Piero Picci, Marco Manfrini, Nicola Fabbri, Marco Gambarotti and Daniel Vanel (eds.)Atlas of Musculoskeletal Tumors and Tumorlike Lesions2014The Rizzoli Case Archive10.1007/978-3-319-01748-8_43
© Springer International Publishing Switzerland 2014
43. Biology of Osteosarcoma
(1)
Laboratory of Experimental Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy
Abstract
Unlike other sarcomas, osteosarcoma (OS) is characterized by complex, unbalanced karyotypes and alterations in multiple genes and pathways. This genetic background originates from the high genetic instability of OS cells, which can lead to multiple malignant cell populations within the same tumor (Hattinger et al. 2010; Atiye et al. 2005).
Unlike other sarcomas, osteosarcoma (OS) is characterized by complex, unbalanced karyotypes and alterations in multiple genes and pathways. This genetic background originates from the high genetic instability of OS cells, which can lead to multiple malignant cell populations within the same tumor (Hattinger et al. 2010; Atiye et al. 2005).
The pathways governed by the tumor suppressor genes P53 and retinoblastoma 1 (RB1) are those that have been most consistently found to be involved OS pathogenesis. In fact, the majority (around 80 %) of OS patients have alterations of one or both pathways (Hattinger et al. 2010). The P53 gene product plays a major role in the cell response to DNA damage and RB1 gene regulates cell cycle progression: alteration of pathways governed by these two genes may allow cells to proliferate and become malignant after the acquisition of additional genetic aberrations. This is the reason why children affected by the Li-Fraumeni syndrome (carrying germline deletion/mutations of P53) or familial retinoblastoma (carrying germline mutations of RB1) have a dramatically higher risk of developing OS.
The study of the natural history of OS has clearly shown that during development and progression tumor cells acquire several genetic changes, which may account for not only the aggressive behavior of this neoplasm but can also be responsible for the development of resistance to chemotherapeutic drugs (Hattinger et al. 2003, 2009). Taking these features into consideration, research on new drugs for novel treatment modalities of high-grade OS has been devoted to identify and validate agents against new candidate therapeutic targets, which have proved or appeared to be relevant for OS pathogenesis, treatment response, or clinical outcome. The current research goal of drug development for OS consists in the identification and validation of agents that can be administered as adjuvant to conventional chemotherapeutics to better control the local and metastatic disease, as well as to improve the efficacy of standard chemotherapy regimens without increasing their collateral adverse toxicity. These facts offer the hope for not only an increased survival probability but also for an improved quality of life of cured patients, which is particularly relevant for tumors mainly affecting young people like OS.
As a complement to these goals, the validation of predictive, prognostic markers for high-grade OS is highly needed in order to allow a patient stratification based on specific characteristics of each tumor and on a precise risk evaluation aimed to identify those subgroups of patients with the highest probability to benefit from each innovative treatment.
Several studies on high-grade OS have drawn attention to clinical parameters like age, tumor size, anatomical location, histological type, or tumor necrosis, but their association with clinical outcome significantly varied across different reports, often resulting contradictory or inconsistent (Hattinger et al. 2010).
An information that clearly emerged from clinical studies is that the major cause of failure of the current treatment protocols for high-grade OS is the natural or acquired drug resistance, which occurs in 35–45 % of patients. Therefore, the identification and validation of drug resistance-related markers as prognostic factors and potential new therapeutic targets are highly warranted. Although several evidences in this field have been reported in the past 10–15 years, a clear picture of molecular determinants of drug unresponsiveness in OS is still far to be completed (Hattinger et al. 2010).
Several studies have indicated that ABCB1 transporter (also named as MDR1 or P-glycoprotein) plays an important role in drug resistance and treatment response of high-grade OS patients. Therefore, targeting this molecule appears to be an interesting therapeutic option to improve treatment results in OS patients which are unresponsive to conventional regimens (Hattinger et al. 2010; Serra et al. 1995, 2003, 2006; Baldini et al. 1995; Scionti et al. 2008).
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