Area of Interest 3: Human Placenta as a Model for Tumor Progression

We discovered that metastatic cancer cells and normal invasive trophoblast cells of the human placenta employ identical molecular mechanisms for invasion, indicating that invasion is not a sufficient prerequisite for malignancy or metastasis. By genetic manipulation we have produced premalignant derivatives of normal trophoblast cells in the test tube. Malignant derivatives have been produced from naturally occuring human choriocarcinomas. Normal trophoblast proliferation, migration and invasiveness is controlled by a molecule called transforming growth factor (TGF)β, produced by the pregnant uterus, whereas choriocarcinomas are resistant to TGFβ action. We have been using these cells to identify molecular and genetic events which make invasive cells premalignant and premalignant cells malignant or metastatic. We have identified numerous genes which are up-regulated or down-regulated at different stages during trophoblastic tumor progression. For example, loss of expression of Smad-3 gene and protein, a transcription factor responsible for mediating the TGFβ action was shown to be partially responsible for TGFβ resistance in choriocarcinomas. This type of knowledge will help designing gene therapy of cancer.

(TGFβ signaling pathway adapted from Massague and Chen, 2000)

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