Bone is one of the most common sites of cancer metastasis in humans and is a significant source of morbidity and mortality. Bone metastases are considered incurable and result in pain, pathologic fracture, and decreased quality of life. Animal models of skeletal metastases are essential to improve the understanding of the molecular pathways of cancer metastasis and growth in bone and to develop new therapies to inhibit and prevent bone metastases. The ideal animal model should be clinically relevant, reproducible, and representative of human disease. Currently, an ideal model does not exist; however, understanding the strengths and weaknesses of the available models will lead to proper study design and successful cancer research. This review provides an overview of the current in vivo animal models used in the study of skeletal metastases or local tumor invasion into bone and focuses on mammary and prostate cancer, lymphoma, multiple myeloma, head and neck squamous cell carcinoma, and miscellaneous tumors that metastasize to bone. Keywordscancer; mammary; prostate; squamous cell carcinoma; dog; cat; parathyroid hormone; related protein; osteoblastic Cancer is the second leading cause of death in the United States, behind only heart disease. Death in patients with cancer is often due to metastasis, and one of the most common sites is bone. 109 Skeletal metastases are frequent in patients with breast, prostate, and lung cancer but also occur in other tumors such as myeloma, thyroid and renal cancer, lymphoma, Ewing sarcoma, and infrequently in other cancers. 110,146 Bone metastases can result in osteolytic (bone-resorbing) or osteoblastic (bone-forming) metastases that can cause pain, pathologic fractures, and mortality. 108,163 The general pathogenesis of bone metastasis involves proliferation of the primary neoplasm, local tissue invasion, intravasation into blood vessels, extravasation into the bone marrow, a Reprints and permission: sagepub.com/journalsPermissions.nav Corresponding Author: T. J. Rosol, Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Rd., Columbus, OH 43210, USA. rosol.1@osu.edu. Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. HHS Public AccessAuthor manuscript Vet Pathol. Author manuscript; available in PMC 2015 September 01. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript variable time of tumor cell dormancy, proliferation in bone, and modification of the bone microenvironment. 30 The current hypothesis for preferential localization of cancer cells in bone is the "seed and soil" hypothesis of Paget, 95 which states that neoplastic cells (seeds) grow or proliferate only in a suitable soil, such as the bone marrow. This hypothesis has remained intact for over 100 years; however, now there is a deeper appreciation for the important role that the bone marrow microenvironment plays in metastasis. The metastatic tumor...

The Ace-1 xenograft is a useful model for investigating the pathogenesis of prostate cancer invasion and mixed osteoblastic/osteolytic bone metastases.

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Muraglitazar, a PPARα/γ agonist, dose-dependently increased urinary bladder tumors in male Harlan Sprague-Dawley (HSD) rats administered 5, 30, or 50 mg/kg/day for up to 2 years. To determine the mode of tumor development, male HSD rats were treated daily for up to 21 months at doses of 0, 1, or 50 mg/kg while being fed either a normal or 1% NH 4 Cl-acidified diet. Muraglitazar-associated, time-dependent changes in urine composition, urothelial mitogenesis and apoptosis, and urothelial morphology were assessed. In control and treated rats fed a normal diet, urine pH was generally ≥ 6.5, which facilitates formation of calcium-and magnesium-containing solids, particularly in the presence of other prolithogenic changes in rat urine. Urinary citrate, an inhibitor of lithogenesis, and soluble calcium concentrations were dose dependently decreased in association with increased calcium phosphate precipitate, crystals and/or microcalculi; magnesium ammonium phosphate crystals and aggregates; and calcium oxalate-containing thin, rod-like crystals. Morphologically, sustained urothelial cytotoxicity and proliferation with a ventral bladder predilection were noted in treated rats by month 1 and urinary carcinomas with a similar distribution occurred by month 9. Urothelial apoptotic rates were unaffected by muraglitazar treatment or diet. In muraglitazar-treated rats fed an acidified diet, urine pH was invariably < 6.5, which inhibited formation of calcium-and magnesium-containing solids. Moreover, dietary acidification prevented the urothelial cytotoxic, proliferative, and tumorigenic responses. Collectively, these data support an indirect pharmacologic mode of urinary bladder tumor development involving alterations in urine composition that predispose to urolithiasis and associated decreases in urine-soluble calcium concentrations.

Feline oral squamous cell carcinoma (OSCC) is the most common oral tumor in cats. There is no effective treatment, and the average duration of survival after diagnosis is only 2 months. Feline OSCC is frequently associated with osteolysis; however, the mechanisms responsible are unknown. The objective of this study was to characterize the epidemiology and pathology of bone-invasive OSCC in cats and to determine the expression of select bone resorption agonists. In sum, 451 cases of feline OSCC were evaluated. There was no sex or breed predisposition, although there were more intact cats in the OSCC group compared to the control group. Gingiva was the most common site, followed by the sublingual region and tongue. Cats with lingual OSCC were younger (mean, 11.9 years) compared to cats with gingival OSCC (mean, 13.6 years). In addition to osteolysis, there was periosteal new bone formation, osseous metaplasia of tumor stroma, and direct apposition of OSCC to fragments of bone, suggestive of bone-binding behavior. Eighty-two cases were selected for immunohistochemical detection of parathyroid hormone-related protein (PTHrP). Specimens with osteolysis had increased PTHrP expression and nuclear localization, compared to OSCC without osteolysis. Thirty-eight biopsies of OSCC with osteolysis were evaluated for tumor necrosis factor α expression, and only 4 biopsies had such expression in a small proportion of tumor cells. Increased tumor expression of PTHrP and increased localization of PTHrP to the nucleus were associated with osteolysis and may play an important role in bone resorption and tumor invasion in cats with OSCC.