Abstract
The outcome of tumor treatment via hyperthermia in the clinic has been reported to be heterogeneous. Here, we assessed how the presence of gastrin-releasing peptide receptor (GRPR) and αvβ3 integrin together with the morphology of the vascularization reflects the growth behavior of tumors after hyperthermia treatment. MDA-MB-231 tumor bearing mice were treated either with high (46 °C) or low dose (42 °C) water hyperthermia for 60 min. Changes of GRPR and αvβ3 integrin expression were assessed via multiplexed optical imaging. Vascularization was reconstructed and quantified by µCT imaging after contrast agent injection. We found that high dose hyperthermia is capable of increasing the expression of GRPR, αvβ3 integrin, CD31, and Ki67 in tumors. Also the morphology of tumor vasculature changed (increased relative blood volume and small-diameter vessel density, decreased expression of α-SMA). Low dose hyperthermia induced comparatively moderate effects on the investigated protein expression pattern and vascular remodeling. We conclude that under defined circumstances, specific temperature doses affect the reorganization of tumor regrowth, which is triggered by residual “dormant” cells even though tumor volumes are transiently decreasing. Further on, GRPR, αvβ3 integrin expression are versatile tools to surveil potential tumor regrow during therapy, beyond the conventional determination of tumor volumes.
Highlights
Hyperthermia has been recognized as a potent therapeutic strategy against cancer
Flow cytometry analysis showed that gastrin-releasing peptide receptor (GRPR) expression was enhanced in cells treated with hyperthermia at 44 °C (24 h post therapy) and increased even more when temperatures increased to 46 °C
A similar situation was encountered via protein analysis: After hyperthermia at temperatures ranging between 40 and 44 °C, no distinct changes were found in GRPR expression between treated and untreated cells
Summary
Hyperthermia has been recognized as a potent therapeutic strategy against cancer. Despite of it, its transfer and implementation into the clinical situation progresses slowly. To the best of our knowledge, there is no consistent understanding of the biomedical reasons which are responsible for the heterogeneity of the therapy success of hyperthermia Such investigations will require the utilization of specific protein structures, which allow the monitoring of the impact of hyperthermia on the target tumor tissue. Imaging approaches on the molecular level make the GRPR a very attractive marker for monitoring of the tumor therapeutic efficiency of hyperthermia. In whole body imaging applications αvβ[3] integrin is capable of assessing the presence of tumor vascularity[16,17,18], in post-therapy monitoring applications[19]. The presence of vascularity is essential for tumor growth and metastasis For this reason, αvβ[3] integrin is an appealing marker for monitoring the effects of hyperthermia on vascularity
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