title: Longitudinal imaging studies of tumor microenvironment in mice treated with the mTOR inhibitor rapamycin.
abstract: Rapamycin is an allosteric inhibitor of mammalian target of rapamycin, and inhibits tumor growth and angiogenesis. Recent studies suggested a possibility that rapamycin renormalizes aberrant tumor vasculature and improves tumor oxygenation. The longitudinal effects of rapamycin on angiogenesis and tumor oxygenation were evaluated in murine squamous cell carcinoma (SCCVII) by electron paramagnetic resonance imaging (EPRI) and magnetic resonance imaging (MRI) to identify an optimal time after rapamycin treatment for enhanced tumor radioresponse. Rapamycin treatment was initiated on SCCVII solid tumors 8 days after implantation (500-750 mm(3)) and measurements of tumor pO(2) and blood volume were conducted from day 8 to 14 by EPRI/MRI. Microvessel density was evaluated over the same time period by immunohistochemical analysis. Tumor blood volume as measured by MRI significantly decreased 2 days after rapamycin treatment. Tumor pO(2) levels modestly but significantly increased 2 days after rapamycin treatment; whereas, it decreased in non-treated control tumors. Furthermore, the fraction of hypoxic area (pixels with pO(2)<10 mm Hg) in the tumor region decreased 2 days after rapamycin treatments. Immunohistochemical analysis of tumor microvessel density and pericyte coverage revealed that microvessel density decreased 2 days after rapamycin treatment, but pericyte coverage did not change, similar to what was seen with anti-angiogenic agents such as sunitinib which cause vascular renormalization. Collectively, EPRI/MRI co-imaging can provide non-invasive evidence of rapamycin-induced vascular renormalization and resultant transient increase in tumor oxygenation. Improved oxygenation by rapamycin treatment provides a temporal window for anti-cancer therapies to realize enhanced response to radiotherapy.
authors.affiliation: Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Keita
authors.initials: K
authors.lastname: Saito
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Hironobu
authors.initials: H
authors.lastname: Yasui
authors.forename: Nallathamby
authors.initials: N
authors.lastname: Devasahayam
authors.forename: Sankaran
authors.initials: S
authors.lastname: Subramanian
authors.forename: Jeeva P
authors.initials: JP
authors.lastname: Munasinghe
authors.forename: Vyomesh
authors.initials: V
authors.lastname: Patel
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.forename: James B
authors.initials: JB
authors.lastname: Mitchell
authors.forename: Murali C
authors.initials: MC
authors.lastname: Krishna
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D003952:Diagnostic Imaging / Q000379:methods*; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008809:Mice, Inbred C3H; D008833:Microcirculation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D020533:Angiogenesis Inhibitors; D015415:Biomarkers; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D010100:Oxygen; D020123:Sirolimus