Monocyte Phenotypic and Functional Differences

Overview

The purpose of this study is to identify phenotypic (cell surface receptor expression) and functional differences in monocyte populations in humans with osteosarcoma as compared to published historical data on normal human monocyte values. The biologic similarity between canine and human osteosarcoma makes it a disease model that holds promise for translational research possibilities. The phenotypic and functional differences the investigators expect to find in canine and human monocytes between normal and osteosarcoma subjects in this pilot work will allow us to launch a program of investigations to further their understanding as to what characteristics are associated with improved survival in canine and human osteosarcoma. Such data will represent the foundation upon which the investigators can plan future investigations designed to exploit the potential anti-tumor capabilities of monocytes and macrophages in canine and human osteosarcoma.

Research on canine osteosarcoma lends itself well to comparative studies of osteosarcoma in humans because dogs develop spontaneous tumors which are similar to human cancers with the added benefit of frequently being more prevalent1. Osteosarcoma is diagnosed in more than 8000 dogs every year, and it affects mostly middle-aged to older dogs.2 The majority (75%) of canine osteosarcoma occurs in the appendicular skeleton.3 Osteosarcoma is diagnosed in 1-3 million humans every year, and is a disease primarily of those between 10 and 25 years old. Human osteosarcoma also occurs primarily in the appendicular skeleton, and like dogs, is most often found in the metaphyses of long bones. Pulmonary metastasis is the most common site of spread in dogs and humans, and is usually the cause of death in patients that have undergone standard of care therapy (surgical resection of tumor, chemotherapy).4 The reported median survival times for canine osteosarcoma have plateaued with no notable improvements in the last 20 years, despite attempts at various permutations of adjunctive chemotherapy.5,6,7 Targeting metastatic disease will be the key to improving survival in both canine and human osteosarcoma. Interestingly, there is one arena in which median survival times in osteosarcoma have been extended - patients who develop infections after limb-spare surgery have been observed to double their median survival time. Lascelles et al. noted that infected dogs were half as likely to die, half as likely to develop metastasis, and these survival effects were due to a delay in metastasis rather than control of local tumor recurrence.8 A similar phenomenon of increased survival in infected human osteosarcoma patients has been observed. Jeys et al.reported that the 10-year survival rate in humans was significantly better in infected limb-spares: 84.5% in the infected patients versus 62.2% in the non-infected patients.9 An upregulation of antitumor immunity has been postulated to be potentially responsible for the favorable survivals in the face of an infection in dogs and humans. Characterization of the phenotype and function of circulating canine and human monocytes in normal subjects, and in osteosarcoma subjects with and without an infection will be crucial in furthering their understanding of how these cells are involved in the pathogenesis and potential suppression of osteosarcoma.