Moon S E, Dame M K, Remick D R, Elder J T, Varani J
Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Br J Cancer. 2001 Nov 16;85(10):1600-5. doi: 10.1054/bjoc.2001.2122.
Organ cultures of human skin were incubated for 8 days under growth factor-free conditions or exposed to 10 ng ml(-1) of human recombinant epidermal growth factor (EGF) during the incubation period. Normal histological features were preserved in the absence of growth factor, while epithelial cells underwent a proliferative response and invaded the underlying stroma in the presence of exogenous EGF. The same concentrations of EGF that induced stromal invasion also resulted in up-regulation of matrix metalloproteinase-9 (MMP-9; 92-kD gelatinase B) in organ culture and keratinocyte monolayer culture, and expression of MMP-1 (interstitial collagenase) in organ culture and fibroblast monolayer culture. When skin organ cultures were exposed to a potent, irreversible EGF-receptor tyrosine kinase (EGF-RTK) antagonist along with EGF, abnormal histological features were reversed, and MMP-9 production was suppressed. In contrast, EGF-RKT antagonism had only a modest inhibitory effect on MMP-1 production. Culture fluid from keratinocytes grown in monolayer culture stimulated fibroblast proliferation and MMP-1 elaboration. Treatment of fibroblasts with the same EGF-RTK antagonist inhibited keratinocyte-induced fibroblast proliferation but had only a modest inhibitory effect (approximately 20% inhibition) on MMP-1 production. In contrast, treatment of dermal fibroblasts with Interleukin-1 Receptor Antagonist had no effect on keratinocyte-induced fibroblast growth but strongly inhibited MMP-1 production (greater than 70% inhibition). These data indicate that stromal invasion by epithelial cells in EGF-treated skin is associated with events occurring in both the epidermis and dermis. The direct effect of the exogenous growth factor appears to be primarily on the epidermis. Dermal events reflect, at least in part, a response to factors elaborated in the epidermis.
将人皮肤器官培养物在无生长因子的条件下孵育8天，或在孵育期间暴露于10 ng/ml的人重组表皮生长因子（EGF）。在无生长因子的情况下，正常的组织学特征得以保留，而在外源性EGF存在时，上皮细胞发生增殖反应并侵入下方的基质。诱导基质侵袭的相同浓度的EGF也导致器官培养物和角质形成细胞单层培养物中基质金属蛋白酶-9（MMP-9；92-kD明胶酶B）的上调，以及器官培养物和成纤维细胞单层培养物中MMP-1（间质胶原酶）的表达。当皮肤器官培养物与EGF一起暴露于一种强效、不可逆的EGF受体酪氨酸激酶（EGF-RTK）拮抗剂时，异常的组织学特征得到逆转，并且MMP-9的产生受到抑制。相比之下，EGF-RKT拮抗作用对MMP-1的产生仅有适度的抑制作用。单层培养的角质形成细胞的培养液刺激成纤维细胞增殖和MMP-1的产生。用相同的EGF-RTK拮抗剂处理成纤维细胞可抑制角质形成细胞诱导的成纤维细胞增殖，但对MMP-1的产生仅有适度的抑制作用（约20%的抑制）。相比之下，用白细胞介素-1受体拮抗剂处理真皮成纤维细胞对角质形成细胞诱导的成纤维细胞生长没有影响，但强烈抑制MMP-1的产生（超过70%的抑制）。这些数据表明，EGF处理的皮肤中上皮细胞的基质侵袭与表皮和真皮中发生的事件相关。外源性生长因子的直接作用似乎主要在表皮。真皮事件至少部分反映了对表皮中产生的因子的反应。
