Animal models of bone metastasis

Abstract

Animal models will continue to be indispensable to investigate the pathogenesis of bone metastasis in vivo, conduct preclinical chemotherapeutic, chemoprevention and genetic therapy studies, test gene delivery mechanisms, and identify metastasis suppressor and inducer genes. It is likely that the bone marrow microenvironment, such as the endothelial cells, stromal cells, hematopoietic cells, bone cells, and the intercellular matrix play important roles in the localization and clonal growth of cancer cells in bone. Given the complexity of bone metastasis, many genes are expected to be involved in the pathogenesis and few are likely indispensable. The use of genomic and proteomic approaches to study these animal models will identify key targets for therapeutic intervention. As we further refine these models and use imaging for real-time evaluation of cells, and eventually target genes, these models will more closely mirror human disease and will hopefully become more predictive of the human response to therapy.

FIGURE 1

Animal models of bone metastasis include spontaneous tumors in rodents and domestic animals, such as dogs and cats; spontaneous tumors in inbred strains of rodents that can be maintained as tumor lines in syngeneic hosts; chemically induced tumors in rodents; transgene-induced tumors in mice; and reconstitution models such as combinations of tumor cells with stromal cells, implantation of human bone in mice, or the formation of ectopic bone ossicles in the subcutis. Xenografts of human tumors and cell lines derived from human cancers can be implanted into immunodeficient mice (such as nude mice) in the subcutis, injected into the left ventricle of the heart (a reliable method for inducing bone metastases), directly injected into bones such as the tibia or femur, injected into the tail vein (induces lung metastases), or injected orthotopically (such as in the mammary gland, prostate gland, or the lungs).

FIGURE 2

Prostate carcinoma in the dog (macroscopic photograph and radiograph of the caudal lumbar vertebrae and sacrum). The tumor invaded the pelvic cavity and induced marked proliferation of periosteal new bone formation along the ventral surfaces of the bodies of the lumbar vertebrae and sacrum. There also was invasion into the medullary cavity of the sacrum (best seen as an area of lysis on the left). Scale bar = 1 cm.

FIGURE 3

Prostate carcinoma in the dog (macroscopic photograph and Faxitron radiograph of the distal femur). Two predominantly osteoblastic and partially osteolytic bone metastases of prostate carcinoma in the diaphysis (ca) and metaphysis/epiphysis. Notice the extensive proliferation of new woven bone trabeculae in the diaphysis and metaphysis induced by the prostate carcinoma (regions between the arrows). Scale bar = 1 cm.

FIGURE 4

Mouse calvaria. (A) Control calvarium. (B) Calvarium demonstrating marked periosteal new bone proliferation on the convex surface induced by implantation of normal canine prostate in the subcutis (not shown) for 2 weeks.

FIGURE 5

In vivo bioluminescent imaging of light emitted from luciferase in human PC-3M-luc prostate carcinoma cells in a nude mouse. Three minutes after injection of 100,000 cells into the left ventricle of the heart, cells were apparent throughout the body with very early localization in the kidney (light green focus). At 15 minutes, the signals from labeled tumor cells localized to the lungs, kidneys, bones (spine, long bones, and maxilla and mandible), and the eyes. There was no detectable signal at 24 hours (data not shown), indicating that most of the carcinoma cells died or were metabolically inactive. Initial metastases were evident in the long bones (blue focus) and spine on Day 20. The scale bar on the right is the relative intensity of light, which is an indirect measure of cell number.