Liposarcoma is one of the most common soft tissue sarcomas,however,its occurrence rate is still rare compared to other cancers.Due to its rarity,in vitro experiments are an essential approach to elucidate liposarcoma ...Liposarcoma is one of the most common soft tissue sarcomas,however,its occurrence rate is still rare compared to other cancers.Due to its rarity,in vitro experiments are an essential approach to elucidate liposarcoma pathobiology.Conventional cell culture-based research(2D cell culture)is still playing a pivotal role,while several shortcomings have been recently under discussion.In vivo,mouse models are usually adopted for pre-clinical analyses with expectations to overcome the issues of 2D cell culture.However,they do not fully recapitulate human dedifferentiated liposarcoma(DDLPS)characteristics.Therefore,three-dimensional(3D)culture systems have been the recent research focus in the cell biology field with the expectation to overcome at the same time the disadvantages of 2D cell culture and in vivo animal models and fill in the gap between them.Given the liposarcoma rarity,we believe that 3D cell culture techniques,including 3D cell cultures/co-cultures,and Patient-Derived tumor Organoids(PDOs),represent a promising approach to facilitate liposarcoma investigation and elucidate its molecular mechanisms and effective therapy development.In this review,we first provide a general overview of 3D cell cultures compared to 2D cell cultures.We then focus on one of the recent 3D cell culture applications,Patient-Derived Organoids(PDOs),summarizing and discussing several PDO methodologies.Finally,we discuss the current and future applications of PDOs to sarcoma,particularly in the field of liposarcoma.展开更多
BACKGROUND Liver metastases are very common in pancreatic neuroendocrine tumors(pNETs).When surgical resection is possible,it is typically associated with survival benefits in patients with pNET and liver metastases.P...BACKGROUND Liver metastases are very common in pancreatic neuroendocrine tumors(pNETs).When surgical resection is possible,it is typically associated with survival benefits in patients with pNET and liver metastases.Patient-derived organoids are a powerful preclinical platform that show great potential for predicting treatment response,and they have been increasingly applied in precision medicine and cancer research.CASE SUMMARY A 51-year-old man was admitted to the hospital with the chief complaint of in-termittent dull pain in the upper abdomen for over 3 years.Computerized to-mography showed multiple space-occupying lesions in the liver and a neoplasm in the pancreatic body.Pathological results suggested a grade 3 pancreas-derived hepatic neuroendocrine tumor.In combination with relevant examinations,the patient was diagnosed with pNET with liver metastases(grade 3).Transarterial chemoembolization was initially performed with oxaliplatin and 5-fluorouracil,after which the chemotherapy regimen was switched to liposomal irinotecan and cisplatin for a subsequent perfusion,guided by organoid-based drug sensitivity testing.Following interventional treatment,the tumor had decreased in size.However,due to poor treatment compliance and the patient’s preference for sur-INTRODUCTION Pancreatic neuroendocrine tumors(pNETs)are a rare and heterogeneous group of neoplasms arising from pancreatic islet cells,with variations in histology,clinical characteristics,and prognosis[1].They may present as non-infiltrative,slow-growing tumors,locally invasive tumors,or even rapidly metastasizing tumors[2].Most metastases localize to the liver,and approximately 28%-77%of patients with pNETs will experience liver metastases in their lifetime[3].Patients with liver metastases may be subjected to local complications such as biliary obstruction,liver insufficiency,and carcinoid syndrome.Additionally,liver metastases are a major risk factor for the prognosis of patients with pNETs[4].When feasible,surgical resection is significantly associated with the best long-term survival outcomes[5].Therefore,for patients with pNET liver metastases,comprehensive assessment and multidisciplinary approaches are required to determine the feasibility of surgical resection and the optimal treatment to improve the prognosis.Over the past decade,the advent of in vitro three-dimensional technologies including organoids has revolutionized the development of human cancer models.Patient-derived organoids(PDOs),an in vitro three-dimensional microstructure,can faithfully recapitulate the intricate spatial architecture and cell heterogeneity of the tissue,and simulate the biological behaviors and functions of parental tumors while preserving biological,genetic and molecular features[6,7].As a po-werful preclinical platform,PDOs have been increasingly applied in precision medicine and cancer research.Importantly,there is a significant association between the use of PDO-based drug sensitivity testing and clinical responses to chemotherapy,radiotherapy and targeted therapy in multiple cancer types[8-10].Although gastroenteropancreatic neuroendocrine neoplasm organoids have been confirmed to retain the pathohistological and functional phenotypes of parental tumors[7],their roles in the prediction of clinical outcomes have not been presented.Here,we report a case of pNET with liver metastases who successfully received surgical resection after personalized treatment guided by PDO-based drug sensitivity testing,resulting in a favorable prognosis.展开更多
Hepatobiliary and pancreatic(HBP)cancers are among the most aggressive malig-nancies,with recurrence and metastasis driven by tumor heterogeneity and drug resistance,presenting considerable challenges to effective tre...Hepatobiliary and pancreatic(HBP)cancers are among the most aggressive malig-nancies,with recurrence and metastasis driven by tumor heterogeneity and drug resistance,presenting considerable challenges to effective treatment.Currently,personalized and accurate treatment prediction models for these cancers are lacking.Patient-derived organoids(PDOs)tumor are three-dimensional in vitro models created from the tumor tissues of individual patients.Recent reports and our cultivation data indicate that the success rate of cultivating organoids for HBP cancers consistently exceeds 70%.The predictive accuracy of these tumor orga-noids has been shown to surpass 90%.However,PDOs still face notable limita-tions,especially in simulating the tumor microenvironment,including tumor angiogenesis and the surrounding cellular context,which require further refi-nement.While co-culture techniques and microfluidic platforms have been deve-loped to mimic multi-cellular environments and functional vascular perfusion,they remain insufficient in accurately recapitulating the complexities of the in vivo environment.Additionally,PDOs are needed to fully assess their potential in predicting the efficacy of multi-drug combination therapies.This review provides an overview of the applications,challenges,and prospects for organoid models in the study of HBP cancer.展开更多
BACKGROUND Patient-derived organoids(PDOs)have been demonstrated to predict the response to drugs in multiple cancer types.However,it remains unclear about its application in cholangiocarcinoma.CASE SUMMARY A 59-year-...BACKGROUND Patient-derived organoids(PDOs)have been demonstrated to predict the response to drugs in multiple cancer types.However,it remains unclear about its application in cholangiocarcinoma.CASE SUMMARY A 59-year-old woman was admitted to the hospital due to upper abdominal pain for over 8 months.According to relevant examinations,she was diagnosed as perihilar cholangiocarcinoma(pCCA)with intrahepatic metastasis and perihilar lymphatic metastasis.After multidisciplinary team discussion,percutaneous transhepatic cholangiodrainage was performed to relieve biliary obstruction,and puncture biopsy was conducted to confirm the pathological diagnosis.Transarterial chemoembolization with nab-paclitaxel was used in combination with toripalimab and lenvatinib,but the levels of tumor markers including alpha fetal protein,carcinoembryonic antigen,carbohydrate antigen 15-3 and cancer antigen 125 were still raised.The PDO for drug screening showed sensitive to gemcitabine and cisplatin.Accordingly,the chemotherapy regimen was adjusted to gemcitabine and cisplatin in combination with toripalimab and lenvatinib.After 4 cycles of treatment,the tumor was assessed resectable,and radical surgical resection was performed successfully.One year after surgery,the patient was still alive,and no recurrence or occurred.CONCLUSION PDOs for drug sensitivity contribute to screening effective chemotherapy drugs for advanced pCCA,promoting conversion therapy and improving the prognosis.展开更多
One of the major bottlenecks in advancing basic cancer research and developing novel cancer therapies is the lack of in vitro pre-clinical models that faithfully recapitulate tumor properties in the patients.Monolayer...One of the major bottlenecks in advancing basic cancer research and developing novel cancer therapies is the lack of in vitro pre-clinical models that faithfully recapitulate tumor properties in the patients.Monolayer cultures of cancer cell lines usually lose the heterogeneity of the parental tumors,while patient-derived xenograft(PDX)suffers from its time-and resource-intensive nature.The emergence of organoid culture system and its application in cancer research provides a unique opportunity to develop novel in vitro cancer pre-clinical models.Here we review the recent advances in utilizing organoids culture system and other related three-dimensional culture systems in studying cancer biology,performing drug screening,and developing cancer therapies.In particular,we discuss the advantages of applying xenograft initiated from patient-derived organoids(PDOs)as a faithful cancer pre-clinical model in basic cancer research and precision medicine.展开更多
Hepatocellular carcinoma(HCC)has become the fourth predominant cause of cancer-related deaths worldwide,and HCC is still one of the worst prognoses for survival as it is poorly responsive to both chemotherapy and surg...Hepatocellular carcinoma(HCC)has become the fourth predominant cause of cancer-related deaths worldwide,and HCC is still one of the worst prognoses for survival as it is poorly responsive to both chemotherapy and surgical treatment due to drug resista nce and great toxic effects.Triptolide(TP),a key ingredient from the traditional Chinese medical herb,has been utilized to treat inflammation and antitumor for centuries.However,investigations of this potent agent have been met with only limited success due to the severe systemic toxicities in patients and low water solubility as well as its high toxicity over the past two decades.Herein,we reported the development of a reduction-responsive drug delive ry system loaded with TP fo r glutathione(GSH)-trigge red drug release for cancer therapy.With the GSH-sensitive TP loaded nanoparticles,the remarkable increases in tumor accumulation and amelioration of drug toxicity in animals are demonstrated,which is likely due to sustained stepwise release of active TP within cancer cells.Moreover,in a patient-derived tumor xenograft model of liver cancer,administration of tritolide nanoparticles enhances the antitumor efficacy relative to administration of free TP.These findings indicate that GSH-sensitive release of TP may be a promising strategy for cancer treatment.展开更多
Objective:Patient-derived xenograft(PDX)models have shown great promise in preclinical and translational applications,but their consistency with primary tumors in phenotypic,genetic,and pharmacodynamic heterogeneity h...Objective:Patient-derived xenograft(PDX)models have shown great promise in preclinical and translational applications,but their consistency with primary tumors in phenotypic,genetic,and pharmacodynamic heterogeneity has not been well-studied.This study aimed to establish a PDX repository for non-small cell lung cancer(NSCLC)and to further elucidate whether it could preserve the heterogeneity within and between tumors in patients.Methods:A total of 75 surgically resected NSCLC specimens were implanted into immunodeficient NOD/SCID mice.Based on the successful establishment of the NSCLC PDX model,we compared the expressions of vimentin,Ki67,EGFR,and PD-L1 proteins between cancer tissues and PDX models using hematoxylin and eosin staining and immunohistochemical staining.In addition,we detected whole gene expression profiling between primary tumors and PDX generations.We also performed whole exome sequencing(WES)analysis in 17 first generation xenografts to further assess whether PDXs retained the patient heterogeneities.Finally,paclitaxel,cisplatin,doxorubicin,atezolizumab,afatininb,and AZD4547 were used to evaluate the responses of PDX models to the standard-of-care agents.Results:A large collection of serially transplantable PDX models for NSCLC were successfully developed.The histology and pathological immunohistochemistry of PDX xenografts were consistent with the patients’tumor samples.WES and RNA-seq further confirmed that PDX accurately replicated the molecular heterogeneities of primary tumors.Similar to clinical patients,PDX models responded differentially to the standard-of-care treatment,including chemo-,targeted-and immuno-therapeutics.Conclusions:Our established PDX models of NSCLC faithfully reproduced the molecular,histopathological,and therapeutic characteristics,as well as the corresponding tumor heterogeneities,which provides a clinically relevant platform for drug screening,biomarker discovery,and translational research.展开更多
AIM To assess the viability of orthotopic and heterotopic patient-derived pancreatic cancer xenografts implanted into nude mice.METHODS This study presents a prospective experimental analytical follow-up of the develo...AIM To assess the viability of orthotopic and heterotopic patient-derived pancreatic cancer xenografts implanted into nude mice.METHODS This study presents a prospective experimental analytical follow-up of the development of tumours in mice upon implantation of human pancreatic adenocarcinoma samples. Specimens were obtained surgically from patients with a pathological diagnosis of pancreatic adenocarcinoma. Tumour samples from pancreatic cancer patients were transplanted into nude mice in three different locations(intraperitoneal, subcutaneous and pancreatic). Histological analysis(haematoxylin-eosin and Masson's trichrome staining) and immunohistochemical assessment of apoptosis(TUNEL), proliferation(Ki-67), angiogenesis(CD31) and fibrogenesis(α-SMA) were performed. When a tumour xenograft reached the target size, it was reimplanted in a new nude mouse. Three sequential tumour xenograft generations were generated(F1, F2 and F3).RESULTS The overall tumour engraftment rate was 61.1%. The subcutaneous model was most effective in terms of tissue growth(69.9%), followed by intraperitoneal(57.6%) and pancreatic(55%) models. Tumour development was faster in the subcutaneous model(17.7 ± 2.6 wk) compared with the pancreatic(23.1 ± 2.3 wk) and intraperitoneal(25.0 ± 2.7 wk) models(P = 0.064). There was a progressive increase in the tumour engraftment rate over successive generations for all three models(F1 28.1% vs F2 71.4% vs F3 80.9%, P < 0.001). There were no significant differences in tumour xenograft differentiation and cell proliferation between human samples and the three experimental models among the sequential generations of tumour xenografts. However, a progressive decrease in fibrosis, fibrogenesis, tumour vascularisation and apoptosis was observed in the three experimental models compared with the human samples. All three pancreatic patient-derived xenograft models presented similar histological and immunohistochemical characteristics.CONCLUSION In our experience, the faster development andgreatest number of viable xenografts could make the subcutaneous model the best option for experimentation in pancreatic cancer.展开更多
Objective:Patient-derived xenograft(PDX)models provide a promising preclinical platform for hepatocellular carcinoma(HCC).However,the molecular features associated with successful engraftment of PDX models have not be...Objective:Patient-derived xenograft(PDX)models provide a promising preclinical platform for hepatocellular carcinoma(HCC).However,the molecular features associated with successful engraftment of PDX models have not been revealed.Methods:HCC tumor samples from 76 patients were implanted in immunodeficient mice.The molecular expression was evaluated by immunohistochemistry.Patient and tumor characteristics as well as tumor molecular expressions were compared for PDX engraftment using the Chi-square test.The independent prediction parameters were identified by logistic regression analyses.Results:The engraftment rate for PDX models from patients with HCC was 39.47%(30/76).Tumors from younger patients and patients with elevated preoperative alpha-fetoprotein level had higher engraftment rates.Tumors with poor differentiation and vascular invasion were related to engraftment success.The positive expression of CK19,CD133,glypican-3(GPC3),and Ki67 in tumor samples was associated with engraftment success.Logistic regression analyses indicated that GPC3 and Ki67 were two of the strongest predictors of PDX engraftment.Tumors with GPC3/Ki67 phenotypes showed heterogeneous engraftment rates,with 71.9%in GPC3^(+)/Ki67^(+)tumors,30.8%in GPC3^(-)/Ki67^(+)tumors,15.0%in GPC3^(+)/Ki67^(-)tumors,and 0 in GPC3^(-)/Ki67^(-)tumors.Conclusions:Successful engraftment of HCC PDXs was significantly related to molecular features.Tumors with the GPC3+/Ki67+phenotype were the most likely to successfully establish HCC PDXs.展开更多
Platinum-based anticancer agents such as cisplatin and its analogues are widely used for treating multiple cancers. However, due to the inferior water-solubility, chemoresistance and consequent adverse side effects, t...Platinum-based anticancer agents such as cisplatin and its analogues are widely used for treating multiple cancers. However, due to the inferior water-solubility, chemoresistance and consequent adverse side effects, their clinical applications are limited. Herein, choles Pt(IV), a lipophilic platinum(IV) prodrug was synthesized for manufacture of Choles Pt(IV)-Liposomes aiming to resolve the predefined obstacles encountered by platinum drugs. Following systematic screening, Choles Pt(IV)-Liposomes showed a small particle size(105.6 nm), the rapid release of platinum(Pt) ions, and notable apoptosis of cancer cells.In addition, according to the fluidity and safety results of animal experiments in mice, Choles Pt(IV)-Liposomes also showed better therapeutic effect, which significantly inhibited the growth of patientderived xenograft tumors of hepatocellular carcinoma with an inhibition ratio of 80.7%, and effectively alleviated the drug toxicity brought by traditional platinum drugs. Overall, this study provides a promising route to enhance the therapeutic efficiency of platinum drugs in cancer treatment.展开更多
AIM To establish patient-individual tumor models of rectal cancer for analyses of novel biomarkers, individual response prediction and individual therapy regimens.METHODS Establishment of cell lines was conducted by d...AIM To establish patient-individual tumor models of rectal cancer for analyses of novel biomarkers, individual response prediction and individual therapy regimens.METHODS Establishment of cell lines was conducted by direct in vitro culturing and in vivo xenografting with subsequent in vitro culturing. Cell lines were in-depth characterized concerning morphological features, invasive and migratory behavior, phenotype, molecular profile including mutational analysis, protein expression, and confirmation of origin by DNA fingerprint. Assessment of chemosensitivity towards an extensive range of current chemotherapeutic drugs and of radiosensitivity was performed including analysis of a combined radioand chemotherapeutic treatment. In addition, glucose metabolism was assessed with 18 F-fluorodeoxyglucose(FDG) and proliferation with 18 F-fluorothymidine.RESULTS We describe the establishment of ultra-low passage rectal cancer cell lines of three patients suffering from rectal cancer. Two cell lines(HROC126, HROC284 Met) were established directly from tumor specimens while HROC239 T0 M1 was established subsequent to xenografting of the tumor. Molecular analysis classified all three cell lines as CIMP-0/non-MSI-H(sporadic standard) type. Mutational analysis revealed following mutational profiles: HROC126: APC^(wt), TP53^(wt), KRAS^(wt), BRAF^(wt), PTEN^(wt); HROC239 T0 M1: APC^(mut), P53^(wt), KRAS^(mut), BRAF^(wt), PTEN^(mut) and HROC284 Met: APC^(wt), P53^(mut), KRAS^(mut), BRAF^(wt), PTEN^(mut). All cell lines could be characterized as epithelial(EpCAM+) tumor cells with equivalent morphologic features and comparable growth kinetics. The cell lines displayed a heterogeneous response toward chemotherapy, radiotherapy and their combined application. HROC126 showed a highly radio-resistant phenotype and HROC284 Met was more susceptible to a combined radiochemotherapy than HROC126 and HROC239 T0 M1. Analysis of 18 F-FDG uptake displayed a markedly reduced FDG uptake of all three cell lines after combined radiochemotherapy. CONCLUSION These newly established and in-depth characterized ultra-low passage rectal cancer cell lines provide a useful instrument for analysis of biological characteristics of rectal cancer.展开更多
Severely immunocompromised NOD.Cg-PrkdcIl2rg(NOG)mice are among the ideal animal recipients for generation of human cancer models.Transplantation of human solid tumors having abundant tumor-i nfiltrating lymphocytes(T...Severely immunocompromised NOD.Cg-PrkdcIl2rg(NOG)mice are among the ideal animal recipients for generation of human cancer models.Transplantation of human solid tumors having abundant tumor-i nfiltrating lymphocytes(TILs)can induce xenogeneic graft-versus-host disease(xGvHD)following engraftment and expansion of the TILs inside the animal body.Wilms’tumor(WT)has not been recognized as a lymphocyte-predominant tumor.However,3 consecutive generations of NOG mice bearing WT patient-derived xenografts(PDX)xenotransplanted from a single donor showed different degrees of inflammatory symptoms after transplantation before any therapeutic intervention.In the initial generation,dermatitis,auto-amputation of digits,weight loss,lymphadenopathy,hepatitis,and interstitial pneumonitis were observed.Despite antibiotic treatment,no response was noticed,and thus the animals were prematurely euthanized(day 47 posttransplantation).Laboratory and histopathologic evaluations revealed lymphoid infiltrates positively immunostained with anti-human CD3 and CD8 antibodies in the xenografts and primary tumor,whereas no microbial infection or lymphoproliferative disorder was found.Mice of the next generation that lived longer(91 days)developed sclerotic skin changes and more severe pneumonitis.Cutaneous symptoms were milder in the last generation.The xenografts of the last 2 generations also contained TILs,and lacked lymphoproliferative transformation.The systemic immunoinflammatory syndrome in the absence of microbial infection and posttransplant lymphoproliferative disorder was suggestive of xGvHD.While there are few reports of xGvHD in severely immunodeficient mice xenotransplanted from lymphodominant tumor xenografts,this report for the first time documented serial xGvHD in consecutive passages of WT PDX-bearing models and discussed potential solutions to prevent such an undesired complication.展开更多
Objective:Bone metastasis occurs in up to 90%of men with advanced prostate cancer and leads to fractures,severe pain and therapy-resistance.Bone metastases induce a spectrum of types of bone lesions which can respond ...Objective:Bone metastasis occurs in up to 90%of men with advanced prostate cancer and leads to fractures,severe pain and therapy-resistance.Bone metastases induce a spectrum of types of bone lesions which can respond differently to therapy even within individual prostate cancer patients.Thus,the special environment of the bone makes the disease more complicated and incurable.A model in which bone lesions are reproducibly induced that mirrors the complexity seen in patients would be invaluable for pre-clinical testing of novel treatments.The microstructural changes in the femurs of mice implanted with PCSD1,a new patient-derived xenograft from a surgical prostate cancer bone metastasis specimen,were determined.Methods:Quantitative micro-computed tomography(micro-CT)and histological analyses were performed to evaluate the effects of direct injection of PCSD1 cells or media alone(Control)into the right femurs of Rag2/gc/male mice.Results:Bone lesions formed only in femurs of mice injected with PCSD1 cells.Bone volume(BV)was significantly decreased at the proximal and distal ends of the femurs(p<0.01)whereas BV(p<0.05)and bone shaft diameter(p<0.01)were significantly increased along the femur shaft.Conclusion:PCSD1 cells reproducibly induced bone loss leading to osteolytic lesions at the ends of the femur,and,in contrast,induced aberrant bone formation leading to osteoblastic lesions along the femur shaft.Therefore,the interaction of PCSD1 cells with different bone region-specific microenvironments specified the type of bone lesion.Our approach can be used to determine if different bone regions support more therapy resistant tumor growth,thus,requiring novel treatments.展开更多
Owing to the high genetic heterogeneity of tumors, small number of therapeutic strategies available, and frequent presentation of drug resistance, the prognosis for patients with advanced gastric cancer(AGC) are unsat...Owing to the high genetic heterogeneity of tumors, small number of therapeutic strategies available, and frequent presentation of drug resistance, the prognosis for patients with advanced gastric cancer(AGC) are unsatisfactory. The utility of traditional cancer cell lines in translational research is limited by their poor correspondence to the genomic alterations and expression profiles that occur in actual patient tumors. In the last decade, increasing attention has been given to patient-derived tumor xenografts(PDTXs), which can faithfully recapitulate the histopathology, molecular characteristics, and therapeutic responses of the patient's tumor. However, the widespread development and utilization of PDTXs is restricted by factors such as the timeframe of establishment, lymphoma transformation during passaging, the immunodeficient microenvironment, and pharmacokinetic differences between mice and humans. In this review, we summarize the establishment and characterization of PDTX models for gastric cancer(GC). We then weigh the advantages and limitations of PDTXs when used to evaluate novel compounds, identify effective biomarkers, demonstrate resistance mechanisms, and predict clinical outcomes.展开更多
Liver cancer is one of the most common malignant tumors worldwide.Currently,the available treatment methods cannot fully control its recurrence and mortality rate.Establishing appropriate animal models for liver cance...Liver cancer is one of the most common malignant tumors worldwide.Currently,the available treatment methods cannot fully control its recurrence and mortality rate.Establishing appropriate animal models for liver cancer is crucial for developing new treatment technologies and strategies.The patient-derived xenograft(PDX)model preserves the tumor’s microenvironment and heterogeneity,which makes it advantageous for biological research,drug evaluation,personalized medicine,and other purposes.This article reviews the development,preparation techniques,application fields,and challenges of PDX models in liver cancer,providing insights for the research and exploration of PDX models in diagnostic and therapeutic strategies of liver cancer.展开更多
Colorectal cancer(CRC)is one of the most popular malignancies globally,with 930000 deaths in 2020.The evaluation of CRC-related pathogenesis and the discovery of po-tential therapeutic targets will be meaningful and h...Colorectal cancer(CRC)is one of the most popular malignancies globally,with 930000 deaths in 2020.The evaluation of CRC-related pathogenesis and the discovery of po-tential therapeutic targets will be meaningful and helpful for improving CRC treat-ment.With huge efforts made in past decades,the systematic treatment regimens have been applied to improve the prognosis of CRC patients.However,the sensitivity of CRC to chemotherapy and targeted therapy is different from person to person,which is an important cause of treatment failure.The emergence of patient-derived xenograft(PDX)models shows great potential to alleviate the straits.PDX models possess similar genetic and pathological characteristics as the features of primary tu-mors.Moreover,PDX has the ability to mimic the tumor microenvironment of the original tumor.Thus,the PDX model is an important tool to screen precise drugs for individualized treatment,seek predictive biomarkers for prognosis supervision,and evaluate the unknown mechanism in basic research.This paper reviews the recent advances in constructed methods and applications of the CRC PDX model,aiming to provide new knowledge for CRC basic research and therapeutics.展开更多
Malignant tumor is the second leading cause of death due to its high incidence, lack of effective treatment and poor prognosis. The evaluation of anticancer drugs used to based on NCI-60 cell line models, but the limi...Malignant tumor is the second leading cause of death due to its high incidence, lack of effective treatment and poor prognosis. The evaluation of anticancer drugs used to based on NCI-60 cell line models, but the limited heterogeneity and the divorce from clinical practice of models lead to extremely low success rate of novel anticancer drugs during clinical trials (less than 10%). In recent years, because of the high heterogeneity and human derived tumor matrix, patient-derived tumor models have been gradually applied to the preclinical evaluation of various antitumor drugs, which shows certain advantages in predicting the clinical efficacy of antitumor drugs. Optimize the drug combination through patient-derived tumor models to achieve individualized medicine has gradually become an indispensable strategy in clinical cancer therapy. The current review summarized the development of patient-derived tumor models, characterized the application, advantages and challenges of them in preclinical antitumor drug evaluation and clinical precise medicine, which will provide a scientific basis and novel insights for further basic research, drug development and clinical application.展开更多
In this letter,we discuss the highlights of the paper by Hu et al,including how patient-derived organoids may be beneficial to hepatobiliary pancreatic research.The article provides a review of how organoids can be us...In this letter,we discuss the highlights of the paper by Hu et al,including how patient-derived organoids may be beneficial to hepatobiliary pancreatic research.The article provides a review of how organoids can be used in drug sensitivity testing;looking at ways in which successful organoids are created.The literature included in the review revealed heterogeneity in organoid establishment inclu-ding some differences between organoids from resected tumours compared with liquid biopsies.Additional research is required in creating organoids from liquid biopsies and optimizing these techniques for widespread clinical practice.The article raises awareness of limitations of organoids with suggestions of how co-culture or microfluid platforms may help to simulate the tumour microenvir-onment for better model fidelity.The article provides a comprehensive review of how organoids are being used in drug testing and ideas about how to harvest or produce these in future.展开更多
Colorectal cancer is the third most diagnosed malignancy and the second-leading cause of cancer-related deaths worldwide.Management includes a combination of surgery,radiotherapy,and systemic therapy that is tailored ...Colorectal cancer is the third most diagnosed malignancy and the second-leading cause of cancer-related deaths worldwide.Management includes a combination of surgery,radiotherapy,and systemic therapy that is tailored to the stage of the disease.However,each tumor has a unique genetic profile that influences the treatment response and the overall prognosis.Biomarkers guide treatment decisions,but many chemotherapeutics lack reliable predictors.To bridge this gap patient-derived xenograft models were developed and are valuable preclinical tools.These systems utilize patient-derived tumor tissue grafted into an animal host that provides a platform for personalized drug profiling.This article surveyed recent advances in mouse and zebrafish colorectal cancer patient-derived xenografts,emphasizing their clinical utility for functional precision oncology.We explored the impact of these models on translational research,discussed current limitations,and outlined key priorities for future development.展开更多
Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug resistance.Here,we applied a multidimensiona...Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug resistance.Here,we applied a multidimensional,high-throughput screening platform comprising patient-derived resistant liver tumor cells(PDCs),organoids(PDOs),and xenografts(PDXs)to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings.Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment,expediting drug repurposing screens.Pharmacological screening identified romidepsin,YM155,apitolisib,NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models.Notably,romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway.A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models.Collectively,our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer,providing a feasible multidimensional platform for personalized medicine.展开更多
文摘Liposarcoma is one of the most common soft tissue sarcomas,however,its occurrence rate is still rare compared to other cancers.Due to its rarity,in vitro experiments are an essential approach to elucidate liposarcoma pathobiology.Conventional cell culture-based research(2D cell culture)is still playing a pivotal role,while several shortcomings have been recently under discussion.In vivo,mouse models are usually adopted for pre-clinical analyses with expectations to overcome the issues of 2D cell culture.However,they do not fully recapitulate human dedifferentiated liposarcoma(DDLPS)characteristics.Therefore,three-dimensional(3D)culture systems have been the recent research focus in the cell biology field with the expectation to overcome at the same time the disadvantages of 2D cell culture and in vivo animal models and fill in the gap between them.Given the liposarcoma rarity,we believe that 3D cell culture techniques,including 3D cell cultures/co-cultures,and Patient-Derived tumor Organoids(PDOs),represent a promising approach to facilitate liposarcoma investigation and elucidate its molecular mechanisms and effective therapy development.In this review,we first provide a general overview of 3D cell cultures compared to 2D cell cultures.We then focus on one of the recent 3D cell culture applications,Patient-Derived Organoids(PDOs),summarizing and discussing several PDO methodologies.Finally,we discuss the current and future applications of PDOs to sarcoma,particularly in the field of liposarcoma.
基金Supported by Chongqing Natural Science Foundation General Project,No.CSTB2023NSCQ-MSX0182 and No.CSTB2023NSCQMSX0252Clinical Research Special Project of The Second Affiliated Hospital of Army Medical University,No.2024 F022.
文摘BACKGROUND Liver metastases are very common in pancreatic neuroendocrine tumors(pNETs).When surgical resection is possible,it is typically associated with survival benefits in patients with pNET and liver metastases.Patient-derived organoids are a powerful preclinical platform that show great potential for predicting treatment response,and they have been increasingly applied in precision medicine and cancer research.CASE SUMMARY A 51-year-old man was admitted to the hospital with the chief complaint of in-termittent dull pain in the upper abdomen for over 3 years.Computerized to-mography showed multiple space-occupying lesions in the liver and a neoplasm in the pancreatic body.Pathological results suggested a grade 3 pancreas-derived hepatic neuroendocrine tumor.In combination with relevant examinations,the patient was diagnosed with pNET with liver metastases(grade 3).Transarterial chemoembolization was initially performed with oxaliplatin and 5-fluorouracil,after which the chemotherapy regimen was switched to liposomal irinotecan and cisplatin for a subsequent perfusion,guided by organoid-based drug sensitivity testing.Following interventional treatment,the tumor had decreased in size.However,due to poor treatment compliance and the patient’s preference for sur-INTRODUCTION Pancreatic neuroendocrine tumors(pNETs)are a rare and heterogeneous group of neoplasms arising from pancreatic islet cells,with variations in histology,clinical characteristics,and prognosis[1].They may present as non-infiltrative,slow-growing tumors,locally invasive tumors,or even rapidly metastasizing tumors[2].Most metastases localize to the liver,and approximately 28%-77%of patients with pNETs will experience liver metastases in their lifetime[3].Patients with liver metastases may be subjected to local complications such as biliary obstruction,liver insufficiency,and carcinoid syndrome.Additionally,liver metastases are a major risk factor for the prognosis of patients with pNETs[4].When feasible,surgical resection is significantly associated with the best long-term survival outcomes[5].Therefore,for patients with pNET liver metastases,comprehensive assessment and multidisciplinary approaches are required to determine the feasibility of surgical resection and the optimal treatment to improve the prognosis.Over the past decade,the advent of in vitro three-dimensional technologies including organoids has revolutionized the development of human cancer models.Patient-derived organoids(PDOs),an in vitro three-dimensional microstructure,can faithfully recapitulate the intricate spatial architecture and cell heterogeneity of the tissue,and simulate the biological behaviors and functions of parental tumors while preserving biological,genetic and molecular features[6,7].As a po-werful preclinical platform,PDOs have been increasingly applied in precision medicine and cancer research.Importantly,there is a significant association between the use of PDO-based drug sensitivity testing and clinical responses to chemotherapy,radiotherapy and targeted therapy in multiple cancer types[8-10].Although gastroenteropancreatic neuroendocrine neoplasm organoids have been confirmed to retain the pathohistological and functional phenotypes of parental tumors[7],their roles in the prediction of clinical outcomes have not been presented.Here,we report a case of pNET with liver metastases who successfully received surgical resection after personalized treatment guided by PDO-based drug sensitivity testing,resulting in a favorable prognosis.
基金Supported by Key Research and Development Program of Zhejiang Province,No.2024C03172Clinical Medical Research Special Fund Project of Zhejiang Medical Association,No.2024ZYC-Z50.
文摘Hepatobiliary and pancreatic(HBP)cancers are among the most aggressive malig-nancies,with recurrence and metastasis driven by tumor heterogeneity and drug resistance,presenting considerable challenges to effective treatment.Currently,personalized and accurate treatment prediction models for these cancers are lacking.Patient-derived organoids(PDOs)tumor are three-dimensional in vitro models created from the tumor tissues of individual patients.Recent reports and our cultivation data indicate that the success rate of cultivating organoids for HBP cancers consistently exceeds 70%.The predictive accuracy of these tumor orga-noids has been shown to surpass 90%.However,PDOs still face notable limita-tions,especially in simulating the tumor microenvironment,including tumor angiogenesis and the surrounding cellular context,which require further refi-nement.While co-culture techniques and microfluidic platforms have been deve-loped to mimic multi-cellular environments and functional vascular perfusion,they remain insufficient in accurately recapitulating the complexities of the in vivo environment.Additionally,PDOs are needed to fully assess their potential in predicting the efficacy of multi-drug combination therapies.This review provides an overview of the applications,challenges,and prospects for organoid models in the study of HBP cancer.
基金Supported by the Chongqing Natural Science Foundation Project,No.CSTB2022NSCQ-MSX0172.
文摘BACKGROUND Patient-derived organoids(PDOs)have been demonstrated to predict the response to drugs in multiple cancer types.However,it remains unclear about its application in cholangiocarcinoma.CASE SUMMARY A 59-year-old woman was admitted to the hospital due to upper abdominal pain for over 8 months.According to relevant examinations,she was diagnosed as perihilar cholangiocarcinoma(pCCA)with intrahepatic metastasis and perihilar lymphatic metastasis.After multidisciplinary team discussion,percutaneous transhepatic cholangiodrainage was performed to relieve biliary obstruction,and puncture biopsy was conducted to confirm the pathological diagnosis.Transarterial chemoembolization with nab-paclitaxel was used in combination with toripalimab and lenvatinib,but the levels of tumor markers including alpha fetal protein,carcinoembryonic antigen,carbohydrate antigen 15-3 and cancer antigen 125 were still raised.The PDO for drug screening showed sensitive to gemcitabine and cisplatin.Accordingly,the chemotherapy regimen was adjusted to gemcitabine and cisplatin in combination with toripalimab and lenvatinib.After 4 cycles of treatment,the tumor was assessed resectable,and radical surgical resection was performed successfully.One year after surgery,the patient was still alive,and no recurrence or occurred.CONCLUSION PDOs for drug sensitivity contribute to screening effective chemotherapy drugs for advanced pCCA,promoting conversion therapy and improving the prognosis.
文摘One of the major bottlenecks in advancing basic cancer research and developing novel cancer therapies is the lack of in vitro pre-clinical models that faithfully recapitulate tumor properties in the patients.Monolayer cultures of cancer cell lines usually lose the heterogeneity of the parental tumors,while patient-derived xenograft(PDX)suffers from its time-and resource-intensive nature.The emergence of organoid culture system and its application in cancer research provides a unique opportunity to develop novel in vitro cancer pre-clinical models.Here we review the recent advances in utilizing organoids culture system and other related three-dimensional culture systems in studying cancer biology,performing drug screening,and developing cancer therapies.In particular,we discuss the advantages of applying xenograft initiated from patient-derived organoids(PDOs)as a faithful cancer pre-clinical model in basic cancer research and precision medicine.
基金the National Natural Science Foundation of China(Nos.81572797,81701817)the Natural Science Foundation of Guangdong Province(No.2019A1515011619)+1 种基金Guangdong Provincial Science and Technology Department(No.2016A030311015)Shenzhen Science and Technology Project(No.JCYJ20180507183842516)。
文摘Hepatocellular carcinoma(HCC)has become the fourth predominant cause of cancer-related deaths worldwide,and HCC is still one of the worst prognoses for survival as it is poorly responsive to both chemotherapy and surgical treatment due to drug resista nce and great toxic effects.Triptolide(TP),a key ingredient from the traditional Chinese medical herb,has been utilized to treat inflammation and antitumor for centuries.However,investigations of this potent agent have been met with only limited success due to the severe systemic toxicities in patients and low water solubility as well as its high toxicity over the past two decades.Herein,we reported the development of a reduction-responsive drug delive ry system loaded with TP fo r glutathione(GSH)-trigge red drug release for cancer therapy.With the GSH-sensitive TP loaded nanoparticles,the remarkable increases in tumor accumulation and amelioration of drug toxicity in animals are demonstrated,which is likely due to sustained stepwise release of active TP within cancer cells.Moreover,in a patient-derived tumor xenograft model of liver cancer,administration of tritolide nanoparticles enhances the antitumor efficacy relative to administration of free TP.These findings indicate that GSH-sensitive release of TP may be a promising strategy for cancer treatment.
基金supported by the National Natural Science Foundation of China(Grant Nos.81101143,81572617,and 81630101)the Sichuan Province Science and Technology Support Program(Grant Nos.2019JDRC0019 and 2018SZ0009)+2 种基金1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(Grant No.ZYJC18026)The Science and Technology Project of the Health Planning Committee of Sichuan(Grant No.19PJ242)Chengdu science and technology Support Program(Grant No.2019-YFYF-00090-SN)。
文摘Objective:Patient-derived xenograft(PDX)models have shown great promise in preclinical and translational applications,but their consistency with primary tumors in phenotypic,genetic,and pharmacodynamic heterogeneity has not been well-studied.This study aimed to establish a PDX repository for non-small cell lung cancer(NSCLC)and to further elucidate whether it could preserve the heterogeneity within and between tumors in patients.Methods:A total of 75 surgically resected NSCLC specimens were implanted into immunodeficient NOD/SCID mice.Based on the successful establishment of the NSCLC PDX model,we compared the expressions of vimentin,Ki67,EGFR,and PD-L1 proteins between cancer tissues and PDX models using hematoxylin and eosin staining and immunohistochemical staining.In addition,we detected whole gene expression profiling between primary tumors and PDX generations.We also performed whole exome sequencing(WES)analysis in 17 first generation xenografts to further assess whether PDXs retained the patient heterogeneities.Finally,paclitaxel,cisplatin,doxorubicin,atezolizumab,afatininb,and AZD4547 were used to evaluate the responses of PDX models to the standard-of-care agents.Results:A large collection of serially transplantable PDX models for NSCLC were successfully developed.The histology and pathological immunohistochemistry of PDX xenografts were consistent with the patients’tumor samples.WES and RNA-seq further confirmed that PDX accurately replicated the molecular heterogeneities of primary tumors.Similar to clinical patients,PDX models responded differentially to the standard-of-care treatment,including chemo-,targeted-and immuno-therapeutics.Conclusions:Our established PDX models of NSCLC faithfully reproduced the molecular,histopathological,and therapeutic characteristics,as well as the corresponding tumor heterogeneities,which provides a clinically relevant platform for drug screening,biomarker discovery,and translational research.
基金Supported by the Andalusian Public Foundation for the Management of Health Research in Seville(FISEVI)
文摘AIM To assess the viability of orthotopic and heterotopic patient-derived pancreatic cancer xenografts implanted into nude mice.METHODS This study presents a prospective experimental analytical follow-up of the development of tumours in mice upon implantation of human pancreatic adenocarcinoma samples. Specimens were obtained surgically from patients with a pathological diagnosis of pancreatic adenocarcinoma. Tumour samples from pancreatic cancer patients were transplanted into nude mice in three different locations(intraperitoneal, subcutaneous and pancreatic). Histological analysis(haematoxylin-eosin and Masson's trichrome staining) and immunohistochemical assessment of apoptosis(TUNEL), proliferation(Ki-67), angiogenesis(CD31) and fibrogenesis(α-SMA) were performed. When a tumour xenograft reached the target size, it was reimplanted in a new nude mouse. Three sequential tumour xenograft generations were generated(F1, F2 and F3).RESULTS The overall tumour engraftment rate was 61.1%. The subcutaneous model was most effective in terms of tissue growth(69.9%), followed by intraperitoneal(57.6%) and pancreatic(55%) models. Tumour development was faster in the subcutaneous model(17.7 ± 2.6 wk) compared with the pancreatic(23.1 ± 2.3 wk) and intraperitoneal(25.0 ± 2.7 wk) models(P = 0.064). There was a progressive increase in the tumour engraftment rate over successive generations for all three models(F1 28.1% vs F2 71.4% vs F3 80.9%, P < 0.001). There were no significant differences in tumour xenograft differentiation and cell proliferation between human samples and the three experimental models among the sequential generations of tumour xenografts. However, a progressive decrease in fibrosis, fibrogenesis, tumour vascularisation and apoptosis was observed in the three experimental models compared with the human samples. All three pancreatic patient-derived xenograft models presented similar histological and immunohistochemical characteristics.CONCLUSION In our experience, the faster development andgreatest number of viable xenografts could make the subcutaneous model the best option for experimentation in pancreatic cancer.
基金supported by grants from the National Science and Technology Major Project of China(No.2017ZX10203205)the National Natural Science Funds for Distinguished Young Scholar of China(No.81625003)+1 种基金Key Program National Natural Science Foundation of China(No.81930016)Key Research&Development Plan of Zhejiang Province(No.2019C03050)。
文摘Objective:Patient-derived xenograft(PDX)models provide a promising preclinical platform for hepatocellular carcinoma(HCC).However,the molecular features associated with successful engraftment of PDX models have not been revealed.Methods:HCC tumor samples from 76 patients were implanted in immunodeficient mice.The molecular expression was evaluated by immunohistochemistry.Patient and tumor characteristics as well as tumor molecular expressions were compared for PDX engraftment using the Chi-square test.The independent prediction parameters were identified by logistic regression analyses.Results:The engraftment rate for PDX models from patients with HCC was 39.47%(30/76).Tumors from younger patients and patients with elevated preoperative alpha-fetoprotein level had higher engraftment rates.Tumors with poor differentiation and vascular invasion were related to engraftment success.The positive expression of CK19,CD133,glypican-3(GPC3),and Ki67 in tumor samples was associated with engraftment success.Logistic regression analyses indicated that GPC3 and Ki67 were two of the strongest predictors of PDX engraftment.Tumors with GPC3/Ki67 phenotypes showed heterogeneous engraftment rates,with 71.9%in GPC3^(+)/Ki67^(+)tumors,30.8%in GPC3^(-)/Ki67^(+)tumors,15.0%in GPC3^(+)/Ki67^(-)tumors,and 0 in GPC3^(-)/Ki67^(-)tumors.Conclusions:Successful engraftment of HCC PDXs was significantly related to molecular features.Tumors with the GPC3+/Ki67+phenotype were the most likely to successfully establish HCC PDXs.
基金financially supported by the GDNRC [Guangdong Nature Resource Center](2020)(037)National Natural Science Foundation of China (Nos. 81773642, 52073139)+3 种基金the Natural Science Foundation of Guangdong Province (No. 2019A1515011619)Guangdong Provincial Science and Technology Department (No.2016A030311015)the Key R&D Plan of Chenzhou (No.ZDYF202008)the Discipline Leader Startup Fund of Huazhong University of Science and Technoloy Union Shenzhen Hospital (No.YN2021002)。
文摘Platinum-based anticancer agents such as cisplatin and its analogues are widely used for treating multiple cancers. However, due to the inferior water-solubility, chemoresistance and consequent adverse side effects, their clinical applications are limited. Herein, choles Pt(IV), a lipophilic platinum(IV) prodrug was synthesized for manufacture of Choles Pt(IV)-Liposomes aiming to resolve the predefined obstacles encountered by platinum drugs. Following systematic screening, Choles Pt(IV)-Liposomes showed a small particle size(105.6 nm), the rapid release of platinum(Pt) ions, and notable apoptosis of cancer cells.In addition, according to the fluidity and safety results of animal experiments in mice, Choles Pt(IV)-Liposomes also showed better therapeutic effect, which significantly inhibited the growth of patientderived xenograft tumors of hepatocellular carcinoma with an inhibition ratio of 80.7%, and effectively alleviated the drug toxicity brought by traditional platinum drugs. Overall, this study provides a promising route to enhance the therapeutic efficiency of platinum drugs in cancer treatment.
基金the German Cancer Foundation to Oliver H Kr?mer,No.KR 2291/7-1
文摘AIM To establish patient-individual tumor models of rectal cancer for analyses of novel biomarkers, individual response prediction and individual therapy regimens.METHODS Establishment of cell lines was conducted by direct in vitro culturing and in vivo xenografting with subsequent in vitro culturing. Cell lines were in-depth characterized concerning morphological features, invasive and migratory behavior, phenotype, molecular profile including mutational analysis, protein expression, and confirmation of origin by DNA fingerprint. Assessment of chemosensitivity towards an extensive range of current chemotherapeutic drugs and of radiosensitivity was performed including analysis of a combined radioand chemotherapeutic treatment. In addition, glucose metabolism was assessed with 18 F-fluorodeoxyglucose(FDG) and proliferation with 18 F-fluorothymidine.RESULTS We describe the establishment of ultra-low passage rectal cancer cell lines of three patients suffering from rectal cancer. Two cell lines(HROC126, HROC284 Met) were established directly from tumor specimens while HROC239 T0 M1 was established subsequent to xenografting of the tumor. Molecular analysis classified all three cell lines as CIMP-0/non-MSI-H(sporadic standard) type. Mutational analysis revealed following mutational profiles: HROC126: APC^(wt), TP53^(wt), KRAS^(wt), BRAF^(wt), PTEN^(wt); HROC239 T0 M1: APC^(mut), P53^(wt), KRAS^(mut), BRAF^(wt), PTEN^(mut) and HROC284 Met: APC^(wt), P53^(mut), KRAS^(mut), BRAF^(wt), PTEN^(mut). All cell lines could be characterized as epithelial(EpCAM+) tumor cells with equivalent morphologic features and comparable growth kinetics. The cell lines displayed a heterogeneous response toward chemotherapy, radiotherapy and their combined application. HROC126 showed a highly radio-resistant phenotype and HROC284 Met was more susceptible to a combined radiochemotherapy than HROC126 and HROC239 T0 M1. Analysis of 18 F-FDG uptake displayed a markedly reduced FDG uptake of all three cell lines after combined radiochemotherapy. CONCLUSION These newly established and in-depth characterized ultra-low passage rectal cancer cell lines provide a useful instrument for analysis of biological characteristics of rectal cancer.
基金supported by the grant received from Tehran University of Medical Sciences(TUMS-38292)。
文摘Severely immunocompromised NOD.Cg-PrkdcIl2rg(NOG)mice are among the ideal animal recipients for generation of human cancer models.Transplantation of human solid tumors having abundant tumor-i nfiltrating lymphocytes(TILs)can induce xenogeneic graft-versus-host disease(xGvHD)following engraftment and expansion of the TILs inside the animal body.Wilms’tumor(WT)has not been recognized as a lymphocyte-predominant tumor.However,3 consecutive generations of NOG mice bearing WT patient-derived xenografts(PDX)xenotransplanted from a single donor showed different degrees of inflammatory symptoms after transplantation before any therapeutic intervention.In the initial generation,dermatitis,auto-amputation of digits,weight loss,lymphadenopathy,hepatitis,and interstitial pneumonitis were observed.Despite antibiotic treatment,no response was noticed,and thus the animals were prematurely euthanized(day 47 posttransplantation).Laboratory and histopathologic evaluations revealed lymphoid infiltrates positively immunostained with anti-human CD3 and CD8 antibodies in the xenografts and primary tumor,whereas no microbial infection or lymphoproliferative disorder was found.Mice of the next generation that lived longer(91 days)developed sclerotic skin changes and more severe pneumonitis.Cutaneous symptoms were milder in the last generation.The xenografts of the last 2 generations also contained TILs,and lacked lymphoproliferative transformation.The systemic immunoinflammatory syndrome in the absence of microbial infection and posttransplant lymphoproliferative disorder was suggestive of xGvHD.While there are few reports of xGvHD in severely immunodeficient mice xenotransplanted from lymphodominant tumor xenografts,this report for the first time documented serial xGvHD in consecutive passages of WT PDX-bearing models and discussed potential solutions to prevent such an undesired complication.
基金We are grateful for the funding support for this work from the Leo and Anne Albert Charitable Foundation and the Phi Beta Psi Sorority.We deeply appreciate the invaluable contributions of Dr.Nissi Varki,Director,and Laarni Gapuz,Manager,Moores Cancer Center Histology Core.
文摘Objective:Bone metastasis occurs in up to 90%of men with advanced prostate cancer and leads to fractures,severe pain and therapy-resistance.Bone metastases induce a spectrum of types of bone lesions which can respond differently to therapy even within individual prostate cancer patients.Thus,the special environment of the bone makes the disease more complicated and incurable.A model in which bone lesions are reproducibly induced that mirrors the complexity seen in patients would be invaluable for pre-clinical testing of novel treatments.The microstructural changes in the femurs of mice implanted with PCSD1,a new patient-derived xenograft from a surgical prostate cancer bone metastasis specimen,were determined.Methods:Quantitative micro-computed tomography(micro-CT)and histological analyses were performed to evaluate the effects of direct injection of PCSD1 cells or media alone(Control)into the right femurs of Rag2/gc/male mice.Results:Bone lesions formed only in femurs of mice injected with PCSD1 cells.Bone volume(BV)was significantly decreased at the proximal and distal ends of the femurs(p<0.01)whereas BV(p<0.05)and bone shaft diameter(p<0.01)were significantly increased along the femur shaft.Conclusion:PCSD1 cells reproducibly induced bone loss leading to osteolytic lesions at the ends of the femur,and,in contrast,induced aberrant bone formation leading to osteoblastic lesions along the femur shaft.Therefore,the interaction of PCSD1 cells with different bone region-specific microenvironments specified the type of bone lesion.Our approach can be used to determine if different bone regions support more therapy resistant tumor growth,thus,requiring novel treatments.
文摘Owing to the high genetic heterogeneity of tumors, small number of therapeutic strategies available, and frequent presentation of drug resistance, the prognosis for patients with advanced gastric cancer(AGC) are unsatisfactory. The utility of traditional cancer cell lines in translational research is limited by their poor correspondence to the genomic alterations and expression profiles that occur in actual patient tumors. In the last decade, increasing attention has been given to patient-derived tumor xenografts(PDTXs), which can faithfully recapitulate the histopathology, molecular characteristics, and therapeutic responses of the patient's tumor. However, the widespread development and utilization of PDTXs is restricted by factors such as the timeframe of establishment, lymphoma transformation during passaging, the immunodeficient microenvironment, and pharmacokinetic differences between mice and humans. In this review, we summarize the establishment and characterization of PDTX models for gastric cancer(GC). We then weigh the advantages and limitations of PDTXs when used to evaluate novel compounds, identify effective biomarkers, demonstrate resistance mechanisms, and predict clinical outcomes.
基金This work was supported by grants from the Capital Health Research and Development of Special(No.2020-2-1152)National Science and Technology Major Special Program of the 13th Five-Year Plan for the Prevention and Control of Major Infectious Diseases(No.2018ZX10302205-005)Beijing Municipal Institute of Public Medical Research Development and Reform Pilot Project(No.Jingyiyan-2021-10).
文摘Liver cancer is one of the most common malignant tumors worldwide.Currently,the available treatment methods cannot fully control its recurrence and mortality rate.Establishing appropriate animal models for liver cancer is crucial for developing new treatment technologies and strategies.The patient-derived xenograft(PDX)model preserves the tumor’s microenvironment and heterogeneity,which makes it advantageous for biological research,drug evaluation,personalized medicine,and other purposes.This article reviews the development,preparation techniques,application fields,and challenges of PDX models in liver cancer,providing insights for the research and exploration of PDX models in diagnostic and therapeutic strategies of liver cancer.
基金National Natural Science Foundation of China Grant(81802305 and 31971192).
文摘Colorectal cancer(CRC)is one of the most popular malignancies globally,with 930000 deaths in 2020.The evaluation of CRC-related pathogenesis and the discovery of po-tential therapeutic targets will be meaningful and helpful for improving CRC treat-ment.With huge efforts made in past decades,the systematic treatment regimens have been applied to improve the prognosis of CRC patients.However,the sensitivity of CRC to chemotherapy and targeted therapy is different from person to person,which is an important cause of treatment failure.The emergence of patient-derived xenograft(PDX)models shows great potential to alleviate the straits.PDX models possess similar genetic and pathological characteristics as the features of primary tu-mors.Moreover,PDX has the ability to mimic the tumor microenvironment of the original tumor.Thus,the PDX model is an important tool to screen precise drugs for individualized treatment,seek predictive biomarkers for prognosis supervision,and evaluate the unknown mechanism in basic research.This paper reviews the recent advances in constructed methods and applications of the CRC PDX model,aiming to provide new knowledge for CRC basic research and therapeutics.
基金the Scientific Research Project Funding of Jianghan University(2023zd053)The Scientific Research Project Funding of Jianghan University(2021jczx-002).
文摘Malignant tumor is the second leading cause of death due to its high incidence, lack of effective treatment and poor prognosis. The evaluation of anticancer drugs used to based on NCI-60 cell line models, but the limited heterogeneity and the divorce from clinical practice of models lead to extremely low success rate of novel anticancer drugs during clinical trials (less than 10%). In recent years, because of the high heterogeneity and human derived tumor matrix, patient-derived tumor models have been gradually applied to the preclinical evaluation of various antitumor drugs, which shows certain advantages in predicting the clinical efficacy of antitumor drugs. Optimize the drug combination through patient-derived tumor models to achieve individualized medicine has gradually become an indispensable strategy in clinical cancer therapy. The current review summarized the development of patient-derived tumor models, characterized the application, advantages and challenges of them in preclinical antitumor drug evaluation and clinical precise medicine, which will provide a scientific basis and novel insights for further basic research, drug development and clinical application.
文摘In this letter,we discuss the highlights of the paper by Hu et al,including how patient-derived organoids may be beneficial to hepatobiliary pancreatic research.The article provides a review of how organoids can be used in drug sensitivity testing;looking at ways in which successful organoids are created.The literature included in the review revealed heterogeneity in organoid establishment inclu-ding some differences between organoids from resected tumours compared with liquid biopsies.Additional research is required in creating organoids from liquid biopsies and optimizing these techniques for widespread clinical practice.The article raises awareness of limitations of organoids with suggestions of how co-culture or microfluid platforms may help to simulate the tumour microenvir-onment for better model fidelity.The article provides a comprehensive review of how organoids are being used in drug testing and ideas about how to harvest or produce these in future.
基金Supported by the European Union,the Romanian Government and the Health Program(Medical Applications of High-Power Lasers-Dr.LASER),cod MySMIS2021/SMIS2021+326475.
文摘Colorectal cancer is the third most diagnosed malignancy and the second-leading cause of cancer-related deaths worldwide.Management includes a combination of surgery,radiotherapy,and systemic therapy that is tailored to the stage of the disease.However,each tumor has a unique genetic profile that influences the treatment response and the overall prognosis.Biomarkers guide treatment decisions,but many chemotherapeutics lack reliable predictors.To bridge this gap patient-derived xenograft models were developed and are valuable preclinical tools.These systems utilize patient-derived tumor tissue grafted into an animal host that provides a platform for personalized drug profiling.This article surveyed recent advances in mouse and zebrafish colorectal cancer patient-derived xenografts,emphasizing their clinical utility for functional precision oncology.We explored the impact of these models on translational research,discussed current limitations,and outlined key priorities for future development.
基金This study was partly supported by the National Natural Science Foundation of China(82122069,82073869,30900650,81372501,81572260,81773299,and H2808/82330065)Guangdong Basic and Applied Basic Research Foundation(2021B1515020004,2020B1515120032,2021B1212040017,and 2023B03J0106,China)+1 种基金the Fundamental Research Funds for the Central Universities(23yxqntd001,China)the Opening Project of Guangdong Provincial Key Laboratory of New Drug Design and Evaluation(2020B1212060034,China).
文摘Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug resistance.Here,we applied a multidimensional,high-throughput screening platform comprising patient-derived resistant liver tumor cells(PDCs),organoids(PDOs),and xenografts(PDXs)to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings.Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment,expediting drug repurposing screens.Pharmacological screening identified romidepsin,YM155,apitolisib,NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models.Notably,romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway.A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models.Collectively,our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer,providing a feasible multidimensional platform for personalized medicine.
