Keck School of Medicine
The Saban Research Institute
Childrens Hospital Los Angeles
- Cancer Cell Biology
Research OverviewMicroenvironment in Tumor Progression
Cancer progression is not only influenced by genetic changes that occur at higher frequency in malignant cells but also by changes that occur in the tumor microenvironment. This tumor environment is made of host-derived cells such as fibroblasts, endothelial cells and inflammatory cells, and numerous proteins that form the extracellular matrix (ECM). The central theme of the research conducted in our laboratory is to understand at a molecular level the mechanisms by which changes in the tumor microenvironment influence the behavior of malignant cells. A first focus of research is on the role of the bone marrow microenvironment in bone metastasis. Studying human neuroblastoma, the second most common solid tumor in children, we have observed that neuroblastoma cells that colonize the bone marrow create a microenvironment that is favorable for cancer progression. Central to this is interleukin-6 (IL-6), a pleiotropic cytokine whose expression is induced in bone marrow stromal cells by galectin-3 binding protein, produced by neuroblastoma cells (Fukaya et al., 2008). IL-6 in the bone marrow microenvironment has multiple effects. It stimulates osteoclast activation (Sohara et al., 2003; Sohara et al., 2005) which is responsible for the formation of osteolytic lesions in neuroblastoma bone metastasis. Accordingly, we showed that inhibition of osteoclast activation with bisphosphonates like zoledronic acid inhibits bone invasion in mice (Peng et al., 2007). Clinical studies lead to the demonstration of the efficacy of zoledronic acid in children with recurrent neuroblastoma metastatic to the bone. IL-6 also has a paracrine effect on neuroblastoma cells and stimulates their proliferation and protects them from drug induced apoptosis (Ara et al., 2009). This paracrine effect is mediated by activation of STAT-3. On the basis of these observations, our laboratory is currently testing the effect of targeting IL-6 and STAT-3 in neuroblastoma progression in preclinical models.
A second focus of our investigation is on examining how the bone marrow also contributes to the microenvironment in the primary tumor. We have observed that the bone marrow is a source of endothelial progenitor cells (derived from hematopoietic stem cells) that contribute in a matrix metalloproteinase-9-dependent mechanism to the formation of a mature vasculature in primary tumors (Chantrain et al., 2006; Jodele et al., 2005). We are currently investigating how mesenchymal stem cells contribute to cancer progression and how chemotherapy and radiation therapy affect the recruitment of these bone marrow-derived cells to the primary tumor.
A third focus of our laboratory is on angiogenesis and in particular on its control by plasminogen activator (PA) and its inhibitor (PAI-1). We have observed a paradoxical elevation of PAI-1 in more aggressive forms of neuroblastoma (Sugiura et al., 1999) and determined that PAI-1 acts as a stimulator rather than an inhibitor of angiogenesis. This proangiogenic effect of PAI-1 resides in the ability of PAI-1 to promote endothelial cell migration from vitronectin toward fibronectin (Isogai et al., 2001) and to protect endothelial cells from Fas-L-mediated apoptosis (Bajou et al., 2008). Our recent data suggest that in the absence of PAI-1 tumors are unable to initiate an angiogenic switch and remain dormant.
A fourth focus of our laboratory is on the role of matrix metalloproteinases in epithelial-mesenchymal transition (EMT) and mammary carcinogenesis. We had shown that inhibition of MMPs delays the occurrence of mammary tumors in MMTV-Wnt mice (Blavier et al.) and inhibit Wnt-induced EMT and Wnt-induced expression of MMP-3 (stromelysin). The mechanism underlying this inhibitory effect is currently investigated. Our data suggest the presence of a feedback loop where MMP-3 expression in Wnt-1 expressing cells further stimulates Wnt-signaling and the translocation of β-catenin to the nucleus.
Our laboratory is sponsored by grants from the NIH/NCI and located on the 5th floor of the Smith Research Tower at the Saban Research Institute of Childrens Hospital Los Angeles.