Children's Cancer Hospital, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
J Aerosol Med Pulm Drug Deliv. 2010 Aug;23(4):189-96. doi: 10.1089/jamp.2009.0812.
Lung metastases are the main cause of death in patients with osteosarcoma (OS). Salvage chemotherapy has been largely unsuccessful in improving the long-term survival of these patients. Understanding the mechanisms that play a role in the metastatic process may identify new therapeutic strategies. We have demonstrated that the cell surface Fas expression, the Fas/FasL signaling pathway, and the constitutive expression of FasL in the lung microenvironment play a critical role in the metastatic potential of OS cells. Here we review the status of Fas expression in two sets of OS cells, human SAOS and LM7 and murine K7 and K7M2, which differ in their ability to metastasize to the lungs. We demonstrated that Fas expression inversely correlated with metastatic potential. Evaluation of Fas expression in a set of lung metastases from patients demonstrated low or no Fas expression consistent with our hypothesis that Fas+ osteosarcoma cells cannot form metastases. The absence of FasL in the lung allows Fas+ osteosarcoma cells to form metastases indicating that the microenvironment is an important contributor to the metastatic potential of osteosarcoma cells. Disruption of the signal transduction pathway using Fas-associated death domain dominant negative (FDN) also allowed Fas+ cells to form lung metastases. Aerosol Gemcitabine (GCB) upregulated Fas expression and induced tumor regression in wild-type Balb/c mice but not Fas L-deficient mice. In conclusion, Fas constitutes an early defense mechanism that allows Fas+ tumor cells to undergo apoptosis when in contact with constitutive FasL in the lung. Fas- cells or cells with a corrupted Fas pathway evade this defense mechanism and form lung metastases. The aerosol delivery of chemotherapeutic agents that upregulate Fas expression may benefit patients with established pulmonary metastases.
肺转移是骨肉瘤（OS）患者死亡的主要原因。挽救性化疗在提高这些患者的长期生存率方面基本上没有成功。了解在转移过程中起作用的机制可能会确定新的治疗策略。我们已经证明，细胞表面 Fas 表达、Fas/FasL 信号通路以及肺微环境中 FasL 的组成型表达在 OS 细胞的转移潜能中起着关键作用。在这里，我们回顾了两组 OS 细胞（人 SAOS 和 LM7 以及鼠 K7 和 K7M2）中 Fas 表达的状况，它们在向肺部转移的能力上有所不同。我们证明 Fas 表达与转移潜能呈负相关。对一组来自患者的肺转移的 Fas 表达评估表明，Fas 表达低或无，这与我们的假设一致，即 Fas+骨肉瘤细胞不能形成转移。FasL 在肺部的缺失允许 Fas+骨肉瘤细胞形成转移，表明微环境是骨肉瘤细胞转移潜能的重要贡献者。使用 Fas 相关死亡结构域显性负（FDN）破坏信号转导通路也允许 Fas+细胞形成肺转移。气溶胶吉西他滨（GCB）上调 Fas 表达并诱导野生型 Balb/c 小鼠中的肿瘤消退，但在 FasL 缺陷型小鼠中则没有。总之，Fas 构成了一种早期防御机制，当 Fas+肿瘤细胞与肺中的组成型 FasL 接触时，允许其发生凋亡。Fas-细胞或具有受损 Fas 途径的细胞逃避这种防御机制并形成肺转移。气溶胶输送可上调 Fas 表达的化疗药物可能使已建立肺转移的患者受益。
