Seftor R E, Seftor E A, Sheng S, Pemberton P A, Sager R, Hendrix M J
Department of Anatomy, The University of Iowa, College of Medicine, Iowa City 52242, USA.
Cancer Res. 1998 Dec 15;58(24):5681-5.
The recently discovered tumor suppressor gene maspin has been shown to inhibit tumor cell motility, invasion, and metastasis in breast cancer by our laboratories. Nonetheless, the exploitation of maspin as a potential diagnostic and/or therapeutic tool has remained limited due to the lack of knowledge concerning its molecular and biological mechanism(s) of action. The work reported here demonstrates that recombinant maspin (rMaspin) has the ability to induce higher cell surface levels of alpha5- and alpha3-containing integrins and reduced levels of alpha2-, alpha4-, alpha6-, alpha(v)-, and some beta1-containing integrins in the metastatic human breast carcinoma cell line MDA-MB-435 concomitant with its ability to inhibit the invasive process in vitro. Furthermore, treatment of MDA-MB-435 cells with rMaspin results in the selective adhesion of the cell to a fibronectin matrix and conversion from a fibroblastic to a more epithelial-like phenotype. In addition, the ability of rMaspin to inhibit the invasive process can be abrogated with a blocking antibody to the alpha5beta1 integrin, which diminishes the ability of the cells to invade through a fibronectin matrix-containing barrier in vitro. Taken together, these data address the hypothesis that rMaspin reduces the invasive phenotype of MDA-MB-435 cells by altering their integrin profile, particularly alpha5, which in turn converts these cells to a more benign epithelial phenotype, with less invasive ability. These data provide new insights into the biological significance of this tumor suppressor gene found in normal mammary epithelium and may form the basis of novel therapeutic strategies in the management of breast carcinoma.
我们实验室已证明，最近发现的肿瘤抑制基因maspin可抑制乳腺癌细胞的运动、侵袭和转移。然而，由于对其分子和生物学作用机制缺乏了解，maspin作为一种潜在诊断和/或治疗工具的应用仍然有限。本文报道的研究表明，重组maspin（rMaspin）能够在转移性人乳腺癌细胞系MDA-MB-435中诱导含α5和α3整合素的细胞表面水平升高，同时降低含α2、α4、α6、α(v)和某些含β1整合素的水平，这与其在体外抑制侵袭过程的能力相关。此外，用rMaspin处理MDA-MB-435细胞会导致细胞选择性黏附于纤连蛋白基质，并从成纤维细胞样表型转变为更上皮样表型。另外，rMaspin抑制侵袭过程的能力可被α5β1整合素的阻断抗体消除，该抗体可降低细胞在体外通过含纤连蛋白基质的屏障进行侵袭的能力。综上所述，这些数据支持了以下假说：rMaspin通过改变MDA-MB-435细胞的整合素谱，特别是α5，来降低其侵袭表型，进而将这些细胞转变为侵袭能力较弱的更良性上皮表型。这些数据为在正常乳腺上皮中发现的这种肿瘤抑制基因的生物学意义提供了新的见解，并可能成为乳腺癌治疗新策略的基础。
