CD26/dipeptidyl peptidase IV in context. The different roles of a multifunctional ectoenzyme in malignant transformation.
CD26/dipeptidyl peptidase IV in context. The different roles of a multifunctional ectoenzyme in malignant transformation.
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DOI：
10.1084/jem.190.3.301
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发表时间：
1999-08-02
期刊：
影响因子：
--
通讯作者：
Morimoto C
中科院分区：
文献类型：
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作者：
Iwata S;Morimoto C
CD 26是T细胞活化分子，是一种110 kD的糖蛋白，也存在于各种组织的上皮细胞上，包括肝、肾和肠。CD 26在其细胞外结构域中具有已知的二肽基肽酶（DPP）IV活性（1）。Wesley等人在本期发表的一篇论文指出，CD 26/DPPIV在抑制黑素细胞向黑色素瘤的恶性转化中可能发挥作用（2）。霍顿及其同事的一系列工作集中在黑色素瘤和黑色素细胞上，表明在黑色素细胞恶性转化为黑色素瘤的过程中，CD 26/DPPIV的表达及其酶活性丧失（3）。然而，其消失的确切病理作用尚不清楚。Wesley等人现在优雅地证明了将CD 26的诱导型基因转导到黑色素瘤细胞中将细胞的恶性表型逆转为“良性”黑色素细胞样表型，其特征在于致瘤性的丧失、锚定依赖性生长的再现、分化阻滞的恢复和血清依赖性。他们进一步表明，缺乏丝氨酸蛋白酶活性的突变体DPPIV也能够恢复黑素瘤细胞中的血清依赖性。最后，另一个丝氨酸蛋白酶，成纤维细胞活化蛋白-，招聘可能部分占这种逆转突变DPPIV。CD 26/DPPIV在黑素细胞和黑色素瘤中的生物学行为的机制是什么？作者提出了CD 26/DPPIV可能降解自分泌生长因子的可能性，这些自分泌生长因子尚未鉴定，因此调节（抑制）良性黑素细胞的生长。这些发现是相当令人印象深刻的，因为它们提供了直接的证据，即CD 26/DPPIV表面表达的丧失在黑素细胞向黑色素瘤的恶性转化中起着关键作用。除了CD 26/DPPIV，该丝氨酸蛋白酶家族还包括一组膜相关酶（外肽酶），包括CD 10/NEP、CD 13/APN和BP-1/6C 3/阿帕，它们是锌金属肽酶（4）。与黑色素瘤中CD 26/DPPIV的缺失类似，在雄激素依赖型前列腺癌发展为雄激素非依赖型前列腺癌的过程中，CD 10/NEP的细胞表面表达缺失（5）。事实上，Shipp et al. (6)证明了CD 10/NEP通过切割蛙皮素样肽抑制肺小细胞癌（SCC）的生长，蛙皮素样肽是这些细胞的自分泌生长因子。他们进一步表明，SCC细胞中CD 10/NEP的表达水平降低，SCC的生长受到CD 10/NEP的抑制，并通过CD 10/NEP抑制而增强。与CD 26的表达和黑素细胞的恶性转化之间的负相关性形成鲜明对比的是，Carbone等报道了T细胞淋巴瘤中疾病侵袭性和CD 26的表达之间的直接相关性。（七）、他们还表明，CD 26和CD 40 L的表达是相互排斥的，CD 40 L在缓慢进展的疾病中表达（7）。根据这些发现，最近在T细胞急性淋巴细胞白血病的病例中报道了肿瘤细胞表面上的CD 26/DPPIV的上调。肿瘤淋巴细胞表面CD 13/APN的表达与B细胞慢性淋巴细胞白血病的临床分期、骨髓浸润呈弥漫性等临床预后不良因素有关。除了恶性血液病，上调...
CD26, the T cell activation molecule, is a 110-kD gly-coprotein that is also present on epithelial cells of various tissues, including the liver, kidney, and intestine. CD26 possesses a known dipeptidyl peptidase (DPP) IV activity in its extracellular domain (1). A paper by Wesley et al. in this issue indicates a possible role for CD26/DPPIV in suppressing malignant transformation of melanocytes to melanoma (2). The series of work by Houghton and colleagues, focusing on melanoma and melanocytes, has shown that loss of expression and its enzymatic activity of CD26/DPPIV occurs during malignant transformation of melanocytes into melanoma (3). The exact pathological role of its disappearance however, has been unclear. Wesley et al. now elegantly demonstrate that the inducible gene transduction of CD26 into melanoma cells reverses the malignant phenotype of the cells toward “benign” melanocyte-like phenotype, characterized by loss of tumorigenicity, reappearance of anchorage-dependent growth, restoration of a block in differentiation, and serum dependence. They further show that mutant DPPIV lacking serine protease activity is also able to restore the serum dependence in melanoma cells. Finally, the recruitment of another serine protease, fibroblast activation protein-, may partly account for this reversal by mutant DPPIV. What is the mechanism of such biological behavior of CD26/DPPIV in melanocytes and melanoma? The authors suggest the possibility that CD26/DPPIV might degrade autocrine growth factors, which are yet unidentified and hence regulate (suppress) the growth of benign melanocytes. These findings are quite impressive, as they present direct evidence that the loss of surface expression of CD26/DPPIV plays a pivotal role in malignant transformation of melanocytes toward melanoma. Besides CD26/DPPIV, this serine protease family also consists of a group of membrane-associated enzymes (ectopeptidases) including CD10/NEP, CD13/APN, and BP-1/6C3/APA, which are zinc metallopeptidases (4). The expression of these ectopeptidases, including CD26/DPPIV, and their roles in various malignancies are under intense investigation.Analogous to the loss of CD26/DPPIV in melanoma, the cell surface expression of CD10/NEP is lost during the development of androgen-independent prostate cancer from its androgen-dependent phenotype (5). Indeed, Shipp et al.(6) demonstrated that CD10/NEP inhibits the growth of small cell carcinoma (SCC) of the lung through the cleavage of bombesin-like peptides, which are autocrine growth factors for those cells. They further showed that expression levels of CD10/NEP in the SCC cells were reduced and that the growth of SCC was inhibited by CD10/NEP and potentiated by CD10/NEP inhibition. In marked contrast to the inverse correlation between the expression of CD26 and malignant transformation of melanocytes, a direct correlation between disease aggressiveness and the expression of CD26 in T cell lymphomas has been reported by Carbone et al.(7). They also showed that the expression of CD26 and CD40L was mutually exclusive, with CD40L being expressed on slowly progressing diseases (7). In accordance with these findings, upregulation of CD26/DPPIV on the surfaces of tumor cells has been recently reported in cases of T cell acute lymphoblastic leukemia. The presence of CD13/APN on neoplastic lymphocytes showed a significant association with such unfavorable clinicoprognostic factors in B cell chronic lymphocytic leukemia as advanced clinical stage and the diffuse pattern of bone marrow infiltration. Besides hematologic malignancies, the upregulation of …