Tgf-beta signaling pathway in lung adenocarcinoma invasion

Abstract

The histologic distinction between bronchioloalveolar carcinoma and other adenocarcinomas is tissue invasion. The clinical importance of lung adenocarcinoma invasion is supported by several recent studies indicating that the risk of death in nonmucinous bronchioloalveolar carcinoma is significantly lower than that of pure invasive tumors and in tumors with greater than 0.5 cm of fibrosis or linear invasion. Using microarray gene expression profiling of human tumors, dysregulation of transforming growth factor-beta signaling was identified as an important mediator of tumor invasion. Subsequent studies showed that the CC chemokine regulated on activation, normal T cell expressed, and presumably secreted was up-regulated in invasive tumors and was required for invasion in cells with repressed levels of the transforming growth factor-beta type II receptor. Taken together, these studies illustrate how information gained from global expression profiling of tumors can be used to identify key pathways and genes mediating tumor growth, invasion, and metastasis.

Figure 1

TGF-β signaling occurs primarily via SMAD dependent pathways. A. Ligand binding to the TGF-β type II receptor (TβRII) induces phosphorylation and activation of type I receptor (TβRI), which phosphorylates and activates the receptor complex SMAD2 and SMAD3. Dissociated SMAD2/3 forms a heterotrimeric complex with SMAD4 that translocates into the nucleus to regulate gene transcription. B. TGF-β signaling may also proceed via SMAD-independent pathways that involve various signaling cascades including Ras/ERK, Rho/ROCK, and TAK1/MAPK. These “non-canonical” pathways are likely to have important roles in mediating the pro-tumorigenic effects of TGF-β. C. The histological distinction between bronchioloalveolar carcinoma (BAC) and other adenocarcinomas is tissue invasion. Invasion requires loss of cell-cell adhesion, migration, membrane degradation with vascular intravasation and extravasation and establishment of the metastatic niche angiogenesis and recruitment of stromal elements (top panel). We have shown that repression of TGF-β type II receptor in lung adenocarcinoma cells increases invasiveness and have used microarray analyses and inhibitor studies to identify the CC chemokine RANTES as an important mediator of lung adenocarcinoma invasion in TβRII deficient tumors. Figure reprinted with permission from the American Thoracic Society