Resistance of malignant trophoblast cells to both the anti-proliferative and anti-invasive effects of transforming growth factor-beta

Exp Cell Res. 1994 Sep;214(1):93-9. doi: 10.1006/excr.1994.1237.


Human placental trophoblast invasion of the uterus is a highly controlled event. We had shown that transforming growth factor-beta (TGF-beta) produced in the pregnant uterus controls invasiveness and reduces proliferation of first trimester placental trophoblasts in vitro. The anti-invasive effect of TGF-beta was due, at least in part, to induction of tissue inhibitor of metalloproteinases (TIMP)-1. In the present study we compared the effects of TGF-beta on proliferation ([3H]-TdR incorporation) and invasiveness (3-day Matrigel invasion assay) of JAR and JEG-3 choriocarcinoma cells vs normal first trimester human trophoblast cells. Transcripts of type IV collagenases (72- and 92-kDa enzymes, i.e., gelatinases A and B) and their inhibitors (TIMP-1 and TIMP-2) in these cells were measured by Northern analysis, and secretion of gelatinases and plasminogen activators (PAs) was evaluated by gel zymography. The results revealed that: (a) TGF-beta inhibited invasiveness and proliferation of normal trophoblast but not JAR and JEG-3 choriocarcinoma cells; (b) gelatinase A mRNA, expressed by the normal trophoblast and JAR cells, was upregulated in the presence of TGF-beta; (c) gelatinase B mRNA was not detected in the total RNA preparations of treated or untreated normal trophoblast or choriocarcinoma cells; (d) TGF-beta significantly upregulated the levels of TIMP-1 mRNA in the normal trophoblasts, but this transcript was very low in treated as well as untreated choriocarcinoma cells; TGF-beta also upregulated the 3.5-kb TIMP-2 message in the normal trophoblast; (e) gelatin zymography revealed a distinct band of approximately 68-kDa (gelatinase A) in the conditioned media of normal trophoblast and JAR cells; however, TGF-beta did not change the level of secretion of this gelatinase; and (f) the normal trophoblast also exhibited significant PA secretion (casein zymography) which was reduced in the presence of TGF-beta. PA secretion by the malignant trophoblast cells was low and unaffected by TGF-beta. These findings suggest that choriocarcinoma cells may become refractory to the mechanisms which control normal trophoblast proliferation and invasiveness. Concurrent resistance to antiproliferative and anti-invasive molecules such as TGF-beta may be highly relevant to tumor progression.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Division / drug effects
  • Cells, Cultured
  • Choriocarcinoma / metabolism*
  • Choriocarcinoma / pathology
  • Collagenases / genetics
  • Collagenases / metabolism
  • Dose-Response Relationship, Drug
  • Drug Resistance
  • Female
  • Gelatinases / genetics
  • Gelatinases / metabolism
  • Glycoproteins / genetics
  • Humans
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism
  • Neoplasm Invasiveness
  • Plasminogen Activators / drug effects
  • Pregnancy
  • Pregnancy Trimester, First
  • Proteins / genetics
  • RNA, Messenger / analysis
  • Tissue Inhibitor of Metalloproteinase-2
  • Tissue Inhibitor of Metalloproteinases
  • Transforming Growth Factor beta / pharmacology*
  • Trophoblasts / metabolism*
  • Trophoblasts / pathology
  • Tumor Cells, Cultured
  • Uterine Neoplasms / metabolism*
  • Uterine Neoplasms / pathology


  • Glycoproteins
  • Proteins
  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinases
  • Transforming Growth Factor beta
  • Tissue Inhibitor of Metalloproteinase-2
  • Plasminogen Activators
  • Collagenases
  • Gelatinases
  • Metalloendopeptidases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9