DMXAA causes tumor site-specific vascular disruption in murine non-small cell lung cancer, and like the endogenous non-canonical cyclic dinucleotide STING agonist, 2'3'-cGAMP, induces M2 macrophage repolarization.

Abstract

The vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a murine agonist of the stimulator of interferon genes (STING), appears to target the tumor vasculature primarily as a result of stimulating pro-inflammatory cytokine production from tumor-associated macrophages (TAMs). Since there were relatively few reports of DMXAA effects in genetically-engineered mutant mice (GEMM), and models of non-small cell lung cancer (NSCLC) in particular, we examined both the effectiveness and macrophage dependence of DMXAA in various NSCLC models. The DMXAA responses of primary adenocarcinomas in K-rasLA1/+ transgenic mice, as well as syngeneic subcutaneous and metastatic tumors, generated by a p53R172HΔg/+; K-rasLA1/+ NSCLC line (344SQ-ELuc), were assessed both by in vivo bioluminescence imaging as well as by histopathology. Macrophage-dependence of DMXAA effects was explored by clodronate liposome-mediated TAM depletion. Furthermore, a comparison of the vascular structure between subcutaneous tumors and metastases was carried out using micro-computed tomography (micro-CT). Interestingly, in contrast to the characteristic hemorrhagic necrosis produced by DMXAA in 344SQ-ELuc subcutaneous tumors, this agent failed to cause hemorrhagic necrosis of either 344SQ-ELuc-derived metastases or autochthonous K-rasLA1/+ NSCLCs. In addition, we found that clodronate liposome-mediated depletion of TAMs in 344SQ-ELuc subcutaneous tumors led to non-hemorrhagic necrosis due to tumor feeding-vessel occlusion. Since NSCLC were comprised exclusively of TAMs with anti-inflammatory M2-like phenotype, the ability of DMXAA to re-educate M2-polarized macrophages was examined. Using various macrophage phenotypic markers, we found that the STING agonists, DMXAA and the non-canonical endogenous cyclic dinucleotide, 2'3'-cGAMP, were both capable of re-educating M2 cells towards an M1 phenotype. Our findings demonstrate that the choice of preclinical model and the anatomical site of a tumor can determine the vascular disrupting effectiveness of DMXAA, and they also support the idea of STING agonists having therapeutic utility as TAM repolarizing agents.

• Authors: Charlene M Downey, Mehrnoosh Aghaei, Reto A Schwendener, Frank R Jirik
• Journal: PloS one (PLoS One) Vol. 9 Issue 6 Pg. e99988 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24940883 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Liposomes
• Membrane Proteins
• Nucleotides, Cyclic
• Sting1 protein, mouse
• Tumor Suppressor Protein p53
• Xanthones
• cyclic guanosine monophosphate-adenosine monophosphate
• Clodronic Acid
• vadimezan
• ras Proteins

Topics

• Adenocarcinoma (blood supply, drug therapy)
• Animals
• Carcinoma, Non-Small-Cell Lung (blood supply, drug therapy, pathology)
• Cell Membrane Permeability (drug effects)
• Cell Polarity (drug effects)
• Clodronic Acid (pharmacology, therapeutic use)
• Humans
• Inflammation (pathology)
• Liposomes (chemistry)
• Lung Neoplasms (blood supply, drug therapy)
• Macrophages (drug effects, pathology)
• Male
• Membrane Proteins (agonists)
• Mice, Transgenic
• Necrosis
• Neovascularization, Pathologic (drug therapy, pathology)
• Nucleotides, Cyclic (pharmacology, therapeutic use)
• Phenotype
• Subcutaneous Tissue (drug effects)
• Tumor Suppressor Protein p53 (metabolism)
• Xanthones (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays
• ras Proteins (metabolism)