311 Webb Nutrition Sciences Building
1675 University Blvd. Birmingham,
The main goal of our laboratory is to define the regulation and function of the matricellular protein, osteopontin (OPN), in normal and pathological conditions. OPN is mainly a secreted, adhesive glycoprotein that is normally expressed in bone and other selective tissues and has been implicated to facilitate osteoclastogenesis and bone formation. Using human bone marrow stromal stem cells (MSC) we found that the expression of OPN correlated with osteoblast differentiation, whereby, MSC express very low levels of OPN and it is later induced in mature osteoblasts, suggesting its association with differentiated cells (unpublished data).
In the context of pathological conditions, OPN is highly induced and current project is to define its mechanism of function in tumorigenesis. OPN expression is elevated in several types of human cancers and premalignant tumors. Evidences from in vitro studies by others and our laboratory suggest the role of OPN as a mediator of tumor promotion. Using the two-stage skin chemically-induced carcinogenesis model, we have shown that induction of OPN expression and secretion into the microenvironment is an important rate-limiting factor in tumor promotion. We postulate that alterations in the matrix microenvironment, such as elevated OPN, is critical to the survival of initiated cells, thereby, resulting in more papilloma formation compared to those of OPN-ablated mice. Our hypothesis is consistent with our photocarcinogenesis model since long-term UVB exposure of OPN-null mice skin showed suppressed squamous cell carcinoma (SCC) development compared to that of wild-type mice (Chang et al., manuscript submitted). Studies are on-going to define the mechanism by which OPN functions to promote tumor development.
To define the role of host-derived OPN in tumor progression and metastasis, we have established an OPN null squamous cell carcinoma (SCC) cell line (named ONSC), which develops SCC and metastasizes to the lung not only in nude mice, but also in both syngeneic wild-type and OPN null mice. This novel cell line allows us to study the role of induced host-derived OPN in regulating SCC tumor progression and metastasis in an immune-competent mouse.