title: Dissection of stromal and cancer cell-derived signals in melanoma xenografts before and after treatment with DMXAA.
abstract: BACKGROUND
  The non-malignant cells of the tumour stroma have a critical role in tumour biology. Studies dissecting the interplay between cancer cells and stromal cells are required to further our understanding of tumour progression and methods of intervention. For proof-of-principle of a multi-modal approach to dissect the differential effects of treatment on cancer cells and stromal cells, we analysed the effects of the stromal-targeting agent 5,6-dimethylxanthenone-4-acetic acid on melanoma xenografts.
  
  
  METHODS
  Flow cytometry and multi-colour immunofluorescence staining was used to analyse leukocyte numbers in xenografts. Murine-specific and human-specific multiplex cytokine panels were used to quantitate cytokines produced by stromal and melanoma cells, respectively. Human and mouse Affymetrix microarrays were used to separately identify melanoma cell-specific and stromal cell-specific gene expression.
  
  
  RESULTS
  5,6-Dimethylxanthenone-4-acetic acid activated pro-inflammatory signalling pathways and cytokine expression from both stromal and cancer cells, leading to neutrophil accumulation and haemorrhagic necrosis and a delay in tumour re-growth of 26 days in A375 melanoma xenografts.
  
  
  CONCLUSIONS
  5,6-Dimethylxanthenone-4-acetic acid and related analogues may potentially have utility in the treatment of melanoma. The experimental platform used allowed distinction between cancer cells and stromal cells and can be applied to investigate other tumour models and anti-cancer agents.
authors.affiliation: Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: K
authors.initials: K
authors.lastname: Henare
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: L-C S
authors.initials: LC
authors.lastname: Wang
authors.forename: L
authors.initials: L
authors.lastname: Thomsen
authors.forename: S
authors.initials: S
authors.lastname: Tijono
authors.forename: C-J J
authors.initials: CJ
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Winkler
authors.forename: P R
authors.initials: PR
authors.lastname: Dunbar
authors.forename: C
authors.initials: C
authors.lastname: Print
authors.forename: L-M
authors.initials: LM
authors.lastname: Ching
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation; D044004:Xanthones / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D018398:Homeodomain Proteins; D044004:Xanthones; C066668:vadimezan; C064658:RAG-1 protein