Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression
Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression
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DOI：
10.1158/0008-5472.can-03-3126
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发表时间：
2004-03-01
期刊：
影响因子：
11.2
通讯作者：
Kalluri, R
中科院分区：
文献类型：
--
作者：
Hamano, Y;Sugimoto, H;Kalluri, R
低剂量环磷酰胺（LDC）诱导肿瘤血管床内内皮细胞选择性凋亡。在这里，我们研究了一个假设，即LDC的影响是由内源性血管生成抑制剂的促凋亡作用介导的。与野生型肿瘤相比，用LDC治疗的肿瘤表现出类似的基质金属蛋白酶表达，也表现出基底膜衍生的血管生成抑制剂，而血小板反应蛋白-1（TSP-1）的表达在LDC治疗的肿瘤中显著升高。我们使用缺乏XVIII型胶原（内皮抑制素）或IV型胶原α 3链（tumstatin）或TSP-1的小鼠来评估这些内源性血管生成抑制剂对LDC介导的肿瘤抑制的贡献。除了肿瘤细胞外，宿主中缺乏TSP-1导致LDC抑制肿瘤生长的能力降低，而内皮抑制素和肿瘤抑制素的缺乏并不改变LDC的作用。LDC治疗主要诱导肿瘤细胞和血管周围细胞中TSP-1的选择性表达，并促进增殖内皮细胞的凋亡，对肿瘤细胞和血管周围细胞的直接影响最小。这些研究表明，TSP-1有助于由LDC诱导的肿瘤生长抑制，并表明表达高基础水平TSP-1的肿瘤可能更容易受到这种方案的肿瘤抑制。这项研究还为TSP-1表达水平作为癌症患者成功使用LDC的潜在预测标志物提供了有力的证据。
Low-dose cyclophosphamide (LDC) induces selective apoptosis of endothelial cells within the vascular bed of tumors. Here, we investigated a hypothesis that the effect of LDC is mediated by the pro-apoptotic action of endogenous inhibitors of angiogenesis. Tumors treated with LDC demonstrate similar expression of matrix metalloproteinases and also basement membrane-derived angiogenesis inhibitors when compared with wild-type tumors, whereas the expression of thrombospondin-1 (TSP-1) is significantly elevated in LDC-treated tumors. We used mice with an absence of type XVIII collagen (endostatin) or type IV collagen alpha3 chain (tumstatin) or TSP-1 to assess the contribution of these endogenous inhibitors of angiogenesis on LDC-mediated tumor suppression. Lack of TSP-1 in the host in addition to tumor cells leads to diminished capacity of LDC to suppress tumor growth, whereas the absence of endostatin and tumstatin did not alter the effect of LDC. LDC treatment predominantly induces selective expression of TSP-1 in tumor cells and peri-vascular cells and facilitates apoptosis of proliferating endothelial cells, with minimal direct effect on tumor cells and peri-vascular cells. These studies indicate that TSP-1 contributes to tumor growth suppression induced by LDC and suggest that tumors that express high basal level of TSP-1 may be more susceptible to tumor suppression by such a regimen. This study also makes a strong case for TSP-1 expression levels as a potential predictive marker for the successful use of LDC in cancer patients.