Study of the autocrine growth inhibitors of the keratinocytes

1.鉴定角质形成细胞的自分泌生长抑制剂：我们鉴定了转化生长因子- β (tgf - β)和激活素作为角质形成细胞的自分泌生长抑制剂。此外，从融合角质形成细胞调节的培养基中纯化了另外两种生长抑制剂。其中一个被认为是胰岛素样生长因子结合蛋白-6 （IGFBP-6）。另一个分子的鉴定仍在进行中。组织分布：tgf - β三种亚型中，仅tgf - β 2存在于正常人皮肤表皮组织中。激活素和IGFBP-6也存在于人表皮中，且均分布在表皮的全细胞层中。另一方面，tgf - β的I型和II型受体以及激活素的IB型和II型受体在角质形成细胞分化的表皮棘层上表达。癌细胞中自分泌生长抑制剂系统的异常：所有15个被检查的鳞状细胞癌细胞系对tgf - β的反应性都消失或降低。然而，在这些细胞系中，大多数细胞系表达了大量的tgf - β受体，只有两种细胞系没有检测到tgf - β受体的水平。这些结果与遗传性非息肉性结肠癌患者的结肠直肠癌复制错误阳性病例不同，其中90%以上的癌细胞发生tgf - β II型受体基因突变，失去受体表达。我们还研究了这些受体在胃癌、前列腺癌、胶质母细胞瘤和T细胞白血病中的异常。大多数癌症对tgf - β的反应性降低，但导致这种现象的分子异常似乎多种多样。

1.Identification of autocrine growth inhibitors of keratinocytes : We identified transforming growth factor-beta (TGF-beta) and activin as autocrine growth inhibitors of the keratinocytes. Additionally, two more growth inhibitors were purified from the culture media conditioned by confluent keratinocytes. One of them was recognized to be insulin-like growth factor binding protein-6 (IGFBP-6). Indentification of the other molecule is still going on.2.Tissue distribution : Among three isoforms of TGF-betas, only TGF-beta2 was detected in epidermal tissue of normal human skin. Activin and IGFBP-6 were also found in human epidermis, and all of these ligands distributed in whole cellular layrs of epidermis. On the other hand, type I and type II receptors for TGF-beta, and type IB and type II receptors for activin were expressed on a spinous layr of the epidermis where keratinocytes were differentiating.3.Abnormality of the autocrine growth inhibitor systems in cancer cells : All of 15 examined squamous cell carcinoma cell lines had abolished or reduced responsiveness to TGF-beta. Among these, however, most cell lines expressed enhanced amounts of TGF-beta receptors, and only two of them did not have detectable level of TGF-beta receptors. These results were different from replication error positive cases of colo-rectal cancer of hereditary non-polypotic colon cancer patients, in which more than 90% cases of cancer cells have mutation on the gene of TGF-beta type II receptor, and lost the receptor expression. We also studied the abnormality of the receptors in gastric cancer, prostatic cancer, glioblastoma and T cell leukemia. Most of these cancers also had reduced responsiveness to TGF-beta but molecular abnormality causing the phenomena seemed diverse.