ヒトExtravillous trophoblastの分化機構および浸潤停止機構の解析(2 ヒト絨毛細胞の機能とその異常)

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During placental development, human trophoblasts differentiate into two main cell lineages : villous and extravillous cells. Extravillous trophoblasts(EVT)invade maternal uterus and also migrate up the spiral arteries, transforming them into large vessels of low resistance. Roles of integrins and proteinases, which are ordinary reported to play an important role in tumor invasion, on EVT invasion has been extensively investigated. However, unlike tumor invasion, EVT invasion is precisely regulated, confined spatially to the uterus and temporally to early pregnancy. The mechanism of controlled EVT invasion is not clarified well. Because failure of EVT invasion has recently been documented in pre-eclampsia, investigation of mechanisms which control EVT invasion are important for successful pregnancy. In addition, this investigation might contribute to the establishment of new therapeutic strategy against tumor invasion and metastases. Therefore in this study, we fiest identified molecules specifically expressed in EVT by several methods. Thereafter, we examined the role of each molecule in human trophoblasts, especially in thier controlled invasiveness. We examined the expression of integrin or proteinase related molecules in human placental tissue. Among these molecules, CD9 and dipeptidyl peptidase IV(DPPIV)revealed to be expressed in non-invasive EVT. Functional analyses using choriocarcinoma cell lines demonstrated that both molecules modulate invasiveness of these cells, which suggest the role of molecules expressed in non-invasive EVT in the control of EVT invasion. We next tried to identify novel molecules which are expressed in EVT by mouse monoclonal antibody(mAb)and cDNA microarray analyses. By these analyses, several molecules including melanoma cell adhesion molecule(MCAM)were found to be expressed in EVT. In addition, at least 2 unknown molecules were identified. We next investigated the regulatory mechanism of EVT invasion by using molecules identified above as parameters of EVT invasiveness. At first, the role of tissue oxygen tension, which is thought to trigger EVT invasion from cell colummn, was investigated. hypoxic condition attenuated the expression of CD9 and DPP IV in choriocarcinoma cell lines, whereas the coculture with decidual tissue did not. Because CD9 and DPP IV are expressed in EVT of deep portion of decidua and myometrium, the role of oxygen tension on the control of EVT invasion in these portion was suggested. Besides EVTs cease their invasion in deep portion of decidua, invasive property of EVTs around spiral arteries appears to be retained. We then examine the factors which regulate EVT invasion around spiral arteries, and Nitric oxide(NO)revealed to attenuate DPP IV expression in JEG-3. From this result, it is suggested that NO derived from spiral arterial endothelium retains the invasive property of EVT by suppressing DPP IV expression. Finally, we investigated the possible role of molecules expressed in non-invasive EVT on the establishment of new strategy against tumor invasion and metastases. Among these molecules, CD9 was found to be intensively expressed in normal endometrial epithelial cells. However in endometrial cancer, expression of CD9 was attenuated. In addition, anti-CD9 mAb enhanced the invasiveness of endometrial cancer derived cell lines. From these results, the possible inhibitory effect of CD9 in endometrial cancer invasion was suggested. In conclusion, we have identified molecules which are expressed in non-invasive EVT. Using these molecule as paramaters of EVT invasiveness, the possible role of oxygen tension in deep portion of EVT invasion and NO around spiral arteries as regulatory mechanisms of EVT invasion were proposed. Further investigation of these molecules may clarify the mechanism of placentation, and the possibility of these molecules toward a new therapeutic strategy against tumor invasion and metastases might be expected in future.
社団法人日本産科婦人科学会の論文
2001-09-01

ヒトExtravillous trophoblastの分化機構および浸潤停止機構の解析(2 ヒト絨毛細胞の機能とその異常)

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