Shapiro R L, Duquette J G, Roses D F, Nunes I, Harris M N, Kamino H, Wilson E L, Rifkin D B
Department of Surgery, Division of Oncology, New York University Medical Center, New York 10016, USA.
Cancer Res. 1996 Aug 1;56(15):3597-604.
Evidence suggests that the plasminogen activators (PAs), in particular urokinase-type PA (uPA), play a pivotal role in tumor invasion and metastasis. We studied the contribution of the PAs to the malignant phenotype through the chemical induction of melanocytic neoplasms in uPA-deficient mice. Primary tumors were induced and promoted concurrently in 35 uPA-/- deficient and 35 uPA+/+ wild-type mice using a single application of 7,12-dimethylbenz(a)anthracene followed by repetitive applications of croton oil. Animals were sacrificed at 60-day intervals for 1 year. At necropsy, the four largest pigmented lesions in each animal were excised, characterized histologically, and evaluated microscopically for evidence of invasion. The regional lymph nodes, lungs, and solid abdominal visceral organs were sectioned and examined microscopically for evidence of metastatic disease. Cellular blue nevi were induced in 100% of uPA-/- and uPA+/+ promoted animals. Although a reduction in the radial and vertical progression of these lesions was noted in the uPA-deficient mice compared with the wild-type group, more than 95% of cellular blue nevi induced in both groups of animals invaded the underlying tissues. These lesions did not metastasize to the regional lymph nodes. Malignant melanoma arose in 5 of 35 (14.3%) of promoted wild-type mice. These tumors were locally aggressive, produced tissue-type PA, but were not metastatic to the regional nodes, lungs, or abdominal viscera. These results indicate that the invasive capability of melanocytic lesions may depend more on tissue-type PA than uPA activity. No melanomas were induced in the uPA-/- mice. The resistance of the uPA -/- strain to melanoma induction suggests that uPA contributes to malignant progression. We propose that the absence of uPA negatively affects tumorigenesis by decreasing the liberation and availability of growth factors such as basic fibroblast growth factor.
有证据表明，纤溶酶原激活剂（PAs），尤其是尿激酶型PA（uPA），在肿瘤侵袭和转移中起关键作用。我们通过化学诱导uPA基因缺陷小鼠的黑素细胞肿瘤，研究了PAs对恶性表型的影响。使用单次涂抹7,12-二甲基苯并(a)蒽，随后重复涂抹巴豆油，在35只uPA - / - 基因缺陷小鼠和35只uPA + / +野生型小鼠中同时诱导和促进原发性肿瘤形成。动物每隔60天处死一次，持续1年。尸检时，切除每只动物身上四个最大的色素沉着病变，进行组织学特征分析，并在显微镜下评估侵袭证据。对区域淋巴结、肺和实性腹部内脏器官进行切片，并在显微镜下检查是否有转移性疾病的证据。在100%的uPA - / - 和uPA + / +促进组动物中均诱导出细胞性蓝色痣。尽管与野生型组相比，uPA基因缺陷小鼠中这些病变的径向和垂直进展有所减少，但两组动物中诱导出的细胞性蓝色痣超过95%侵袭了下方组织。这些病变未转移至区域淋巴结。在35只促进组野生型小鼠中有5只（14.3%）发生了恶性黑色素瘤。这些肿瘤具有局部侵袭性，产生组织型PA，但未转移至区域淋巴结、肺或腹部内脏。这些结果表明，黑素细胞病变的侵袭能力可能更多地取决于组织型PA而非uPA活性。在uPA - / - 小鼠中未诱导出黑色素瘤。uPA - / - 品系对黑色素瘤诱导的抗性表明uPA有助于恶性进展。我们认为，uPA的缺失通过减少诸如碱性成纤维细胞生长因子等生长因子的释放和可用性，对肿瘤发生产生负面影响。
