P3-18-01: cMET Inhibitor and the Inhibition of Growth of Breast Cancer Cells in Bone Marrow Matrix Environment.

Abstract

Abstract Background: Hepatocyte growth factor (HGF) is a cytokine that has a diverse but potential role in cancer including breast cancer. HGF, which action is mediated by its specific receptor, cMET, stimulate the aggressiveness of cancer cells by increasing the invasiveness and cellular migration. HGF is also a potent angiogenic factor. Small inhibitors to the HGF receptor are currently investigated in clinical trials of various cancers. In solid tumours which have potency of bone metastasis, HGF and particularly the HGF receptor, cMET, have been found to be particularly over-expressed in tumour cells metastasised to bones. Materials and methods. A panel of breast cancer cell lines were used. Cell growth was determined using a colorimetic method. Cell adhesion and migration were investigated using a ECIS model. Bone matrix proteins were prepared from fresh bones. A small inhibitor to human cMET, PF02341066 was used in the present study in all the cell models. Results. Depending on cell types, cancer cells tended to grow at a faster rate in bone marrow microenvironment than under normal conditions (12% higher for MDA MB 231 cells, for example). While PF02341066 have a concentration dependent effect on the growth of breast cancer, this effect became more marked when cells were growing in the bone marrow matrix. Breast cancer cells migrated rapidly in the presence of bone marrow environment, in comparison with controls. This was also inhibited by the cMET inhibitor. The study further showed that cells over-expressing a molecule linked to bone metastasis, namely ALCAM (1,2), responded more vigorously to cMET inhibitor in the matrix adhesion and cellular migration. Conclusions. The present study has shown that the HGF receptor inhibitor has an inhibitory effect on breast cancer cells. This is particularly so when cells are grown in bone matrix microenvironment. It is concluded therefore that inhibitors to the HGF receptor may have a particular role in the management of bone metastasis in breast cancer.