Mazzone Massimiliano, Basilico Cristina, Cavassa Silvia, Pennacchietti Selma, Risio Mauro, Naldini Luigi, Comoglio Paolo M, Michieli Paolo
Division of Molecular Oncology, Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo, Italy.
J Clin Invest. 2004 Nov;114(10):1418-32. doi: 10.1172/JCI22235.
Scatter factor (SF), also known as hepatocyte growth factor, is ubiquitously present in the extracellular matrix of tissues in the form of an inactive precursor (pro-SF). In order to acquire biological activity, pro-SF must be cleaved by specific proteases present on the cell surface. The mature form of SF controls invasive cues in both physiological and pathological processes through activation of its receptor, the Met tyrosine kinase. By substituting a single amino acid in the proteolytic site, we engineered an unprocessable form of pro-SF (uncleavable SF). Using lentivirus vector technology, we achieved local or systemic delivery of uncleavable SF in mice. We provide evidence that (a) uncleavable SF inhibits both protease-mediated pro-SF conversion and active SF-induced Met activation; (b) local expression of uncleavable SF in tumors suppresses tumor growth, impairs tumor angiogenesis, and prevents metastatic dissemination; and (c) systemic expression of uncleavable SF dramatically inhibits the growth of transplanted tumors and abolishes the formation of spontaneous metastases without perturbing vital physiological functions. These data show that proteolytic activation of pro-SF is a limiting step in tumor progression, thus suggesting a new strategy for the treatment or prevention of the malignant conversion of neoplastic lesions.
散射因子（SF），也被称为肝细胞生长因子，以无活性前体（前SF）的形式普遍存在于组织的细胞外基质中。为了获得生物活性，前SF必须被细胞表面存在的特定蛋白酶切割。成熟形式的SF通过激活其受体Met酪氨酸激酶，在生理和病理过程中控制侵袭信号。通过在蛋白水解位点替换单个氨基酸，我们构建了一种不可加工的前SF形式（不可切割SF）。利用慢病毒载体技术，我们在小鼠体内实现了不可切割SF的局部或全身递送。我们提供的证据表明：（a）不可切割SF抑制蛋白酶介导的前SF转化以及活性SF诱导的Met激活；（b）肿瘤中不可切割SF的局部表达抑制肿瘤生长、损害肿瘤血管生成并防止转移扩散；（c）不可切割SF的全身表达显著抑制移植肿瘤的生长并消除自发转移灶的形成，同时不干扰重要的生理功能。这些数据表明，前SF的蛋白水解激活是肿瘤进展中的一个限制步骤，从而提示了一种治疗或预防肿瘤性病变恶性转化的新策略。
