Please use this identifier to cite or link to this item: https://doi.org/10.1158/1078-0432.CCR-04-2048
Title: Elevated physiologic tumor pressure promotes proliferation and chemosensitivity in human osteosarcoma
Authors: Nathan, S.S 
DiResta, G.R
Casas-Ganem, J.E
Hoang, B.H
Sowers, R
Yang, R
Huvos, A.G
Gorlick, R
Healey, J.H
Keywords: cisplatin
doxorubicin
ifosfamide
methotrexate
transcription factor E2F1
transcription factor E2F4
adolescent
adult
article
blood flow
cancer cell
cancer chemotherapy
cancer growth
cancer surgery
cancer survival
cell cycle S phase
cell proliferation
chemosensitivity
clinical article
controlled study
correlation analysis
Doppler flowmetry
female
human
human cell
hydrostatic pressure
male
osteosarcoma
osteosarcoma cell
priority journal
school child
tissue pressure
tumor biopsy
tumor necrosis
Adolescent
Adult
Animals
Antibiotics, Antineoplastic
Antineoplastic Agents
Atmospheric Pressure
Blood Flow Velocity
Bone Neoplasms
Cell Proliferation
Child
Cisplatin
Doxorubicin
Drug Resistance, Neoplasm
Extracellular Fluid
Female
Humans
Male
Middle Aged
Necrosis
Osteosarcoma
S Phase
Survival Rate
Tumor Cells, Cultured
Issue Date: 2005
Citation: Nathan, S.S, DiResta, G.R, Casas-Ganem, J.E, Hoang, B.H, Sowers, R, Yang, R, Huvos, A.G, Gorlick, R, Healey, J.H (2005). Elevated physiologic tumor pressure promotes proliferation and chemosensitivity in human osteosarcoma. Clinical Cancer Research 11 (6) : 2389-2397. ScholarBank@NUS Repository. https://doi.org/10.1158/1078-0432.CCR-04-2048
Rights: Attribution 4.0 International
Abstract: Purpose: This study investigates the effect of constitutively raised interstitial fluid pressure on osteosarcoma physiology and chemosensitivity. Experimental Design: 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. ©2005 American Association for Cancer Research.
Source Title: Clinical Cancer Research
URI: https://scholarbank.nus.edu.sg/handle/10635/181094
ISSN: 10780432
DOI: 10.1158/1078-0432.CCR-04-2048
Rights: Attribution 4.0 International
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