World-Class Research Institute

The Saban Research Institute is one of the largest and most productive pediatric research facilities in the United States.

With its dedication in 2003, the facility doubled the amount of usable space that could be dedicated to research to nearly 120,000 square feet.

Three floors of the five-story laboratory building are dedicated to research, with the ground floor housing a state-of-the-art auditorium and research administration space. The facility also houses an imaging core.

Currently, The Saban Research Institute is home to the work of: 128 investigators conducting 267 laboratory studies, clinical trials and community-based research. It is one of the few freestanding research centers in the nation to combine scientific inquiry with patient clinical care – dedicated exclusively to children.

Investigators at The Saban Research Institute are working to create a world in which all children are healthy – a world in which they are no longer threatened by such diseases as cancer, congenital heart defects, diabetes, sickle cell anemia, epilepsy, immune deficiencies and respiratory disorders. They ask basic questions about human biology, find new ways to see inside the body, explore genetic mysteries, develop promising drug treatments and test preventive strategies – scientific inquiries that benefit both children and adults.

Mesenchymal

The bone is the third most common site of cancer metastasis. To invade the bone, tumor cells produce osteoclast-activating factors that increase bone resorption by osteoclasts. Here we report that human neuroblastoma cells that form osteolytic lesions in vivo do not produce osteoclast-activating factors but rather stimulate osteoclast activity in the presence of human bone marrow mesenchymal stem cells. This alternative pathway of osteoclast activation involves a nonadhesive interaction between neuroblastoma cells and bone marrow mesenchymal stem cells. Stimulated bone marrow mesenchymal stem cells express markedly increased levels of interleukin- 6, which is then responsible for osteoclast activation. This report describes a critical role of bone marrow mesenchymal stem cells in bone destruction in cancer. (Cancer Res 2005; 65(4): 1129-35)

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Neuroblastoma

Advanced stages of neuroblastoma show increased expression of matrix metalloproteinases MMP-2 and MMP-9 (Y. Sugiura et al., Cancer Res., 58: 2209–2216, 1998) that have been implicated in many steps of tumor progression, suggesting that they play a contributory role. Using pharmacological and genetic approaches, we have examined the role of these MMPs in progression of SK-N-BE (2).10 human neuroblastoma tumors orthotopically xenotransplanted into immunodeficient mice. Mice treated with Prinomastat, a synthetic inhibitor of MMPs, showed an inhibition of tumor cell proliferation in implanted tumors and a prolonged survival (50 versus 39 days in control group, P < 0.035). Treatment with Prinomastat did not affect formation of liver metastases (P 0.52) but inhibited intravascular colonization by the tumor cells in the lung by 73.8% (P 0.03) and angiogenesis in both primary tumors and experimental liver metastases.

The primary tumors from Prinomastat-treated mice showed a 39.3% reduction in endothelial area detected by PECAM/CD31 staining in tumor sections (P < 0.001), primarily due to the presence of smaller vessels (P 0.004). MMP-2 is expressed by neuroblastoma tumor cells and stromal cells, whereas MMP-9 is exclusively expressed by stromal cells, particularly vascular cells. To examine the contribution of MMP-9 to tumor angiogenesis, we generated RAG1/MMP-9 double-deficient mice. We observed a significant inhibition of angiogenesis in the immunodeficient RAG1/MMP-9 double-deficient mice orthotopically implanted with tumor cells (P 0.043) or implanted s.c. with a mixture of tumor cells and Matrigel (P < 0.001). Using an FITC-labeled lectin, we demonstrated an inhibition in the architecture of the tumor vasculature in MMP-9-deficient mice, resulting in fewer and smaller blood vessels. These changes were associated with a 48% decrease in pericytes present along microvessels. Taken together, the data demonstrate that in neuroblastoma, stromally derived MMP-9 contributes to angiogenesis by promoting blood vessel morphogenesis and pericyte recruitment.

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