Genetic alterations in chondrosarcomas -keys to targeted therapies?

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• 作者：Andre M. Samuel (1)
  Jose Costa (2)
  Dieter M. Lindskog (3)
  
• 关键词：Chondrosarcoma ; Tumorigenesis ; Indian hedgehog ; Parathyroid hormone ; related protein ; Isocitrate dehydrogenase
• 刊名：Cellular Oncology
• 出版年：2014
• 出版时间：April 2014
• 年：2014
• 卷：37
• 期：2
• 页码：95-105
• 全文大小：370 KB
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• 作者单位：Andre M. Samuel (1)
  Jose Costa (2)
  Dieter M. Lindskog (3)
  
  1. Yale School of Medicine, 333 Cedar St, New Haven, CT, 06510, USA
  2. Department of Pathology, Yale School of Medicine, 310 Cedar Street LH 108, PO Box 208023, New Haven, CT, 06520-8023, USA
  3. Department of Orthop?dics and Rehabilitation, Yale School of Medicine, Yale Physicians Building, 800 Howard Avenue, P.O. Box 208071, New Haven, CT, 06520-8071, USA
  
• ISSN：2211-3436

文摘

Background Chondrosarcomas are malignant tumors of chondrocytes and represent the second most common type of primary bone tumors. Within the context of normal chondrogenesis, this review summarizes results from recent research outlining the key molecular changes that occur during the development of this sarcoma type. Results Current data support the notion that a two-hit scenario, common to many tumors, also underlies chondrosarcoma formation. First, early-stage mutations alter the normal proliferation and differentiation of chondrocytes, thereby predisposing them to malignant transformation. These early-stage mutations, found in both benign cartilaginous lesions and chondrosarcomas, include alterations affecting the IHH/PTHrP and IDH1/IDH2 pathways. As they are not observed in malignant cells, mutations in the EXT1 and EXT2 genes are considered early-stage events providing an environment that alters IHH/PTHrP signaling, thereby inducing mutations in adjacent cells. Due to normal cell cycle control that remains active, a low rate of malignant transformation is seen in benign cartilaginous lesions with early-stage mutations. In contrast, late-stage mutations, seen in most malignant chondrosarcomas, appear to induce malignant transformation as they are not found in benign cartilaginous lesions. These late-stage mutations primarily involve cell cycle pathway regulators including p53 and pRB, two genes that are also known to be implicated in numerous other human tumor types. Conclusions Now the key genetic alterations involved in both early and late stages of chondrosarcoma development have been identified, focus should be shifted to the identification of druggable molecular targets for the design of novel chondrosarcoma-specific therapies.