Abstract
Simple SummaryFAPI represents a novel class of radiotracers demonstrating promising results in terms of a high uptake in concordance with low background noise in several malignancies. Thereby, FAPI-PET/CT achieves sharp contrasts facilitating staging as well as tumor delineation and detection. However, FAP is also overexpressed for several non-oncological reasons allowing for benign indications as well. This review summarizes the current state of oncological and non-oncological FAPI-PET/CT in accordance with FAP in order to highlight future perspectives and identify areas where research is urgently warranted.A fibroblast activation protein (FAP) is an atypical type II transmembrane serine protease with both endopeptidase and post-proline dipeptidyl peptidase activity. FAP is overexpressed in cancer-associated fibroblasts (CAFs), which are found in most epithelial tumors. CAFs have been implicated in promoting tumor cell invasion, angiogenesis and growth and their presence correlates with a poor prognosis. However, FAP can generally be found during the remodeling of the extracellular matrix and therefore can be detected in wound healing and benign diseases. For instance, chronic inflammation, arthritis, fibrosis and ischemic heart tissue after a myocardial infarction are FAP-positive diseases. Therefore, quinoline-based FAP inhibitors (FAPIs) bind with a high affinity not only to tumors but also to a variety of benign pathologic processes. When these inhibitors are radiolabeled with positron emitting radioisotopes, they provide new diagnostic and prognostic tools as well as insights into the role of the microenvironment in a disease. In this respect, they deliver additional information beyond what is afforded by conventional FDG PET scans that typically report on glucose uptake. Thus, FAP ligands are considered to be highly promising novel tracers that offer a new diagnostic and theranostic potential in a variety of diseases.
Highlights
Fibroblast activation protein (FAP), a membrane-anchored serine protease with dipeptidyl peptidase and endopeptidase activity, is overexpressed by cancer-associated fibroblasts (CAFs) [1]
Fibroblast activation protein (FAP) is a serine protease containing both dipeptidyl peptidase (DPP) and endopeptidase activities [39], which differentiates it from other DPP IV family members
Immunohistochemistry revealed FAP expression on the surface of the cartilage and on chondrocyte membranes [55]. These findings are supported by a report of a patient with an intense uptake within the joints who was undergoing a FAP inhibitors (FAPIs)-PET/CT scan based on a history of shoulder osteoarthritis [56]
Summary
Fibroblast activation protein (FAP), a membrane-anchored serine protease with dipeptidyl peptidase and endopeptidase activity, is overexpressed by cancer-associated fibroblasts (CAFs) [1]. Cancer-associated fibroblasts are joined by endothelial cells, the basement membrane, the extracellular matrix and immune cells in the tumor microenvironment (TME) and act as a supporting cast for tumor growth. These resting fibroblasts harbor the ability to be activated under various circumstances This process was first described in connection with wound healing [9] and subsequently at sites of inflammation and tissue fibrosis [10,11,12]. Wound healing leads to inflammation and the recruitment of immune cells and fibroblasts [12,17,18] as part of the repair mechanism. The growth of cancer cells presents recurring tissue damage ensuring a permanent wound healing response leading to stromal or cancer fibrosis [17]. CAFs co-evolve alongside neoplastic cells and provide continuous support to cancer growth
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