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Study of the autocrine growth inhibitors of the keratinocytes

角质形成细胞自分泌生长抑制剂的研究

基本信息

批准号：
05670187
负责人：
NOSE Masato
金额：
$ 1.41万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1995
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05670187/
关键词：
Growth Inhibitor Autocrine Keratinocytes Histogenesis Cancer 精製単クローン抗体

项目摘要

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.

1.角化细胞自分泌生长抑制剂的鉴定：我们鉴定了转化生长因子-β（TGF-β）和激活素作为角化细胞的自分泌生长抑制剂。另外，从由汇合的角质形成细胞调节的培养基中纯化另外两种生长抑制剂。胰岛素样生长因子结合蛋白-6（IGFBP-6）是其中之一。2.组织分布：在TGF-β 3种亚型中，只有TGF-β 2在正常人皮肤表皮组织中有表达。在人表皮中也发现了Activin和IGFBP-6，它们均分布于表皮的整个细胞层。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。3.癌细胞自分泌生长抑制系统的异常：15个检测的鳞状细胞癌细胞系均对TGF-β的反应性消失或降低。然而，在这些细胞系中，大多数细胞系表达增强量的TGF-β受体，并且其中只有两个细胞系没有可检测水平的TGF-β受体。这一结果不同于遗传性非息肉性结肠癌患者中大肠癌复制错误阳性病例，后者90%以上病例的癌细胞存在TGF-β II型受体基因突变，受体表达缺失。我们还研究了胃癌、前列腺癌、胶质母细胞瘤和T细胞白血病的受体异常。这些癌症中的大多数也对TGF-β的反应性降低，但导致这种现象的分子异常似乎是多种多样的。