Cantiani Lara, Manara Maria Cristina, Zucchini Cinzia, De Sanctis Paola, Zuntini Monia, Valvassori Luisa, Serra Massimo, Olivero Martina, Di Renzo Maria Flavia, Colombo Mario Paolo, Picci Piero, Scotlandi Katia
Laboratory of Oncology Research, Rizzoli Orthopaedic Institute, Italy.
Cancer Res. 2007 Aug 15;67(16):7675-85. doi: 10.1158/0008-5472.CAN-06-4697.
Caveolin-1 (Cav-1) is highly expressed in normal osteoblasts. This article reports that Cav-1 down-regulation is part of osteoblast transformation and osteosarcoma progression and validates its role as oncosuppressor in human osteosarcoma. A survey of 6-year follow-up indicates a better overall survival for osteosarcoma expressing a level of Cav-1 similar to osteoblasts. However, the majority of primary osteosarcoma shows significantly lower levels of Cav-1 than normal osteoblasts. Accordingly, Met-induced osteoblast transformation is associated with Cav-1 down-regulation. In vitro, osteosarcoma cell lines forced to overexpress Cav-1 show reduced malignancy with inhibited anchorage-independent growth, migration, and invasion. In vivo, Cav-1 overexpression abrogates the metastatic ability of osteosarcoma cells. c-Src and c-Met tyrosine kinases, which are activated in osteosarcoma, colocalize with Cav-1 and are inhibited on Cav-1 overexpression. Thus, Cav-1 behaves as an oncosuppressor in osteosarcoma. Altogether, data suggest that Cav-1 down-modulation might function as a permissive mechanism, which, by unleashing c-Src and Met signaling, enables osteosarcoma cells to invade neighboring tissues. These data strengthen the rationale to target c-Src family kinases and/or Met receptor to improve the extremely poor prognosis of metastatic osteosarcoma.
小窝蛋白-1（Cav-1）在正常成骨细胞中高表达。本文报道Cav-1的下调是成骨细胞转化和骨肉瘤进展的一部分，并验证了其在人类骨肉瘤中作为肿瘤抑制因子的作用。一项6年随访调查表明，表达与成骨细胞相似水平Cav-1的骨肉瘤患者总体生存率更高。然而，大多数原发性骨肉瘤中Cav-1的水平明显低于正常成骨细胞。因此，Met诱导的成骨细胞转化与Cav-1下调有关。在体外，被迫过表达Cav-1的骨肉瘤细胞系显示出恶性程度降低，其非锚定依赖性生长、迁移和侵袭受到抑制。在体内，Cav-1过表达消除了骨肉瘤细胞的转移能力。在骨肉瘤中被激活的c-Src和c-Met酪氨酸激酶与Cav-1共定位，且在Cav-1过表达时受到抑制。因此，Cav-1在骨肉瘤中表现为肿瘤抑制因子。总之，数据表明Cav-1下调可能作为一种许可机制，通过释放c-Src和Met信号，使骨肉瘤细胞能够侵袭邻近组织。这些数据强化了靶向c-Src家族激酶和/或Met受体以改善转移性骨肉瘤极差预后的理论依据。
