Melanoma angiogenesis and metastasis modulated by ribozyme targeting of the secreted growth factor pleiotrophin
Melanoma angiogenesis and metastasis modulated by ribozyme targeting of the secreted growth factor pleiotrophin
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DOI：
10.1073/pnas.93.25.14753
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发表时间：
1996-12-10
影响因子：
11.1
通讯作者：
Wellstein, A
中科院分区：
文献类型：
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作者：
Czubayko, F;Schulte, AM;Wellstein, A
临床和实验证据表明，恶性细胞从局部肿瘤（转移）的扩散与原发性肿瘤中微血管的数量直接相关。这种肿瘤血管生成被认为是由肿瘤细胞衍生的生长因子介导的。然而，大多数肿瘤细胞表达大量的候选血管生成因子，并且难以破译其中哪些是体内的限速因子。在此，我们使用核酶靶向多效生长因子（PTN）在转移性人黑色素瘤细胞，以评估这种分泌的生长因子的血管生成和转移的意义。作为模型，我们使用表达高水平PTN并从实验动物的皮下肿瘤转移到肺的人黑素瘤细胞（1205LU）。在这些黑色素瘤细胞中，我们通过转染PTN靶向核酶降低PTN mRNA和生长因子活性，并产生表达不同水平PTN的细胞系。我们发现PTN的减少并不影响体外黑色素瘤细胞的生长，然而，在裸鼠中，肿瘤生长和血管生成的减少与PTN水平的减少平行，肿瘤中的凋亡增加，同时，阻止了肿瘤从皮下部位向肺的转移扩散。这些研究支持肿瘤血管生成和转移之间的直接联系，通过分泌的生长因子，并确定PTN作为一个候选因素，可能是人类黑色素瘤转移的限速。
Clinical and experimental evidence suggests that spreading of malignant cells from a localized tumor (metastasis) is directly related to the number of microvessels in the primary tumor. This tumor angiogenesis is thought to be mediated by tumor-cell-derived growth factors. However, most tumor cells express a multitude of candidate angiogenesis factors and it is difficult to decipher which of these are rate-limiting factors in vivo. Herein we use ribozyme targeting of pleiotrophin (PTN) in metastatic human melanoma cells to assess the significance of this secreted growth factor for angiogenesis and metastasis. As a model we used human melanoma cells (1205LU) that express high levels of PTN and metastasize from subcutaneous tumors to the lungs of experimental animals. In these melanoma cells, we reduced PTN mRNA and growth factor activity by transfection with PTN-targeted ribozymes and generated cell lines expressing different levels of PTN. We found that the reduction of PTN does not affect growth of the melanoma cells in vitro, In nude mice, however, tumor growth and angiogenesis were decreased in parallel with the reduced PTN levels and apoptosis in the tumors was increased, Concomitantly, the metastatic spread of the tumors from the subcutaneous site to the lungs was prevented. These studies support a direct link between tumor angiogenesis and metastasis through a secreted growth factor and identify PTN as a candidate factor that may be rate-limiting for human melanoma metastasis.