{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T03:51:22Z","timestamp":1791345082239,"version":"4.3.1"},"reference-count":59,"publisher":"Canadian Science Publishing","issue":"2","license":[{"start":{"date-parts":[[2002,2,1]],"date-time":"2002-02-01T00:00:00Z","timestamp":1012521600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.nrcresearchpress.com\/page\/about\/CorporateTextAndDataMining"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Can. J. Physiol. Pharmacol."],"published-print":{"date-parts":[[2002,2,1]]},"abstract":"<jats:p>The human placenta is a highly invasive tumor-like structure in which a subpopulation of placental trophoblast cells known as the \"extravillous trophoblast\" (EVT) invades the uterine decidua and its vasculature to establish adequate fetal\u0096maternal exchange of molecules. By utilizing in vitro-propagated short-lived EVT cell lines we found that molecular mechanisms responsible for their invasiveness are identical to those of cancer cells; however, unlike cancer cells, their proliferation, migration, and invasiveness in situ are stringently controlled by decidua-derived transforming growth factor (TGF)-\u03b2. By SV40T antigen transfection of normal EVT cells followed by a forced crisis regimen in culture we produced an immortalized premalignant derivative that is hyperproliferative, hyperinvasive, and deficient in gap-junctional intercellular communication. Both premalignant and malignant EVT (JAR and JEG-3 choriocarcinoma) cell lines were found to be TGF-\u03b2-resistant. Using these cell lines, we investigated genetic changes responsible for transition of the normal EVT cells to premalignant and malignant phenotype. Hyperinvasiveness in both cases resulted from a downregulation of tissue inhibitor of metalloprotease (TIMP)-1 and plasminogen activator inhibitor (PAI)-1 genes. In contrast to normal EVT cells, both cell types failed to upregulate these genes in response to TGF-\u03b2. Loss of TGF-\u03b2 response in malignant EVT cells was explained by the loss of expression of Smad3 gene. Differential mRNA display of normal and premalignant EVT cells identified up- and down-regulation of numerous known or novel genes in premalignant EVT cells, with potential oncogenic and (or) tumor-suppressor functions, e.g., loss of fibronectin and insulin-like growth factor binding protein (IGFBP-5). Premalignant EVT cells also lost IGF receptor type 2 (IGFR-II). IGFBP-5 was shown to be a negative regulator of IGF-1-induced proliferation of premalignant EVT cells, so that loss of IGFBP-5 as well as IGFR-II permitted their unrestricted proliferation in an IGF-I-rich microenvironment of the fetal\u0096maternal interface. The present model may be a good prototype for identifying genetic changes underlying epithelial tumor progression.Key words: trophoblast, TGF-\u03b2, IGFBP-5, fibronectin, choriocarcinoma.<\/jats:p>","DOI":"10.1139\/y02-006","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T10:57:36Z","timestamp":1027767456000},"page":"142-149","source":"Crossref","is-referenced-by-count":67,"title":["Human placental trophoblast as an in vitro model for tumor progression"],"prefix":"10.1139","volume":"80","author":[{"given":"P K","family":"Lala","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B P","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Chakraborty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"155","reference":[{"key":"p_1\/p_1_1","first-page":"F899","volume":"273","author":"Abrass C.K.","year":"1997","journal-title":"Am. 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