Adams y adamtss en cáncer de pulmònpapel de nuevas isoformas de adam8 en el fenotipo invasivo tumoral

Résumé

ADAMs (a disintegrin and metalloprotease) are type I transmembrane proteins involved in a variety of physiological processes and tumorigenesis. Recently, ADAM8 has been associated with poor prognosis of lung cancer. To gain insight into the function of ADAM8 in the context of bone metastasis, we screened a panel of human lung cancer cells for expression patterns of ADAM8. We found that native ADAM8 expression was downregulated in lung cancer cell lines, whereas several new splicing isoforms were differentially upregulated in tumor cells compared with normal human bronchioepithelial (NHBE) cells. Two of the spliced isoforms that lack their transmembrane and cytoplasmic domains, Δ18a and Δ14¿, were present in tumor cell lines but expressed at low levels in NHBE cells. Retroviral overexpression of the native and Δ18a isoforms in a lung cancer cell line resulted in enhanced invasive activity, whereas ADAM8-shRNA markedly decreased the invasive ability, in cocultures of lung cancer cells with the ST-2 stromal cell line, which mimics the bone-marrow environment, ADAM8 and its Δ14¿ isoform expression levels were markedly increased in lung cancer cells. Moreover, addition of cell-free supernatants from Δ14¿-overexpressing cells resulted in a significant increase in TRAP+ cells in osteoclast cultures in vitro. These findings were associated with increased IL-8 and IL-6 levels in conditioned media. Furthermore, in a murine model of bone metastasis, intracardiac inoculation of lung cancer cells overexpressing Δ14¿ was found to increase prometastatic activity with a high tumor burden by X-ray image analysis. Thus, the expression of truncated forms of ADAM8 by lung cancer cells may result in the specific up-regulation of their invasive and osteoclastogenic activities in the bone microenvironment. These findings suggest a novel mechanism of tumor-induced osteolysis in metastatic bone colonization.