Taraboletti G, Belotti D, Giavazzi R, Sobel M E, Castronovo V
Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy.
J Natl Cancer Inst. 1993 Feb 3;85(3):235-40. doi: 10.1093/jnci/85.3.235.
Stable anchorage of circulating cancer cells to the vasculature is a critical step in the formation of hematogenous metastases. Although the basement membrane glycoprotein laminin clearly plays a crucial role in this event, the exact interactive pathways among cancer cells, laminin, and the vessel wall have not been elucidated. In a previous study, we identified synthetic peptide G, which contains the laminin-binding domain of the 67-kd laminin receptor and which inhibits tumor cell adhesion to endothelial cells.
To assess the role of the interaction between laminin and the 67-kd laminin receptor in hematogenous metastasis formation, we studied the effect of peptide G on melanoma cell behavior in vivo and in vitro.
The effect of peptide G and control peptides was studied in vivo on lung retention and colonizing potential of murine (B16BL6) and human (A2058) melanoma cells injected intravenously in C57BL/6 and nude mice, respectively. In addition, their effect on cell adhesion and chemotaxis to laminin and on binding of iodine 125-labeled laminin to cells was studied in vitro.
In vivo, pretreatment of cells with peptide G resulted in a two- to 10-fold significant increase in the number of experimental lung metastases. A significant relative increase in lung retention of peptide G-treated tumor cells was observed 48 hours after injection, although after 4 hours a partial reduction was observed. In vitro, peptide G significantly increased laminin binding and cancer cell adhesion to laminin and subendothelial matrix, whereas chemotaxis to laminin was significantly inhibited.
Peptide G differentially affected the biological response of cancer cells to laminin. In vitro, it increased laminin binding and cell adhesion to laminin and subendothelial matrix, whereas it inhibited cell chemotaxis to laminin. In vivo, the overall effect of peptide G was an augmentation of lung metastasis.
Our findings suggest that direct adhesion of tumor cells to the subendothelial matrix is a main pathway for hematogenous metastases and that tumor cell-matrix interaction may be more relevant than tumor cell-endothelial cell attachment in this process.
循环肿瘤细胞与脉管系统的稳定锚定是血行转移形成的关键步骤。尽管基底膜糖蛋白层粘连蛋白显然在此过程中发挥关键作用，但癌细胞、层粘连蛋白和血管壁之间确切的相互作用途径尚未阐明。在先前的一项研究中，我们鉴定出了合成肽G，它包含67-kd层粘连蛋白受体的层粘连蛋白结合结构域，并且能抑制肿瘤细胞与内皮细胞的黏附。
为了评估层粘连蛋白与67-kd层粘连蛋白受体之间的相互作用在血行转移形成中的作用，我们研究了肽G对体内外黑色素瘤细胞行为的影响。
分别在C57BL/6小鼠和裸鼠体内研究了肽G和对照肽对静脉注射的鼠源（B16BL6）和人源（A2058）黑色素瘤细胞的肺滞留和定植潜能的影响。此外，在体外研究了它们对细胞与层粘连蛋白的黏附及趋化作用以及对125碘标记的层粘连蛋白与细胞结合的影响。
在体内，用肽G预处理细胞导致实验性肺转移瘤数量显著增加2至10倍。注射后48小时观察到肽G处理的肿瘤细胞在肺中的滞留显著相对增加，尽管在4小时后观察到部分减少。在体外，肽G显著增加层粘连蛋白结合以及癌细胞与层粘连蛋白和内皮下基质的黏附，而对层粘连蛋白的趋化作用则受到显著抑制。
肽G对癌细胞对层粘连蛋白的生物学反应有不同影响。在体外，它增加层粘连蛋白结合以及细胞与层粘连蛋白和内皮下基质的黏附，而抑制细胞对层粘连蛋白的趋化作用。在体内，肽G的总体作用是增加肺转移。
我们的研究结果表明，肿瘤细胞与内皮下基质的直接黏附是血行转移的主要途径，并且在此过程中肿瘤细胞与基质的相互作用可能比肿瘤细胞与内皮细胞的附着更为重要。
