Ito Akihiko, Hagiyama Man, Mimura Takeshi, Matsumoto Masaki, Wakayama Tomohiko, Iseki Shoichi, Yokozaki Hiroshi, Okada Morihito
Division of Pathology, Graduate School of Medicine, Kobe University, Kobe, Japan.
Lab Invest. 2008 May;88(5):504-14. doi: 10.1038/labinvest.2008.15. Epub 2008 Mar 10.
Cell adhesion molecule 1 (CADM1), formerly referred to as SgIGSF, TSLC1, or Necl-2, has been characterized as a mast-cell adhesion molecule that mediates efficient interactions with mesothelial cells. Here, we examined whether CADM1 might be involved in the diffuse tumor growth over the pleural surface that characterizes malignant pleural mesothelioma (MPM). Immunohistochemical and western blot analyses revealed that 14 (25%) of 57 MPMs expressed the full-length form of CADM1 on the cell membrane, but non-neoplastic mesothelial cells did not express it at all. The majority of available MPM cell lines also expressed the full-length form of CADM1. We compared CADM1-positive and -negative MPM cells in culture within soft agar and in coculture on mesothelial or fibroblastic monolayers. Within soft agar, CADM1-negative MPM cells were capable of forming colonies, whereas CADM1-positive cells were not, suggesting that CADM1 is a potential tumor suppressor of MPM, consistent with the past characterization of this molecule in other types of tumors. However, in coculture on mesothelial cell monolayers lacking full-length CADM1, CADM1-positive MPM cells spread more widely and grew more quickly, whereas the CADM1-negative cells piled up. Transfection of the CADM1-negative cells with CADM1 cDNA caused them to behave like the CADM1-positive cells, with faster, more widespread growth. These phenotypic differences were not detectable in cocultures on lung fibroblastic monolayers, in which all MPM cells grew much more slowly than on mesothelial cells, irrespective of CADM1 positivity. CADM1 thus appears to mediate efficient adhesion and growth of MPM cells specifically on mesothelial cells, probably via trans-heterophilic binding, and thus may be involved in the manifestation of a considerable subset of MPMs as diffusely growing tumors disseminated over the pleural surface.
细胞黏附分子1（CADM1），以前被称为SgIGSF、TSLC1或Necl-2，已被鉴定为一种肥大细胞黏附分子，可介导与间皮细胞的有效相互作用。在此，我们研究了CADM1是否可能参与了恶性胸膜间皮瘤（MPM）特征性的胸膜表面弥漫性肿瘤生长。免疫组织化学和蛋白质印迹分析显示，57例MPM中有14例（25%）在细胞膜上表达全长形式的CADM1，但非肿瘤性间皮细胞根本不表达。大多数现有的MPM细胞系也表达全长形式的CADM1。我们在软琼脂中以及在间皮或成纤维细胞单层上共培养时，比较了培养的CADM1阳性和阴性MPM细胞。在软琼脂中，CADM1阴性的MPM细胞能够形成集落，而CADM1阳性细胞则不能，这表明CADM1是MPM的一种潜在肿瘤抑制因子，这与该分子在其他类型肿瘤中的既往特征一致。然而，在缺乏全长CADM1的间皮细胞单层上共培养时，CADM1阳性的MPM细胞扩散得更广泛且生长更快，而CADM1阴性细胞则堆积在一起。用CADM1 cDNA转染CADM1阴性细胞使其表现得像CADM1阳性细胞，生长更快、更广泛。在肺成纤维细胞单层上共培养时未检测到这些表型差异，在这种情况下，所有MPM细胞的生长都比在间皮细胞上慢得多，与CADM1的阳性情况无关。因此，CADM1似乎通过反式嗜异性结合特异性地介导MPM细胞在间皮细胞上的有效黏附和生长，因此可能参与了相当一部分MPM表现为弥漫性生长肿瘤在胸膜表面播散的过程。
