title: 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.affiliation: Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada; The McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Charlene M
authors.initials: CM
authors.lastname: Downey
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada; The McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Mehrnoosh
authors.initials: M
authors.lastname: Aghaei
authors.affiliation: Institute of Molecular Cancer Research, Laboratory of Liposome Research, University of Zurich, Zurich, Switzerland.
authors.forename: Reto A
authors.initials: RA
authors.lastname: Schwendener
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada; The McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Frank R
authors.initials: FR
authors.lastname: Jirik
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D002463:Cell Membrane Permeability / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects*; D004002:Clodronic Acid / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008081:Liposomes / Q000737:chemistry; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy; D008264:Macrophages / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000819:agonists*; D008822:Mice, Transgenic; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D009712:Nucleotides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use*; D010641:Phenotype; D040521:Subcutaneous Tissue / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044004:Xanthones / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000378:metabolism; D000099197:STING Protein
chemical_list: D004002:Clodronic Acid; D008081:Liposomes; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; D016159:Tumor Suppressor Protein p53; D044004:Xanthones; D018631:ras Proteins; C530855:Sting1 protein, mouse; D000099197:STING Protein; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C066668:vadimezan