AIM:To evaluate the clinical efficacy of small-diameter acellular porcine corneal stroma(SAPS)for the treatment of peripheral corneal ulceration(PCU).METHODS:This retrospective clinical study included 18 patients(18 e...AIM:To evaluate the clinical efficacy of small-diameter acellular porcine corneal stroma(SAPS)for the treatment of peripheral corneal ulceration(PCU).METHODS:This retrospective clinical study included 18 patients(18 eyes)with PCU between April 2018 and December 2020.All patients had PCU and underwent lamellar keratoplasty with SAPS.Observation indicators included preoperative and postoperative best-corrected visual acuity(BCVA)and transparency of SAPS.The infection control rate in the surgical eye-lesion area was also calculated.RESULTS:Eighteen patients underwent lamellar keratoplasty with SAPS to treat PCU.None of the patients experienced rejection after 6mo(18/18)and 12mo(16/16)of follow-up.The BCVA(0.47±0.30)at the 6mo followup after operation was significantly improved compared with the baseline(0.99±0.80),and the difference was statistically significant(Z=-3.415,P<0.05).The BCVA at the 12mo follow-up after operation was not statistically significant compared to the 6mo(Z=0,P=1).With time,the SAPS graft gradually became transparent.At the 6mo(18/18)and 12mo(16/16)follow-up,none of the patients had recurrent corneal infection.CONCLUSION:SAPS is clinically effective in the treatment of PCU,improving the patient’s BCVA and reducing the incidence of rejection after keratoplasty.展开更多
Several studies have shown that the immune system is highly regulated by tryptophan metabolism,which serves as an immunomodulatory factor.The indoleamine 2,3-dioxygenase 1(IDO1),as an intracellular enzyme that partici...Several studies have shown that the immune system is highly regulated by tryptophan metabolism,which serves as an immunomodulatory factor.The indoleamine 2,3-dioxygenase 1(IDO1),as an intracellular enzyme that participates in metabolism of the essential amino acid tryptophan in the kynurenine pathway,is an independent prognostic marker for pancreatic cancer(PC).First,overexpression of IDO1 inhibits the maturation of dendritic cells and T-cell proliferation in the liver and spleen.Second,the high expression of kynurenine induces and activates the aryl hydrocarbon receptor,resulting in upregulated programmed cell death protein 1 expression.Third,the induction of IDO1 can lead to loss of the T helper 17 cell/regulatory T cell balance,mediated by the proximal tryptophan catabolite from IDO metabolism.In our study,we found that overexpression of IDO1 upregulated CD8+T cells and reduced natural killer T cells in pancreatic carcinoma in mice.Hence,it may be essential to pay more attention to tryptophan metabolism in patients,especially those who are tolerant to immunotherapy for PC.展开更多
BACKGROUND Papillary thyroid carcinoma(PTC)is regarded as a fairly common endocrine malignancy,which can be divided into different multiple variants due to wide morphologic differences.The majority of PTC variants hav...BACKGROUND Papillary thyroid carcinoma(PTC)is regarded as a fairly common endocrine malignancy,which can be divided into different multiple variants due to wide morphologic differences.The majority of PTC variants have been reported,but PTC with nodular fasciitis-like stroma(NFS)is a rare pathological variant and has been infrequently reported in the relevant literature.This condition involves abundant reactive stromal components rich in spindle cells,which may account for 60%-80%of the tumor along with a typical papillary carcinoma.CASE SUMMARY A 44-year-old man presented with a 4-mo history of a palpable mass over the anterior aspect of the left neck,the tumor demonstrated gradual enlargement but was painless during the 4 mo prior to discovery.Thyroid function test results were normal.Physical examination showed an enormous and firm nodular mass in the left lobe of the thyroid gland extending to the level of the hyoid bone.Ultrasonography of the neck revealed a well-defined heterogeneous lesion measuring around 5.0 cm×4.0 cm with a hypoechoic complex nodule,decreased vascularity and speckles of microcalcification.The patient underwent left thyroidectomy with central compartment lymph node dissection.Final histopathological examination confirmed the diagnosis of PTC with extensive fibromatosis-like stroma combined with typical PTC.The patient was asymptomatic at the 3-mo follow-up.CONCLUSION PTC-NFS is a rare pathological variant and its diagnosis and prognosis may be similar to typical papillary carcinoma.展开更多
It is now well established that the biology of cancer is influenced by not only malignant cells but also other components of the tumour microenvironment.Chronic inflammation and fibrosis have long been postulated to b...It is now well established that the biology of cancer is influenced by not only malignant cells but also other components of the tumour microenvironment.Chronic inflammation and fibrosis have long been postulated to be involved in carcinogenesis.Chronic inflammation can promote tumorigenesis via growth factor/cytokine-mediated cellular proliferation,apoptotic resistance,immunosuppression;and free-radical-induced oxidative deoxyribonucleic acid damage.Fibrosis could cause a perturbation in the dynamics of the tumour microenvironment,potentially damaging the genome surveillance machinery of normal epithelial cells.In this review,we will provide an in-depth discussion of various diseases characterised by inflammation and fibrosis that have been associated with an increased risk of malignancy.In particular,we will present a comprehensive overview of the impact of alterations in stromal composition on tumorigenesis,induced as a consequence of inflammation and/or fibrosis.Strategies including the application of various therapeutic agents with stromal manipulation potential and targeted cancer screening for certain inflammatory diseases which can reduce the risk of cancer will also be discussed.展开更多
AIM:To establish an untransfected human corneal stromal(HCS) cell line and characterize its biocompatibility to acellular porcine corneal stroma(aPCS).· METHODS:Primary culture was initiated with a pure populatio...AIM:To establish an untransfected human corneal stromal(HCS) cell line and characterize its biocompatibility to acellular porcine corneal stroma(aPCS).· METHODS:Primary culture was initiated with a pure population of HCS cells in DMEM/F12 media(pH 7.2) containing 20% fetal bovine serum and various necessary growth factors.The established cell line was characterized by growth property,chromosome analysis,tumorigenicity assay,expression of marker proteins and functional proteins.Furthermore,the biocompatibility of HCS cells with aPCS was examined through histological and immunocytochemistry analyses and with light,electron microscopies.· RESULTS:HCS cells proliferated to confluence 2 weeks later in primary culture and have been subcultured to passage 140 so far.A continuous untransfected HCS cell line with a population doubling time of 41.44 hours at passage 80 has been determined.Results of chromosome analysis,morphology,combined with the results of expression of marker protein and functional proteins suggested that the cells retained HCS cell properties.Furthermore,HCS cells have no tumorigenicity,and with excellent biocompatibility to aPCS.· CONCLUSION:An untransfected and non-tumorigenic HCS cell line has been established,and the cells maintained positive expression of marker proteins and functional proteins.The cell line,with excellent biocompatibility to aPCS,might be used for in vitro reconstruction of tissue-engineered HCS.展开更多
Pancreatic cancer is characterised by a prominent desmoplastic/stromal reaction that has received little attention until recent times. Given that treatments focusing on pancreatic cancer cells alone have failed to sig...Pancreatic cancer is characterised by a prominent desmoplastic/stromal reaction that has received little attention until recent times. Given that treatments focusing on pancreatic cancer cells alone have failed to significantly improve patient outcome over many decades, research efforts have now moved to understanding the pathophysiology of the stromal reaction and its role in cancer progression. In this regard, our Group was the first to identify the cells(pancreatic stellate cells, PSCs) that produced the collagenous stroma of pancreatic cancer and to demonstrate that these cells interacted closely with cancer cells to facilitate local tumour growth and distant metastasis. Evidence is accumulating to indicate that stromal PSCs may also mediate angiogenesis, immune evasion and the well known resistance of pancreatic cancer to chemotherapy and radiotherapy. This review will summarise current knowledge regarding the critical role of pancreatic stellate cells and the stroma in pancreatic cancer biologyand the therapeutic approaches being developed to target the stroma in a bid to improve the outcome of this devastating disease.展开更多
Pancreatic cancer remains one of medicine’s largest areas of unmet need.With five-year survival rates of<8%,little improvement has been made in the last 50 years.Typically presenting with advance stage disease,tre...Pancreatic cancer remains one of medicine’s largest areas of unmet need.With five-year survival rates of<8%,little improvement has been made in the last 50 years.Typically presenting with advance stage disease,treatment options are limited.To date,surgery remains the only potentially curative option,however,with such late disease presentation,the majority of patients are unresectable.Thus,new therapeutic options and a greater understanding of the complex stromal interactions within the tumour microenvironment are sorely needed to revise the dismal outlook for pancreatic cancer patients.Natural killer(NK)cells are crucial effector units in cancer immunosurveillance.Often used as a prognostic biomarker in a range of malignancies,NK cells have received much attention as an attractive target for immunotherapies,both as cell therapy and as a pharmaceutical target.Despite this interest,the role of NK cells in pancreatic cancer remains poorly defined.Nevertheless,increasing evidence of the importance of NK cells in this dismal prognosis disease is beginning to come to light.Here,we review the role of NK cells in pancreatic cancer,examine the complex interactions of these crucial effector units within pancreatic cancer stroma and shed light on the increasingly attractive use of NK cells as therapy.展开更多
In adults, adipose tissue is abundant and can be easily sampled using liposuction. Largely involved in obesity and associated metabolic disorders, it is now described as a reservoir of immature stromal cells. These ce...In adults, adipose tissue is abundant and can be easily sampled using liposuction. Largely involved in obesity and associated metabolic disorders, it is now described as a reservoir of immature stromal cells. These cells, called adipose-derived stromal cells (ADSCs) must be distinguished from the crude stromal vascular fraction (SVF) obtained after digestion of adipose tissue. ADSCs share many features with mesenchymal stem cells derived from bone marrow, including paracrine activity, but they also display some specific features, including a greater angiogenic potential. Their angiogenic properties as well as their paracrine activity suggest a putative tumor-promoting role for ADSCs although contradictory data have been published on this issue. Both SVF cells and ADSCs are currently being investigated in clinical trials in several fields (chronic inflammation, ischemic diseases, etc. ). Apart from a phase Ⅲ trial on the treatment of fistula,most of these are in phaseⅠand use autologous cells. In the near future, the end results of these trials should provide a great deal of data on the safety of ADSC use.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
Pancreatic cancer(PC) is the most aggressive type of common cancers, and in 2014, nearly 40000 patients died from the disease in the United States. Pancreatic ductal adenocarcinoma, which accounts for the majority of ...Pancreatic cancer(PC) is the most aggressive type of common cancers, and in 2014, nearly 40000 patients died from the disease in the United States. Pancreatic ductal adenocarcinoma, which accounts for the majority of PC cases, is characterized by an intense stromal desmoplastic reaction surrounding the cancer cells. Cancer-associated fibroblasts(CAFs) are the main effector cells in the desmoplastic reaction, and pancreatic stellate cells are the most important source of CAFs. However, other important components of the PC stroma are inflammatory cells and endothelial cells. The aim of this review is to describe the complex interplay between PC cells and the cellular and noncellular components of the tumour stroma. Published data have indicated that the desmoplastic stroma protects PC cells against chemotherapy and radiation therapy and that it might promote the proliferation and migration of PC cells. However, in animal studies, experimental depletion of the desmoplastic stroma and CAFs has led to more aggressive cancers. Hence, the precise role of the tumour stroma in PC remains to be elucidated. However, it is likely that a contextdependent therapeutic modification, rather than pure depletion, of the PC stroma holds potential for the development of new treatment strategies for PC patients.展开更多
AIM: To investigate the clinicopathological significance and prognostic value of caveolin-1(CAV-1) in both tumor and stromal cells in colorectal cancer(CRC).METHODS: A total of 178 patients with CRC were included in t...AIM: To investigate the clinicopathological significance and prognostic value of caveolin-1(CAV-1) in both tumor and stromal cells in colorectal cancer(CRC).METHODS: A total of 178 patients with CRC were included in this study. The correlation between CAV-1expression and clinicopathologic features and survival was studied.RESULTS: CAV-1 expression was detected in tumor and stromal cells. The expression of stromal CAV-1 was closely associated with histological type(P = 0.022), pathologic tumor-node-metastasis stage(P = 0.047), pathologic N stage(P = 0.035) and recurrence(P = 0.000). However, tumor cell CAV-1 did not show any correlation with clinical parameters. Additionally, the loss of stromal CAV-1 expression was associated with shorter disease-free survival(P = 0.000) and overall survival(P = 0.000). Multivariate analysis revealed that the loss of stromal CAV-1 expression was an independent prognostic factor for both overall survival(P = 0.014) and disease-free survival(P = 0.006).CONCLUSION: The loss of stromal CAV-1 expression in CRC was associated with poor prognosis and could be a prognostic factor for CRC patients.展开更多
BACKGROUND Micronodular thymic tumors with lymphoid stroma include micronodular thymoma with lymphoid stroma(MNT)and micronodular thymic carcinoma with lymphoid hyperplasia(MNC),whose micromorphological features are l...BACKGROUND Micronodular thymic tumors with lymphoid stroma include micronodular thymoma with lymphoid stroma(MNT)and micronodular thymic carcinoma with lymphoid hyperplasia(MNC),whose micromorphological features are lymphoid stromal hyperplasia and nodular arrangement of tumor epithelial cells.This type of tumor is rare;therefore,the corresponding clinical guidelines,histopathological diagnostic criteria,prognostic factors,and therapeutic regimens have not been established.CASE SUMMARY This study covers a novel presentation of MNC in a patient and summarizes the clinicopathological characteristics of this type of tumor by using pooled-analysis methods.Morphologically,this tumor type is a series of benign to malignant pedigrees.We establish the following criteria for the classification of micronodular thymic tumors with lymphoid stroma:(1)Tumor cells with moderate-to-severe dysplasia;(2)Tumor cell mitotic figures>2/10 high-power fields;(3)Appearance of neoplastic necrosis;(4)No terminal deoxynucleotidyl transferase-positive immature T lymphocytes within the tumor;(5)Tumor cells with a Ki-67 index≥10%;and(6)Tumor cells express CD5.Cases that fall into the borders of two categories in terms of morphology are attributed to atypical MNT.It is proposed that the diagnosis of MNT should be established on the diagnostic criteria mentioned above.CONCLUSION Our diagnostic algorithm can effectively distinguish malignant tumors from benign tumors and provides a potent basis for predicting a prognosis,which offers a practical reference for oncologists and pathologists.展开更多
Epithelial ovarian cancer is the most lethal type of gynecologic malignancy. Sixty percent of women who are diagnosed with ovarian cancer present with advancedstage disease that involves the peritoneal cavity and thes...Epithelial ovarian cancer is the most lethal type of gynecologic malignancy. Sixty percent of women who are diagnosed with ovarian cancer present with advancedstage disease that involves the peritoneal cavity and these patients have a 5-year survival rate of less than 30%. For more than two decades, tumor-debulking surgery followed by platinum-taxane combination chemotherapy has remained the conventional first-line treatment of ovarian cancer. Although the initial response rate is 70%-80%, most patients with advancedstage ovarian cancer eventually relapse and succumb to recurrent chemoresistant disease. A number of molecular aberrations that drive tumor progression have been identified in ovarian cancer cells and intensive efforts have focused on developing therapeutic agents that target these aberrations. However, increasing evidence indicates that reciprocal interactions between tumor cells and various types of stromal cells also play important roles in driving ovarian tumor progression and that these stromal cells represent attractive therapeutic targets. Unlike tumor cells, stromal cells within the tumor microenvironment are in general geneticallystable and are therefore less likely to become resistant to therapy. This concise review discusses the biological significance of the cross-talk between ovarian cancer cells and three major types of stromal cells(endothelial cells, fibroblasts, macrophages) and the development of new-generation therapies that target the ovarian tumor microenvironment.展开更多
Stem cells are known to maintain sternness at least in part through secreted factors that promote stem-like phenotypesin resident cells. Accumulating evidence has clarified that stem cells release nano-vesicles, known...Stem cells are known to maintain sternness at least in part through secreted factors that promote stem-like phenotypesin resident cells. Accumulating evidence has clarified that stem cells release nano-vesicles, known as exosomes,which may serve as mediators of cell-to-cell communication and may potentially transmit stem cell phenotypes torecipient cells, facilitating stem cell maintenance, differentiation, self-renewal, and repair. It has become apparent thatstem cell-derived exosomes mediate interactions among stromal elements, promote genetic instability in recipientcells, and induce malignant transformation. This review will therefore discuss the potential of stem cell-derivedexosomes in the context of stromal remodeling and their ability to generate cancer-initiating cells in a tumor nicheby inducing morphologic and functional differentiation of fibroblasts into tumor-initiating fibroblasts. In addition, theimmunosuppressive potential of stem cell-derived exosomes in cancer immunotherapy and their prospective applicationsin cell-free therapies in future translational medicine is discussed.展开更多
Background: Pancreatic ductal adenocarcinoma(PDAC) is a highly malignant solid tumor with a dismal prognosis. The stroma component makes up to 90% of the tumor mass and is thought to be one of the main reasons for the...Background: Pancreatic ductal adenocarcinoma(PDAC) is a highly malignant solid tumor with a dismal prognosis. The stroma component makes up to 90% of the tumor mass and is thought to be one of the main reasons for the tumor's high chemoresistance. Cancer associated fibroblasts(CAFs) have previously been identified to be the key stromal players. This is the first time we provide detailed in vitro experiments investigating tumor–stromal interactions when exposed to three well-known chemotherapeutic agents. Methods: Monocultures, indirect and direct co-cultures of two PDAC cell lines(AsPC and Panc-1) and six primary patients derived CAFs were treated with gemcitabine, nab-paclitaxel and the γ-secretaseinhibitor(GSI) DAPT. The cell viability of each component was measured with XTT. Finally, IL-6 concentrations of the supernatants were analyzed. Results: On the contrary to PDAC cell lines, CAF monocultures hardly responded to any treatment which suggested that stroma(CAFs) itself is more resistant to standard chemo-treatments than the epithelial cancer cells. Moreover, only a weak chemotherapeutic response was observed in direct co-cultures of cancer cells with CAFs. A change in the morphology of direct co-cultures was accompanied with the chemoresistance. CAFs were observed to build cage-like structures around agglomerates of tumor cells. High levels of IL-6 were also associated with a reduced response to therapy. Indirect co-cultures make the tumor–stromal interaction more complex. Conclusions: CAFs are highly chemoresistant. Direct cell–cell contact and high levels of IL-6 correlate with a high chemoresistance.展开更多
AIM: To investigate the survival impact of common pharmaceuticals, which target stromal interactions, following a pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. METHODS: Data was collected retrospective...AIM: To investigate the survival impact of common pharmaceuticals, which target stromal interactions, following a pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. METHODS: Data was collected retrospectively for 164 patients who underwent a pancreaticoduodenectomy for pancreatic ductal adenocarcinoma(PDAC). Survival analysis was performed on patients receiving the following medications: angiotensin-converting enzyme inhibitors(ACEI)/angiotensin Ⅱ receptor blockers(ARB), calcium channel blockers(CCB), aspirin, and statins. Statistical analysis included Kaplan-meier survival estimates and cox multivariate regression; the latter of which allowed for any differences in a range of prognostic indicators between groups. Medications showing a significant survival benefit were investigated in combination with other medications to evaluate synergistic effects.RESULTS: No survival benefit was observed with respect to ACEI/ARB(n = 41), aspirin or statins on individual drug analysis(n = 39). However, the entire CCB group(n = 26) showed a significant survival benefit on multivariate cox regression; hazard ratio(HR) of 0.475(CI = 0.250-0.902, P = 0.023). Further analysis revealed that this was influenced by a group of patients who were taking aspirin in combination with CCB; median survival was significantly higher in the CCB + aspirin group(n = 15) compared with the group taking neither drug(n = 98); 1414 d vs 601 d(P = 0.029, logrank test). Multivariate cox regression revealed neither aspirin nor CCB had a statistically significant impact on survival when given alone, however in combination the survival benefit was significant; HR = 0.332(CI = 0.126-0.870, P = 0.025). None of the other medications showed a survival benefit in any combination.CONCLUSION: Aspirin + CCB in combination appears to increase survival in patients with PDAC, highlighting the potential clinical use of combination therapy to target stromal interactions in pancreatic cancer.展开更多
Despite the availability of potent chemotherapy regimens, such as 5-fluorouracil, folinic acid, irinotecan, and oxaliplatin(FOLFIRINOX) and nab-paclitaxel plus gemcitabine, treatment outcomes in metastatic pancreatic ...Despite the availability of potent chemotherapy regimens, such as 5-fluorouracil, folinic acid, irinotecan, and oxaliplatin(FOLFIRINOX) and nab-paclitaxel plus gemcitabine, treatment outcomes in metastatic pancreatic cancer(PC) remain unsatisfactory. The presence of an abundant fibrous stroma in PC is considered a crucial factor for its unfavorable condition. Apparently, stroma acts as a physical barrier to restrict intratumoral cytotoxic drug penetration and creates a hypoxic environment that reduces the efficacy of radiotherapy. In addition, stroma plays a vital supportive role in the development and progression of PC, which has prompted researchers to assess the potential benefits of agents targeting several cellular(e.g., stellate cells) and acellular(e.g., hyaluronan) elements of the stroma. This study aims to briefly review the primary structural properties of PC stroma and its interaction with cancer cells and summarize the current status of antistromal therapies in the management of metastatic PC.展开更多
Objective To evaluate the effect of alendronate on osteoprotegerin(OPG)and receptor of activator of nuclear factor κB-ligand(RANKL)expression in human marrow stroma cells(hMSCs)in vitro.Methods hMSCs were isolated fr...Objective To evaluate the effect of alendronate on osteoprotegerin(OPG)and receptor of activator of nuclear factor κB-ligand(RANKL)expression in human marrow stroma cells(hMSCs)in vitro.Methods hMSCs were isolated from human marrow,cultured in vitro,and randomly divided into two groups:alendronate group,hMSCs culture fluid containing 1×10-7mol/L alendronate;control group,no special treatment but culturing hMSCs in DMEM.Two weeks after treatment,the expressions of OPG and RANKL were evaluated by RT-PCR and Western blot.Results hMSCs became uniform spindle-shaped fibroblasts.As cells proliferated,they formed colonies and showed whirlpool arrangement.After one week's treatment,hMSCs in alendronate group had reduced processes and gradually showed disc shape,which did not happen in control group but kept fibroblast shape and just increased in density.In RT-PCR,the ratio of OPG/RANKL in alendronate group and control group was 8.77±1.16 and 4.58±1.27,respectively.In Western blot,the ratio of OPG/RANKL in alendronate group and control group was 2.58±0.47 and 1.52±0.32,respectively.The ratio of OPG/RANKL was higher in alendronate group than in control group(P<0.01).Conclusion Alendronate enhances OPG expression and inhibits RANKL expression of hMSCs in vitro.展开更多
Pancreatic ductal adenocarcinoma(PDAC)is projected to emerge as the second leading cause of cancer-related death after 2030.Extreme treatment resistance is perhaps the most significant factor that underlies the poor p...Pancreatic ductal adenocarcinoma(PDAC)is projected to emerge as the second leading cause of cancer-related death after 2030.Extreme treatment resistance is perhaps the most significant factor that underlies the poor prognosis of PDAC.To date,combination chemotherapy remains the mainstay of treatment for most PDAC patients.Compared to other cancer types,treatment response of PDAC tumors to similar chemotherapy regimens is clearly much lower and shorterlived.Aside from typically harboring genetic alterations that to date remain undruggable and are drivers of treatment resistance,PDAC tumors are uniquely characterized by a densely fibrotic stroma that has well-established roles in promoting cancer progression and treatment resistance.However,emerging evidence also suggests that indiscriminate targeting and near complete depletion of stroma may promote PDAC aggressiveness and lead to detrimental outcomes.These conflicting results undoubtedly warrant the need for a more in-depth understanding of the heterogeneity of tumor stroma in order to develop modulatory strategies in favor of tumor suppression.The advent of novel techniques including single cell RNA sequencing and multiplex immunohistochemistry have further illuminated the complex heterogeneity of tumor cells,stromal fibroblasts,and immune cells.This new knowledge is instrumental for development of more refined therapeutic strategies that can ultimately defeat this disease.Here,we provide a concise review on lessons learned from past stromatargeting strategies,new challenges revealed from recent preclinical and clinical studies,as well as new prospects in the treatment of PDAC.展开更多
基金Key R&D Plan of Shaanxi Province(No.2021SF-331).
文摘AIM:To evaluate the clinical efficacy of small-diameter acellular porcine corneal stroma(SAPS)for the treatment of peripheral corneal ulceration(PCU).METHODS:This retrospective clinical study included 18 patients(18 eyes)with PCU between April 2018 and December 2020.All patients had PCU and underwent lamellar keratoplasty with SAPS.Observation indicators included preoperative and postoperative best-corrected visual acuity(BCVA)and transparency of SAPS.The infection control rate in the surgical eye-lesion area was also calculated.RESULTS:Eighteen patients underwent lamellar keratoplasty with SAPS to treat PCU.None of the patients experienced rejection after 6mo(18/18)and 12mo(16/16)of follow-up.The BCVA(0.47±0.30)at the 6mo followup after operation was significantly improved compared with the baseline(0.99±0.80),and the difference was statistically significant(Z=-3.415,P<0.05).The BCVA at the 12mo follow-up after operation was not statistically significant compared to the 6mo(Z=0,P=1).With time,the SAPS graft gradually became transparent.At the 6mo(18/18)and 12mo(16/16)follow-up,none of the patients had recurrent corneal infection.CONCLUSION:SAPS is clinically effective in the treatment of PCU,improving the patient’s BCVA and reducing the incidence of rejection after keratoplasty.
基金National Natural Science Foundation of China,No.82200695。
文摘Several studies have shown that the immune system is highly regulated by tryptophan metabolism,which serves as an immunomodulatory factor.The indoleamine 2,3-dioxygenase 1(IDO1),as an intracellular enzyme that participates in metabolism of the essential amino acid tryptophan in the kynurenine pathway,is an independent prognostic marker for pancreatic cancer(PC).First,overexpression of IDO1 inhibits the maturation of dendritic cells and T-cell proliferation in the liver and spleen.Second,the high expression of kynurenine induces and activates the aryl hydrocarbon receptor,resulting in upregulated programmed cell death protein 1 expression.Third,the induction of IDO1 can lead to loss of the T helper 17 cell/regulatory T cell balance,mediated by the proximal tryptophan catabolite from IDO metabolism.In our study,we found that overexpression of IDO1 upregulated CD8+T cells and reduced natural killer T cells in pancreatic carcinoma in mice.Hence,it may be essential to pay more attention to tryptophan metabolism in patients,especially those who are tolerant to immunotherapy for PC.
文摘BACKGROUND Papillary thyroid carcinoma(PTC)is regarded as a fairly common endocrine malignancy,which can be divided into different multiple variants due to wide morphologic differences.The majority of PTC variants have been reported,but PTC with nodular fasciitis-like stroma(NFS)is a rare pathological variant and has been infrequently reported in the relevant literature.This condition involves abundant reactive stromal components rich in spindle cells,which may account for 60%-80%of the tumor along with a typical papillary carcinoma.CASE SUMMARY A 44-year-old man presented with a 4-mo history of a palpable mass over the anterior aspect of the left neck,the tumor demonstrated gradual enlargement but was painless during the 4 mo prior to discovery.Thyroid function test results were normal.Physical examination showed an enormous and firm nodular mass in the left lobe of the thyroid gland extending to the level of the hyoid bone.Ultrasonography of the neck revealed a well-defined heterogeneous lesion measuring around 5.0 cm×4.0 cm with a hypoechoic complex nodule,decreased vascularity and speckles of microcalcification.The patient underwent left thyroidectomy with central compartment lymph node dissection.Final histopathological examination confirmed the diagnosis of PTC with extensive fibromatosis-like stroma combined with typical PTC.The patient was asymptomatic at the 3-mo follow-up.CONCLUSION PTC-NFS is a rare pathological variant and its diagnosis and prognosis may be similar to typical papillary carcinoma.
文摘It is now well established that the biology of cancer is influenced by not only malignant cells but also other components of the tumour microenvironment.Chronic inflammation and fibrosis have long been postulated to be involved in carcinogenesis.Chronic inflammation can promote tumorigenesis via growth factor/cytokine-mediated cellular proliferation,apoptotic resistance,immunosuppression;and free-radical-induced oxidative deoxyribonucleic acid damage.Fibrosis could cause a perturbation in the dynamics of the tumour microenvironment,potentially damaging the genome surveillance machinery of normal epithelial cells.In this review,we will provide an in-depth discussion of various diseases characterised by inflammation and fibrosis that have been associated with an increased risk of malignancy.In particular,we will present a comprehensive overview of the impact of alterations in stromal composition on tumorigenesis,induced as a consequence of inflammation and/or fibrosis.Strategies including the application of various therapeutic agents with stromal manipulation potential and targeted cancer screening for certain inflammatory diseases which can reduce the risk of cancer will also be discussed.
基金National High Technology Research and Development Program("863" Program) of China(No.2006AA02A132)
文摘AIM:To establish an untransfected human corneal stromal(HCS) cell line and characterize its biocompatibility to acellular porcine corneal stroma(aPCS).· METHODS:Primary culture was initiated with a pure population of HCS cells in DMEM/F12 media(pH 7.2) containing 20% fetal bovine serum and various necessary growth factors.The established cell line was characterized by growth property,chromosome analysis,tumorigenicity assay,expression of marker proteins and functional proteins.Furthermore,the biocompatibility of HCS cells with aPCS was examined through histological and immunocytochemistry analyses and with light,electron microscopies.· RESULTS:HCS cells proliferated to confluence 2 weeks later in primary culture and have been subcultured to passage 140 so far.A continuous untransfected HCS cell line with a population doubling time of 41.44 hours at passage 80 has been determined.Results of chromosome analysis,morphology,combined with the results of expression of marker protein and functional proteins suggested that the cells retained HCS cell properties.Furthermore,HCS cells have no tumorigenicity,and with excellent biocompatibility to aPCS.· CONCLUSION:An untransfected and non-tumorigenic HCS cell line has been established,and the cells maintained positive expression of marker proteins and functional proteins.The cell line,with excellent biocompatibility to aPCS,might be used for in vitro reconstruction of tissue-engineered HCS.
基金Supported by National Health and Medical Research Council of Australia,the Cancer Council of New South Wales and the Cancer Institute NSW
文摘Pancreatic cancer is characterised by a prominent desmoplastic/stromal reaction that has received little attention until recent times. Given that treatments focusing on pancreatic cancer cells alone have failed to significantly improve patient outcome over many decades, research efforts have now moved to understanding the pathophysiology of the stromal reaction and its role in cancer progression. In this regard, our Group was the first to identify the cells(pancreatic stellate cells, PSCs) that produced the collagenous stroma of pancreatic cancer and to demonstrate that these cells interacted closely with cancer cells to facilitate local tumour growth and distant metastasis. Evidence is accumulating to indicate that stromal PSCs may also mediate angiogenesis, immune evasion and the well known resistance of pancreatic cancer to chemotherapy and radiotherapy. This review will summarise current knowledge regarding the critical role of pancreatic stellate cells and the stroma in pancreatic cancer biologyand the therapeutic approaches being developed to target the stroma in a bid to improve the outcome of this devastating disease.
基金Supported by the PhD Studentship Awarded by Barts Charity(London,United Kingdom)and A*STAR(Singapore)the Cancer Research UK Post-doctoral Fellowshipand the PCRF Postdoctoral Fellowship.
文摘Pancreatic cancer remains one of medicine’s largest areas of unmet need.With five-year survival rates of<8%,little improvement has been made in the last 50 years.Typically presenting with advance stage disease,treatment options are limited.To date,surgery remains the only potentially curative option,however,with such late disease presentation,the majority of patients are unresectable.Thus,new therapeutic options and a greater understanding of the complex stromal interactions within the tumour microenvironment are sorely needed to revise the dismal outlook for pancreatic cancer patients.Natural killer(NK)cells are crucial effector units in cancer immunosurveillance.Often used as a prognostic biomarker in a range of malignancies,NK cells have received much attention as an attractive target for immunotherapies,both as cell therapy and as a pharmaceutical target.Despite this interest,the role of NK cells in pancreatic cancer remains poorly defined.Nevertheless,increasing evidence of the importance of NK cells in this dismal prognosis disease is beginning to come to light.Here,we review the role of NK cells in pancreatic cancer,examine the complex interactions of these crucial effector units within pancreatic cancer stroma and shed light on the increasingly attractive use of NK cells as therapy.
文摘In adults, adipose tissue is abundant and can be easily sampled using liposuction. Largely involved in obesity and associated metabolic disorders, it is now described as a reservoir of immature stromal cells. These cells, called adipose-derived stromal cells (ADSCs) must be distinguished from the crude stromal vascular fraction (SVF) obtained after digestion of adipose tissue. ADSCs share many features with mesenchymal stem cells derived from bone marrow, including paracrine activity, but they also display some specific features, including a greater angiogenic potential. Their angiogenic properties as well as their paracrine activity suggest a putative tumor-promoting role for ADSCs although contradictory data have been published on this issue. Both SVF cells and ADSCs are currently being investigated in clinical trials in several fields (chronic inflammation, ischemic diseases, etc. ). Apart from a phase Ⅲ trial on the treatment of fistula,most of these are in phaseⅠand use autologous cells. In the near future, the end results of these trials should provide a great deal of data on the safety of ADSC use.
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Supported by University of Southern DenmarkOdense University Hospital Research Fund
文摘Pancreatic cancer(PC) is the most aggressive type of common cancers, and in 2014, nearly 40000 patients died from the disease in the United States. Pancreatic ductal adenocarcinoma, which accounts for the majority of PC cases, is characterized by an intense stromal desmoplastic reaction surrounding the cancer cells. Cancer-associated fibroblasts(CAFs) are the main effector cells in the desmoplastic reaction, and pancreatic stellate cells are the most important source of CAFs. However, other important components of the PC stroma are inflammatory cells and endothelial cells. The aim of this review is to describe the complex interplay between PC cells and the cellular and noncellular components of the tumour stroma. Published data have indicated that the desmoplastic stroma protects PC cells against chemotherapy and radiation therapy and that it might promote the proliferation and migration of PC cells. However, in animal studies, experimental depletion of the desmoplastic stroma and CAFs has led to more aggressive cancers. Hence, the precise role of the tumour stroma in PC remains to be elucidated. However, it is likely that a contextdependent therapeutic modification, rather than pure depletion, of the PC stroma holds potential for the development of new treatment strategies for PC patients.
基金Supported by National Natural Science Foundation of China,No.81072049
文摘AIM: To investigate the clinicopathological significance and prognostic value of caveolin-1(CAV-1) in both tumor and stromal cells in colorectal cancer(CRC).METHODS: A total of 178 patients with CRC were included in this study. The correlation between CAV-1expression and clinicopathologic features and survival was studied.RESULTS: CAV-1 expression was detected in tumor and stromal cells. The expression of stromal CAV-1 was closely associated with histological type(P = 0.022), pathologic tumor-node-metastasis stage(P = 0.047), pathologic N stage(P = 0.035) and recurrence(P = 0.000). However, tumor cell CAV-1 did not show any correlation with clinical parameters. Additionally, the loss of stromal CAV-1 expression was associated with shorter disease-free survival(P = 0.000) and overall survival(P = 0.000). Multivariate analysis revealed that the loss of stromal CAV-1 expression was an independent prognostic factor for both overall survival(P = 0.014) and disease-free survival(P = 0.006).CONCLUSION: The loss of stromal CAV-1 expression in CRC was associated with poor prognosis and could be a prognostic factor for CRC patients.
文摘BACKGROUND Micronodular thymic tumors with lymphoid stroma include micronodular thymoma with lymphoid stroma(MNT)and micronodular thymic carcinoma with lymphoid hyperplasia(MNC),whose micromorphological features are lymphoid stromal hyperplasia and nodular arrangement of tumor epithelial cells.This type of tumor is rare;therefore,the corresponding clinical guidelines,histopathological diagnostic criteria,prognostic factors,and therapeutic regimens have not been established.CASE SUMMARY This study covers a novel presentation of MNC in a patient and summarizes the clinicopathological characteristics of this type of tumor by using pooled-analysis methods.Morphologically,this tumor type is a series of benign to malignant pedigrees.We establish the following criteria for the classification of micronodular thymic tumors with lymphoid stroma:(1)Tumor cells with moderate-to-severe dysplasia;(2)Tumor cell mitotic figures>2/10 high-power fields;(3)Appearance of neoplastic necrosis;(4)No terminal deoxynucleotidyl transferase-positive immature T lymphocytes within the tumor;(5)Tumor cells with a Ki-67 index≥10%;and(6)Tumor cells express CD5.Cases that fall into the borders of two categories in terms of morphology are attributed to atypical MNT.It is proposed that the diagnosis of MNT should be established on the diagnostic criteria mentioned above.CONCLUSION Our diagnostic algorithm can effectively distinguish malignant tumors from benign tumors and provides a potent basis for predicting a prognosis,which offers a practical reference for oncologists and pathologists.
基金Supported by Cancer and Prevention Research Institute of Texas grant,NO.RP120390(HN)United States National Institutes of Health grant,NO.CA141078(HN)
文摘Epithelial ovarian cancer is the most lethal type of gynecologic malignancy. Sixty percent of women who are diagnosed with ovarian cancer present with advancedstage disease that involves the peritoneal cavity and these patients have a 5-year survival rate of less than 30%. For more than two decades, tumor-debulking surgery followed by platinum-taxane combination chemotherapy has remained the conventional first-line treatment of ovarian cancer. Although the initial response rate is 70%-80%, most patients with advancedstage ovarian cancer eventually relapse and succumb to recurrent chemoresistant disease. A number of molecular aberrations that drive tumor progression have been identified in ovarian cancer cells and intensive efforts have focused on developing therapeutic agents that target these aberrations. However, increasing evidence indicates that reciprocal interactions between tumor cells and various types of stromal cells also play important roles in driving ovarian tumor progression and that these stromal cells represent attractive therapeutic targets. Unlike tumor cells, stromal cells within the tumor microenvironment are in general geneticallystable and are therefore less likely to become resistant to therapy. This concise review discusses the biological significance of the cross-talk between ovarian cancer cells and three major types of stromal cells(endothelial cells, fibroblasts, macrophages) and the development of new-generation therapies that target the ovarian tumor microenvironment.
文摘Stem cells are known to maintain sternness at least in part through secreted factors that promote stem-like phenotypesin resident cells. Accumulating evidence has clarified that stem cells release nano-vesicles, known as exosomes,which may serve as mediators of cell-to-cell communication and may potentially transmit stem cell phenotypes torecipient cells, facilitating stem cell maintenance, differentiation, self-renewal, and repair. It has become apparent thatstem cell-derived exosomes mediate interactions among stromal elements, promote genetic instability in recipientcells, and induce malignant transformation. This review will therefore discuss the potential of stem cell-derivedexosomes in the context of stromal remodeling and their ability to generate cancer-initiating cells in a tumor nicheby inducing morphologic and functional differentiation of fibroblasts into tumor-initiating fibroblasts. In addition, theimmunosuppressive potential of stem cell-derived exosomes in cancer immunotherapy and their prospective applicationsin cell-free therapies in future translational medicine is discussed.
基金supported by a grant from Charité–Universitaetsmedizin Berlin in house funding
文摘Background: Pancreatic ductal adenocarcinoma(PDAC) is a highly malignant solid tumor with a dismal prognosis. The stroma component makes up to 90% of the tumor mass and is thought to be one of the main reasons for the tumor's high chemoresistance. Cancer associated fibroblasts(CAFs) have previously been identified to be the key stromal players. This is the first time we provide detailed in vitro experiments investigating tumor–stromal interactions when exposed to three well-known chemotherapeutic agents. Methods: Monocultures, indirect and direct co-cultures of two PDAC cell lines(AsPC and Panc-1) and six primary patients derived CAFs were treated with gemcitabine, nab-paclitaxel and the γ-secretaseinhibitor(GSI) DAPT. The cell viability of each component was measured with XTT. Finally, IL-6 concentrations of the supernatants were analyzed. Results: On the contrary to PDAC cell lines, CAF monocultures hardly responded to any treatment which suggested that stroma(CAFs) itself is more resistant to standard chemo-treatments than the epithelial cancer cells. Moreover, only a weak chemotherapeutic response was observed in direct co-cultures of cancer cells with CAFs. A change in the morphology of direct co-cultures was accompanied with the chemoresistance. CAFs were observed to build cage-like structures around agglomerates of tumor cells. High levels of IL-6 were also associated with a reduced response to therapy. Indirect co-cultures make the tumor–stromal interaction more complex. Conclusions: CAFs are highly chemoresistant. Direct cell–cell contact and high levels of IL-6 correlate with a high chemoresistance.
文摘AIM: To investigate the survival impact of common pharmaceuticals, which target stromal interactions, following a pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. METHODS: Data was collected retrospectively for 164 patients who underwent a pancreaticoduodenectomy for pancreatic ductal adenocarcinoma(PDAC). Survival analysis was performed on patients receiving the following medications: angiotensin-converting enzyme inhibitors(ACEI)/angiotensin Ⅱ receptor blockers(ARB), calcium channel blockers(CCB), aspirin, and statins. Statistical analysis included Kaplan-meier survival estimates and cox multivariate regression; the latter of which allowed for any differences in a range of prognostic indicators between groups. Medications showing a significant survival benefit were investigated in combination with other medications to evaluate synergistic effects.RESULTS: No survival benefit was observed with respect to ACEI/ARB(n = 41), aspirin or statins on individual drug analysis(n = 39). However, the entire CCB group(n = 26) showed a significant survival benefit on multivariate cox regression; hazard ratio(HR) of 0.475(CI = 0.250-0.902, P = 0.023). Further analysis revealed that this was influenced by a group of patients who were taking aspirin in combination with CCB; median survival was significantly higher in the CCB + aspirin group(n = 15) compared with the group taking neither drug(n = 98); 1414 d vs 601 d(P = 0.029, logrank test). Multivariate cox regression revealed neither aspirin nor CCB had a statistically significant impact on survival when given alone, however in combination the survival benefit was significant; HR = 0.332(CI = 0.126-0.870, P = 0.025). None of the other medications showed a survival benefit in any combination.CONCLUSION: Aspirin + CCB in combination appears to increase survival in patients with PDAC, highlighting the potential clinical use of combination therapy to target stromal interactions in pancreatic cancer.
文摘Despite the availability of potent chemotherapy regimens, such as 5-fluorouracil, folinic acid, irinotecan, and oxaliplatin(FOLFIRINOX) and nab-paclitaxel plus gemcitabine, treatment outcomes in metastatic pancreatic cancer(PC) remain unsatisfactory. The presence of an abundant fibrous stroma in PC is considered a crucial factor for its unfavorable condition. Apparently, stroma acts as a physical barrier to restrict intratumoral cytotoxic drug penetration and creates a hypoxic environment that reduces the efficacy of radiotherapy. In addition, stroma plays a vital supportive role in the development and progression of PC, which has prompted researchers to assess the potential benefits of agents targeting several cellular(e.g., stellate cells) and acellular(e.g., hyaluronan) elements of the stroma. This study aims to briefly review the primary structural properties of PC stroma and its interaction with cancer cells and summarize the current status of antistromal therapies in the management of metastatic PC.
基金supported by the National Natural Science Foundation of China(No.30600624)
文摘Objective To evaluate the effect of alendronate on osteoprotegerin(OPG)and receptor of activator of nuclear factor κB-ligand(RANKL)expression in human marrow stroma cells(hMSCs)in vitro.Methods hMSCs were isolated from human marrow,cultured in vitro,and randomly divided into two groups:alendronate group,hMSCs culture fluid containing 1×10-7mol/L alendronate;control group,no special treatment but culturing hMSCs in DMEM.Two weeks after treatment,the expressions of OPG and RANKL were evaluated by RT-PCR and Western blot.Results hMSCs became uniform spindle-shaped fibroblasts.As cells proliferated,they formed colonies and showed whirlpool arrangement.After one week's treatment,hMSCs in alendronate group had reduced processes and gradually showed disc shape,which did not happen in control group but kept fibroblast shape and just increased in density.In RT-PCR,the ratio of OPG/RANKL in alendronate group and control group was 8.77±1.16 and 4.58±1.27,respectively.In Western blot,the ratio of OPG/RANKL in alendronate group and control group was 2.58±0.47 and 1.52±0.32,respectively.The ratio of OPG/RANKL was higher in alendronate group than in control group(P<0.01).Conclusion Alendronate enhances OPG expression and inhibits RANKL expression of hMSCs in vitro.
基金National Institutes of Health/National Cancer Institute,No.5R37CA219697-01(to Lim KH)American Cancer Society,No.RSG-17-203-01-TBG(to Lim KH)+1 种基金and Alvin J.Siteman Cancer Center Siteman Investment Program(from Barnard Trust and The Foundation for Barnes-Jewish Hospital)(to Lim KH)and Emerson Collective Grant(to Grierson PM).
文摘Pancreatic ductal adenocarcinoma(PDAC)is projected to emerge as the second leading cause of cancer-related death after 2030.Extreme treatment resistance is perhaps the most significant factor that underlies the poor prognosis of PDAC.To date,combination chemotherapy remains the mainstay of treatment for most PDAC patients.Compared to other cancer types,treatment response of PDAC tumors to similar chemotherapy regimens is clearly much lower and shorterlived.Aside from typically harboring genetic alterations that to date remain undruggable and are drivers of treatment resistance,PDAC tumors are uniquely characterized by a densely fibrotic stroma that has well-established roles in promoting cancer progression and treatment resistance.However,emerging evidence also suggests that indiscriminate targeting and near complete depletion of stroma may promote PDAC aggressiveness and lead to detrimental outcomes.These conflicting results undoubtedly warrant the need for a more in-depth understanding of the heterogeneity of tumor stroma in order to develop modulatory strategies in favor of tumor suppression.The advent of novel techniques including single cell RNA sequencing and multiplex immunohistochemistry have further illuminated the complex heterogeneity of tumor cells,stromal fibroblasts,and immune cells.This new knowledge is instrumental for development of more refined therapeutic strategies that can ultimately defeat this disease.Here,we provide a concise review on lessons learned from past stromatargeting strategies,new challenges revealed from recent preclinical and clinical studies,as well as new prospects in the treatment of PDAC.
