Sehgal I, Baley P A, Thompson T C
Urology Research Laboratory, Veterans Affairs Medical Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Cancer Res. 1996 Jul 15;56(14):3359-65.
Tumor progression to the stage of metastasis may result in part from the selection of certain primary tumor cell clones which are phenotypically competent for survival, invasion, and growth at secondary sites. Selection for traits such as loss of growth inhibitory responses, acquisition of increased adhesiveness, increased local immunosuppression, and enhanced motility and collagenase activities likely contribute to cancer progression and may be regulated through the action of growth factors. The transforming growth factors (TGF-beta) family of growth factors has often been associated with these traits and tumor progression; therefore, elimination or subversion of TGF-beta-responsive pathways should be considered as a mechanistic framework for metastatic events. In this report, we have compared growth and extracellular matrix responses to TGF-beta in six metastatic and six primary tumor-derived cell lines in a mouse model of prostate cancer. We have found that tumor cell lines derived from focal pulmonary metastasis secreted relatively greater quantities of total TGF-betas, lost most or all TGF-beta1 growth inhibition, but responded to TGF-beta1 through induction of the type IV collagenase matrix metalloproteinase-9, whereas cell lines derived from tumors which proliferated at the primary site retained the growth inhibition but lacked collagenase activity. Synthesis of another extracellular matrix protein, plasminogen activator inhibitor 1, was stimulated by TGF-beta1 in both primary as well as metastatic tumors. These results suggest that acquisition of differential responses to the TGF-beta family could result in phenotypic traits which facilitate tumor metastasis from certain primary site clones.
肿瘤进展到转移阶段可能部分源于某些原发性肿瘤细胞克隆的选择，这些克隆在表型上具备在继发部位存活、侵袭和生长的能力。对生长抑制反应丧失、黏附性增加、局部免疫抑制增强以及运动性和胶原酶活性增强等特性的选择，可能有助于癌症进展，并且可能通过生长因子的作用受到调控。转化生长因子（TGF-β）家族的生长因子常常与这些特性及肿瘤进展相关联；因此，TGF-β反应通路的消除或颠覆应被视为转移事件的一个机制框架。在本报告中，我们在前列腺癌小鼠模型中比较了六种转移性和六种原发性肿瘤来源的细胞系对TGF-β的生长及细胞外基质反应。我们发现，源自局灶性肺转移的肿瘤细胞系分泌相对大量的总TGF-β，失去了大部分或全部TGF-β1生长抑制作用，但通过诱导IV型胶原酶基质金属蛋白酶-9对TGF-β1产生反应，而源自原发性部位增殖肿瘤的细胞系保留了生长抑制作用，但缺乏胶原酶活性。在原发性肿瘤和转移性肿瘤中，TGF-β1均刺激另一种细胞外基质蛋白纤溶酶原激活物抑制剂1的合成。这些结果表明，对TGF-β家族获得不同反应可能导致表型特性，从而促进某些原发性部位克隆的肿瘤转移。
