The Endothelin axis in the primary tumour, the tumour microenvironment and the premetastatic niche – Visualization by target-specific imaging
Hematology, Oncology
Final Report Abstract
The prognosis of malignant disease is mainly determined by the individual potential of the tumour to spread systemically and form distant metastases. The endothelin (ET) axis, composed of three peptide hormones (ET-1, -2 and -3) and the two receptor subtypes ETAR and ETBR, is a potent regulator of immune cell recruitment and activation, putatively involved in the induction of tumour-associated immune cells and premetastatic tissue priming. In recent years, activation of intrinsic immune defence mechanisms for combatting tumour growth and spread and the inhibition of tumour-supportive immune signalling have been established as a promising therapeutic option. The formation of distant metastases by seeding of tumour cells within a fostered premetastatic niche is also a process putatively dependent on this interaction. The aim of this project was to visualize the influence of the endothelin axis on immune response within the tumour and the tumour microenvironment (TME) by utilizing small molecular fluorescent probes for optical and optoacoustic in vivo imaging of murine breast cancer. Therefore, the development of an ETBR selective probe was necessary; an ETAR selective probe was already at hand. After initial in vitro investigations in receptor-based assays, first in vivo experiments provided data of the biodistribution and about pharmacokinetic parameters. A simultaneous detection of ETAR and ETBR directed probes in murine breast cancer models was then realized by labelling of the two probes with different fluorescent dyes, which could be distinguished by the imaging systems’ filter settings. The two syngeneic murine breast cancer cell lines used in these experiments, of which one has a high malignant potential, showed a markedly different accumulation of the two probes, hinting at a differential and defined regulation during tumour growth. To pinpoint possible relationships to the activated immune system, we analysed a set of immune cells within the TME concerning their co-expression of ET receptors. We found that especially ETBR was co-expressed with immune cell markers CD19, Ly6C and F4/80. ETAR was mainly found co-expressed with CD4 and Ly6C, but not as frequent as ETBR. In general, the more aggressive tumour expressed more ET receptors on immune cells.
Publications
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Exploring the Influence of Different Albumin Binders on Molecular Imaging Probe Distribution. Molecular Pharmaceutics, 18(7), 2574-2585.
Höltke, Carsten; Grewer, Martin; Stölting, Miriam; Geyer, Christiane; Wildgruber, Moritz & Helfen, Anne
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How Different Albumin-Binders Drive Probe Distribution of Fluorescent RGD Mimetics. Frontiers in Chemistry, 9.
Höltke, Carsten; Alsibai, Wael; Grewer, Martin; Stölting, Miriam; Geyer, Christiane; Eisenblätter, Michel; Wildgruber, Moritz & Helfen, Anne
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New tools for imaging the endothelial axis in the tumor microenvironment; European Molecular Imaging Meeting, Thessaloniki 2022
Delahaye J., Stölting M., Geyer C., Helfen A., Eisenblätter M. & Höltke C.
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Development, synthesis and evaluation of novel fluorescent Endothelin-B receptor probes. European Journal of Medicinal Chemistry, 258, 115568.
Delahaye, Juliette; Stölting, Miriam; Geyer, Christiane; Vogl, Thomas; Eisenblätter, Michel; Helfen, Anne & Höltke, Carsten
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Simultaneous in vivo evaluation of endothelin-A and -B receptors in a murine breast tumor model by fluorescence imaging; European Molecular Imaging Meeting, Salzburg 2023
Delahaye J., Stölting M., Geyer C., Helfen A., Eisenblätter M., Vogl T. & Höltke C.
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Comparison of the endothelin-A and -B receptors expression in different murine tumor models by simultaneous fluorescence imaging; Clinical Science 2024 May;138;A90-A91
Delahaye J., Stölting M., Geyer C., Eisenblätter M., Vogl T., Helfen A. & Höltke C.
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Linking the endothelin signaling axis and cancer immunology within the tumor micro-environment using optical imaging; European Molecular Imaging Meeting, Porto 2024
Delahaye J., Stölting M., Geyer C., Mallik M., Eisenblätter M., Helfen A., Vogl T. & Höltke C.
