title: Elevated physiologic tumor pressure promotes proliferation and chemosensitivity in human osteosarcoma.
abstract: OBJECTIVE
  This study investigates the effect of constitutively raised interstitial fluid pressure on osteosarcoma physiology and chemosensitivity.
  
  
  METHODS
  We did pressure and blood flow assessments at the time of open biopsy in patients with the diagnosis of high-grade osteosarcoma and correlated this to survival and chemotherapy-associated tumor necrosis. Osteosarcoma cell lines were then evaluated for proliferative and therapeutic indices in a replicated high-pressure environment.
  
  
  RESULTS
  Sixteen osteosarcomas in vivo were assessed and exhibited elevated interstitial fluid pressures (mean 35.2 +/- SD, 18.6 mmHg). This was not associated with significantly impeded blood flow as measured by a Doppler probe at a single site (P < 0.12). Nonetheless, greater chemotherapy-associated necrosis and associated longer survival were seen in tumors with higher interstitial fluid pressures (P < 0.05). In vitro, cells undergo significant physiologic changes under pressure. Osteosarcoma cell lines grown in a novel hydrostatically pressurized system had variable cell line-specific growth proportional to the level of pressure. They were more proliferative as indicated by cell cycle analysis with more cells in S phase after 48 hours of pressurization (P < 0.01). There was a significant elevation in the cell cycle-related transcription factors E2F-1 (P < 0.03) and E2F-4 (P < 0.002). These changes were associated with increased chemosensitivity. Cells tested under pressure showed an increased sensitivity to cisplatin (P < 0.00006) and doxorubicin (P < 0.03) reminiscent of the increased chemotherapy-associated necrosis seen in tumors with higher interstitial fluid pressure in the clinical study.
  
  
  CONCLUSIONS
  The results of this study suggest that cells in the in vivo pressurized environment are at a higher state of regenerative activity than is demonstrable in conventional cell culture systems. Variations in tumor interstitial fluid pressure have the potential to alter chemotherapeutic effects.
authors.affiliation: Orthopaedic Surgery Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275A York Avenue, New York, NY 10021, USA.
authors.forename: Saminathan S
authors.initials: SS
authors.lastname: Nathan
authors.forename: Gene R
authors.initials: GR
authors.lastname: DiResta
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Casas-Ganem
authors.forename: Bang H
authors.initials: BH
authors.lastname: Hoang
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sowers
authors.forename: Rui
authors.initials: R
authors.lastname: Yang
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Huvos
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.forename: John H
authors.initials: JH
authors.lastname: Healey
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001274:Atmospheric Pressure; D001783:Blood Flow Velocity; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002648:Child; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D045604:Extracellular Fluid / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology*; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004317:Doxorubicin; D002945:Cisplatin