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.
To clarify the roles of integrin and extracellular matrix (ECM) in the process of non-small cell lung cancer (NSCLC) brain metastasis, we established an in vivo model of brain metastasis of human NSCLC cell line EBC-1/original in athymic mice, and established highly brain metastatic subclone EBC-1/brain and highly bone metastatic subclone EBC-1/bone. Integrin expression of these subclones was evaluated by flow cytometry. In vitro cell attachment, migration and proliferation assays with ECMs were performed using these subclones. Expression of integrin α α α α3 subunit was higher in EBC-1/brain than in both EBC-1/original and EBC-1/ bone. In vitro cell attachment, migration, and proliferation assays revealed that EBC-1/brain had higher affinity and higher reactivity to laminin than EBC-1/original and EBC-1/bone. Blocking of integrin α α α α3β β β β1 significantly (P < ung cancer patients often suffer from brain metastasis. Indeed, clinical data in Japan show that more than half of metastatic brain tumors originates from lung cancer, 1) implying that most lung cancers have high potential for metastasis to brain.
A 58-year-old woman presenting with idiopathic granulomatous mastitis mimicking breast carcinoma is described. The mass was elastic, hard and painless, and located in the upper outer quadrant of the right breast. Fine needle aspiration cytology did not provide any diagnostic information. Mammography, ultrasonography and magnetic resonance imaging (MRI) strongly suggested malignancy. Excisional biopsy was performed for definitive diagnosis, and idiopathic granulomatous mastitis was demonstrated histopathologically. Neither wound complication nor recurrence has been identified in the patient, although corticosteroids were not used post operatively. We reviewed the literature, and found that our present case is rare in older patients, and that mammography, ultrasonography and MRI provide little information for differentiating between granulomatous mastitis and carcinoma.
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