Elevated physiologic tumor pressure promotes proliferation and chemosensitivity in human osteosarcoma Journal Article
| 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. |
| Article Title: | Elevated physiologic tumor pressure promotes proliferation and chemosensitivity in human osteosarcoma |
| 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. |
| Keywords: | osteosarcoma; adolescent; adult; cancer chemotherapy; cancer survival; child; clinical article; controlled study; school child; bone neoplasms; middle aged; cancer surgery; survival rate; human cell; cisplatin; doxorubicin; cancer growth; antineoplastic agents; methotrexate; cell proliferation; animals; cell cycle s phase; tumor biopsy; drug resistance, neoplasm; tumor cells, cultured; chemosensitivity; necrosis; ifosfamide; correlation analysis; cancer cell; antibiotics, antineoplastic; blood flow; extracellular fluid; tissue pressure; transcription factor e2f1; s phase; osteosarcoma cell; blood flow velocity; tumor necrosis; doppler flowmetry; hydrostatic pressure; atmospheric pressure; transcription factor e2f4 |
| Journal Title: | Clinical Cancer Research |
| Volume: | 11 |
| Issue: | 6 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2005-03-15 |
| Start Page: | 2389 |
| End Page: | 2397 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-04-2048 |
| PUBMED: | 15788690 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 32" - "Export Date: 24 October 2012" - "CODEN: CCREF" - "Source: Scopus" |
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