title: Interstitial fluid pressure, vascularity and metastasis in ectopic, orthotopic and spontaneous tumours.
abstract: BACKGROUND
  High tumour interstitial fluid pressure (IFP) has been adversely linked to poor drug uptake in patients, and to treatment response following radiotherapy in cervix cancer patients. In this study we measured IFP values in a selection of murine and xenograft models, spontaneously arising or transplanted either intramuscularly (i/m) or orthotopically and analysed their relationship to tumour vascularity and metastatic spread.
  
  
  METHODS
  KHT-C murine fibrosarcoma, ME180 and SiHa human cervix carcinoma were grown either intramuscularly (i/m), sub-cutaneously (s/c) or orthotopically. Polyoma middle-T (MMTV-PyMT) transgenic spontaneous mammary tumours were studied either as spontaneous tumours or following orthotopic or i/m transplantation. IFP was measured in all tumours using the wick-in-needle method. Spontaneous metastasis formation in the lungs or lymph nodes was assessed in all models. An immunohistochemical analysis of tumour hypoxia, vascular density, lymphatic vascular density and proliferation was carried out in ME180 tumours grown both i/m and orthotopically. Blood flow was also assessed in the ME180 model using high-frequency micro-ultrasound functional imaging.
  
  
  RESULTS
  Tumour IFP was heterogeneous in all the models irrespective of growth site: KHT-C i/m: 2-42 mmHg, s/c: 1-14 mmHg, ME180: i/m 5-68 mmHg, cervix 4-21 mmHg, SiHa: i/m 20-56 mmHg, cervix 2-26 mmHg, MMTV-PyMT: i/m: 13-45 mmHg, spontaneous 2-20 mmHg and transplanted 2-22 mmHg. Additionally, there was significant variation between individual tumours growing in the same mouse, and there was no correlation between donor and recipient tumour IFP values. Metastatic dissemination to the lungs or lymph nodes demonstrated no correlation with tumour IFP. Tumour hypoxia, proliferation, and lymphatic or blood vessel density also showed no relationship with tumour IFP. Speckle variance analysis of ultrasound images showed no differences in vascular perfusion between ME180 tumours grown i/m versus orthotopically despite differences in IFP.
  
  
  CONCLUSIONS
  Our studies across a range of different tumour models showed substantial heterogeneity in tumour IFP, suggesting differences in the vascular development and interstitial fluid dynamics in the individual tumours. The results demonstrate a strong stochastic aspect to tumour IFP development, notably the variation apparent between different tumours within the same animal and the lack of correlation between donor and recipient tumours.
authors.affiliation: Ontario Cancer Institute, Princess Margaret Hospital, University of Toronto, 610 University Ave, Toronto, Ontario, M5G 2M9, Canada. slunt@uhnres.utoronto.ca
authors.forename: Sarah Jane
authors.initials: SJ
authors.lastname: Lunt
authors.forename: Tuula Mk
authors.initials: TM
authors.lastname: Kalliomaki
authors.forename: Allison
authors.initials: A
authors.lastname: Brown
authors.forename: Victor X
authors.initials: VX
authors.lastname: Yang
authors.forename: Michael
authors.initials: M
authors.lastname: Milosevic
authors.forename: Richard P
authors.initials: RP
authors.lastname: Hill
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D045604:Extracellular Fluid; D005260:Female; D006801:Humans; D000860:Hypoxia; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000473:pathology*; D011312:Pressure; D014463:Ultrasonography