The role of the bone microenvironment in skeletal metastasis

Abstract

The bone microenvironment provides a fertile soil for cancer cells. It is therefore not surprising that the skeleton is a frequent site of cancer metastasis. It is believed that reciprocal interactions between tumour and bone cells, known as the "vicious cycle of bone metastasis" support the establishment and orchestrate the expansion of malignant cancers in bone. While the full range of molecular mechanisms of cancer metastasis to bone remain to be elucidated, recent research has deepened our understanding of the cell-mediated processes that may be involved in cancer cell survival and growth in bone. This review aims to address the importance of the bone microenvironment in skeletal cancer metastasis and discusses potential therapeutic implications of novel insights.

Keywords: Bone metastasis; Bone microenvironment; Bone remodelling; Cancer.

Fig. 1

Schematic representation of the ‘vicious cycle’. Up-regulation of RANKL in bone cells and subsequent osteoclast activation is driven primarily by tumour-derived factors such as PTHrP and IL-6. Accelerated bone resorption then triggers the release of growth factors from the degraded bone matrix, which in turn promote further tumour growth.

Fig. 2

Overexpressing PTHrP in MDA-MB-231 cells accelerates bone metastases. MDA/TβRIIΔcyt cells were created in MDA-MB-231 cells that expressed the dominant–negative of the TGF-β type II receptor rendered the human breast cancer cell line MDA-MB-231 unresponsive to TGF-β. MDA-MB-231 and MDA/TβRIIΔcyt cell clones that overexpress PTHrP (TβRIIΔcyt+PTHrP; two clones) or the empty vector (TβRIIΔcyt+pcDNA3.1zeo) were used. (A) Representative radiographs of hindlimbs from mice bearing two different TβRIIΔcyt+PTHrP clones or TβRIIΔcyt+pcDNA3.1zeo control 31 days after tumour inoculation. Osteolytic lesions are indicated by the arrows. (B) Osteolytic lesion number and area on radiographs as measured by computerized image analysis of forelimbs and hindlimbs. Respective tumour cells were inoculated on day 0. Values represent the mean±SEM (n=5) per group. From Ref. with permission from the Publisher.

Fig. 3

Effect of OPG treatment on histomorphometric indices of skeletal Colon-26 tumour burden. OPG treatment (1 mg/kg and 3 mg/kg) significantly reduced the average tumour area at each dose. *, Significantly different from 0 mg/kg OPG. Data represent the means±SE (n=10 mice/group). From Ref. with permission from the Publisher.

Fig. 4

Osteoprotegerin and ibandronate treatment completely inhibits the enlargement of osteolytic bone lesions. (A) Representative radiographs of osteolytic lesions in tibiae of nude mice before treatment (Day 10; a–c) or after treatment (Day 17; d–f) with vehicle (PBS) osteoprotegerin (OPG) or ibandronate (IBN). At day 10, small but distinct osteolytic lesions (arrows) are detected in the tibiae (a–c). The size of these osteolytic lesions in untreated bones is markedly increased 7 days later, at day 17 (e). In contrast, in all treated bones, increase in size of these lytic lesions is inhibited (e–f). (B) Effects of osteoprotegerin (OPG) and ibandronate (IBN) treatment on the progression of established osteolytic bone lesions. Data are mean±SD and n=10 in each group. *significantly different from vehicle-treated group at Day 17 (p<0.01), ^#different to Day 10 (p<0.01). From Ref. with permission from the Publisher.

Fig. 5

Low dietary calcium promotes breast cancer growth in bone. Mice fed a low calcium diet and injected intratibially with breast cancer MDA-MB-231 cells develop larger lytic lesions (left and centre) and larger tumours (right) compared to mice on a normal diet. *p<0.01. From Ref. with permission from the Publisher.

Fig. 6

Biochemical assessment of mice receiving vitamin D deficient or vitamin D sufficient diets. (A) Plasma 25(OH)D levels are profoundly reduced at 6 and 11 weeks. (B and C) Plasma levels of PINP and TRAcP5b were significantly increased in vitamin D deficient mice at week 6. At week 11, plasma PINP levels were still significantly higher in vitamin D deficient compared to vitamin D sufficient mice. There was no difference between TRAcP5b levels. Data are shown as mean±SD for group sizes of n =9. *, P<0.05, **, P<0.01, compared to vitamin D sufficient mice. From Ref. with permission from the Publisher.

Fig. 7

Radiographic assessment of osteolytic and osteosclerotic lesions in vitamin D sufficient and vitamin D deficient mice. Vitamin D deficient mice had developed significantly larger osteolytic (B) and osteosclerotic lesions (C) than vitamin D sufficient mice (arrows indicate sclerotic lesions, (A)), when implanted with prostate cancer PC-3 cell into tibiae of mice. Data are shown as mean±SE for group sizes of n =9. *, P<0.05, compared to vitamin D sufficient mice. From Ref. with permission from the Publisher.