Abstract 1366: Inhibition of Tie2+ macrophage infiltration into tumors in combination with CA-4-P therapy may enhance the clinical efficacy of this vascular disrupting agent
Authors: Welford Abigail F. , Venneri Mary A. , Biziato Daniele , Naldini Luigi , Palma Michele De , Lewis Claire E. , Tozer Gillian M. 
Published: February 2011

Rationale & Hypothesis: Combretastatin A-4-phosphate (CA-4-P), a tubulin-binding, vascular-disrupting agent (VDA), induces rapid and selective tumour vascular shutdown and secondary tumour cell death. However, acute revascularisation contributes to treatment resistance. A group of myeloid cells in tumours, tumour associated macrophages (TAMs) are known to drive tumour angiogenesis and progression. A potently pro-angiogenic subpopulation of TAMs has also been identified which are Tie2 expressing monocytes (TEMs). We hypothesize that TAMs and/or TEMs infiltrate tumours treated with CA-4-P and promote tumour angiogenesis from residual vessels in the tumour periphery, driving tumour recovery.

Methodology & Conclusions: Late stage Polyoma Middle T (PyMT) spontaneous murine breast adenocarcinomas were excised from CA-4-P- and saline-treated mice. Twenty-four hours following a single injection of 50mg/kg CA-4-P, there was significant tumour necrosis (19.37 ± 4.60%) compared with 1.76 ± 0.34% in saline controls. This was accompanied by tumour infiltration of F4/80+ macrophages, 5.61 ± 0.46%, compared with 0.71± 0.08% in saline controls. Macrophages were primarily located in stromal regions between tumour lobules and showed co-localisation with CA4-P-induced hypoxia. A subset were Tie2+, and expressed MMP-9, a potently angiogenic molecule, which increases the bioavailability of VEGF. Significant increases in the number of MMP-9 expressing macrophages were evident following CA-4-P treatment (5.72 ± 0.34% compared with 2.66 ± 0.25% in saline controls).

Furthermore, in a N202 murine mammary carcinoma model, specific depletion of TEMs, via genetic manipulation and bone marrow transplantation revealed heightened efficacy of CA-4-P in eliciting tumour damage. Tumour necrosis was increased significantly when CA-4-P was administered in combination with TEM depletion (22.45%), compared to saline controls (0.37%) and CA-4-P therapy alone (12.89%). This was attributed to a significant reduction in the number of MMP-9 positive TEMs (0.08 ± 0.18% compared with 1.37 ± 0.21% in saline controls and 3.67± 0.11% in CA-4-P treated tumours).

The significant increase in tumour necrosis following depletion of TEMs suggests that these cells are involved in the recovery of tumours following CA-4-P treatment. The role of MMP-9 expression by TEMs warrants further investigation. Targeting TEMs, in combination with vascular-disrupting drugs such as CA-4-P, has potential as a novel therapeutic strategy for solid tumours.

Funded by Cancer Research UK

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1366.