Abstract
BackgroundSublethal photon irradiation was recently suspected to increase tumor cell motility and promote locoregional recurrence of disease. This study was set up to describe mechanisms underlying increased glioma cell migration through photon irradiation and to analyse the modifiability of photon-altered glioma cell motility by integrin inhibition.MethodsEight μm pore size membranes were coated with vitronectin (VN), collagen I and collagen IV. U87 and Ln229 glioma cells were analysed in migration experiments with and without radiotherapy (RT), serum stimulation and addition of monoclonal antibodies directed to human integrins ανβ3 and ανβ5. Quantitative FACS analysis of integrins was performed in U87 and Ln229 glioma cells following RT. Statistical analysis was performed using Student's t-test.ResultsGlioma cell migration is serum-dependent and can be increased by photon RT which leads to enhanced expression of Vn receptor integrins. Blocking of either ανβ3 or ανβ5 integrins by antibodies inhibits Vn-based migration of both untreated and photon-irradiated glioma cells.ConclusionsPeripheral glioma cells are at risk of attraction into the adjacent healthy brain by serum components leaking through the blood brain barrier (BBB). Radiation therapy is associated with upregulation of Vn receptor integrins and enhanced glioma cell migration at sublethal doses. This effect can be inhibited by specific integrin blockade. Future therapeutical benefit may be derived from pharmacological integrin inhibition in combination with photon irradiation.
Highlights
Despite continuously evolving therapy regimes including extensive neurosurgery, multiagent chemotherapy, and dose-escalated conformal radiotherapy, primary brain tumors have not ceased to account for high lethality after short periods of time in most patients
Glioma cell migration is promoted by serum exposition Modified Boyden chamber assays were performed to analyse transmigration of U87 glioma cells through 8 μm pore size polycarbonate membranes coated with Vn and collagen I and IV
Sublethal photon irradiation enhances glioma cell migration Since photon irradiation is implemented in most glioma treatment protocols, we irradiated U87 glioma cells with single photon doses of 2 Gy and analysed transmigration 24 hours afterwards
Summary
Despite continuously evolving therapy regimes including extensive neurosurgery, multiagent chemotherapy, and dose-escalated conformal radiotherapy, primary brain tumors have not ceased to account for high lethality after short periods of time in most patients. Deep locoregional tumor cell infiltration that eludes modern imaging techniques and hampers complete local resection was accounted responsible for early relapse and spread of disease throughout the brain. Current glioma therapy involves surgical tumor resection followed by adjuvant radiotherapy combined with concomitant and adjuvant chemotherapy [1]. Deregulated tumor cell migration is typically associated with infiltration and dissemination, resulting in local disease progression and metastases, both of which account for the majority of cancer-associated deaths. Sublethal photon irradiation was recently suspected to increase tumor cell motility and promote locoregional recurrence of disease. This study was set up to describe mechanisms underlying increased glioma cell migration through photon irradiation and to analyse the modifiability of photon-altered glioma cell motility by integrin inhibition
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