Ploplis V A, Tipton H, Menchen H, Castellino F J
WM Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN 46556, USA.
J Pathol. 2007 Nov;213(3):266-74. doi: 10.1002/path.2236.
The interaction of urokinase-type plasminogen activator (uPA) and its receptor, uPAR, on cell surfaces facilitates the generation of cell-bound plasmin, thus allowing cells to establish a proteolytic front that enables their migration through protein barriers. This complex also activates cell signalling pathways that influence cell functions. Clinical studies have identified uPA as an indicator of poor overall survival in patients with colorectal cancer. In the current study, a mouse model of colon cancer, Apc(Min/+), with an additional deficiency of uPA (Apc(Min/+)/Plau-/-) was used to determine the effects of uPA on tumour initiation and growth. Utilizing this model, it was found that the number of tumours was diminished in these mice relative to Apc(Min/+) mice, which correlated with the decreased leukocyte infiltration in the tumours. However, tumour growth was not impeded in Apc(Min/+)/Plau-/- mice, and proliferation and tumour vascularization were, in fact, enhanced in Apc(Min/+)/Plau-/- mice. These latter effects are consistent with a mechanism involving up-regulation of COX-2 expression and Akt pathway activation in Apc(Min/+)/Plau-/- mice. The results from this study suggest that uPA plays dual and opposing roles in regulating lesion development: one early, during the transition from normal epithelia to dysplastic lesions, and another later during tumour growth.
尿激酶型纤溶酶原激活剂（uPA）与其受体uPAR在细胞表面的相互作用促进了细胞结合型纤溶酶的生成，从而使细胞能够建立一个蛋白水解前沿，使其能够穿过蛋白质屏障进行迁移。这种复合物还激活影响细胞功能的细胞信号通路。临床研究已将uPA确定为结直肠癌患者总体生存率低的一个指标。在本研究中，利用一种结肠癌小鼠模型Apc(Min/+)，该模型额外缺乏uPA（Apc(Min/+)/Plau-/-）来确定uPA对肿瘤起始和生长的影响。利用该模型发现，相对于Apc(Min/+)小鼠，这些小鼠的肿瘤数量减少，这与肿瘤中白细胞浸润减少相关。然而，Apc(Min/+)/Plau-/-小鼠的肿瘤生长并未受到阻碍，事实上，Apc(Min/+)/Plau-/-小鼠的增殖和肿瘤血管生成增强。后一种效应与Apc(Min/+)/Plau-/-小鼠中COX-2表达上调和Akt途径激活的机制一致。本研究结果表明，uPA在调节病变发展中发挥双重且相反的作用：一个作用发生在早期，即从正常上皮向发育异常病变转变期间；另一个作用发生在后期，即肿瘤生长期间。
