MEMBRANE PROTEASES AS POTENTIAL DIAGNOSTIC AND THERAPEUTIC TARGETS FOR BREAST MALIGNANCY
MEMBRANE PROTEASES AS POTENTIAL DIAGNOSTIC AND THERAPEUTIC TARGETS FOR BREAST MALIGNANCY
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DOI：
10.1007/bf00666155
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发表时间：
1994-01-01
影响因子：
3.8
通讯作者：
MUELLER, SC
中科院分区：
文献类型：
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作者：
CHEN, WT;LEE, CC;MUELLER, SC
转移的癌细胞可以利用质膜突起（称为侵入伪足）侵入细胞外基质，接触并溶解基质。位于侵袭足膜上的各种膜相关蛋白酶负责细胞外基质的降解。我们实验室的工作表明，分泌型蛋白酶（包括明胶酶 A）和高分子整合膜蛋白酶与细胞表面侵袭伪足有关。三种细胞类型，包括劳斯肉瘤病毒转化的鸡胚细胞、人恶性黑色素瘤细胞系LOX和人乳腺癌细胞系MDA-MB-231，在体外保留侵袭表型，表达侵袭伪足，降解并进入富含纤连蛋白的胶原基质。我们认为侵袭足相关蛋白酶是癌症诊断和治疗的理想靶点，因为它们与原发性肿瘤相关的存在可能预示着转移潜力的增加。开发乳腺恶性肿瘤新预后标记物的方法涉及生产针对糖蛋白混合物中的膜蛋白酶的单克隆抗体。使用已知的侵袭伪足标记物的双重免疫荧光技术旨在选择在癌细胞的侵袭伪足上共定位于侵袭前沿的特异性单克隆抗体。因此，通过开发阻断其活性的特异性抗体和抑制剂，以及使用单克隆抗体将细胞毒性分子靶向微转移，可以利用细胞表面的膜蛋白酶可及性来实现治疗进展。此外，这种相同的可访问性可能可用于检测微转移上的表面蛋白酶或检测血清中微转移脱落的成分。
Metastasizing cancer cells can invade the extracellular matrix using plasma membrane protrusions, termed invadopodia, that contact and dissolve the matrix. Various membrane associated proteases localized on the invadopodial membranes are responsible for the extracellular matrix degradation. Work from our laboratory shows that secreted proteases including Gelatinase A, and high molecular: weight integral membrane proteases are associated with cell surface invadopodia. Three cell types, including chicken embryonic cells transformed by Rous sarcoma virus, human malignant melanoma cell line LOX, and human breast carcinoma cell line MDA-MB-231, retain the invasive phenotype in vitro, express invadopodia, degrade and enter into a fibronectin-rich collagenous matrix. We suggest that invadopodium-associated proteases are ideal targets for the diagnosis and treatment of cancer as their presence in association with primary tumors may signal increased metastatic potential. An approach toward the development of new prognostic markers for breast malignancy involved production of monoclonal antibodies directed against membrane proteases in a mixture of glycoproteins. Double immunofluorescent technique using a known invadopodium marker is designed to select specific monoclonal antibodies colocalizing at the invasion front, on invadopodia of cancer cells. Membrane protease accessibility at the cell surface can therefore be exploited for therapeutic advances by the development of specific antibodies and inhibitors that block their activities, and by the use of monoclonal antibodies to target cytotoxic molecules to micrometastases. Also, this same accessibility may potentially be used to detect surface proteases on micrometastases or to detect components shed by micrometastases in serum.