C-KIT AS A POSSIBLE HOMING RECEPTOR FOR BONE METASTASIS OF EWING’S SARCOMA

K. Scotlandi, N. Baldini, V. Cerisano, S. Benini, M.C. Manara, M. Serra, P. Nanni*, L. Landuzzi§, G. Nicoletti§, P. Picci. (Laboratorio di Ricerca Oncologica, Istituti Ortopedici Rizzoli,§ I.S.T., Istituto di Ricerche per la Ricerca sul Cancro, Unità Satellite di Biotecnologie di Bologna, and * Isituto di Cancerologia, Università degli Studi di Bologna, Bologna, Italy)

Ewing’s sarcoma (ES), the second most frequent primary tumor of bone, shows a high tendency to give pulmonary and bone metastases. In particular, skeletal involvement may appear, at the onset or during the course of the disease, also in the absence of lung metastases. The pathogenesis of these lesions, however, is still poorly understood due to the lack of appropriate models. We describe the ability of TC-71 ES cells to metastasize to bone after intravenous injection of tumor cells in nude mice. Besides the fast appearance of large bone colonies, inoculation of ES cells also gave a small number of lung metastases, the size of which was definitively lower than that of bone lesions. Differently to other sarcomas, ES cells did not appear to arrest in the lung, but proceeded into the arterial circulation up to the bones. The poor number of lung colonies observed following the intravenous injection of TC-71 cells might reflect their scarce ability to adhere to and invade through the basement membrane of pulmonary vessels, possibly due to their relatively small size. Moreover, TC-71 cells showed a low production of MMP-2 and MMP-9 metalloproteases, which are able to degrade a major component of the basement membrane and whose expression is associated with metastatic ability to the lungs. The distribution and the clinical and pathological characteristics of bone lesions in mice was in agreement with the pattern of metastatic spread in humans, and, in particular, indicated that only bones rich in hematopoietic marrow are affected. Bone marrow appears to be the organ that best supports ES colonization, as suggested by the bigger size of bone metastases as compared to lung metastases. This could be due to the presence of "homing" receptors on ES cells, that function to promote adherence, survival and growth in the bone marrow environment. TC-71 ES cells showed high expression levels of c-Kit receptor, and its ligand SCF, which is produced by human bone marrow fibroblasts, might act as a chemoattractant for ES cells in vitro. This animal model of bone metastases of ES closely mimics the pattern of metastatic disease in humans, and indicates c-Kit as a possible "homing" receptor.