Stimulation of bone resorption results in a selective increase in the growth rate of spontaneously metastatic Walker 256 cancer cells in bone

Abstract

To test the hypothesis that bone metastasis is related to the rate of bone remodeling, we have examined the effect of enhanced bone resorption on the growth of spontaneously metastatic Walker 256 (W256) cancer cells. Bone resorption was stimulated in male Fischer rats by injecting Rice H-500 Leydig tumor cells subcutaneously. The resorptive response of the skeleton was confirmed in a pilot study by evaluating parameters of bone morphometry after 4, 7 and 10 days of tumor burden. The distal femoral epiphyses had 35 +/- 10% more osteoclast surface, 83 +/- 11% less osteoblast surface, and 46 +/- 5% less trabecular bone after 10 days of tumor burden, compared to non-tumor-bearing controls. To evaluate the effect of Leydig tumor-induced bone resorption on the growth response of W256 cells, 20 rats were injected intramuscularly with 2 x 10(7) W256 cells, and 20 rats were vehicle-injected. Two days later, 10 rats from each group were injected subcutaneously with Leydig tumor cells. Twelve days after W256/vehicle injection, rats were injected with [3H]thymidine, killed 2 h later, and their femurs, liver, lungs and kidneys were processed for histology. In rats injected with Leydig tumor cells only, enhanced bone resorption was confirmed by a 40 +/- 4% increase in serum calcium concentration, a 48 +/- 8% decrease in trabecular bone content, and a 72 +/- 15% decrease in osteoblast surface, compared with non-tumor-bearing rats. Metastatic W256 cells adjacent to trabecular bone in Leydig tumor-bearing rats had a 56 +/- 18% greater relative [3H]thymidine labeling index (TdR) than did W256 cells in the bones of non-Leydig tumor-bearing rats. The TdRs of W256 cells in the liver, lungs, and kidneys were not affected by Leydig tumor burden. In this model, enhanced bone resorption was associated with the selective growth promotion of metastatic W256 cells in bone, suggesting the existence of a bone-derived factor which is mitogenic to W256 cells.

Interference with the Microenvironmental Support Impairs the De novo Formation of Bone Metastases In vivo

“…Evidence from animal studies and more recently of human studies supports the concept that the rate of bone remodeling is directly related to the occurrence and progression of bone metastases (10)(11)(12)(13)(14)(15).…”

Stimulation of Cyclooxygenase-2 Expression by Bone-Derived Transforming Growth Factor-β Enhances Bone Metastases in Breast Cancer

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MEK5 overexpression is associated with metastatic prostate cancer, and stimulates proliferation, MMP-9 expression and invasion

“…Bone metastasis is associated with a significantly worse outcome and is a frequent late complication. The pathophysiology of bone metastases in prostate cancer is poorly understood, although in other tumour types accumulating evidence suggests that osteotropism may be related to an ability to activate osteoclasts and stimulate bone resorption (Kostenuik et al, 1992;Thomas et al, 1999). In prostate cancer, factors associated with metastasis include bone morphogenetic protein-6 (BMP-6), transforming growth factor b1 (TGF-b1) (Eastham et al, 1995;Hamdy et al, 1997), interleukin-6 (IL-6) and IL-6 receptor (Okamoto et al, 1997;Adler et al, 1999).…”