The activity of zoledronic Acid on neuroblastoma bone metastasis involves inhibition of osteoclasts and tumor cell survival and proliferation.

Metastasis to the bone is seen in 56% of patients with neuroblastoma and contributes to morbidity and mortality. Using a murine model of bone invasion, we have reported previously that neuroblastoma cells invade the bone by activating osteoclasts. Here, we investigated the antitumoral and antiosteolytic activities of zoledronic acid, a bisphosphonate inhibitor of osteoclasts, in combination with cytotoxic chemotherapy in our model.

Requirement of multiple signaling pathways for the augmented production of hyaluronan by v-Src.

Malignant transformation of cells is frequently associated with an augmented production of hyaluronan and the subsequent formation of a hyaluronan-matrix. In v-Src-transformed cells, hyaluronan directly activate cell motility in a tumor-specific manner. Despite its importance, the mechanism by which v-Src activates hyaluronan production remains unclear.

Multimodal imaging analysis of tumor progression and bone resorption in a murine cancer model.

Objective: This study evaluates the use of multimodal imaging to qualitatively and quantitatively measure tumor progression and bone resorption in a xenotransplanted tumor model of human neuroblastoma.

Methods: Human neuroblastoma cells expressing a luciferase reporter gene were injected into the femur of nu/nu mice. Tumor progression with and without zoledronic acid treatment was monitored using radiographs, D-luciferin-induced luminescence, micro-computer tomography (CT) and micro-magnetic resonance imaging (MRI).

A role for PI3K-Akt signaling in pulmonary metastatic nodule formation of the osteosarcoma cell line, LM8.

To search for the intracellular signaling pathway critical for the pulmonary metastasis of osteosarcoma, we examined two osteosarcoma cell lines with different metastatic capability, Dunn and LM8. While parental Dunn is poorly metastatic to lung, LM8, derived from Dunn by in vivo selection through pulmonary metastasis, displays clear capability of pulmonary metastasis. We found that LM8 had higher levels of Akt phosphorylation and Ezrin expression than Dunn.

Mechanisms of bone invasion and metastasis in human neuroblastoma.

Bone is the second most common site of metastasis in neuroblastoma. Over the last several years, our understanding of the mechanism of bone metastasis in neuroblastoma has significantly improved. Like breast cancer and myeloma, neuroblastoma cells activate osteoclasts to form osteolytic lesions.

Bone marrow mesenchymal stem cells provide an alternate pathway of osteoclast activation and bone destruction by cancer cells.

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.

Lytic bone lesions in human neuroblastoma xenograft involve osteoclast recruitment and are inhibited by bisphosphonate.

Neuroblastoma is the second most common solid tumor in childhood and frequently metastasizes to the bone marrow and the bone matrix. The mechanism involved in bone metastasis and destruction in neuroblastoma is poorly understood. Using a model of bone invasion in immunodeficient mice, we demonstrated that neuroblastoma cells recruited osteoclasts to generate osteolytic lesions and invade the bone matrix.

Hyaluronan-CD44s signaling regulates matrix metalloproteinase-2 secretion in a human lung carcinoma cell line QG90.

We investigated the production of matrix metalloproteinase (MMP) by hyaluronan(HA) stimulation in a human cancer cell line, QG90, that expresses a large amount of CD44s, a HA receptor. Treatment of QG90 with HA strongly activated MMP-2 secretion in a time- and dose-dependent manner. We found that expression of antisense CD44s in QG90 cells substantially inhibited the HA-dependent secretion of MMP-2, whereas overexpression of full-length CD44s augmented the HA-dependent secretion of MMP-2.

A role for focal adhesion kinase in hyluronan-dependent MMP-2 secretion in a human small-cell lung carcinoma cell line, QG90.

Hyluronan (HA), a nonsulfated high-molecular mass glycoaminoglycan, has been assigned as a clinical marker for the progression of various tumors. We found that HA stimulation of QG90, a cell line derived from human small-cell lung carcinoma, activates the secretion of matrix metalloproteinase-2 (MMP-2) in a focal adhesion kinase (FAK)-dependent manner. HA stimulation of QG90 cells activated MMP-2 secretion in a time-dependent manner.