Galectin-3 Targeting in Thyroid Orthotopic Tumors Opens New Ways to Characterize Thyroid Cancer

Abstract

Preoperative characterization of thyroid nodules is challenging since thyroid scintigraphy fails to distinguish between benign and malignant lesions. Galectin-3 (gal-3) is expressed in well-differentiated and in undifferentiated thyroid cancer types but not in normal thyrocytes and benign thyroid lesions. Herein, we aimed to validate gal-3 targeting as a specific method to detect non-radioiodine-avid thyroid cancer in thyroid orthotopic tumor models. Methods: Papillary (BcPAP) and anaplastic (CAL62 and FRO82-1) thyroid carcinoma cell lines were characterized via Western blot and polymerase chain reaction for gal-3 and sodium-iodide symporter (NIS) expression. An 89 Zr-labeled F(ab′) 2 antigal-3 was generated and characterized for binding versus 125 I on 2-and 3-dimensional cell cultures. The thyroid carcinoma cells were inoculated into the left thyroid lobe of athymic nude mice, and the orthotopic tumor growth was monitored via ultrasound and fluorescence molecular tomography. Head-to-head PET/CT comparison of 124 I versus 89 Zr-deferoxamine (DFO)-F(ab′) 2 antigal-3 was performed, followed by biodistribution studies and immunohistochemical analysis for gal-3 and NIS expression. Results: The thyroid carcinoma cells investigated were invariably gal-3-positive while presenting low or lost NIS expression. 89 Zr-DFO-F(ab′) 2 antigal-3 tracer showed high affinity to gal-3 (dissociation constant, ∼3.9 nM) and retained immunoreactivity (.75%) on 2-dimensional cell cultures and on tumor spheroids. 125 I internalization in FRO82-1, BcPAP, and CAL62 was directly dependent on NIS expression, both in 2-dimensional and tumor spheroids. PET/CT imaging showed 89 Zr-DFO-F(ab′) 2 antigal-3 signal associated with the orthotopically implanted tumors only; no signal was detected in the tumor-free thyroid lobe. Conversely, PET imaging using 124 I showed background accumulation in tumor-infiltrated lobe, a condition simulating the presence of non-radioiodine-avid thyroid cancer nodules, and high accumulation in normal thyroid lobe. Imaging data were confirmed by tracer biodistribution studies and immunohistochemistry. Conclusion: A specific and selective visualization of thyroid tumor by targeting gal-3 was demonstrated in the absence of radioiodine uptake. Translation of this method into the clinical setting promises to improve the management of patients by avoiding the use of unspecific imaging methodologies and reducing unnecessary thyroid surgery.

Lectin affinity chromatography and quantitative proteomic analysis reveal that galectin-3 is associated with metastasis in nasopharyngeal carcinoma

“…The released Galectin-3 can bind to components of extracellular matrix and its membrane counterparts of other cells, which have in a wide range of biological events including cellular homeostasis, immune function, angiogenesis, tumor invasion and metastasis 25 . Galectin-3 has been reported as a diagnostic or prognostic marker linked to metastasis in many types of cancer such as thyroid 26,27 , breast cancer 28 , melanoma 29 , lung cancer 30 , sarcoma 31 , gastric cancer 32 , prostate cancer 33 and oral tongue cancer 34 . Here, we showed that Galectin-3 was greatly expressed in highly metastatic NPC cells compared to lowly metastatic cells.…”

TP53 drives abscopal effect by secretion of senescence-associated molecular signals in non-small cell lung cancer

“…Consecutive 4-μm-thick tumor sections of formalin-fixed/paraffin-embedded xenografts were stained for Hematoxylin & Eosin (H&E), Lipofuscin detection or macrophage infiltration, as reported [ 25 ] and detailed in Supplementary notes .…”

Imaging atherosclerotic plaques by targeting Galectin-3 and activated macrophages using (89Zr)-DFO- Galectin3-F(ab')2 mAb

“…The conjugation with the AlexaFluor488 fluorescent dye and with a Cy5.5-NHS ester derivative, as well as the conjugation to desferrioxamine (DFO) and radiolabeling with 89 Z was carried out as previously reported ( supplementary material ) 20 .…”

“…Tracer biodistribution and organ accumulation analyses were evaluated as previously described 20 . Whole length aortas (from the sinotubular junction to the iliac bifurcation) were excised under a dissection microscope (Zeiss Stemi DV4 SPOT) as described earlier 23 .…”

“…These characteristics make Gal3 a potential target for non-invasive molecular imaging of atherosclerosis and in particular plaque vulnerability. Radiotracers based on a full Gal3 monoclonal antibody (mAb) and its F(ab') 2 fragment derivative have been developed and used for non-invasive imaging of Gal3-expressing tumors 18 - 20 . Here, we aimed at investigating whether it is feasible to specifically target and visualize Gal3 expression on the cells present in plaques, i.e.…”