Willett C G, Wang M H, Emanuel R L, Graham S A, Smith D I, Shridhar V, Sugarbaker D J, Sunday M E
Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Am J Respir Cell Mol Biol. 1998 Apr;18(4):489-96. doi: 10.1165/ajrcmb.18.4.2978.
Previously, we identified macrophage-stimulating protein (MSP) as being expressed during hamster lung injury induced by nitrosamine carcinogens. Transient, generalized epithelial-cell hyperplasia during the preneoplastic period, and eventually nonneuroendocrine (non-NE) lung tumors, are known to develop in these nitrosamine-treated hamsters. We wished to test the hypothesis that MSP and its tyrosine kinase receptor, RON, might represent an autocrine/paracrine system involved in the pathogenesis of human nonneuroendocrine lung tumors, the non-small-cell carcinomas (NSCLCs). We found that this occurred in a paracrine fashion in three of eight primary human NSCLCs that expressed messenger RNA (mRNA) for MSP at high levels in histologically normal lung adjacent to the tumor, but not in the primary tumor, together with mRNA for RON in both normal and tumor tissue. MSP and RON could also constitute an autocrine/paracrine system in human NSCLC cell lines: five of 16 cell lines (squamous and adenosquamous) expressed both MSP and RON; and an additional five of 16 cell lines expressed RON without detectable MSP. Although three cases of primary squamous-cell carcinomas expressed MSP (two of three in the tumor and one of three in nonneoplastic lung), mRNA for RON was not detectable in these cases. RON was functional in all tested RON mRNA-positive cell lines, with exogenous MSP inducing RON-mediated tyrosine phosphorylation. Treatment of a RON-positive adenosquamous carcinoma cell line with MSP additionally resulted in increased motility in a cell-migration assay, suggesting that MSP might promote cell migration of some NSCLCs. In conclusion, MSP and RON might represent an autocrine/paracrine system involved in the pathogenesis of lung cancer, although the nature of the biologic responses in different cell types might vary considerably.
此前，我们发现巨噬细胞刺激蛋白（MSP）在亚硝胺致癌物诱导的仓鼠肺损伤过程中表达。已知在这些经亚硝胺处理的仓鼠中，癌前期会出现短暂的全身性上皮细胞增生，最终发展为非神经内分泌（non-NE）性肺肿瘤。我们希望验证这样一个假说，即MSP及其酪氨酸激酶受体RON可能代表一种自分泌/旁分泌系统，参与人类非神经内分泌性肺肿瘤即非小细胞肺癌（NSCLC）的发病机制。我们发现，在8例原发性人类NSCLC中，有3例以旁分泌方式发生这种情况，在肿瘤旁组织学正常的肺组织中，这3例高水平表达MSP信使核糖核酸（mRNA），但在原发性肿瘤中不表达，同时正常组织和肿瘤组织中均有RON的mRNA。MSP和RON在人类NSCLC细胞系中也可能构成自分泌/旁分泌系统：16个细胞系（鳞状和腺鳞癌）中有5个同时表达MSP和RON；另外16个细胞系中有5个表达RON但未检测到MSP。尽管3例原发性鳞状细胞癌表达MSP（3例中有2例在肿瘤中表达，3例中有1例在非肿瘤性肺组织中表达），但在这些病例中未检测到RON的mRNA。RON在所有检测的RON mRNA阳性细胞系中均有功能，外源性MSP可诱导RON介导的酪氨酸磷酸化。用MSP处理一个RON阳性的腺鳞癌细胞系，在细胞迁移试验中还导致细胞运动性增加，这表明MSP可能促进某些NSCLC的细胞迁移。总之，MSP和RON可能代表一种参与肺癌发病机制的自分泌/旁分泌系统，尽管不同细胞类型中生物学反应的性质可能有很大差异。
