Increased cell proliferation and decreased apoptosis characterize congenital cystic adenomatoid malformation of the lung

Abstract

Background/purpose: Congenital cystic adenomatoid malformations (CCAM) are lung lesions that demonstrate abnormalities of both mesenchymal and epithelial tissues. The pathogenesis of these tumors remains unknown. Because normal organogenesis requires a balance between cell proliferation and programmed cell death (apoptosis), the authors hypothesized that CCAM results from an increase in cell proliferation or a decrease in apoptosis within the developing lung, possibly mediated by keratinocyte growth factor (KGF).

Methods: To examine cell cycle control in CCAM, we measured indices of cell proliferation and apoptosis in lesions requiring fetal (n = 4) or neonatal (n = 8) resection compared with those of normal fetal (14 to 28 weeks' gestation; n = 14) and neonatal (n = 3) human lung. Cell proliferation was analyzed by immunostaining for a proliferation marker (Ki-67). Apoptosis was examined using an in situ digoxigenin end-labeling technique to localize apoptotic bodies. The expression of KGF protein and KGF mRNA in CCAM and normal lung was examined using immunohistochemistry and semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR).

Results: CCAM lesions in general showed a twofold increase in cell proliferation index (19.2% +/- 1.4% v 9.6% +/- 0.7%, P < .00005) and a fivefold decrease in apoptotic bodies (0.9 +/- 0.2 v 4.5 +/- 0.5, P < .0005) compared with age-matched normal lung. CCAMs that required resection before birth had the highest cell proliferation index. There were no differences in the expression of KGF protein or KGF mRNA in CCAM and normal lung.

Conclusions: These results demonstrate that CCAM differs from normal lung by increased cell proliferation and decreased apoptosis. The increased proliferation does not appear to be mediated by the pneumocyte mitogen KGF. An examination of factors that control cell proliferation and apoptosis in CCAM may provide further insight into the pathogenesis of this tumor.