de Vries T J, Kitson J L, Silvers W K, Mintz B
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Cancer Res. 1995 Oct 15;55(20):4681-7.
The Tyr-SV40E transgenic mouse model of malignant skin melanoma has been used here to generate melanomas in genetically identical (C57BL/6) mice for analysis of the plasminogen activator (PA) system during tumor development and progression. Twenty-two melanocytic lesions were examined by in situ zymography for PA activity and by immunohistochemistry for concomitant visualization of PA proteins; these lesions encompassed 3 nevi and 19 primary melanomas ranging from melanotic through mixed tumors to amelanotic tumors. Although urokinase-type plasminogen activator (u-Pa) activity was not detected at premalignant stages, it began to appear early in tumorigenesis and became more prominent in later stages of a majority of the tumors. The activity was largely attributable to the endothelium of sprouting capillaries and to a lesser degree to granulocytes, fibroblastic cells, and occasional melanoma cells within tumors. Tissue-type plasminogen activator (t-PA) was undetectable or low in all cases. Of the inhibitors (PAI), PAI-1 was seen in endothelial and fibroblastic cells and in the extracellular matrix, whereas PAI-2 occurred in only one case and was melanoma cell associated. Eleven additional melanomas were analyzed by reverse transcription-PCR for PA expression in RNA extracts from relatively large tumor samples. These were obtained from eight primary melanomas and three metastases, again spanning melanotic, mixed, and amelanotic cases. From four of the mixed primary tumors with distinct melanotic and amelanotic zones, the respective components were propagated separately in transgenic hosts as s.c. transplants to obtain data for clearly identifiable melanotic versus amelanotic parts. u-PA and PAI-1 mRNAs were expressed in all. t-PA expression varied greatly and was notably high in several amelanotic tumors or tumor components, possibly as a result of large blood vessels, as such vessels were seen to be t-PA positive in normal tissue. The u-PA activity in sprouting capillaries may indicate a role in neoangiogenesis. Therefore, according to these mouse models, u-PA may indirectly be a potential therapeutic target against melanoma progression.
在此使用恶性皮肤黑色素瘤的Tyr-SV40E转基因小鼠模型，在基因相同的（C57BL/6）小鼠中生成黑色素瘤，以分析肿瘤发生和发展过程中的纤溶酶原激活剂（PA）系统。通过原位酶谱分析PA活性，并通过免疫组织化学同时观察PA蛋白，对22个黑素细胞病变进行了检查；这些病变包括3个痣和19个原发性黑色素瘤，范围从黑素瘤到混合瘤再到无黑素瘤。虽然在癌前阶段未检测到尿激酶型纤溶酶原激活剂（u-Pa）活性，但它在肿瘤发生早期开始出现，并在大多数肿瘤的后期变得更加明显。该活性主要归因于新生毛细血管的内皮细胞，在较小程度上归因于肿瘤内的粒细胞、成纤维细胞和偶尔的黑色素瘤细胞。组织型纤溶酶原激活剂（t-PA）在所有病例中均未检测到或含量较低。在抑制剂（PAI）中，PAI-1可见于内皮细胞和成纤维细胞以及细胞外基质中，而PAI-2仅在1例中出现，且与黑色素瘤细胞相关。通过逆转录-聚合酶链反应（RT-PCR）对另外11个黑色素瘤进行分析，以检测相对较大肿瘤样本的RNA提取物中的PA表达。这些样本来自8个原发性黑色素瘤和3个转移瘤，同样涵盖黑素瘤、混合瘤和无黑素瘤病例。从4个具有明显黑素瘤和无黑素瘤区域的混合原发性肿瘤中，将各自的成分作为皮下移植分别在转基因宿主中传代，以获取清晰可辨的黑素瘤与无黑素瘤部分的数据。所有样本均表达u-PA和PAI-1 mRNA。t-PA表达差异很大，在几个无黑素瘤肿瘤或肿瘤成分中明显较高，可能是由于大血管所致，因为在正常组织中可见此类血管为t-PA阳性。新生毛细血管中的u-PA活性可能表明其在新生血管形成中起作用。因此，根据这些小鼠模型，u-PA可能间接成为对抗黑色素瘤进展的潜在治疗靶点。
