VERSICAN G-3 DOMAIN INFLUENCES BREAST CARCINOMA METASTASES TO BONE

Abstract

Versican is a large extracellular proteoglycan that is expressed in a variety of tissues and primary malignancies including infiltrating breast carcinoma. It also appears that versican can inhibit intercellular adhesion of normal as well as malignant cells. With the observation of selectin-like properties of versican G3 the investigators hypothesise that versican G3 influences not only local tumour invasiveness but also systemic metastases including the spread to bony sites. The present study aimed to test the hypothesis of versican G3 associated metastatic invasiveness in a murine osteolytic metastatic model of human breast carcinoma.

Human carcinoma cells (MT-1), transfected with the either a versican-G3-construct (n=7) or a vector-control (n=8) gene, were injected intracardically female athymic rats. The rats were examined clinically at serial time-points following injection and animal weight recorded. Animals were euthanised three weeks after tumour cell injection. On digital lateral radiographs of the scapula osteolytic areas were measured. Additionally, histomorphometry was performed on sections stained with human EGFr antibody to evaluate tumour burden within rodent vertebrae. Statistical analyses were performed using one way ANOVA.

All rats demonstrated weight loss approximately three weeks following tumour cell injection. However, the extent of weight loss observed over time was greater for the versicanG3 group (p< 0.05). Osteolytic metastases were observed using fine detail radiography at the day of euthanasia. Osteolytic burden was greater (p < 0.002) in the G3 transfected group (34.7 %; lytic area scapula) when compared to vector-control animals (8 %).

Versican G3 domain appears to influence the development of metastases to bone and soft tissue. The propensity of versican G3 to influence tumour invasion to bone and the mechanisms of versican G3 mediated osteolysis warrants ongoing study. With the known interactions between versican G3 and beta1 integrin in other cancer cell types and the increasing knowledge regarding several beta3 integrin-expressing cell populations, including osteoclasts in breast cancer tumour progression, the potential interaction between versican G3 and integrin receptors in bone may influence tumour mediating chemotactic and haptotactic migration towards bone factors.