Animal Models of Bone Metastasis

Abstract

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 rational use of animal models in the evaluation of novel bone regenerative therapies

“…The first determinant depends on the availability of an animal model that mimics a human disease involving bone repair so that the data generated can be used to predict the drug efficacy and safety in patients. Examples of animal models with good predictability of clinical outcomes include models of postmenopausal osteoporosis [87][88][89][90][91][92], models of glucocorticoid induced bone loss [93][94][95][96], models of cancer metastasis to bone [97], disuse models [98,99], fracture healing models [100][101][102][103] and several others. The second determinant of successful experimentation relates to translational biomarkers of novel therapy efficacy and safety that can be accurately predicted and monitored in patients.…”

MTA1 drives malignant progression and bone metastasis in prostate cancer

“…Therefore, to delineate the role of MTA1 in bone metastasis, we utilized the experimental bone metastasis model with injections of cells into the left cardiac ventricle of athymic mice (Chong Seow Khoon, 2015; Holzapfel et al ., 2014; Miftakhova et al ., 2016; Rosol et al ., 2004). Metastases were monitored by weekly bioluminescence imaging until day 34, when mice were sacrificed.…”

Sequence and partial functional analysis of canine Bcl-2 family proteins

“…Rodent models, including genetically modified mice and xenografts in immunocompromised mice, are indispensable tools for cancer research (Rosol et al, 2003;Kelland, 2004;Sharpless and Depinho, 2006). They have evolved in recent years to a vast array of sophisticated models that are continuously broadening and deepening our knowledge of cancer biology (Cheon and Orsulic, 2011;Ruggeri et al, 2014).…”

“…In addition, canines are genetically more closely related to humans than rodents as shown from whole genome comparisons of the three species (Lindblad-Toh et al, 2005), which is also reflected by a greater similarity at the metabolic level. Canines develop a range of spontaneous neoplasms often with histological characteristics and biologic behaviour similar to human tumors, including non-Hodgkin's lymphoma, soft-tissue sarcomas and osteosarcoma (Vail and MacEwen, 2000;Rosol et al, 2003;Khanna et al, 2004). Dogs share a common environment with people.…”