitamin D) or excess (76,500 IU/kg vitamin D), compared to control diet (1,500 IU/kg vitamin D), we measured the effect of variation of dietary vitamin D on tumor kinetics. No measurable impact of dietary vitamin D was found on pancreatic acinar cell carcinoma development, growth or mortality, casting further doubt on the already equivocal data supporting potential therapeutic use in humans. The lack of any detectable effect of vitamin D, within the physiological range of dietary deficiency or supplementation, in this model further erodes confidence in vitamin D as an effective antitumor therapeutic in pancreatic acinar cell carcinoma.

Keywords: in vivo; magnetic resonance imaging; pancreatic acinar carcinoma; pancreatic cancer; vitamin D.

Figure 1

Longitudinal monitoring of tumor growth following modification of dietary vitamin D in mice. TAg⁺ mice were placed on either control, vitamin D deficient, or vitamin D excess diets in utero and aged on the same diets to 21 weeks of age. From 7 weeks onward, mice were assessed through Magnetic Resonance Imaging for tumor size. Individual total predicted tumor volume curves for (A) female mice on control diet (n = 7), (B) female mice on vitamin D-deficient diet (n = 6), (C) female mice on vitamin D excess diet (n = 4), (D) male mice on control diet (n = 5), (E) male mice on vitamin D-deficient diet (n = 6), and (F) male mice on vitamin D excess diet (n = 9).

Figure 2

No consistent effect of dietary vitamin D on tumor onset in a pancreatic cancer model. TAg⁺ mice were placed on either control, vitamin D-deficient, or vitamin D excess diets in utero and aged on the same diets to 21 weeks of age. Cumulative incidence of pancreatic cancer was recorded as a function of age at tumor detection, in (A) female (n = 7, 6, 4) and (B) male (n = 5, 6, 9) mice. The P values were calculated using the log-rank test. (C) Violin plots showing the mean, SD, and kernel probability density of the age at tumor onset under each condition. The P values were calculated using two-tailed unpaired t test.

Figure 3

No effect of dietary vitamin D on tumor growth in a pancreatic cancer model. TAg⁺ mice were placed on either control, vitamin D-deficient or vitamin D excess diets in utero and aged on the same diets to 21 weeks of age. From 7 weeks onward, mice were assessed through Magnetic Resonance Imaging for tumor size. Total predicted tumor volumes were square root transformed and normalized to age of first detection for (A) female mice on control diet (n = 7), (B) female mice on vitamin D-deficient diet (n = 6), (C) female mice on vitamin D excess diet (n = 4), (D) male mice on control diet (n = 5), (E) male mice on vitamin D-deficient diet (n = 6), and (F) male mice on vitamin D excess diet (n = 9). (G) Violin plots showing the mean, SD, and kernel probability density of the percentage of tumor volume increase every 2 weeks. The P values were calculated using two-tailed unpaired t test.

Figure 4

No consistent impact of dietary vitamin D on survival in a transgenic pancreatic cancer model. TAg⁺ mice were placed on either control, vitamin D-deficient or vitamin D excess diets in utero and aged on the same diets to 21 weeks of age. Kaplan–Meier plots showing the overall pancreatic cancer survival in (A) female (n = 7, 6, 4) and (B) male (n = 5, 6, 9) mice on control, vitamin D-deficient and vitamin D excess diets. The P values were calculated using the log-rank test.