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 mm3) and measurements of tumor pO2 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 pO2 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 pO2<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.
Highlights
Multiple genetic and epigenetic events are known to result in the dysregulation of several signaling pathways that have an impact on neoplastic disease progression, such as squamous cell carcinomas (SCC) [1,2]
A recent study using a reverse-pharmacology approach, which involved the expression of a rapamycin-insensitive form of mammalian target of rapamycin (mTOR) in squamous cancer cells, showed that cancer cells are the primary targets of rapamycin in vivo, and that mTOR controls the expression of hypoxia-inducible factor-1a (HIF-1a), a key transcription factor that orchestrates the cellular response to hypoxic stress, including the regulation of the expression of angiogenic factors, providing a likely mechanism by which rapamycin exerts its tumor suppressive and antiangiogenic effects [13]
These results suggest that the SCCVII implants in C3H mice were sensitive to rapamycin as evidenced by the tumor growth inhibition
Summary
Multiple genetic and epigenetic events are known to result in the dysregulation of several signaling pathways that have an impact on neoplastic disease progression, such as squamous cell carcinomas (SCC) [1,2] One such pathway, the phosphatidylinositol 3-kinase (PI3K)-Akt pathway is frequently activated in many cancers, and controls cellular metabolism, growth, and proliferation [3,4,5,6]. The mammalian target of rapamycin (mTOR) is an atypical serine/ threonine kinase, which acts downstream of PI3K/Akt and, has become an attractive therapeutic target [7,8,9,10] It follows that inhibitors of mTOR, such as rapamycin and its derivatives are currently being evaluated for molecular targeted therapy of neoplastic diseases [9]. Blocking mTOR pathway in SCC tumors was shown to prevent accumulation of HIF-1a resulting in inhibition of processes involved in glucose metabolism as well as decrease in proangiogenic factors such as vascular endothelial growth factor (VEGF) [13]
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