Influence of components of tumour microenvironment on the response of HCT-116 colorectal cancer to the ruthenium-based drug NAMI-A

Solid tumours are constituted of tumour cells, healthy cells recruited from the host tissues and soluble factors released by both these cell types. The present investigation examines the capacity of co-cultures between the HCEC colon epithelial cells and the HCT-116 colorectal cancer cells (mimicking the primary site of tumour growth) and between IHH hepatocytes and the HCT-116 colorectal cancer cells (metastatic site) to influence the effects of NAMI-A (imidazolium trans-imidazoledimethylsulphoxidetetrachloro ruthenate) on the tumour cells themselves. The growth of HCT-116 cells is significantly influenced when the cancer cells are sown on a monolayer of HCEC. The release of soluble factors by the healthy cells promotes, in HCT-116 colorectal cancer cells, the transcription of genes involved in growth, invasion and migration. NAMI-A is not cytotoxic to HCT-116 cells grown on plastics or co-cultured with HCEC or IHH cells, and maintains its ability to control the cell pseudo-metastatic ability, mimicked by the migration in the scratch test. The effects of NAMI-A on HCT-116 migration are supported by its inhibition of the transcription of the ABL-2, ATF-3 and RND-1 genes. In conclusion the study highlights the need of test systems more complex than a single cancer cell culture to study an anticancer drug in vitro and reinforces the hypothesis that NAMI-A targets the ability of the cancer cell to interact with the tumour microenvironment and with the signals that support its metastatic ability.