Positron emission tomography/computed tomography(PET/CT)with radiolabeled fibroblast activation protein inhibitors(FAPI)is an increasingly relevant molecular diagnostic image in oncology given the high expression of F...Positron emission tomography/computed tomography(PET/CT)with radiolabeled fibroblast activation protein inhibitors(FAPI)is an increasingly relevant molecular diagnostic image in oncology given the high expression of FAP in cancer associated fibroblast,being present in almost 90%of the epithelial carcinomas,which allows imaging with excellent diagnostic performance and can also become a therapeutic strategy.This review summarizes the literature on FAPIPET/CT for the cancer evaluation and compares it in some scenarios with the 18FFluorodeoxyglucose PET/CT.展开更多
AIM: To examine fibroblast activation protein (FAP) expression in pancreatic ductal adenocarcinoma (PDAC) and to analyze its relationship with the clinicopathology of PDAC. METHODS: FAP expression was examined in 134 ...AIM: To examine fibroblast activation protein (FAP) expression in pancreatic ductal adenocarcinoma (PDAC) and to analyze its relationship with the clinicopathology of PDAC. METHODS: FAP expression was examined in 134 PDAC specimens by immunohistochemistry, and in four pancreatic cancer cell lines (SW1990, Miapaca-2, AsPC-1 and BxPC-3) by Western blotting assay. We also analyzed the association between FAP expression in PDAC cells and the clinicopathology of PDAC patients. RESULTS: The results showed that the FAP was expressed in both stromal fibroblast cells (98/134, 73.1%) and carcinoma cells (102/134, 76.1%). All 4 pancreatic cancer cell lines expressed FAP protein at different levels. Protein bands corresponding to the proteolytically active 170-kDa seprase dimer and its88-kDa seprase subunit were identif ied. Higher FAP expression in carcinoma cells was associated with tumor size (P < 0.001), fi brotic focus (P = 0.003), perineural invasion (P = 0.009) and worse clinical outcome (P = 0.0085). CONCLUSION: FAP is highly expressed in carcinoma cells and f ibroblasts in PDAC tissues, and its expression is associated with desmoplasia and worse prognosis.展开更多
Quinoline-based fibroblast activation protein(FAP)inhibitor(FAPI)-based positron emission tomography(PET)imaging and radioligand therapy(RLT)are being investigated for use in a wide variety of diseases,and recent resu...Quinoline-based fibroblast activation protein(FAP)inhibitor(FAPI)-based positron emission tomography(PET)imaging and radioligand therapy(RLT)are being investigated for use in a wide variety of diseases,and recent results have been promising.This review summarizes the current status of FAPI radiopharmaceuticals in PET imaging of malignant tumors and benign conditions and compares their diagnostic efficacy with ^(18)F-fluorodeoxyglucose.In addition,we summarize the previously published FAP-targeted RLT data and discuss its current clinical use and future potential.Our qualitative summary can inform future research directions,medical guidelines,and optimal clinical decision-making.展开更多
The activation proteins released by fibroblasts in the tumor microenvironment regulate tumor growth,migration,and treatment response,thereby influencing tumor progression and therapeutic outcomes.Owing to the prolifer...The activation proteins released by fibroblasts in the tumor microenvironment regulate tumor growth,migration,and treatment response,thereby influencing tumor progression and therapeutic outcomes.Owing to the proliferation and metastasis of tumors,fibroblast activation protein(FAP)is typically highly expressed in the tumor stroma,whereas it is nearly absent in adult normal tissues and benign lesions,making it an attractive target for precision medicine.Radiolabeled agents targeting FAP have the potential for targeted cancer diagnosis and therapy.This comprehensive review aims to describe the evolution of FAPI-based radiopharmaceuticals and their structural optimization.Within its scope,this review summarizes the advances in the use of radiolabeled small molecule inhibitors for tumor imaging and therapy as well as the modification strategies for FAPIs,combined with insights from structure-activity relationships and clinical studies,providing a valuable perspective for radiopharmaceutical clinical development and application.展开更多
An investigation of the mangrove-derived fungus Penicillium sp.DM27 led to the isolation of 19 new compounds,including three pairs of piperidinone enantiomers(±)-1,(±)-2,and(±)-3,two pairs of pyrrolidin...An investigation of the mangrove-derived fungus Penicillium sp.DM27 led to the isolation of 19 new compounds,including three pairs of piperidinone enantiomers(±)-1,(±)-2,and(±)-3,two pairs of pyrrolidinone enantiomers(±)-4 and(±)-5,and nine pyrrolidine derivatives 6−14.The structures of 1−14 were elucidated through NMR and HRESIMS analysis,coupled with experimental and calculated ECD spectroscopy and the modified Mosher method.Quantitative real time PCR and Western bolt analyses revealed that 11 blocked EMT in TGF-β1-treated HK-2 cells and suppressed fibroblast activation in TGF-β1-stimulated NIH-3T3 cells.Molecular simulations demonstrated that compound 11 could dock ADAM17,showing a high negative binding affinity.Additionally,the overexpression of ADAM17 by lentiviral infection triggered renal tubular EMT,while compound 11 suppressed this process.Overall,our research suggests that pyrrolidine derivatives may be potential therapeutic agents for the treatment of fibrotic kidney disease.展开更多
Hepatectomy is a critical treatment for liver cancer,but achieving complete tumor removal remains challenging.The development of tumor-targeting probes capable of accurately identifying tumor locations and providing r...Hepatectomy is a critical treatment for liver cancer,but achieving complete tumor removal remains challenging.The development of tumor-targeting probes capable of accurately identifying tumor locations and providing real-time intraoperative navigation is of significant clinical importance.We synthesize a tumor-targeted probe by conjugating a fibroblast activation protein inhibitor(FAPI)with near-infrared organic room temperature phosphorescence(RTP)material.We then analyze its surgical navigation performance in the liver cancer model and its imaging performance in fresh patient-derived samples.In vivo validation reveals that the probe exhibits optimal phosphorescence intensity within 48 h(8.53×10^(5)p s^(−1)cm^(−2)sr^(−1))and an average signal-to-noise ratio of 16.The probe could effectively identify FAP-positive samples from liver cancer patients.The successful application of phosphorescence-guided surgery suggests that the near-infrared RTP probe holds significant clinical translational value and could serve as an auxiliary tool for the surgical treatment of liver cancer.展开更多
Targeted alpha therapy(TAT)is an innovative approach in cancer treatment that aims to selectively deliver high-energy radiation to cancer cells while minimizing damage to healthy tissues.^(225)Ac,an alpha radionuclide...Targeted alpha therapy(TAT)is an innovative approach in cancer treatment that aims to selectively deliver high-energy radiation to cancer cells while minimizing damage to healthy tissues.^(225)Ac,an alpha radionuclide with a half-life of 10 days and emitting 4 alpha particles and 2 beta particles in its decay chain,has shown promise for TAT.Fibroblast activation protein(FAP)has emerged as a valuable target for the development of radiopharmaceuticals in the context of TAT,given its expression in various cancers.However,a challenge arises when using FAPtargeting agents such as FAP inhibitors(FAPIs)in combination with^(225)Ac due to their rapid clearance from the tumor.To address this challenge,the FAP-targeting antibody PKU525 was developed as a TAT drug.The conjugation ratios of the chelator and the labeling procedure were systematically investigated,resulting in an efficient and stable radiolabeling method.Biodistribution studies were conducted using[^(225)Ac]Ac-DOTA-PKU525 with average drug-to-antibody ratios(DARs)of 1.85,3.87,and 7.72.A single dose of 11.1 kBq of[^(225)Ac]Ac-DOTA-PKU525 with DAR 3.87 demonstrated significant inhibition of 4T1-hFAP tumor growth.No significant weight changes were observed throughout the treatment period,and histological examination of the major organs revealed no adverse side effects.In conclusion,[^(225)Ac]Ac-DOTA-PKU525 exhibited both safety and efficacy in 4T1-hFAP tumor-bearing mice,indicating its potential for clinical translation in FAP-targeted alpha therapy.Further development and evaluation of this TAT approach hold promise for improving cancer treatment outcomes.展开更多
Fibroblast activation protein(FAP)is overexpressed in cancer-associated fibroblasts across various cancer types.Numerous radiolabeled FAP inhibitors(FAPIs)(Fig.S1A)currently under clinical investigation have shown rem...Fibroblast activation protein(FAP)is overexpressed in cancer-associated fibroblasts across various cancer types.Numerous radiolabeled FAP inhibitors(FAPIs)(Fig.S1A)currently under clinical investigation have shown remarkable potential in cancer theranostics.展开更多
Objective:To compare the protein profile of culture supernatants in stimulated and unstimulated human fibroblasts to find some proteins indicating the presence of fibroblasts and their activation status.Methods:Dermal...Objective:To compare the protein profile of culture supernatants in stimulated and unstimulated human fibroblasts to find some proteins indicating the presence of fibroblasts and their activation status.Methods:Dermal fibroblasts were stimulated with phorbol 12-myristate 13-acetate(PMA)/ionomycine for 72 h.MTT assay was done to determine cell viability and A/E fluorescent staining was used to evaluate the cell death pattern.Protein analysis was performed by gradient SDS polyacrylamide gel electrophoresis 8%–16%.Results:The supernatant of 24 h cultured both stimulated and unstimulated fibroblasts showed two bands in SDS-PAGE analysis with relative molecular weights of 8.59 and78.8 k Da.These bands density was decreased during the next 48 h in unstimulated cells while their expression was continued in PMA or PMA/ionomycine stimulated cells and a new 85.3 k Da band was appeared in unstimulated and 72 h PMA stimulated cells.Moreover,we found another seven small size(10–19.5 k Da) proteins in supernatants of48 h and 72 h unstimulated but not in PMA or PMA/Ionomycine stimulated fibroblasts.Most of these proteins expression were down regulated following fibroblast activation.This down-regulation is consistent with our finding that PMA or PMA/ionomycine stimulated cells exhibited a significant level of apoptosis cell death.Conclusions:Human fibroblasts produce some small to intermediate sized proteins with specific SDS-PAGE profile upon cell activation.Most of these proteins can be excreted in urine and can be immunogen theoretically so this data provided a reliable clue for fibrosis biomarker screening based on designation of an appropriated immunoassay.展开更多
Inflammation plays an important role in the development of several cancers.Inflammatory cytokines,including tumor necrosis factor-α(TNF-α),are associated with the induction of inflammation.Chronic inflammation contr...Inflammation plays an important role in the development of several cancers.Inflammatory cytokines,including tumor necrosis factor-α(TNF-α),are associated with the induction of inflammation.Chronic inflammation contributes to the progression of cancer through several mechanisms,including increased cytokine production and activation of transcription factors,such as nuclear factor-κB(NF-κB).Zerumbone(ZER),a component of subtropical ginger(Zingiber zerumbet Smith),seems to have anti-inflammatory,anti-cancer,and antioxidant activities.In this study,we aimed to explore the protective function and mechanisms of ZER against TNF-α-induced cancer-promoting cytokines.We found that the viability of stimulated human fibroblast cell lines was reduced after treatment with ZER(IC50=18µmol/L),compared to un-stimulated fibroblasts(IC50=40µmol/L).Besides,ZER inhibited mRNA expression and protein secretion of transforming growth factor-β(TGF-β),interleukin-33(IL-33),monocyte chemoattractant protein-1(MCP-1),and stromal cell-derived factor 1(SDF-1),which were produced by TNF-α-induced fibroblasts,as measured by quantitative real time-PCR(qRT-PCR)and ELISA assays.The mRNA expression levels of TGF-β,IL-33,SDF-1,and MCP-1 showed 8,5,2.5,and 4-fold reductions,respectively.Moreover,secretion of TGF-β,IL-33,SDF-1,and MCP-1 was reduced to 3.65±0.34 ng/mL,6.3±0.26,1703.6±295.2,and 5.02±0.18 pg/mL,respectively,compared to the untreated group.In addition,the conditioned media(CM)of TNF-α-stimulated fibroblasts increased the NF-κB expression in colorectal cancer cell lines(HCT-116 and Sw48),while in the vicinity of ZER,the expression of NF-κB was reversed.Considering the significant effects of ZER,this component can be used as an appropriate alternative herbal treatment for cancer-related chronic inflammation.展开更多
Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures...Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la （HIF-la） in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.展开更多
Colorectal cancer (CRC) is a major global health concern. Accumulation of cancer-associated fibroblasts(CAFs) in CRC is associated with poor prognosis and disease recurrence. CAFs are the main cellular component ofthe...Colorectal cancer (CRC) is a major global health concern. Accumulation of cancer-associated fibroblasts(CAFs) in CRC is associated with poor prognosis and disease recurrence. CAFs are the main cellular component ofthe tumor microenvironment. CAF-tumor cell interplay, which is facilitated by various secretomes, drives colorectalcarcinogenesis. The complexity of CAF populations contributes to the heterogeneity of CRC and influences patientsurvival and treatment response. Due to their significant roles in colorectal carcinogenesis, different clinicalapplications utilizing or targeting CAFs have been suggested. Circulating CAFs (cCAFs) which can be detected inblood samples, have been proposed to help in determining patient prognosis and enables the detection of cancerthrough liquid biopsy. Liquid biopsy is gaining traction as it is non-invasive, allows frequent and easy sampling, andshows concordance to tissue biopsy analysis. In addition, CAF-targeted therapy is currently being studied extensivelyto be used as one of the treatment avenues for CRC. Various mechanisms of CAF-targeted therapy have beenreported, including blocking the signaling pathways involving CAFs and cancer cells, thus abolishing the CAF-tumorcell crosstalk and subsequently hindering tumorigenesis. These translational applications of cCAFs and utilization ofCAFs as key targets for CRC therapy, although still in the early phases of development, will potentially improve CRCpatient management in the future.展开更多
Background The CREG is an important lysosomal protein involved in a variety of cellular functions including promoting cell differentiation,sustaining mature homeostasis, and antagonizing apoptosis.Deficiency of CREG i...Background The CREG is an important lysosomal protein involved in a variety of cellular functions including promoting cell differentiation,sustaining mature homeostasis, and antagonizing apoptosis.Deficiency of CREG in cell and tissue results in a pathologic apoptosis.The present study aimed to elucidate the mechanism of CREG regulation apoptosis.Methods We firstly generated stable NIH3T3 fibroblasts by transfection of pDS_shCREGs vectors.Furthermore, PI-Annexin V and TUNEL staining were used to identify that CREG knockdown promoted the cell apoptosis in NIH3T3 fibroblasts.Western blotting and immunofluorescence staining was used to identify the expression and localization of M6P/ IGF2R and cathepsin L in cytoplasm.Results pDS_shCREGs vector transfection produced an approximately 80%decrease in CREG levels both in the lysate and in the media.The expression and localization of M6P/IGF2R and cathepsin L in cytoplasma changed obviously associated with down-regulated of CREG.In addition,the retention and secretion of cathepsin L enhanced significantly.Using the specific inhibitor or siRNA to block cathepsin L activation attenuated the apoptosis mediated by CREG downregulation.Conclusions Our findings indicated that inhibition of CREG expression in NIH3T3 fibroblasts leads to impaired cathepsin L sorting function mediated by M6P/IGF2R and subsequently promotes pathological cell apoptosis.展开更多
Objective To investigate the effects of transforming growth factor-β1 (TGF-β1 ) on the expression of plasminogen activator inhibitor type 1 (PAI-1 ) mRNA in renal interstitial fibrosis in vitro. Methods Human renal ...Objective To investigate the effects of transforming growth factor-β1 (TGF-β1 ) on the expression of plasminogen activator inhibitor type 1 (PAI-1 ) mRNA in renal interstitial fibrosis in vitro. Methods Human renal interstitial fibroblasts were isolated and cultured in vitro. The cells wers stimulated by TGF-β1 with different concentration (0 to 10ng/ml ) at different time (0 to 48h). The expression of PAI-1 mRNA was assayed by RT-PCR. Results TGF-β1, had dose-dependent and time-dependent effects on the expression of PAI-1 mRNA in renal interstitial fibroblasts. Conclusion TGF-β1 may partic- ipate in renal fibrosis with inducing the expression of PAI-1 mRNA in renal fibroblasts and affecting the synthesis and degradation of extracellular matrix (ECM).展开更多
BACKGROUND This report describes a rare case of a small gastric cancer lesion with widespread bone metastases and markedly elevated alkaline phosphatase levels that was initially misdiagnosed as rheumatoid arthritis,a...BACKGROUND This report describes a rare case of a small gastric cancer lesion with widespread bone metastases and markedly elevated alkaline phosphatase levels that was initially misdiagnosed as rheumatoid arthritis,as the patient’s sole clinical manifestation was chronic bone pain persisting for 1 year.CASE SUMMARY An 83-year-old man was admitted due to worsening generalized joint pain over 1 year.Serum alkaline phosphatase levels were markedly elevated,and technetium-99m methylene diphosphonate single-photon emission computed tomography(CT)and fluorine-18 sodium fluoride positron emission tomography(PET)/CT images showed symmetrical diffuse uptake of the radiotracers throughout the skeleton.Initially,Paget’s disease was suspected,but abnormal hematologic tumor markers and bone biopsy confirmed metastatic adenocarcinoma.Fluorine-18-fluorodeoxyglucose PET/CT did not reveal a primary tumor.The patient had a history of colon polypectomy and tubulovillous adenoma with atypical hy-perplasia on pathological examination 10 years prior.Further investigation using gallium-68-labeled fibroblast-activation protein inhibitor PET/CT images showed increased punctate uptake in the gastric antrum.Gastroscopy demonstrated a 1.0 cm ulcerated mass in the prepyloric region,and histopathological evaluation of the biopsy specimen revealed poorly differentiated adenocarcinoma.The incidence of bone metastases from gastric cancer is very low,especially with such extensive involvement.CONCLUSION Occult gastric carcinomas with bone metastases necessitate proactive high-risk surveillance and multidisciplinary integration to improve diagnostic accuracy and clinical outcomes.展开更多
Gastric cancer is a major global health challenge,associated with high mortality and limited therapeutic options.Ginsenoside Rg3(Rg3),a bioactive compound derived from ginseng,has been shown to possess significant ant...Gastric cancer is a major global health challenge,associated with high mortality and limited therapeutic options.Ginsenoside Rg3(Rg3),a bioactive compound derived from ginseng,has been shown to possess significant anticancer properties,particularly through immune modulation.In this study,we explored the therapeutic potential of Ginsenoside Rg3 hydrogel in the treatment of gastric cancer,focusing on its ability to target fibroblast activation protein(FAP),a key mediator of tumor progression.Using reverse molecular docking and gene expression analysis,we identified FAP as a primary molecular target of Rg3.Preclinical evaluations revealed that Rg3 hydrogel effectively inhibited the proliferation and invasion of gastric cancer cells in vitro.Furthermore,the hydrogel promoted immunogenic cell death,resulting in a robust immune response against the tumor.Our findings suggest that Ginsenoside Rg3 hydrogel holds promise as a novel immune-based therapeutic strategy for gastric cancer,offering a potential pathway to improved clinical outcomes and treatment strategies.展开更多
Melanoma is a malignant neoplasm with a high propensity to metastasize,arising from melanocytes and contributing significantly to global morbidity and mortality.Despite the demonstrated efficacy of many immunotherapy ap...Melanoma is a malignant neoplasm with a high propensity to metastasize,arising from melanocytes and contributing significantly to global morbidity and mortality.Despite the demonstrated efficacy of many immunotherapy approaches,these methods rely on direct destruction of tumor cells with minimal impact on the aggregate of nearby non-tumor cells,the extracellular matrix,and blood vessels that form the tumor microenvironment(TME).The TME is known to be heterogeneous and dynamic,exerting both antitumor and pro-tumor effects depending on the specific features and stage of carcinogenesis.TME has been shown in several studies to promote malignancy,angiogenesis,and metastasis in tumors in general and melanoma in particular.Consequently,a significant number of studies in thefield of melanoma therapy have been redirected to investigate the effects of individual TME constituents,their prognostic significance for patients,and the potential of therapeutic intervention to improve overall patient survival.This review highlights novel therapeutic approaches targeting two key resident cell types in the melanoma microenvironment:tumor-associated macrophages(TAMs)and cancer-associatedfibroblasts(CAFs).The review discusses their role in disease progression and summarizes the results of preclinical and clinical trials of targeted therapies against these cell types in the melanoma TME.展开更多
Pancreatic ductal adenocarcinoma(PDA)is among the deadliest cancers in the United States and in the world.Late diagnosis,early metastasis and lack of effective therapy are among the reasons why only 6%of patients diag...Pancreatic ductal adenocarcinoma(PDA)is among the deadliest cancers in the United States and in the world.Late diagnosis,early metastasis and lack of effective therapy are among the reasons why only 6%of patients diagnosed with PDA survive past 5 years.Despite development of targeted therapy against other cancers,little progression has been made in the treatment of PDA.Therefore,there is an urgent need for the development of new treatments.However,in order to proceed with treatments,the complicated biology of PDA needs to be understood first.Interestingly,majority of the tumor volume is not made of malignant epithelial cells but of stroma.In recent years,it has become evident that there is an important interaction between the stromal compartment and the less prevalent malignant cells,leading to cancer progression.The stroma not only serves as a growth promoting source of signals but it is also a physical barrier to drug delivery.Understanding the tumor-stroma signaling leading to development of desmoplastic reaction and tumor progression can lead to the development of therapies to decrease stromal activity and improve drug delivery.In this review,we focus on how the current understanding of biology of the pancreatic tumor microenvironment can be translated into the development of targeted therapy.展开更多
Objective Fibroblast activation protein(FAP)has been widely studied and exploited for its clinical applications.One of the difficulties in interpreting reports of FAP-targeted theranostics is due to the lack of accura...Objective Fibroblast activation protein(FAP)has been widely studied and exploited for its clinical applications.One of the difficulties in interpreting reports of FAP-targeted theranostics is due to the lack of accurate controls,making the results less specific and less confirmative.This study aimed to establish a pair of cell lines,in which one highly expresses FAP(HT1080-hFAP)and the other has no detectable FAP(HT1080-vec)as control,to accurately evaluate the specificity of the FAP-targeted theranostics in vitro and in vivo.Methods The cell lines of the experimental group(HT1080-hFAP)and no-load group(HT1080-vec)were obtained by molecular construction of the recombinant plasmid pIRES-hFAP.The expression of hFAP in HT1080 cells was detected by PCR,Western blotting and flow cytometry.CCK-8,Matrigel transwell invasion assay,scratch test,flow cytometry and immunofluorescence were used to verify the physiological function of FAP.The activities of human dipeptidyl peptidase(DPP)and human endopeptidase(EP)were detected by ELISA in HT1080-hFAP cells.PET imaging was performed in bilateral tumor-bearing nude mice models to evaluate the specificity of FAP.Results RT-PCR and Western blotting demonstrated the mRNA and protein expression of hFAP in HT1080-hFAP cells but not in HT1080-vec cells.Flow cytometry confirmed that nearly 95%of the HT1080-hFAP cells were FAP positive.The engineered hFAP on HT1080 cells had its ability to retain enzymatic activities and a variety of biological functions,including internalization,proliferation-,migration-,and invasion-promoting activities.The HT1080-hFAP xenografted tumors in nude mice bound and took up^(68)GA-FAPI-04 with superior selectivity.High image contrast and tumor-organ ratio were obtained by PET imaging.The HT1080-hFAP tumor retained the radiotracer for at least 60 min.Conclusion This pair of HT1080 cell lines was successfully established,making it feasible for accurate evaluation and visualization of therapeutic and diagnostic agents targeting the hFAP.展开更多
Cancer-associated fibroblasts(CAFs)are a major constituent of the tumor microenvironment(TME)and an important contributor to cancer progression and therapeutic resistance.Regulation of CAF activation is a promising st...Cancer-associated fibroblasts(CAFs)are a major constituent of the tumor microenvironment(TME)and an important contributor to cancer progression and therapeutic resistance.Regulation of CAF activation is a promising strategy to influence cancer outcomes.Here,we report that ovarian cancer cells(OCs)and TME cells promote the activation of ovarian CAFs,whereas gold nanoparticles(GNPs)of 20 nm in diameter inhibit the activation,as demonstrated by the changes in cell morphology,migration,and molecular markers.GNPs exert the effect by altering the levels of multiple fibroblast activation or inactivation proteins,such as TGF-β1,PDGF,uPA and TSP1,secreted by OCs and TME cells.Thus,GNPs represent a potential tool to help understand multicellular communications existing in the TME as well as devise strategies to disrupt the communication.展开更多
文摘Positron emission tomography/computed tomography(PET/CT)with radiolabeled fibroblast activation protein inhibitors(FAPI)is an increasingly relevant molecular diagnostic image in oncology given the high expression of FAP in cancer associated fibroblast,being present in almost 90%of the epithelial carcinomas,which allows imaging with excellent diagnostic performance and can also become a therapeutic strategy.This review summarizes the literature on FAPIPET/CT for the cancer evaluation and compares it in some scenarios with the 18FFluorodeoxyglucose PET/CT.
基金Supported by The National Key Project of Scientific and Technical Supporting Programs of China, No. 2006BAI02A14National Natural Science Foundation of China, No. 30770996 and No. 81172310
文摘AIM: To examine fibroblast activation protein (FAP) expression in pancreatic ductal adenocarcinoma (PDAC) and to analyze its relationship with the clinicopathology of PDAC. METHODS: FAP expression was examined in 134 PDAC specimens by immunohistochemistry, and in four pancreatic cancer cell lines (SW1990, Miapaca-2, AsPC-1 and BxPC-3) by Western blotting assay. We also analyzed the association between FAP expression in PDAC cells and the clinicopathology of PDAC patients. RESULTS: The results showed that the FAP was expressed in both stromal fibroblast cells (98/134, 73.1%) and carcinoma cells (102/134, 76.1%). All 4 pancreatic cancer cell lines expressed FAP protein at different levels. Protein bands corresponding to the proteolytically active 170-kDa seprase dimer and its88-kDa seprase subunit were identif ied. Higher FAP expression in carcinoma cells was associated with tumor size (P < 0.001), fi brotic focus (P = 0.003), perineural invasion (P = 0.009) and worse clinical outcome (P = 0.0085). CONCLUSION: FAP is highly expressed in carcinoma cells and f ibroblasts in PDAC tissues, and its expression is associated with desmoplasia and worse prognosis.
基金Key Scientific Research Program for Young Scholars in Fujian,Grant/Award Number:2021ZQNZD016Fujian Natural Science Foundation for Distinguished Young Scholars,Grant/Award Number:2022D005+3 种基金Medical and Health Guidance Projects of Xiamen,Grant/Award Numbers:3502Z20209269,3502Z20224ZD1001National Natural Science Foundation of China,Grant/Award Numbers:82071961,82102094Fujian Natural Science Foundation for Youth Innovation,Grant/Award Number:2022J05314Fujian Research and Training Grants for Young and Middle-Aged Leaders in Healthcare。
文摘Quinoline-based fibroblast activation protein(FAP)inhibitor(FAPI)-based positron emission tomography(PET)imaging and radioligand therapy(RLT)are being investigated for use in a wide variety of diseases,and recent results have been promising.This review summarizes the current status of FAPI radiopharmaceuticals in PET imaging of malignant tumors and benign conditions and compares their diagnostic efficacy with ^(18)F-fluorodeoxyglucose.In addition,we summarize the previously published FAP-targeted RLT data and discuss its current clinical use and future potential.Our qualitative summary can inform future research directions,medical guidelines,and optimal clinical decision-making.
基金supported by the National Natural Science Foundation of China(No.82372002)the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences(No.2022-RC350-04)+6 种基金the CAMS Innovation Fund for Medical Sciences(Nos.2024-12M-ZH-009,2023-I2M-2-006,2023-I2M-QJ010,2021-I2M-1-026,and 2021-I2M-3-001,China)the Beijing Nova Program and Beijing Nova Program Interdisciplinary Cooperation Project to Ksupported by the Beijing Natural Science Foundation(Nos.L234044,L248087,L246051 and 7252206,China)the Fundamental Research Funds for the Central Universities(Nos.3332023044,3332023151,China)the China Postdoctoral Science Foundation(No.2025M773592)the China National Nuclear Corporation Young Talent Program,the special project of“Technological Innovation”project of CNNC Medical Industry Co.Ltd(ZHYLYB2021005)Medical+X Innovation Team of the Discipline Construction Enhancement Project,the Second Affiliated Hospital of Soochow University(XKTJ-TD202410).
文摘The activation proteins released by fibroblasts in the tumor microenvironment regulate tumor growth,migration,and treatment response,thereby influencing tumor progression and therapeutic outcomes.Owing to the proliferation and metastasis of tumors,fibroblast activation protein(FAP)is typically highly expressed in the tumor stroma,whereas it is nearly absent in adult normal tissues and benign lesions,making it an attractive target for precision medicine.Radiolabeled agents targeting FAP have the potential for targeted cancer diagnosis and therapy.This comprehensive review aims to describe the evolution of FAPI-based radiopharmaceuticals and their structural optimization.Within its scope,this review summarizes the advances in the use of radiolabeled small molecule inhibitors for tumor imaging and therapy as well as the modification strategies for FAPIs,combined with insights from structure-activity relationships and clinical studies,providing a valuable perspective for radiopharmaceutical clinical development and application.
基金supported by the National Key Research and Development Program of China(No.2021YFC2100600),the National Natural Science Foundation of China(Nos.81973201,82200773,82370696,82204225,82200807),the Natural Science Foundation of Hubei Province(Nos.2021CFB347,2021CFB061),the Fundamental Research Funds for Central University(2042022kf1140),the Program of Excellent Doctoral(Postdoctoral)of Zhongnan Hospital of Wuhan University(ZNYB2021029),the Hubei Province Health and Family Planning Scientific Research Project(WJ2019MB103),the Clinical Research Project for Wu Jieping Medical Foundation(320.6750.19089-58),and the Research Fund from Medical Sci-Tech Innovation Platform of Zhongnan Hospital,Wuhan University(PTXM2020028,XKJS202035).We thank Dr.Ran Zhang from the Core Facility of Wuhan University and Dr.Xue Zhou from the Core Research Facilities of CCMS(WHU)for their assistance with NMR analysis.
文摘An investigation of the mangrove-derived fungus Penicillium sp.DM27 led to the isolation of 19 new compounds,including three pairs of piperidinone enantiomers(±)-1,(±)-2,and(±)-3,two pairs of pyrrolidinone enantiomers(±)-4 and(±)-5,and nine pyrrolidine derivatives 6−14.The structures of 1−14 were elucidated through NMR and HRESIMS analysis,coupled with experimental and calculated ECD spectroscopy and the modified Mosher method.Quantitative real time PCR and Western bolt analyses revealed that 11 blocked EMT in TGF-β1-treated HK-2 cells and suppressed fibroblast activation in TGF-β1-stimulated NIH-3T3 cells.Molecular simulations demonstrated that compound 11 could dock ADAM17,showing a high negative binding affinity.Additionally,the overexpression of ADAM17 by lentiviral infection triggered renal tubular EMT,while compound 11 suppressed this process.Overall,our research suggests that pyrrolidine derivatives may be potential therapeutic agents for the treatment of fibrotic kidney disease.
基金supported by the National Natural Science Foundation of China(W2411008,823B2043,22122504,and 22235006)the Cancer Research and Translational Platform Project of Zhongnan Hospital of Wuhan University(ZLYNXM202004).
文摘Hepatectomy is a critical treatment for liver cancer,but achieving complete tumor removal remains challenging.The development of tumor-targeting probes capable of accurately identifying tumor locations and providing real-time intraoperative navigation is of significant clinical importance.We synthesize a tumor-targeted probe by conjugating a fibroblast activation protein inhibitor(FAPI)with near-infrared organic room temperature phosphorescence(RTP)material.We then analyze its surgical navigation performance in the liver cancer model and its imaging performance in fresh patient-derived samples.In vivo validation reveals that the probe exhibits optimal phosphorescence intensity within 48 h(8.53×10^(5)p s^(−1)cm^(−2)sr^(−1))and an average signal-to-noise ratio of 16.The probe could effectively identify FAP-positive samples from liver cancer patients.The successful application of phosphorescence-guided surgery suggests that the near-infrared RTP probe holds significant clinical translational value and could serve as an auxiliary tool for the surgical treatment of liver cancer.
基金funded by the Beijing Municipal Natural Science Foundation(Grant No.Z200018)the National Natural Science Foundation of China(Grant No.22225603)the Ministry of Science and Technology of the People's Republic of China(Grant Nos.2021YFA1601400).
文摘Targeted alpha therapy(TAT)is an innovative approach in cancer treatment that aims to selectively deliver high-energy radiation to cancer cells while minimizing damage to healthy tissues.^(225)Ac,an alpha radionuclide with a half-life of 10 days and emitting 4 alpha particles and 2 beta particles in its decay chain,has shown promise for TAT.Fibroblast activation protein(FAP)has emerged as a valuable target for the development of radiopharmaceuticals in the context of TAT,given its expression in various cancers.However,a challenge arises when using FAPtargeting agents such as FAP inhibitors(FAPIs)in combination with^(225)Ac due to their rapid clearance from the tumor.To address this challenge,the FAP-targeting antibody PKU525 was developed as a TAT drug.The conjugation ratios of the chelator and the labeling procedure were systematically investigated,resulting in an efficient and stable radiolabeling method.Biodistribution studies were conducted using[^(225)Ac]Ac-DOTA-PKU525 with average drug-to-antibody ratios(DARs)of 1.85,3.87,and 7.72.A single dose of 11.1 kBq of[^(225)Ac]Ac-DOTA-PKU525 with DAR 3.87 demonstrated significant inhibition of 4T1-hFAP tumor growth.No significant weight changes were observed throughout the treatment period,and histological examination of the major organs revealed no adverse side effects.In conclusion,[^(225)Ac]Ac-DOTA-PKU525 exhibited both safety and efficacy in 4T1-hFAP tumor-bearing mice,indicating its potential for clinical translation in FAP-targeted alpha therapy.Further development and evaluation of this TAT approach hold promise for improving cancer treatment outcomes.
基金supported by the grants provided by Zhuhai People's Hospital,China(Grant No.:2021KYQD-03)the National Natural Science Foundation of China(Grant No.:22176016).
文摘Fibroblast activation protein(FAP)is overexpressed in cancer-associated fibroblasts across various cancer types.Numerous radiolabeled FAP inhibitors(FAPIs)(Fig.S1A)currently under clinical investigation have shown remarkable potential in cancer theranostics.
基金Supported by the Research and Technology Council of Babol University of Medical Sciences with Grant No.9031029
文摘Objective:To compare the protein profile of culture supernatants in stimulated and unstimulated human fibroblasts to find some proteins indicating the presence of fibroblasts and their activation status.Methods:Dermal fibroblasts were stimulated with phorbol 12-myristate 13-acetate(PMA)/ionomycine for 72 h.MTT assay was done to determine cell viability and A/E fluorescent staining was used to evaluate the cell death pattern.Protein analysis was performed by gradient SDS polyacrylamide gel electrophoresis 8%–16%.Results:The supernatant of 24 h cultured both stimulated and unstimulated fibroblasts showed two bands in SDS-PAGE analysis with relative molecular weights of 8.59 and78.8 k Da.These bands density was decreased during the next 48 h in unstimulated cells while their expression was continued in PMA or PMA/ionomycine stimulated cells and a new 85.3 k Da band was appeared in unstimulated and 72 h PMA stimulated cells.Moreover,we found another seven small size(10–19.5 k Da) proteins in supernatants of48 h and 72 h unstimulated but not in PMA or PMA/Ionomycine stimulated fibroblasts.Most of these proteins expression were down regulated following fibroblast activation.This down-regulation is consistent with our finding that PMA or PMA/ionomycine stimulated cells exhibited a significant level of apoptosis cell death.Conclusions:Human fibroblasts produce some small to intermediate sized proteins with specific SDS-PAGE profile upon cell activation.Most of these proteins can be excreted in urine and can be immunogen theoretically so this data provided a reliable clue for fibrosis biomarker screening based on designation of an appropriated immunoassay.
基金This study was supported by a grant from Hamadan University of Medical Sciences(No.9511267103).
文摘Inflammation plays an important role in the development of several cancers.Inflammatory cytokines,including tumor necrosis factor-α(TNF-α),are associated with the induction of inflammation.Chronic inflammation contributes to the progression of cancer through several mechanisms,including increased cytokine production and activation of transcription factors,such as nuclear factor-κB(NF-κB).Zerumbone(ZER),a component of subtropical ginger(Zingiber zerumbet Smith),seems to have anti-inflammatory,anti-cancer,and antioxidant activities.In this study,we aimed to explore the protective function and mechanisms of ZER against TNF-α-induced cancer-promoting cytokines.We found that the viability of stimulated human fibroblast cell lines was reduced after treatment with ZER(IC50=18µmol/L),compared to un-stimulated fibroblasts(IC50=40µmol/L).Besides,ZER inhibited mRNA expression and protein secretion of transforming growth factor-β(TGF-β),interleukin-33(IL-33),monocyte chemoattractant protein-1(MCP-1),and stromal cell-derived factor 1(SDF-1),which were produced by TNF-α-induced fibroblasts,as measured by quantitative real time-PCR(qRT-PCR)and ELISA assays.The mRNA expression levels of TGF-β,IL-33,SDF-1,and MCP-1 showed 8,5,2.5,and 4-fold reductions,respectively.Moreover,secretion of TGF-β,IL-33,SDF-1,and MCP-1 was reduced to 3.65±0.34 ng/mL,6.3±0.26,1703.6±295.2,and 5.02±0.18 pg/mL,respectively,compared to the untreated group.In addition,the conditioned media(CM)of TNF-α-stimulated fibroblasts increased the NF-κB expression in colorectal cancer cell lines(HCT-116 and Sw48),while in the vicinity of ZER,the expression of NF-κB was reversed.Considering the significant effects of ZER,this component can be used as an appropriate alternative herbal treatment for cancer-related chronic inflammation.
基金supported by NIH grants AR049510 (TLC) and AR045955 (LDQ)
文摘Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la （HIF-la） in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.
基金supported by the Ministry of Higher Education Malaysia for Fundamental Research Grant Scheme with Project Code:FRGS/1/2020/SKK0/USM/03/10 and USM.
文摘Colorectal cancer (CRC) is a major global health concern. Accumulation of cancer-associated fibroblasts(CAFs) in CRC is associated with poor prognosis and disease recurrence. CAFs are the main cellular component ofthe tumor microenvironment. CAF-tumor cell interplay, which is facilitated by various secretomes, drives colorectalcarcinogenesis. The complexity of CAF populations contributes to the heterogeneity of CRC and influences patientsurvival and treatment response. Due to their significant roles in colorectal carcinogenesis, different clinicalapplications utilizing or targeting CAFs have been suggested. Circulating CAFs (cCAFs) which can be detected inblood samples, have been proposed to help in determining patient prognosis and enables the detection of cancerthrough liquid biopsy. Liquid biopsy is gaining traction as it is non-invasive, allows frequent and easy sampling, andshows concordance to tissue biopsy analysis. In addition, CAF-targeted therapy is currently being studied extensivelyto be used as one of the treatment avenues for CRC. Various mechanisms of CAF-targeted therapy have beenreported, including blocking the signaling pathways involving CAFs and cancer cells, thus abolishing the CAF-tumorcell crosstalk and subsequently hindering tumorigenesis. These translational applications of cCAFs and utilization ofCAFs as key targets for CRC therapy, although still in the early phases of development, will potentially improve CRCpatient management in the future.
文摘Background The CREG is an important lysosomal protein involved in a variety of cellular functions including promoting cell differentiation,sustaining mature homeostasis, and antagonizing apoptosis.Deficiency of CREG in cell and tissue results in a pathologic apoptosis.The present study aimed to elucidate the mechanism of CREG regulation apoptosis.Methods We firstly generated stable NIH3T3 fibroblasts by transfection of pDS_shCREGs vectors.Furthermore, PI-Annexin V and TUNEL staining were used to identify that CREG knockdown promoted the cell apoptosis in NIH3T3 fibroblasts.Western blotting and immunofluorescence staining was used to identify the expression and localization of M6P/ IGF2R and cathepsin L in cytoplasm.Results pDS_shCREGs vector transfection produced an approximately 80%decrease in CREG levels both in the lysate and in the media.The expression and localization of M6P/IGF2R and cathepsin L in cytoplasma changed obviously associated with down-regulated of CREG.In addition,the retention and secretion of cathepsin L enhanced significantly.Using the specific inhibitor or siRNA to block cathepsin L activation attenuated the apoptosis mediated by CREG downregulation.Conclusions Our findings indicated that inhibition of CREG expression in NIH3T3 fibroblasts leads to impaired cathepsin L sorting function mediated by M6P/IGF2R and subsequently promotes pathological cell apoptosis.
基金Supported by the Shanghai Municipal Lead Medical Science Foundation(94-Ⅲ-006)
文摘Objective To investigate the effects of transforming growth factor-β1 (TGF-β1 ) on the expression of plasminogen activator inhibitor type 1 (PAI-1 ) mRNA in renal interstitial fibrosis in vitro. Methods Human renal interstitial fibroblasts were isolated and cultured in vitro. The cells wers stimulated by TGF-β1 with different concentration (0 to 10ng/ml ) at different time (0 to 48h). The expression of PAI-1 mRNA was assayed by RT-PCR. Results TGF-β1, had dose-dependent and time-dependent effects on the expression of PAI-1 mRNA in renal interstitial fibroblasts. Conclusion TGF-β1 may partic- ipate in renal fibrosis with inducing the expression of PAI-1 mRNA in renal fibroblasts and affecting the synthesis and degradation of extracellular matrix (ECM).
文摘BACKGROUND This report describes a rare case of a small gastric cancer lesion with widespread bone metastases and markedly elevated alkaline phosphatase levels that was initially misdiagnosed as rheumatoid arthritis,as the patient’s sole clinical manifestation was chronic bone pain persisting for 1 year.CASE SUMMARY An 83-year-old man was admitted due to worsening generalized joint pain over 1 year.Serum alkaline phosphatase levels were markedly elevated,and technetium-99m methylene diphosphonate single-photon emission computed tomography(CT)and fluorine-18 sodium fluoride positron emission tomography(PET)/CT images showed symmetrical diffuse uptake of the radiotracers throughout the skeleton.Initially,Paget’s disease was suspected,but abnormal hematologic tumor markers and bone biopsy confirmed metastatic adenocarcinoma.Fluorine-18-fluorodeoxyglucose PET/CT did not reveal a primary tumor.The patient had a history of colon polypectomy and tubulovillous adenoma with atypical hy-perplasia on pathological examination 10 years prior.Further investigation using gallium-68-labeled fibroblast-activation protein inhibitor PET/CT images showed increased punctate uptake in the gastric antrum.Gastroscopy demonstrated a 1.0 cm ulcerated mass in the prepyloric region,and histopathological evaluation of the biopsy specimen revealed poorly differentiated adenocarcinoma.The incidence of bone metastases from gastric cancer is very low,especially with such extensive involvement.CONCLUSION Occult gastric carcinomas with bone metastases necessitate proactive high-risk surveillance and multidisciplinary integration to improve diagnostic accuracy and clinical outcomes.
文摘Gastric cancer is a major global health challenge,associated with high mortality and limited therapeutic options.Ginsenoside Rg3(Rg3),a bioactive compound derived from ginseng,has been shown to possess significant anticancer properties,particularly through immune modulation.In this study,we explored the therapeutic potential of Ginsenoside Rg3 hydrogel in the treatment of gastric cancer,focusing on its ability to target fibroblast activation protein(FAP),a key mediator of tumor progression.Using reverse molecular docking and gene expression analysis,we identified FAP as a primary molecular target of Rg3.Preclinical evaluations revealed that Rg3 hydrogel effectively inhibited the proliferation and invasion of gastric cancer cells in vitro.Furthermore,the hydrogel promoted immunogenic cell death,resulting in a robust immune response against the tumor.Our findings suggest that Ginsenoside Rg3 hydrogel holds promise as a novel immune-based therapeutic strategy for gastric cancer,offering a potential pathway to improved clinical outcomes and treatment strategies.
基金performed at the expense of the subsidy allocated to Kazan Federal University for the fulfillment of the stated task in the field of scientific activity,No.FZSM-2023-0011.
文摘Melanoma is a malignant neoplasm with a high propensity to metastasize,arising from melanocytes and contributing significantly to global morbidity and mortality.Despite the demonstrated efficacy of many immunotherapy approaches,these methods rely on direct destruction of tumor cells with minimal impact on the aggregate of nearby non-tumor cells,the extracellular matrix,and blood vessels that form the tumor microenvironment(TME).The TME is known to be heterogeneous and dynamic,exerting both antitumor and pro-tumor effects depending on the specific features and stage of carcinogenesis.TME has been shown in several studies to promote malignancy,angiogenesis,and metastasis in tumors in general and melanoma in particular.Consequently,a significant number of studies in thefield of melanoma therapy have been redirected to investigate the effects of individual TME constituents,their prognostic significance for patients,and the potential of therapeutic intervention to improve overall patient survival.This review highlights novel therapeutic approaches targeting two key resident cell types in the melanoma microenvironment:tumor-associated macrophages(TAMs)and cancer-associatedfibroblasts(CAFs).The review discusses their role in disease progression and summarizes the results of preclinical and clinical trials of targeted therapies against these cell types in the melanoma TME.
基金Supported by NIH R01 CA169702-01A1(to Zheng L)NIH K23 CA148964-01(to Zheng L)+6 种基金Johns Hopkins School of Medicine Clinical Scientist Award(to Zheng L)Viragh Foundation and the Skip Viragh Pancreatic Cancer Center at Johns Hopkins(to Zheng L)The National Pancreas Foundation(to Zheng L)Lefkofsky Family Foundation(to Zheng L)the NCI SPORE in Gastrointestinal Cancers P50 CA062924(to Zheng L)Lustgarten Foundation(to Zheng L)the Sol Goldman Pancreatic Cancer Center grants(to Zheng L)
文摘Pancreatic ductal adenocarcinoma(PDA)is among the deadliest cancers in the United States and in the world.Late diagnosis,early metastasis and lack of effective therapy are among the reasons why only 6%of patients diagnosed with PDA survive past 5 years.Despite development of targeted therapy against other cancers,little progression has been made in the treatment of PDA.Therefore,there is an urgent need for the development of new treatments.However,in order to proceed with treatments,the complicated biology of PDA needs to be understood first.Interestingly,majority of the tumor volume is not made of malignant epithelial cells but of stroma.In recent years,it has become evident that there is an important interaction between the stromal compartment and the less prevalent malignant cells,leading to cancer progression.The stroma not only serves as a growth promoting source of signals but it is also a physical barrier to drug delivery.Understanding the tumor-stroma signaling leading to development of desmoplastic reaction and tumor progression can lead to the development of therapies to decrease stromal activity and improve drug delivery.In this review,we focus on how the current understanding of biology of the pancreatic tumor microenvironment can be translated into the development of targeted therapy.
基金This work was supported by the National Natural Science Foundation of China(No.82171986).
文摘Objective Fibroblast activation protein(FAP)has been widely studied and exploited for its clinical applications.One of the difficulties in interpreting reports of FAP-targeted theranostics is due to the lack of accurate controls,making the results less specific and less confirmative.This study aimed to establish a pair of cell lines,in which one highly expresses FAP(HT1080-hFAP)and the other has no detectable FAP(HT1080-vec)as control,to accurately evaluate the specificity of the FAP-targeted theranostics in vitro and in vivo.Methods The cell lines of the experimental group(HT1080-hFAP)and no-load group(HT1080-vec)were obtained by molecular construction of the recombinant plasmid pIRES-hFAP.The expression of hFAP in HT1080 cells was detected by PCR,Western blotting and flow cytometry.CCK-8,Matrigel transwell invasion assay,scratch test,flow cytometry and immunofluorescence were used to verify the physiological function of FAP.The activities of human dipeptidyl peptidase(DPP)and human endopeptidase(EP)were detected by ELISA in HT1080-hFAP cells.PET imaging was performed in bilateral tumor-bearing nude mice models to evaluate the specificity of FAP.Results RT-PCR and Western blotting demonstrated the mRNA and protein expression of hFAP in HT1080-hFAP cells but not in HT1080-vec cells.Flow cytometry confirmed that nearly 95%of the HT1080-hFAP cells were FAP positive.The engineered hFAP on HT1080 cells had its ability to retain enzymatic activities and a variety of biological functions,including internalization,proliferation-,migration-,and invasion-promoting activities.The HT1080-hFAP xenografted tumors in nude mice bound and took up^(68)GA-FAPI-04 with superior selectivity.High image contrast and tumor-organ ratio were obtained by PET imaging.The HT1080-hFAP tumor retained the radiotracer for at least 60 min.Conclusion This pair of HT1080 cell lines was successfully established,making it feasible for accurate evaluation and visualization of therapeutic and diagnostic agents targeting the hFAP.
基金This study was supported by National Institutes of Health Grants CA220237,CA136494,CA213278(to P.M.)and HL120585(to both P.M.and R.B.)We thank the Peggy and Charles Stephenson Cancer Center at the University of Oklahoma Health Sciences Center for a seed grant and an Institutional Development Award(IDeA)from the National Institute of General Medical Sciences of the NIH under grant number P20 GM103639 for the use of Histology and Immunohistochemistry Core+1 种基金Research reported in this publication was also supported in part by the NCI Cancer Center Support Grant P30CA225520 awarded to the University of Oklahoma Stephenson Cancer Center and used the Office of Cancer ResearchThe authors thank Drs.Andy E.Madden,Preston Larson and Julian Sabisch for technical assistance with EDS,XRD and TEM.
文摘Cancer-associated fibroblasts(CAFs)are a major constituent of the tumor microenvironment(TME)and an important contributor to cancer progression and therapeutic resistance.Regulation of CAF activation is a promising strategy to influence cancer outcomes.Here,we report that ovarian cancer cells(OCs)and TME cells promote the activation of ovarian CAFs,whereas gold nanoparticles(GNPs)of 20 nm in diameter inhibit the activation,as demonstrated by the changes in cell morphology,migration,and molecular markers.GNPs exert the effect by altering the levels of multiple fibroblast activation or inactivation proteins,such as TGF-β1,PDGF,uPA and TSP1,secreted by OCs and TME cells.Thus,GNPs represent a potential tool to help understand multicellular communications existing in the TME as well as devise strategies to disrupt the communication.
