Maier G D, Vellody K, Meisinger J, Djordjevic A, Lozano Y, Young M R
Department of Pathology, Loyola University Stritch School of Medicine, Maywood, IL, USA.
Clin Exp Metastasis. 1996 May;14(3):314-22. doi: 10.1007/BF00053905.
Tumor cell adhesion to and migration through the extracellular matrix (ECM) can influence their capacity to disseminate. Since prior studies with Lewis lung carcinoma (LLC) tumors had shown metastatic clones to have more protein kinase A (PKA) activity than nonmetastatic clones, the present study assessed if PKA regulates the interaction between tumor and the ECM, and how this may be associated with the metastatic capacity of the tumor cells. This was accomplished with the use of metastatic (LLC-LN7) and nonmetastatic (LLC-C8) variants that had been stably transfected to overexpress the PKA Calpha subunit or to have blocked PKA activity. Cells with increased PKA activity were less adherent to vitronectin, laminin, and collagen I, and could more readily migrate through these ECM components than could transfectants with reduced PKA activity. PKA did not regulate adhesion to or migration through fibronectin, and did not appear to be associated with changes in expression of surface integrins. In addition to modulating tumor adhesion and migration in vitro, PKA activation caused an increased formation of metastases from s.c. tumors, but did not regulate formation of experimental metastases by i.v. injected tumor cells. These results suggest that PKA signaling is important for modulating the tumor-ECM interaction and can facilitate tumor transit from the primary tumor site.
肿瘤细胞与细胞外基质（ECM）的黏附及通过ECM的迁移会影响其扩散能力。由于先前对Lewis肺癌（LLC）肿瘤的研究表明，转移克隆比非转移克隆具有更高的蛋白激酶A（PKA）活性，因此本研究评估了PKA是否调节肿瘤与ECM之间的相互作用，以及这可能如何与肿瘤细胞的转移能力相关联。这是通过使用已稳定转染以过表达PKAα亚基或阻断PKA活性的转移（LLC-LN7）和非转移（LLC-C8）变体来实现的。与PKA活性降低的转染细胞相比，PKA活性增加的细胞对玻连蛋白、层粘连蛋白和I型胶原的黏附性更低，并且能够更轻易地穿过这些ECM成分。PKA不调节对纤连蛋白的黏附或通过纤连蛋白的迁移，并且似乎与表面整合素表达的变化无关。除了在体外调节肿瘤黏附和迁移外，PKA激活还导致皮下肿瘤转移灶形成增加，但不调节静脉注射肿瘤细胞的实验性转移形成。这些结果表明，PKA信号传导对于调节肿瘤-ECM相互作用很重要，并且可以促进肿瘤从原发肿瘤部位的转移。
