A Model of Lymphangioleiomyomatosis in a Three-Dimensional Culture System.

BACKGROUND

Lymphangioleiomyomatosis (LAM) is a tumor consisting of benign-looking neoplastic cells, but its wretched clinical outcome often resembles a malignant disease. LAM cell clusters (LCCs), unique microstructures commonly found in LAM-associated chylous effusion, are aggregates of LAM cells rimmed by lymphatic endothelium. LCCs seem to be crucial participants in the dissemination and progression of LAM.

METHODS AND

RESULTS

LCCs isolated from LAM-associated chylous effusion were embedded in a three-dimensional (3-D) culture gels, and then placed in a humidified CO2 incubator. During serial observations of their morphological changes, we found tube formations with lymphatic endothelial cells when LCCs settled side by side in 3-D gels. On the other hand, when LCCs were embedded separately enough to be isolated at their initial sites of settlement in the gels, each of LCCs gradually broke down, leaving a "cyst-like" hole after 7 days at the site where LCCs initially resided. Finally, we demonstrated that "cyst-like" hole formation in 3-D gels was inhibited with treatment with doxycycline or recombinant human VEGF receptor-3.

CONCLUSIONS

We consider that our observation of this sequence in vitro illustrates how LCCs behave in vivo while enacting their important role in the progression of LAM. Our results indicate that the 3-D gel culture system for LCCs is a useful tool for exploring the effects of new therapeutic drugs under conditions when LCCs are constantly available.