Background and Aims:
Colorectal liver metastases (CRLM) is mainly derived from haematogenous dissemination however, lymphatic dissemination may also contribute to its spread. SAR131675 is a potent and selective VEGFR-3 inhibitor. This study aims to analyse the SAR131675 effects on tumour dissemination in a mouse model of CRLM.
Methods.
CRLM were induced in CBA mice by intra-splenic tumour injection of a mouse colorectal tumour cell line (MoCR). Animals were allocated into SAR131675 treatment or vehicle control groups. SAR131675 (100 mg/kg) was given daily from day 10 post-tumour induction until day 21, when tissues were collected. Tumour stereology Tumour volume and burden were assessed by sterealogy. Immunostaining was used to determine lymphatic and blood vessel density (podoplanin/ CD31 and CD34), proliferation (Ki67), apoptosis (caspase3), VEGFR3 expression (VEGFR3, macrophages (F4-80) and T cells (CD3). Serum cytokines were evaluated using.
Results.
Treatment with SAR131675 significantly reduced the number of metastases and tumour burden compared to control (p<0.02). No significant differences were seen in lymphatic and blood vessel density and in VEGFR3, ki-67 and caspase expression between groups. However significant reduction in macrophage numbers were seen in the treated group (in the liver and around the tumour vascular beds). Additionally there was a decrease in serum IL-10 and an increase in IFNγ in SAR131675 treated mice (p<0.05), denoting a T helper 1(Th1) immune response.
Conclusion.
SAR131675 treatment inhibits tumour progression at least in part through the modulation of the immune system possibly by reversing the immunosuppressive tumour microenvironment and inducing a tumouricidal immune response.