TGF-beta specifically enhances the metastatic attributes of murine lung adenocarcinoma: implications for human non-small cell lung cancer.

Lung cancer is the most frequent and one of the most deadly cancer types and is classified into small cell lung cancer and non-small cell lung cancer (NSCLC). Transforming growth factor beta (TGFß) regulates a wide array of cell functions and plays a major role in lung diseases, including NSCLC. TGFß signals through the complex of TGFß type I and type II receptors, triggering Smad and non-Smad signaling pathways such as PI3K/Akt and MEK1/ERK. We investigated the role of TGFß1 on the progression of the murine lung adenocarcinoma cell line LP07. Furthermore, we undertook a retrospective study with tissue samples from stage I and II NSCLC patients to assess the clinical pathologic role and prognostic significance of TßRI expression. We demonstrated that although lung cancer cell monolayers responded to TGFß1 anti-mitogenic effects and TGFß1 pulse (24 h treatment) delayed tumor growth at primary site; a switch towards malignant progression upon TGFß1 treatment was observed at the metastatic site. In our model, TGFß1 modulated in vitro clonogenicity, protected against stress-induced apoptosis and increased adhesion, spreading, lung retention and metastatic outgrowth. PI3K and MEK1 signaling pathways were involved in TGFß1-mediated metastasis stimulation. Several of these TGFß responses were also observed in human NSCLC cell lines. In addition, we found that a higher expression of TßRI in human lung tumors is associated with poor patient's overall survival by univariate analysis, while multivariate analysis did not reach statistical significance. Although additional detailed analysis of the endogenous signaling in vivo and in vitro is needed, these studies may provide novel molecular targets for the treatment of lung cancer.

TGF-ß autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression.

Breast cancer progression and metastasis have been linked to abnormal signaling by transforming growth factor-ß (TGF-ß) cytokines. In early-stage breast cancers, TGF-ß exhibits tumor suppressor activity by repressing cell proliferation and inducing cell death, whereas in advanced-stage tumors, TGF-ß promotes invasion and metastatic dissemination. The molecular mechanisms underlying pro-oncogenic activities of TGF-ß are not fully understood. The present study validates the role of TGF-ß signaling in cancer progression and explores mediators of pro-oncogenic TGF-ß activities using the LM3 mammary adenocarcinoma cell line, derived from a spontaneous murine mammary adenocarcinoma. Expression of kinase-inactive TGF-ß receptors decreased both basal and TGF-ß-induced invasion. Analysis of signal transduction mediators showed that p38MAPK and MEK contribute to TGF-ß stimulation of cell motility and invasion. TGF-ß disrupted the epithelial actin structures supporting cell-cell adhesions, and increased linear actin filaments. Moreover, MEK and p38MAPK pathways showed opposite effects on actin remodeling in response to TGF-ß. Blockade of Raf-MEK signaling enhanced TGF-ß induction of actin stress-fibers whereas p38MAPK inhibitors blocked this effect. A novel observation was made that TGF-ß rapidly activates the actin nucleation Arp2/3 complex. In addition, TGF-ß stimulated matrix metalloproteinase MMP-9 secretion via a MAPK-independent pathway. Experiments using syngeneic mice showed that kinase-inactive TGF-ß receptors inhibit the first stages of LM3 tumor growth in vivo. Our studies demonstrate that autocrine TGF-ß signaling contributes to the invasive behavior of mammary carcinoma cells. Moreover, we show that both MAPK-dependent and -independent pathways are necessary for TGF-ß-induced effects. Therefore, MEK-ERK and p38 MAPK pathways are potential venues for therapeutic intervention in pro-oncogenic TGF-ß signaling.