Inhibition of metastatic tumor formation in vivo by a bacteriophage display-derived galectin-3 targeting peptide

Abstract

Galectin-3 (gal-3) is involved in the metastatic cascade and interacts with the cancer-associated carbohydrate, Thomsen-Freidenreich (TF) antigen during early stages of metastatic adhesion and tumor formation. Our laboratory previously utilized bacteriophage display to select a peptide, G3-C12, with high specificity and affinity for gal-3 that was able to inhibit cancer cell adhesion. We hypothesized that G3-C12 would inhibit TF/gal-3 and gal-3/gal-3 interactions in vitro and in vivo and would moderate early steps of the metastatic cascade leading to reduced carcinogenesis in vivo. To test this, adhesion of multiple breast carcinoma cell lines to purified gal-3 and a TF-mimic was measured in the presence/absence of G3-C12 resulting in an average reduction of cellular adhesion by 50 and 59 %, respectively. Sensitive optical imaging experiments were utilized to monitor the fate of intravenously injected MDA-MB-231 human breast carcinoma cells expressing luciferase into athymic nude mice in the presence/absence of G3-C12 in vivo. Intravenous administration of G3-C12 reduced lung colonization of MDA-MB-231-luciferase cells within mice by 72 % when compared to saline, whereas, control peptide treatments resulted in no significant reduction of colonization. Histologic examination of excised lung tissue, at day 70, revealed that mice treated with G3-C12 possessed 4.63 ± 3.07 tumors compared to 14.13 ± 3.56 tumors within mice treated with saline. Also, within both saline and control peptide treatment groups, 37 % of mouse lungs contained tumor thrombi, compared to 0 % within the G3-C12 treatment group. This study demonstrated that G3-C12 significantly reduced metastatic cell deposition and consequent outgrowth within vasculature of mice.

The E2F Transcription Factors Regulate Tumor Development and Metastasis in a Mouse Model of Metastatic Breast Cancer

“…For instance, it has been shown that the LGALS3 protein, galectin-3, mediates tumor cell adhesion to the ECM (66) and promotes the dissemination of tumor cells from the primary tumor (67). Galectin-3 has also been shown to be critical for the recognition and interaction of human breast cancer cells with endothelial cells of the vasculature (68,69), and those tumor cell-endothelial cell interactions are necessary for tumor cell invasion and metastasis (70). In the later steps of metastasis, galectin-3 induces apoptosis in T cells and monocytes (65).…”

Tumor‐associated antigens: Tn antigen, sTn antigen, and T antigen

“…Numerous studies have reported that the interaction of Gal‐3 with MUC‐1 via T antigen was a central principle of metastatic cell adhesion in cancer progression . Furthermore, when using the peptide G3‐012, which has a high affinity for Gal‐3, inhibition of binding between Gal‐3 and T antigen led to a decrease in lung colonization . T antigen can also be used to detect disseminated tumor cells (DTCs) from bone marrow samples, as T antigen is co‐expressed (96%–98%) with DTCs .…”

Synthesis and cell-selective antitumor properties of amino acid conjugated tumor-associated carbohydrate antigen-coated gold nanoparticles

“…57,58,62,63 It is now well established that TF ag engages a specific galectin, Galectin-3 (Gal-3), during the metastatic spread of certain TF ag -bearing tumors, and that this interaction can dictate the aggressiveness of the tumor. 55,63–66 Since the majority of biologically relevant carbohydrate-protein interactions require multivalent binding for enhanced avidity 67 , many of these studies have utilized platforms where the TF ag or a TF ag mimic is displayed in multiple copies for a more potent inhibitory effect.…”