Malignant soft-tissue sarcomas (STS) of adult onset are highly invasive tumors of mesenchymal origin that afflict ∼8,000 individuals each year in the US. Although this number represents only about 1% of adult malignancies, effective management of the disease is an extremely challenging task. Local recurrences appear at a median interval of 18 months for 60% of abdominal cases and about a third of patients with tumors of the extremities. Moreover, close to 50% of patients with primary soft tissue sarcoma die within 5 years due to the development of lung metastases. Our investigations have been directed towards gaining a better understanding of the molecular mechanisms involved in the progression of STS in order to develop specific targets for therapeutic intervention. Since well-characterized sets of tissue samples appropriate for conducting such comprehensive analyses are not readily available for this relatively infrequently occurring disease, we have developed a model system using sarcomas that spontaneously arise from chronic inflammatory reactions in domestic cats (a species whose genome bears a remarkable degree of syntenic conservation with that of humans). Our investigations indicate that these tumors resemble human fibrosarcomas in histopathology, invasiveness, and propensity for local post-surgical recurrence and distant metastasis. Similarities between the human disease and feline model also extend to p53 tumor suppressor gene alterations (which are associated with a poor prognosis in both species). In the feline model, deletion of one copy of the p53 gene is significantly associated with tumor recurrence and development of a more aggressive phenotype as measured by evaluation of H&E stained sections; immunohistochemical analyses with markers such as PCNA; colony formation and anchorage independent growth of cell lines in soft agar; in vitro measurements of drug resistance; cellular migration and invasion assays; as well as tumorigenicity and metastasis experiments in nude mice. The deletion in p53 also appears to occur in an allele specific manner. Ongoing comparative gene expression studies conducted on matched sets of cell lines from primary tumors with intact p53 and corresponding post-surgical recurrences with an allelic deletion at the locus provide indications on down-stream processes that may be associated with the cellular alterations that occur during disease progression. These leads are being validated using human sarcoma samples and may prove to be useful targets for therapeutic intervention. Overall, the feline model is proving to be clinically relevant and has great potential for enhancing our understanding of the role that wound healing and inflammation at surgical sites may play in development of recurrent tumors with more aggressive characteristics.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]