Abstract
Trop2 is a transmembrane glycoprotein encoded by the Tacstd2 gene. It is an intracellular calcium signal transducer that is differentially expressed in many cancers. It signals cells for self-renewal, proliferation, invasion, and survival. It has stem cell-like qualities. Trop2 is expressed in many normal tissues, though in contrast, it is overexpressed in many cancers and the overexpression of Trop2 is of prognostic significance. Several ligands have been proposed that interact with Trop2. Trop2 signals the cells via different pathways and it is transcriptionally regulated by a complex network of several transcription factors. Trop2 expression in cancer cells has been correlated with drug resistance. Several strategies target Trop2 on cancer cells that include antibodies, antibody fusion proteins, chemical inhibitors, nanoparticles, etc. The in vitro studies and pre-clinical studies, using these various therapeutic treatments, have resulted in significant inhibition of tumor cell growth both in vitro and in vivo in mice. A clinical study is underway using IMMU-132 (hrS7 linked to SN38) in patients with epithelial cancers. This review describes briefly the various characteristics of cancer cells overexpressing Trop2 and the potential application of Trop2 as both a prognostic biomarker and as a therapeutic target to reverse resistance.
Highlights
The transmembrane glycoprotein Trop2 is highly expressed in many cancers, but not all, and has differential expression in certain normal tissues
This review describes briefly the various characteristics of cancer cells overexpressing Trop2 and the potential application of Trop2 as both a prognostic biomarker and as a therapeutic target to reverse resistance
CD74 is a suitable target for antibodydrug conjugates (ADCs) in some solid tumor xenografts, with efficacy largely influenced by uniformity of CD74 expression and with SN-38 conjugates providing the best therapeutic responses; SN38 conjugates were preferable in solid cancers, such as melanoma, hepatoma, pancreatic, and gastric, whereas doxorubicin ADC was better in lymphoma [79]
Summary
The transmembrane glycoprotein Trop is highly expressed in many cancers, but not all, and has differential expression in certain normal tissues. Regulated Intramembrane Proteolysis (RIP) is required for Trop activity; it is necessary for Trop2’s enhanced cell growth and self-renewal activity in prostate cancer. Two products are made: the extracellular domain (ECD) is shed and is found on the plasma membrane and in the cytoplasm, and the intracellular domain (ICD) is released from the membrane and accumulates in the nucleus ( some is found on the membrane). Β-catenin colocalizes with the ICD in the nucleus, leading to Trop proliferation. This process could possibly occur in other cancers. The largest part of the molecule is the N- terminal extracellular part, known as the ectodomain (Trop2EC) It is composed of 3 domains, anchored via a single transmembrane helix (TM) followed by a short intracellular tail of 26 amino acid residues (Trop2IC). The released Trop2IC indirectly influences cell proliferation and self-renewal through the β-catenin signaling pathway (see below) [9]
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