Fibroblast-activating Protein Research Articles

Nebulized milk exosomes loaded with siTGF-β1 ameliorate pulmonary fibrosis by inhibiting EMT pathway and enhancing collagen permeability

Pulmonary Fibrosis (PF) is a fatal disease in the interstitial lung associated with high mortality, morbidity, and poor prognosis. Transforming growth factor-β1 (TGF-β1) is a fibroblast-activating protein that promotes fibrous diseases. Herein, an inhalable system was first developed using milk exosomes (M-Exos) encapsulating siRNA against TGF-β1 (MsiTGF-β1), and their therapeutic potential for bleomycin (BLM)-induced PF was investigated. M-siTGF-β1 was introduced into the lungs of mice with PF through nebulization. The collagen penetration effect and lysosomal escape ability were verified in vitro. Inhaled MsiTGF-β1 notably alleviated inflammatory infiltration, attenuated extracellular matrix (ECM) deposition, and increased the survival rate of PF mice by 4.7-fold. M-siTGF-β1 protected lung tissue from BLM toxicity by efficiently delivering specific siRNA to the lungs, leading to TGF-β1 mRNA silencing and epithelial mesenchymal transition pathway inhibition. Therefore, M-siTGF-β1 offers a promising avenue for therapeutic intervention in fibrosis-related disorders.

Unlocking precision gene therapy: harnessing AAV tropism with nanobody swapping at capsid hotspots.

Adeno-associated virus (AAV) has been remarkably successful in the clinic, but its broad tropism is a practical limitation of precision gene therapy. A promising path to engineer AAV tropism is the addition of binding domains to the AAV capsid that recognize cell surface markers present on a targeted cell type. We have recently identified two previously unexplored capsid regions near the 2/5-fold wall and 5-fold pore of the AAV capsid that are amenable to insertion of larger protein domains, including nanobodies. Here, we demonstrate that these hotspots facilitate AAV tropism switching through simple nanobody replacement without extensive optimization in both VP1 and VP2. Our data suggest that engineering VP2 is the preferred path for maintaining both virus production yield and infectivity. We demonstrate highly specific targeting of human cancer cells expressing fibroblast activating protein (FAP). Furthermore, we found that the combination of FAP nanobody insertion plus ablation of the heparin binding domain can reduce off-target infection to a minimum, while maintaining a strong infection of FAP receptor-positive cells. Taken together, our study shows that nanobody swapping at multiple capsid locations is a viable strategy for nanobody-directed cell-specific AAV targeting.

Prognostic value of CAF marker expression in the intratumoral and marginal areas of soft tissue sarcoma.

The tumor microenvironment of sarcomas has not been studied in detail; in particular, little is known about cancer-associated fibroblasts (CAFs). Sarcoma cells are difficult to distinguish from CAFs, either histomorphologically or immunohistochemically. We scored expression of individual CAF markers (fibroblast activating protein (FAP), CD10, and podoplanin) in the intratumoral and marginal areas of 133 sarcomas. We also examined the association between these markers, as well as the number of CD163-positive macrophages (i.e., tumor-associated macrophages), and clinical outcome. In all cases, the log-rank test revealed that those with high marker scores and macrophage counts (except for marginal CD10+ CAFs) showed significantly worse disease-free survival (DFS). Grade 2/3 cases with high CAF scores (excluding the marginal FAP and CD10 scores) showed significantly worse DFS, whereas those with high intratumoral FAP/CD10 and marginal podoplanin scores showed significantly worse metastasis-free survival (MFS), and those with a high intratumoral CD10 score showed significantly worse local recurrence-free survival (LFS). Multivariate analysis identified intratumoral CD10/podoplanin scores and marginal FAP/podoplanin scores as independent prognostic factors for DFS, intratumoral FAP/CD10 and marginal FAP/podoplanin/CD163-positive macrophage scores as independent prognostic factors for MFS, and the intratumoral podoplanin score as an independent prognostic factor for LFS. There was a weak-to-moderate correlation between each score and CD163-positive macrophage counts. Patients with high CAF marker expression in the intratumoral and marginal areas have a poorer outcome.

Development and efficacy evaluation of nanoliposomes targeting CAFs-LCSCs communication for hepatocellular carcinoma treatment

Hepatocellular carcinoma (HCC) is a prevalent global malignancy, presenting significant challenges in developing safe and effective treatments to prevent recurrence. This is mainly attributed to the inability of traditional treatments to eliminate liver cancer stem cells (LCSCs). LCSCs exhibit resistance to standard therapies, such as radiotherapy and chemotherapy, playing a noticeable role in drug resistance, metastasis, and recurrence of HCC. Their “stemness” is maintained by cancer-associated fibroblasts (CAFs), especially dense CAFs that form a barrier, hindering drug delivery. These two components interact to drive the progression of HCC. Regarding this unique tumor microenvironment, a novel nanoliposome (CAP@CD133-D/X-Lip) was developed. This nanoliposome could initially target CAFs by leveraging fibroblast activating protein (FAP) overexpression on their surface, activating CAP-degrading peptides upon reaching CAFs. Subsequent size reduction and exposure of CD133 aptamers enable secondary targeting of LCSCs, leading to the release of the antitumor drug doxorubicin hydrochloride (DOX) and the LCSCs’ inhibitor XAV-939 in deep tumor regions. The efficacy of CAP@CD133-D/X-Lip was validated in vitro and in vivo, demonstrating its ability to target therapeutic drugs and disrupt the ’CAFs-LCSCs’ communication, thereby slowing HCC progression and enhancing treatment outcomes. This approach holds significant promise for the clinical management of HCC.

Carborane-FAPI conjugate: A potential FAP-targeted boron agent with improved boron content

Boron neutron capture therapy (BNCT) has received extensive attention as an advanced binary radiotherapy method. However, BNCT still faces poor selectivity of boron agent and is insufficient boron content in tumor tissues. To improve the tumor-targeted ability and boron content, this research aims to design, synthesize and preliminary evaluate a new borane agent Carborane-FAPI, which coupling the o-carborane to the compound skeleton of a mature fibroblast activating protein (FAP) inhibitor (FAPI). FAP is a tumor-associated antigen. FAP expressed lowly in normal organs and highly expressed in tumors, so it is a potential target for diagnosis and treatment. Boronophenylalanine (BPA) is the most widely investigated BNCT drug in present. Compared with BPA, the boron content of a single molecule is increased and drug targeting is enhanced. The results show that Carboaren-FAPI has low toxicity to normal cells, and selective enrichment in tumor tissues. It is a promising boron drug that has the potential to be used in BNCT.

Applications of FAPI PET/CT in the diagnosis and treatment of breast and the most common gynecologic malignancies: a literature review.

The fibroblast activating protein (FAP) is expressed by some fibroblasts found in healthy tissues. However, FAP is overexpressed in more than 90% of epithelial tumors, including breast and gynecological tumors. As a result, the FAP ligand could be used as a target for diagnosis and treatment purposes. Positron emission tomography/computed tomography (PET/CT) is a hybrid imaging technique commonly used to locate and assess the tumor's molecular and metabolic functions. PET imaging involves the injection of a radiotracer that tends to accumulate more in metabolically active lesions such as cancer. Several radiotracers have been developed to target FAP in PET/CT imaging, such as the fibroblast-activation protein inhibitor (FAPI). These tracers bind to FAP with high specificity and affinity, allowing for the non-invasive detection and quantification of FAP expression in tumors. In this review, we discussed the applications of FAPI PET/CT in the diagnosis and treatment of breast and the most common gynecologic malignancies. Radiolabeled FAPI can improve the detection, staging, and assessment of treatment response in breast and the most common gynecologic malignancies, but the problem with normal hormone-responsive organs remains insurmountable. Compared to the diagnostic applications of FAPI, further research is needed for future therapeutic applications.

FAPi-Based Agents in Thyroid Cancer: A New Step towards Diagnosis and Therapy? A Systematic Review of the Literature.

(1) Background: Thyroid cancer (TC) is often treated with surgery followed by iodine-131. Up to 50% of the instances of TC lose their avidity to 131I, becoming more aggressive. In this scenario, [18F]FDG PET/CT imaging is used for evaluating the widespread nature of the disease, despite its low sensitivity and a false negative rate of 8-21.1%. A novel class of PET agents targeting the fibroblast activation protein inhibitor (FAPi) has emerged, studied particularly for their potential application to theranostics. (2) Methods: A search of the literature was performed by two independent authors (P.G. and L.E.) using the PubMed, Scopus, Web of Science, Cochrane Library, and EMBASE databases. The following terms were used: "FAP" or "FAPi" or "Fibroblast activating protein" and "thyroid" or "thyroid cancer", in different combinations. The included papers were original articles, clinical studies, and case reports in the English language. No time limits were used. Editorials, conference papers, reviews, and preclinical studies were excluded. (3) Results: There were 31 papers that were selected. Some studies reported a low or absent FAPi uptake in TC lesions; others reported promising findings for the detection of metastases. (4) Conclusions: The preliminary results are encouraging. FAPI agents are an alternative to [18F]FDG and a promising theranostic tool. However, further studies with a larger population are needed.

Preclinical study and first-in-human imaging of [18F]FAP-2286, and comparison with 2-[18F]FDG PET/CT in various cancer patients.

Fibroblast-activated protein (FAP) is highly expressed in cancer-associated fibroblasts (CAFs) of many solid cancers, but low or absent in normal tissues. Our study aimed to develop a novel FAP-specific tracer, namely [18F]FAP-2286, and evaluated its performance in comparison with well-established agents such as [18F]FAPI-42 and [68Ga]Ga-FAP-2286 in preclinical research, as well as 2-[18F]FDG in pilot clinical study. [18F]FAP-2286 was manually synthesized in accordance with Good Manufacturing Practice (GMP). Subsequent investigations encompassed cell uptake, competitive binding affinity, internalization and efflux assays using HT-1080hFAP cell lines. PET imaging and biodistribution studies were conducted in HEK-293ThFAP, A549hFAP, HT-1080hFAP tumor-bearing mice as well as HEK-293T, A549 and HT-1080 control groups. Furthermore, clinical evaluation of [18F]FAP-2286 was performed in fifteen patients with various cancers compared to 2-[18F]FDG PET. The radiolabeling yield of [18F]FAP-2286 was 30.53 ± 5.20%, with a radiochemical purity exceeding 97%. In cell assays, [18F]FAP-2286 showed specific uptake, high internalization fraction and low cellular efflux. Rapid tumor uptake and satisfactory tumor retention was observed on micro-PET imaging and cancer patients. Meanwhile, the clinical research demonstrated that [18F]FAP-2286 may represent an alternative for low glucose-metabolism malignant tumors PET imaging such as gastric cancers. [18F]FAP-2286 showed superior imaging quality including rapid and high target uptake and satisfactory retention in both tumor-bearing mice and cancer patients. It may emerge as a promising candidate for early or delayed phase imaging and 2-[18F]FDG non-avid cancers PET scan.

Myofibroblastic cancer-associated fibroblast subtype heterogeneity in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) has a fibrotic stroma that has both tumor-promoting and tumor-restraining properties. Different types of cancer-associated fibroblasts (CAFs) have been described. Here, we investigated whether CAFs within the same subtype exhibit heterogeneous functions. We evaluated the gene and protein expression differences in two myofibroblastic CAF (myCAF) lines using single-cell and bulk RNA-sequencing. We utilized proliferation and migration assays to determine the effect of different CAF lines on a tumor cell line. We found that myCAF lines express an activated stroma subtype gene signature, which is associated with a shorter survival in patients. Although both myCAF lines expressed α-smooth muscle actin (α-SMA), platelet-derived growth factor-α (PDGFR-α), fibroblast-activated protein (FAP), and vimentin, we observed heterogeneity between the two lines. Similarly, despite being consistent with myCAF gene expression overall, heterogeneity within specific genes was observed. We found that these differences extended to the functional level where the two myCAF lines had different effects on the same tumor cell line. The myCAF216 line, which had slightly increased inflammatory CAF-like gene expression and higher protein expression of α-SMA, PDGFR-α, and FAP was found to restrain migration of tumor cells. We found that two myCAF lines with globally similar expression characteristics had different effects on the same tumor cell line, one promoting and the other restraining migration. Our study highlights that there may be unappreciated heterogeneity within CAF subtypes. Further investigation and attention to specific genes or proteins that may drive this heterogeneity will be important.

Utilizing MRI, [18F]FDG-PET and [89Zr]Zr-DFO-28H1 FAP-PET tracer to assess inflammation and fibrogenesis in a reproducible lung injury rat model: a multimodal imaging study

ObjectiveAccurate imaging biomarkers that indicate disease progression at an early stage are highly important to enable timely mitigation of symptoms in progressive lung disease. In this context, reproducible experimental models and readouts are key. Here, we aim to show reproducibility of a lung injury rat model, by inducing disease and assessing disease progression by multi-modal non-invasive imaging techniques at two different research sites. Furthermore, we evaluated the potential of fibroblast activating protein (FAP) as an imaging biomarker in the early stage of lung fibrosis.MethodsAn initial lung injury rat model was set up at one research site (Lund University, Lund, Sweden) and repeated at a second site (Radboudumc, Nijmegen, The Netherlands). To induce lung injury, Sprague-Dawley rats received intratracheal instillation of bleomycin as one single dose (1,000 iU in 200 µL) or saline as control. Thereafter, longitudinal images were acquired to track inflammation in the lungs, at 1 and 2 weeks after the bleomycin challenge by magnetic resonance imaging (MRI) and [18F]FDG-PET. After the final [18F]FDG-PET scan, rats received an intravenous tracer [89Zr]Zr-DFO-28H1 (anti-FAP antibody) and were imaged at day 15, to track fibrogenesis. Upon termination, bronchoalveolar lavage (BAL) was performed to assess cell and protein concentration. Subsequently, the biodistribution of [89Zr]Zr-DFO-28H1 was measured ex vivo and the spatial distribution in lung tissue was studied by autoradiography. Lung sections were stained, and fibrosis assessed using the modified Ashcroft score.ResultsBleomycin-challenged rats showed body weight loss and increased numbers of immune cells and protein concentrations after BAL compared with control animals. The initiation and progression of the disease were reproduced at both research sites. Lung lesions in bleomycin-exposed rats were visualized by MRI and confirmed by histology. [18F]FDG uptake was higher in the lungs of bleomycin-challenged rats compared with the controls, similar to that observed in the Lund study. [89Zr]Zr-DFO-28H1 tracer uptake in the lung was increased in bleomycin-challenged rats compared with control rats (p = 0.03).ConclusionHere, we demonstrate a reproducible lung injury model and monitored disease progression using conventional imaging biomarkers MRI and [18F]FDG-PET. Furthermore, we showed the first proof-of-concept of FAP imaging. This reproducible and robust animal model and imaging experimental set-up allows for future research on new therapeutics or biomarkers in lung disease.

Unraveling the Role and Spatial Architecture of Cancer-Associated Fibroblasts in Classical Hodgkin Lymphoma

Introduction: Cancer-associated fibroblasts (CAFs) constitute an important stromal component of the tumor microenvironment (TME). They are a heterogeneous population of cells, which can modulate the immune system and have both pro-tumorigenic and anti-tumorigenic effects in a context-dependent manner. In solid tumors, the impact of CAFs in shaping the TME is well recognized, although challenges, including lack of specific CAF markers, still exist. In classical Hodgkin lymphoma (cHL), the role of CAFs has remained largely undefined. Here, we aimed to characterize distinct CAF subsets as well as their interactions with other TME cells and associate the findings with clinical characteristics and outcome of patients with previously untreated cHL. Methods: We used a tissue microarray (TMA) containing formalin-fixed paraffin-embedded samples from 115 diagnostic cHL tumors. The TMA was stained with a 7-plex immunohistochemistry panel to characterize CAFs [platelet-derived growth factor (PDGFR) -alpha and -beta, fibroblast-activating protein (FAP), secreted protein acidic and rich in cysteine (SPARC)], macrophages (CD68), Hodgkin-Reed Sternberg (HRS) cells (CD30), and leukocytes (CD45). Image processing and quality control were performed by combining Ilastik and CellProfiler softwares, and nuclei segmented by a pretrained deep learning segmentation model. Single cell features from the images were extracted using HistoCAT software. We utilized the Phenograph clustering algorithm for cell phenotyping and a permutation test by HistoCAT for neighborhood analysis. Results: We identified a total of 952,099 single cells, which were split into 25 distinct phenotype subsets by the Phenograph clustering spanning CAFs, macrophages, leukocytes, and HRS cells. CAFs were classified into seven distinct subsets based on the status of the different CAF markers. Median proportion of all CAFs was 28% (range 2-80%), the proportion being higher in the nodular sclerosis subtype compared to the others. In general, higher proportions of CAFs associated with favorable freedom from treatment failure (FFTF) independently of the subtype, age, and stage (P<0.01). On the contrary, a subcluster of CD45+ immune cells with strong FAP-positivity, which were characterized as macrophages, was enriched in other than nodular sclerosis subtype (P<0.001) and associated with worse FFTF independently of age, stage, and subtype (P=0.01). The neighborhood analysis allowed identification of colocalization and statistically significant interaction or avoidance between pairs of cell phenotypes. For instance, higher proportions of FAP+PDGFRalpha+ CAFs interacting with other cells predicted better FFTF (P<0.01), whereas interactions of FAP+ macrophages with other cells were associated with worse FFTF. Despite the positive impact of CAF proportions on cHL outcome, patients with CD30+ HRS cells surrounded by PDGFRbeta+ CAFs had worse FFTF (P<0.001). Conclusions: We have characterized distinct CAF subsets in cHL and demonstrate their favorable clinical impact on cHL outcome. We also identified a novel subset of FAP-positive macrophages, the proportions and interactions of which translated to poor outcome. Our data highlight that not only the cell proportions, but the cell-cell interactions and spatial context play a crucial role. Further validation of the findings is ongoing.

Abstract 13851: CAR-T Cells: A Potential Novel Strategy for Mitigating Fibrosis in Duchenne Muscular Dystrophy

Introduction: Chimeric Antigen T (CAR)-T cells have proven effective preclinically for mitigating cardiac fibrosis in hypertensive cardiomyopathy. Hypothesis: We assessed whether this approach could be applied to Duchenne Muscular Dystrophy (DMD) by targeting Fibroblast Activating Protein (FAP)-expressing activated fibroblasts in cardiac and skeletal muscle fibrosis. Methods: A protocol for the lymphodepletion conditioning of mice was developed to optimize the dosing of cyclophosphamide. Next, immune-magnetically selected T cells were retrovirally transduced to target FAP (FAP-CAR) and quality-controlled by co-culture killing assays using FAP-expressing HEK target cells. Finally, lymphodepleted D2. mdx mice were intravenously injected with 10 7 FAP-CAR T cells (n=9) or 10 7 GFP-T cells (n=9) or Bovine Serum Albumin (BSA, n=8). Cardiac and skeletal muscle end points were assessed 2 and 5 weeks after treatment. Results: In vitro , the engineered CAR-T cells expressed activation markers (CD69, PD-1) and released large amounts of granzyme, perforin and interferon γ upon exposure to FAP-expressing target cells. One IP injection of cyclophosphamide (3mg) 4 days before treatment was safe and induced a lymphodepletion which enabled robust in vivo expansion of FAP-CAR T cell assessed by flow cytometry in lymphoid organs and blood: 10 5 , 2.10 6 and 10 7 detected CAR-T cells at day 3, 5 and 7 post-injections, respectively. This was paralleled by a more than a 2-fold decrease in endogenous FAP expression in skeletal muscles, as assessed by PCR at day 5 post-injections, and measurable FAP-CAR levels in the spleen compared with GFP-T cell controls. In vivo , FAP-CAR T cells significantly improved LV function with an EF change from baseline (Mean±SEM) of 33.1% ± 6.7% in FAP-CAR vs. 3.7% ± 6.4% and -9.6% ± 7.9% in GFP-T and BSA ( p <0.037 and p <0.005, respectively) at 2 weeks. The benefit was maintained at 5 weeks post-treatment. Several markers of fibrosis, particularly collagens 1 and 3, were also down-regulated in heart and muscles. Conclusions: FAP-CAR-T cells might represent a new therapeutic option for mitigating fibrosis in DMD, likely in conjunction with approaches aimed at addressing the root cause of the disease through a re-expression of a functional dystrophin.

Elevated FAPI Activity in Ulcerative Fungal Esophagitis.

We report a case of ulcerative fungal esophagitis with elevated activity of 18F-FDG and 68Ga-FAPI (fibroblast-activating protein inhibitor). Our findings suggest that ulcerative fungal esophagitis should be considered in the differential diagnosis of cancer-like esophageal mass with increased 68Ga-FAPI uptake.

Fibroblast activating protein (FAP) is reduced in FGR in regions of the villous tree with disturbed differentiation of perivascular myofibroblasts

Fibroblast activating protein (FAP) is reduced in FGR in regions of the villous tree with disturbed differentiation of perivascular myofibroblasts

Nano-drug delivery system targeting FAP for the combined treatment of oral leukoplakia.

Oral leukoplakia (OLK) has received much attention due to its potential risk of malignant transformation. Studies have shown that when drug therapy is combined with photothermal therapy (PTT), not only can the cytotoxicity of the drug be enhanced, but also the heat energy can be used to kill the lesion cells, so we can combine drug therapy with PTT to enhance the therapeutic effect on OLK. However, with certain drawbacks due to its lack of targeting, fibroblast activating protein (FAP) has become an attractive target for OLK combination therapy. In this study, we used NGO-PEG loaded with FAP-targeting peptide (F-TP) and celecoxib (CXB) to construct a nano-drug delivery system CGPF for targeting OLK with high FAP expression and confirmed the biocompatibility and therapeutic efficacy of CGPF by in vitro and in vivo experiments. Overall, the novel nano-drug delivery system CGPF proposed in this study showed a very significant potential for the combination therapy of OLK.

Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma.

Recent transcriptomic-based analysis of diffuse large B cell lymphoma (DLBCL) has highlighted the clinical relevance of LN fibroblast and tumor-infiltrating lymphocyte (TIL) signatures within the tumor microenvironment (TME). However, the immunomodulatory role of fibroblasts in lymphoma remains unclear. Here, by studying human and mouse DLBCL-LNs, we identified the presence of an aberrantly remodeled fibroblastic reticular cell (FRC) network expressing elevated fibroblast-activated protein (FAP). RNA-Seq analyses revealed that exposure to DLBCL reprogrammed key immunoregulatory pathways in FRCs, including a switch from homeostatic to inflammatory chemokine expression and elevated antigen-presentation molecules. Functional assays showed that DLBCL-activated FRCs (DLBCL-FRCs) hindered optimal TIL and chimeric antigen receptor (CAR) T cell migration. Moreover, DLBCL-FRCs inhibited CD8+ TIL cytotoxicity in an antigen-specific manner. Notably, the interrogation of patient LNs with imaging mass cytometry identified distinct environments differing in their CD8+ TIL-FRC composition and spatial organization that associated with survival outcomes. We further demonstrated the potential to target inhibitory FRCs to rejuvenate interacting TILs. Cotreating organotypic cultures with FAP-targeted immunostimulatory drugs and a bispecific antibody (glofitamab) augmented antilymphoma TIL cytotoxicity. Our study reveals an immunosuppressive role of FRCs in DLBCL, with implications for immune evasion, disease pathogenesis, and optimizing immunotherapy for patients.

Fibroblast activating protein promotes the proliferation, migration, and activation of fibroblasts in oral submucous fibrosis.

Fibroblast activating protein (FAP) is associated with various organ fibrosis. However, the expression and molecular function of FAP in oral submucous fibrosis (OSF) is still unclear. The high-performance liquid chromatography was used to detect the presence of alkaloids in areca nut extract (ANE). Real-time qPCR, Western blot, and Immunohistochemistry assay were used to analyze the expression of FAP mRNA or protein in OSF and normal oral tissue. A chi-squared test analyzed the relationship between FAP protein expression and clinicopathological data of OSF patients. CCK-8, Wound-healing, and Transwell migration assay were employed to assess the effect of the proliferation and migration ability of hOMF cells with FAP overexpression or knockdown. The expression level of a-SMA, FSP1, and P13K-Akt signaling pathways-related protein in hOMF cells transfected with FAP overexpression or knockdown plasmid was verified by western blot assay. The four specific areca alkaloids (Arecoline, Guvacine, Arecaidine, and Guvacoline) were successfully detected in the ANE. The viability of hOMF cells was significantly improved in the 50 μg/mL ANE group and was inhibited in the 5 and 50 mg/mL ANE groups. The expression of FAP was upregulated in OSF tissues, and hOMF cells treated with 50 μg/mL ANE and was related to pathology grade, clinical stage, and history of chewing betel nut. Additionally, FAP may promote the proliferation, migration, and activation of hOMF cells through the P13K-Akt signaling pathway. This study found that ANE had a bidirectional effect on the viability of hOMF cells, and the FAP gene was a potential therapeutic target in OSF.

Research progress of FAPI PET/CT in the diagnosis of malignant liver tumors

Malignant liver tumors have a high incidence and mortality rate. Therefore, it is of great significance to promptly learn about tumor advancement status through relevant examinations for patients' follow-up, diagnosis, and therapy as well as the improvement of the five-year survival rate. The primary lesions and intrahepatic metastases of malignant liver tumors have been better demonstrated in the clinical study with the use of various isotope-labeled fibroblast activating protein inhibitors because of their low uptake in liver tissues and high tumor/background ratio, which provides a new method for early diagnosis, precise staging, and radionuclide therapy. In light of this context, a review of the research progress of fibroblast-activating protein inhibitors for the diagnosis of liver malignant tumors is presented.

Diagnostic Performance of Positron Emission Tomography with Fibroblast-Activating Protein Inhibitors in Gastric Cancer: A Systematic Review and Meta-Analysis.

Various papers have introduced the use of positron emission tomography (PET) with [68Ga]Ga-radiolabeled fibroblast-activation protein inhibitor (FAPi) radiopharmaceuticals in different subtypes of gastric cancer (GC). Our aim was to assess the diagnostic performance of this novel molecular imaging technique in GC with a systematic review and meta-analysis. A straightforward literature search of papers concerning the diagnostic performance of FAP-targeted PET imaging was performed. Original articles evaluating this novel molecular imaging examination in both newly diagnosed GC patients and GC patients with disease relapse were included. The systematic review included nine original studies, and eight of them were also eligible for meta-analysis. The quantitative synthesis provided pooled detection rates of 95% and 97% for the assessment of primary tumor and distant metastases, respectively, and a pooled sensitivity and specificity of 74% and 89%, respectively, for regional lymph node metastases. Significant statistical heterogeneity among the included studies was found only in the analysis of the primary tumor detection rate (I2 = 64%). Conclusions: Beyond the limitations of this systematic review and meta-analysis (i.e., all the included studies were conducted in Asia, and using [18F]FDG PET/CT as a comparator of the index test), the quantitative data provided demonstrate the promising diagnostic performance of FAP-targeted PET imaging in GC. Nevertheless, more prospective multicentric studies are needed to confirm the excellent performances of FAP-targeted PET in this cluster of patients.

Noninvasive imaging of FAP expression using positron emission tomography: A comparative evaluation of a [18F]-labeled glycopeptide-containing FAPI with [18F]FAPI-42.

Research on fibroblast activating protein (FAP)-targeting inhibitor (FAPI) has become an important focus for cancer imaging and radiotherapy. Quinoline-based tracers [68Ga]FAPI-04 and [18F]FAPI-42 have been widely used for positron emission tomography (PET) imaging of most tumors. However, there exist some limitations of these tracers with high uptake in biliary duct system and unstable uptake in pancreas, unsuitable for abdominal tumors PET imaging. Here we developed a [18F]-labeled glycopeptide-containing FAPI tracer (named [18F]FAPT) for PET imaging of FAP in cancers. [18F]FAPT was synthesized manually and automatically. The competitive binding to FAP, cellular internalization, and efflux characteristics were examined in vitro using A549-FAP cells. Dynamic MicroPET and biodistribution studies of [18F]FAPT were then conducted in A549-FAP and U87MG xenograft tumor mouse models compared with [18F]FAPI-42. Five healthy volunteers and three patients with cancer underwent [18F]FAPT PET/CT. Preclinical and clinical studies showed specific binding of [18F]FAPT to FAP and favorable pharmacokinetic properties with better hydrophilicity, lower uptake in biliary duct system, higher tumor uptake and longer tumor retention compared with [18F]FAPI-42. The biodistribution of [18F]FAPT in healthy volunteers and patients with cancer displayed low uptake in most normal tissues except for pancreas, thyroid and salivary gland, which could contribute to high tumor-to-background ratios in most cancers. [18F]FAPT is better PET tracer than [18F]FAPI-42 for imaging of biliary duct system cancer, potentially providing a tool to examine FAP expression in most cancers with high tumor-to-background ratios.