Overexpression of ADAM9 in Non-Small Cell Lung Cancer Correlates with Brain Metastasis

Abstract

The "a disintegrin and metalloprotease" (ADAM) family contributes to regulation of the cell-cell and cell-matrix interactions that are critical determinants of malignancy. To determine the relationship between metastasis and ADAM proteins, we compared the mRNA levels of ADAM9, -10, -12, -15, and -17 in sublines of an EBC-1 lung cancer cell line that were highly metastatic to either brain or bone. ADAM9 mRNA levels were significantly higher in highly brain-metastatic sublines than in the parent or highly bone-metastatic sublines. To elucidate the role of ADAM9 in brain metastasis, we stably transfected A549 and EBC-1 cells with a full-length ADAM9 expression vector. Compared with mock-transfectants, ADAM9 overexpression resulted in increased invasive capacity in response to nerve growth factor, increased adhesion to brain tissue, and increased expression of integrin ␣3 and ␤1 subunits. Administration of the anti-␤1 monoclonal antibody attenuated this increase in invasive and adhesive activity. Intravenous administration of ADAM9-overexpressing A549 cells to mice resulted in micrometastatic foci in the brain and multiple metastatic colonies in the lungs. In contrast, administration of parent and mock-transfected A549 cells to mice resulted in lung tumors without brain metastasis. These results suggest that ADAM9 overexpression enhances cell adhesion and invasion of non-small cell lung cancer cells via modulation of other adhesion molecules and changes in sensitivity to growth factors, thereby promoting metastatic capacity to the brain.

A Secreted Form of ADAM9 Promotes Carcinoma Invasion through Tumor-Stromal Interactions

“…of ADAM9 in non-small cell lung cancer has been correlated with brain metastases (24); furthermore, ADAM9 expression in pancreatic cancer has been suggested to be a prognostic factor in ductal adenocarcinoma (51). However, our studies, for the first time, point to the stromal component of an invasive tumor as the source of ADAM9 expression and thus suggest a functional role for stroma-derived ADAM9 in the context of local invasion of metastatic cancer cells.…”

“…However, it was recently reported that in breast carcinoma increased expression of ADAM9 correlates with cancer progression (22) and elevated mRNA levels of both ADAM9 and ADAM12 have been found in liver metastases from colon carcinomas (23). Moreover, overexpression of ADAM9 in nonsmall cell lung cancer correlates with metastasis to the brain (24).…”

Id-1gene downregulation by sulindac sulfide and its upregulation during tumor development in gastric cancer

“…ADAM9 expression was increased in nonsmall cell lung cancer and correlated with brain metastasis, and the administration of anti-ADAM9 inhibited gastric cancer cell growth. 35,36 Overexpression of PPT1 protects cells against apoptosis mediated by the ras-akt (protein kinase B) caspase pathway in neuroblastoma cells, whereas anti-sense PPT1 increases cell death. 37,38 The ectopic expression of GRN promotes cancer cells invasiveness and forms large tumors in nude mice, whereas GRN expression depletion diminishes tumor growth and cell proliferation.…”

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…As induction of ADAM-8 production increases the invasive phenotype of cancer cells, this molecule might play a role in promoting disease dissemination. ADAM-9 mRNA and protein expression levels are enhanced in EBC-1 lung cancer cell line displaying a tropism for brain metastasis as compared to parent EBC-1 or EBC-1 cell line with a tropism for bone tissue [110]. Overexpression of ADAM-9 in EBC-1 and A549 lung cancer cells results in an increase of NGF-induced invasion and a higher adhesion of cells to brain tissue.…”