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Aging and disease
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Calcitriol Analogues Decrease Lung Metastasis but Impair Bone Metabolism in Aged Ovariectomized Mice Bearing 4T1 Mammary Gland Tumours
Artur Anisiewicz1, Beata Filip-Psurska1, Agata Pawlik1, Anna Nasulewicz-Goldeman1, Tomasz Piasecki2, Konrad Kowalski3, Magdalena Maciejewska1, Joanna Jarosz1, Joanna Banach1, Diana Papiernik1, Andrzej Mazur4, Andrzej Kutner5, Jeanette A. Maier6, Joanna Wietrzyk1,*
1Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland.
2Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland.
3Masdiag Sp. z o.o., Żeromskiego 33, Warsaw, Poland.
4Université Clermont Auvergne, INRA, UNH, Unité de Nutrition Humaine, F-63000 Clermont-Ferrand, France.
5Pharmaceutical Research Institute, 01-793 Warsaw, Poland.
6Università di Milano, Dept. Biomedical and Clinical Sciences, 20157 Milano, Italy
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Calcitriol and its analogues are considered drugs supporting the anticancer treatment of breast cancer and preventing the osteoporosis that results from the development of cancer or from chemotherapy or hormone therapy. Following the orthotopic implantation of 4T1 mammary carcinoma cells into aged ovariectomized (OVX) mice, we evaluated the effects of calcitriol and its two analogues, PRI-2191 and PRI-2205, on metastatic spread and bone homeostasis. Calcitriol and its analogues temporarily inhibited the formation of metastases in the lungs. Unexpectedly, only mice treated with calcitriol analogues showed a deterioration of bone-related parameters, such as bone column density, marrow column density and the CaPO4 coefficient. These findings correlated with an increased number of active osteoclasts differentiated from bone marrow-derived macrophages in mice treated with the analogues. Interestingly, in the tumours from mice treated with PRI-2191 and PRI-2205, the expression of Tnfsf11 (RANKL) was increased. On the other hand, osteopontin (OPN) levels in plasma and tumour tissue, as well as TRAC5b levels in tumours, were diminished by calcitriol and its analogues. Despite a similar action of both analogues towards bone metabolism, their impact on vitamin D metabolism differed. In particular, PRI-2191 and calcitriol, not PRI-2205 treatment significantly diminished the levels of both 25(OH)D3 and 24,25(OH)2D3. In conclusion, though there is evident antimetastatic activity in old OVX mice, signs of increased bone metabolism and deterioration of bone mineralization during therapy with calcitriol analogues were observed.

Keywords breast cancer      elderly      ovariectomized mice      metastasis      calcitriol      vitamin D analogues     
Corresponding Authors: Joanna Wietrzyk   
Just Accepted Date: 28 September 2018  
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Artur Anisiewicz
Beata Filip-Psurska
Agata Pawlik
Anna Nasulewicz-Goldeman
Tomasz Piasecki
Konrad Kowalski
Magdalena Maciejewska
Joanna Jarosz
Joanna Banach
Diana Papiernik
Andrzej Mazur
Andrzej Kutner
Jeanette A. Maier
Joanna Wietrzyk
Cite this article:   
Artur Anisiewicz,Beata Filip-Psurska,Agata Pawlik, et al. Calcitriol Analogues Decrease Lung Metastasis but Impair Bone Metabolism in Aged Ovariectomized Mice Bearing 4T1 Mammary Gland Tumours[J]. Aging and disease, 10.14336/AD.2018.0921
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Figure 1.  Time course of experiment.
Figure 2.  The effect of calcitriol and its analogues on tumour progression in aged OVX mice. (A) Kinetics of tumour growth. (B) Tumour volume measured on the 21st day of the experiment. (C) Body weight kinetics. (D) Tumour blood perfusion estimated by ultrasound imaging as time to peak values measured on day 24 after 4T1 mammary gland inoculation. (E) Representative images of tumour perfusion in sham operated mice and OVX mice treated with vehicle or OVX mice treated with calcitriol (i) before and (ii) after contrast agent injection. (F) The number of mice diagnosed with metastases; graphs represent the number of mice with macroscopic metastatic nodules on days 14 and 21 (grey) and the number of mice in the group (N, blue). On the next days of observation in all animals, metastatic nodules were detected. (G) The number of lung metastases counted in fixed lungs on days 21, 28 and 33. Mice were ovariectomized (OVX) or sham operated (Sham); after 4 weeks, they were inoculated orthotopically with 4T1 cells (day 0). From day 7 (7 days after tumour inoculation), vitamin D analogues or vehicle were administered subcutaneously (s.c.) thrice weekly. The single doses of compounds were as follows: calcitriol, 0.5 µg/kg; PRI-2191, 1.0 µg/kg; and PRI-2205, 10.0 µg/kg. The number of mice analysed was 4-7 per group. Control mice (receiving the vehicle) are described as follows: "sham" - sham operated, tumour bearing mice; "control" - OVX, tumour bearing mice. Data presentation: (A) and (C) mean with standard deviation (SD); (B), (D) and (G) data for individual animals with mean and (SD). Statistical analysis: Kruskal-Wallis multiple comparison test. *P<0.05.
Figure 3.  The influence of calcitriol and its analogues on bone mineralization in mice bearing 4T1 tumours (day 0 and day 28). (A-E) Analysis performed on aged OVX mice. (F-I) Analysis performed on young mice. (A) and (F) Bone column density (corrected X-ray extinction for the cylindrical bone). (B) and (G) Marrow column density (corrected X-ray extinction for the marrow). (C) and (H) Bone density. (D) and (I) CaPO4 coefficient. (E) Representative X-ray pictures of aged OVX mice. Bruker In-Vivo FX PRO imaging equipped with an X-ray unit was used. Mice were ovariectomized (OVX) or sham operated (Sham), and after 4 weeks, they were inoculated orthotopically with 4T1 cells (day 0). From day 7 (7 days after tumour inoculation), vitamin D analogues or vehicle were administered subcutaneously (s.c.) thrice weekly. The single doses of compounds were as follows: calcitriol, 0.5 µg/kg; PRI-2191, 1.0 µg/kg; and PRI-2205, 10.0 µg/kg. Both femurs of 3-6 mice were used for analysis. Control mice (receiving the vehicle) are described as follows: "sham" - sham operated, tumour bearing mice; "control" - OVX, tumour bearing mice. Day 0 means mice not inoculated with cancer cells, sham-operated or OVX. Statistical analysis: Kruskal-Wallis multiple comparison test. *p<0.05 compared to control mice on the relevant day of treatment or as indicated.
Figure 4.  Ca2+ plasma concentration and vitamin D metabolites in the blood; plasma and tumour cytokine levels in aged OVX mice bearing 4T1 mammary gland tumours and treated with calcitriol and its analogues. (A) Plasma concentration of Ca2+. The amount of vitamin D metabolites in whole blood: (B) 25(OH)D3, (C) 24,25(OH)2D3, (D) 25(OH)D2. (E) Osteopontin (OPN) level in mouse plasma and (F) tumour tissue. Plasma concentration of (G) RANKL and (I) osteocalcin. Tumour tissue levels of (H) RANKL, (J) osteocalcin, (K) TRAC5b. Mice were ovariectomized (OVX) or sham operated (Sham); after 4 weeks, they were inoculated orthotopically with 4T1 cells (day 0). From day 7 (7 days after tumour inoculation), vitamin D analogues or vehicle were administered subcutaneously (s.c.) thrice weekly. The single doses of compounds were as follows: calcitriol, 0.5 µg/kg; PRI-2191, 1.0 µg/kg; and PRI-2205, 10.0 µg/kg. Number of samples analysed per group: 3-7. Control mice (receiving the vehicle) are described as follows: "sham" - sham operated, tumour bearing mice; "control" - OVX, tumour bearing mice. Day 0 means mice not inoculated with cancer cells, sham-operated or OVX. Statistical analysis: Kruskal-Wallis multiple comparison test. *P<0.05 compared to control mice on the relevant day of treatment or as indicated.
Figure 5.  Ex vivo osteoclastogenesis of bone marrow macrophages in aged OVX mice bearing 4T1 mammary gland tumours and treated with calcitriol or its analogues. (A) Active osteoclasts. TRAP-positive cells characterized by acid phosphatase staining (dark purple colour visible in the cytoplasm of cells) and more than five nuclei. BMDMs derived from mice on day 28 of the experiment were cultured with M‐CSF (20 ng/ml) and RANKL (20 ng/ml). Mice were ovariectomized (OVX) or sham operated (Sham); after 4 weeks, they were inoculated orthotopically with 4T1 cells (day 0). From day 7 (7 days after tumour inoculation), vitamin D analogues or vehicle were administered subcutaneously (s.c.) thrice weekly. The single doses of compounds were as follows: calcitriol, 0.5 µg/kg; PRI-2191, 1.0 µg/kg; and PRI-2205, 10.0 µg/kg. Data are presented as the mean and standard deviation (SD). The percentage of cells compared to control mice is presented. The number of samples analysed was 4 per group. "Control" means OVX, tumour bearing mice. Statistical analysis: Sidak’s multiple comparison test. *P<0.05 compared to control mice. (B) Representative microphotographs of TRAP-positive osteoclasts. Scale bar = 1 mm.
Figure 6.  Heat maps of tumour tissue real-time PCR screening performed using the Mouse T Helper Cell Differentiation RT2 Profiler Array. Real-time PCR screening was performed using tumour tissue harvested on day 21. Data are presented as the mean fold change. The fold change (RQ) of target genes was defined using the double delta Ct method in reference to the heat shock protein 90 alpha (cytosolic), class B member 1 (Hsp90ab1). The results were adjusted to the values obtained for the control group (OVX, tumour-bearing, vehicle treated). Data analysis was performed using Qiagen online software suitable for the purchased kits (Qiagen, Hilden, Germany). Each reaction contained 0.5 µg of cDNA (for each mouse in the group; 3 or 4 mice per group).
Figure 7.  The main differences in the response to treatment with calcitriol and its analogues PRI-2191 and PRI-2205 between aged OVX and young mice bearing 4T1 breast cancer. Selected results of the analyses performed are presented. Young 6- to 8-week-old mice and aged 60-week-old ovariectomized (OVX) mice received an orthotopic injection of 4T1 mouse mammary gland cancer cells. Calcitriol (0.5 µg/kg), PRI-2191 (1 µg/kg) and PRI-2205 (10 µg/kg) were injected subcutaneously starting from day 7 and continuing three times a week to the end of the experiment.
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