title: Collagen induced arthritis increases secondary metastasis in MMTV-PyV MT mouse model of mammary cancer.
abstract: BACKGROUND
  Several studies have demonstrated that sites of chronic inflammation are often associated with the establishment and growth of various malignancies. A common inflammatory condition in humans is autoimmune arthritis (AA). Although AA and cancer are different diseases, many of the underlying processes that contribute to the disorders of the joints and connective tissue that characterize AA also affect cancer progression and metastasis. Systemically, AA can lead to cellular infiltration and inflammation of the lungs. Several studies have reported statistically significant risk ratios between AA and breast cancer. Despite this knowledge being available, there has been minimal research linking breast cancer, arthritis, and metastasis associated with breast cancer. Notably both diseases are extremely prevalent in older post-menopausal women.
  
  
  METHODS
  To establish the novel link between arthritis induced inflammation and secondary metastasis associated with breast cancer, PyV MT mice that spontaneously develop mammary gland carcinoma were injected with Type II collagen (CII) to induce arthritis at 9 and 18 weeks of age for pre-metastatic and metastatic condition. The sites of secondary metastasis and the associated inflammatory microenvironment were evaluated.
  
  
  RESULTS
  A significant increase in breast cancer-associated secondary metastasis to the lungs and bones was observed in the arthritic versus the non-arthritic PyV MT mice along with an increase in primary tumor burden. We report significant increases in the levels of interstitial cellular infiltrates and pro-inflammatory cytokines such as interleukin-17 (IL-17), interleukin-6 (IL-6), Pro- Matrix metallopeptidase 9 (Pro-MMP9), insulin like growth factor-II (GF-II) and macrophage colony stimulating factor (M-CSF) in the arthritic lung and bone milieu as well as in the circulation. These pro-inflammatory cytokines along with the inflammatory microenvironment may be the underlying factors facilitating tumor progression and metastasis in arthritic PyV MT mice. This was further substantiated by treatment with celecoxib, an anti-inflammatory drug + αIL-17 antibody that significantly reduced the secondary metastasis to lung and bone.
  
  
  CONCLUSIONS
  The data generated not only reveal the underlying mechanism of high susceptibility to bone and lung metastasis in an arthritic condition but our combination therapies may lead to treatment modalities that will be capable of reducing tumor burden, and preventing relapse and metastasis in arthritic patients with breast cancer.
authors.affiliation: University of North Carolina at Charlotte, Dept, of Biology, 9201 University City Blvd., NC 29223, USA.
authors.forename: Lopamudra Das
authors.initials: LD
authors.lastname: Roy
authors.forename: Sriparna
authors.initials: S
authors.lastname: Ghosh
authors.forename: Latha B
authors.initials: LB
authors.lastname: Pathangey
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Tinder
authors.forename: Helen E
authors.initials: HE
authors.lastname: Gruber
authors.forename: Pinku
authors.initials: P
authors.lastname: Mukherjee
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary; D000068579:Celecoxib; D024043:Collagen Type II; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000378:metabolism; D005260:Female; D006651:Histocytochemistry; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000556:secondary*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D024043:Collagen Type II; D052246:Cyclooxygenase 2 Inhibitors; D004792:Enzyme Precursors; D020381:Interleukin-17; D015850:Interleukin-6; D011720:Pyrazoles; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D007335:Insulin-Like Growth Factor II; D016173:Macrophage Colony-Stimulating Factor; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9; D000068579:Celecoxib