Objective: Vasculogenic mimicry(VM) channels that are lined by tumor cells are a functional blood supply in malignant tumors.However, the role of VM-initiating cells remains poorly understood. Cancer stem-like cells(C...Objective: Vasculogenic mimicry(VM) channels that are lined by tumor cells are a functional blood supply in malignant tumors.However, the role of VM-initiating cells remains poorly understood. Cancer stem-like cells(CSCs) are positively correlated with VM. In this study, triple-negative breast cancer(TNBC) enriched with CSCs was used to investigate the relationship between VM and CSCs.Methods: The expression of several CSC markers was detected by immunohistochemistry in 100 human breast cancer samples.The clinical significance of CSC markers and the relationship between VM, CSCs, breast cancer subtypes, and VM-associated proteins were analyzed. CD133+ and ALDH+ human and mouse TNBC cells were isolated by FACS to examine the ability of VM formation and the spatial relationship between VM and CSCs.Results: CSCs were associated with TNBC subtype and VM in human invasive breast cancer. CSCs in TNBC MDA-MB-231 cells formed more VM channels and expressed more molecules promoting VM than the non-TNBC MCF-7 cells in vitro. MDA-MB-231 cells that encircled VM channels on Matrigel expressed CD133. Moreover, CSCs were located near VM channels in the 3D reconstructed blood supply system in human TNBC grafts. The CD133+ and ALDH+ cells isolated from TA2 mouse breast cancer formed more VM channels in vivo.Conclusions: CSCs line VM channels directly. Additionally, CSCs provide more VM-related molecules to synergize VM formation. The signaling pathways that control CSC differentiation may also be potential treatment targets for TNBC.展开更多
Objective: Hypoxia is a significant feature of solid tumors, including pancreatic ductal adenocarcinoma(PDAC). It is associated with tumor invasion, metastasis, and drug resistance. However, the spatial distribution o...Objective: Hypoxia is a significant feature of solid tumors, including pancreatic ductal adenocarcinoma(PDAC). It is associated with tumor invasion, metastasis, and drug resistance. However, the spatial distribution of hypoxia-related heterogeneity in PDAC remains unclear.Methods: Spatial transcriptomics(STs), a new technique, was used to investigate the ST features of engrafted human PDAC in the ischemic hind limbs of nude mice. Transcriptomes from ST spots in the hypoxic tumor and the control were clustered using differentially-expressed genes. These data were compared to determine the spatial organization of hypoxia-induced heterogeneity in PDAC. Clinical relevance was validated using the Tumor Cancer Genome Atlas and KM-plotter databases. The CMAP website was used to identify molecules that may serve as therapeutic targets for PDAC.Results: ST showed that the tumor cell subgroups decreased to 7 subgroups in the hypoxia group, compared to 9 subgroups in the control group. Different subgroups showed positional characteristics and different gene signatures. Subgroup 6 located at the invasive front showed a higher proliferative ability under hypoxia. Subgroup 6 had active functions including cell proliferation, invasion, and response to stress. Expressions of hypoxia-related genes, LDHA, TPI1, and ENO1, induced changes. CMAP analysis indicated that ADZ-6482, a PI3 K inhibitor, was targeted by the invasive subgroup in hypoxic tumors.Conclusions: This study is the first to describe hypoxic microenvironment-induced spatial transcriptome changes in PDAC, and to identify potential treatment targets for PDAC. These data will provide the basis for further investigations of the prognoses and treatments of hypoxic tumors.展开更多
Objective: Hypoxia is an important feature of pancreatic ductal adenocarcinoma(PDAC). Previously, we found that hypoxia promotes ENO1 expression and PDAC invasion. However, the underlying molecular mechanism was remai...Objective: Hypoxia is an important feature of pancreatic ductal adenocarcinoma(PDAC). Previously, we found that hypoxia promotes ENO1 expression and PDAC invasion. However, the underlying molecular mechanism was remains unclear.Methods: The relationship between ENO1 expression and clinicopathological characteristics was analyzed in 84 patients with PADC. The effects of CoCl2-induced hypoxia and ENO1 downregulation on the apoptosis, invasion, and proliferation of PDAC cells were evaluated in vitro and in vivo. Hypoxia-and ENO1-induced gene expression was analyzed by transcriptomic sequencing.Results: The prognosis of PDAC with high ENO1 expression was poor(P < 0.05). High ENO1 expression was closely associated with histological differentiation and tumor invasion in 84 PDAC cases(P < 0.05). Hypoxia increased ENO1 expression in PDAC and promoted its migration and invasion. Apoptotic cells and the apoptosis marker caspase-3 in the CoCl_(2)-treated ENO1-sh group were significantly elevated(P < 0.05). Transcriptomic sequencing indicated that CoCl_(2)-induced PDAC cells initiated MAPK signaling. Under hypoxic conditions, PDAC cells upregulated ENO1 expression, thereby accelerating ERK phosphorylation and inhibiting apoptosis(P < 0.05). Consistent results were also observed in a PDAC-bearing mouse hindlimb ischemia model.Conclusions: Hypoxia-induced ENO1 expression promotes ERK phosphorylation and inhibits apoptosis, thus leading to PDAC survival and invasion. These results suggest that ENO1 is a potential therapeutic target for PDAC.展开更多
Polarized red, green, and blue light emitting diodes(LEDs) are successfully fabricated using polyfluorene and its derivatives, namely, poly(9,9-dioctylfluorene)(PFO), poly(9,9-dioctylfluorene-co-benzothiadiazole)(F8BT...Polarized red, green, and blue light emitting diodes(LEDs) are successfully fabricated using polyfluorene and its derivatives, namely, poly(9,9-dioctylfluorene)(PFO), poly(9,9-dioctylfluorene-co-benzothiadiazole)(F8BT),and poly(triphenylamine-co-4,7-di(thiophen-2-yl)benzo[c][1,2,5]thiadiazole-co-benzo[c]thiadiazole-co-9,9-dioctyl-9 Hfluorene)(Red F).Rubbed hole transport layer poly(3,4-ethylenedioxythiophene): poly(styrene sulfonate)(PEDOT:PSS)is employed in the devices as the alignment layer to achieve fully monodomain alignment in all polymer layers.Red F is blended with F8BT to realize the polarized electroluminescence of red light(dichroic ratio ~3.3), despite having no liquid crystallinity itself.Comparing PFO/F8BT blend to F8BT, higher efficiency of polarized emission is found due to the energy transfer.All the polarized LEDs exhibit pronounced dichroism and efficient polarized emission compared to the non-alignment regular devices.展开更多
VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors.Nevertheless,pancreatic adenocarcinoma(PAAD)cells can reinstate tumor angiogenesis via activation of VEGF-indep...VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors.Nevertheless,pancreatic adenocarcinoma(PAAD)cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways,thereby conferring resistance to VEGF inhibitors.Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD.The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth,and worse prognosis.In cells and mice with xenograft tumors,BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent manner.Mechanistically,as an RNA binding protein,BICC1 bounds to the 3’UTR of Lipocalin-2(LCN2)mRNA and post-transcriptionally up-regulated LCN2 expression in PAAD cells.When its level is elevated,LCN2 binds to its receptor 24p3R,which directly phosphorylates JAK2 and activates JAK2/STAT3 signal,leading to increased production of an angiogenic factor CXCL1.Blocking of the BICC1/LCN2 signalling reduced the microvessel density and tumor volume of PAAD cell grafts in mice,and increased the tumor suppressive effect of gemcitabine.In conclusion,BICC1 plays a pivotal role in the process of VEGF-independent angiogenesis in pancreatic cancer,leading to resistance to VEGF inhibitors.BICC1/LCN2 signaling may serve as a promising anti-angiogenic therapeutic target for pancreatic cancer patients.展开更多
基金supported by the Student’s Platform for Innovation and Entrepreneurship Training Program, China (Grant No. 201510062001)
文摘Objective: Vasculogenic mimicry(VM) channels that are lined by tumor cells are a functional blood supply in malignant tumors.However, the role of VM-initiating cells remains poorly understood. Cancer stem-like cells(CSCs) are positively correlated with VM. In this study, triple-negative breast cancer(TNBC) enriched with CSCs was used to investigate the relationship between VM and CSCs.Methods: The expression of several CSC markers was detected by immunohistochemistry in 100 human breast cancer samples.The clinical significance of CSC markers and the relationship between VM, CSCs, breast cancer subtypes, and VM-associated proteins were analyzed. CD133+ and ALDH+ human and mouse TNBC cells were isolated by FACS to examine the ability of VM formation and the spatial relationship between VM and CSCs.Results: CSCs were associated with TNBC subtype and VM in human invasive breast cancer. CSCs in TNBC MDA-MB-231 cells formed more VM channels and expressed more molecules promoting VM than the non-TNBC MCF-7 cells in vitro. MDA-MB-231 cells that encircled VM channels on Matrigel expressed CD133. Moreover, CSCs were located near VM channels in the 3D reconstructed blood supply system in human TNBC grafts. The CD133+ and ALDH+ cells isolated from TA2 mouse breast cancer formed more VM channels in vivo.Conclusions: CSCs line VM channels directly. Additionally, CSCs provide more VM-related molecules to synergize VM formation. The signaling pathways that control CSC differentiation may also be potential treatment targets for TNBC.
基金supported by grants from the National Natural Science Key Foundation of China (Grants Nos. 82030092 and 81230050)。
文摘Objective: Hypoxia is a significant feature of solid tumors, including pancreatic ductal adenocarcinoma(PDAC). It is associated with tumor invasion, metastasis, and drug resistance. However, the spatial distribution of hypoxia-related heterogeneity in PDAC remains unclear.Methods: Spatial transcriptomics(STs), a new technique, was used to investigate the ST features of engrafted human PDAC in the ischemic hind limbs of nude mice. Transcriptomes from ST spots in the hypoxic tumor and the control were clustered using differentially-expressed genes. These data were compared to determine the spatial organization of hypoxia-induced heterogeneity in PDAC. Clinical relevance was validated using the Tumor Cancer Genome Atlas and KM-plotter databases. The CMAP website was used to identify molecules that may serve as therapeutic targets for PDAC.Results: ST showed that the tumor cell subgroups decreased to 7 subgroups in the hypoxia group, compared to 9 subgroups in the control group. Different subgroups showed positional characteristics and different gene signatures. Subgroup 6 located at the invasive front showed a higher proliferative ability under hypoxia. Subgroup 6 had active functions including cell proliferation, invasion, and response to stress. Expressions of hypoxia-related genes, LDHA, TPI1, and ENO1, induced changes. CMAP analysis indicated that ADZ-6482, a PI3 K inhibitor, was targeted by the invasive subgroup in hypoxic tumors.Conclusions: This study is the first to describe hypoxic microenvironment-induced spatial transcriptome changes in PDAC, and to identify potential treatment targets for PDAC. These data will provide the basis for further investigations of the prognoses and treatments of hypoxic tumors.
基金supported by grants from the National Natural Science Key Foundation of China(Grant No.82030092).
文摘Objective: Hypoxia is an important feature of pancreatic ductal adenocarcinoma(PDAC). Previously, we found that hypoxia promotes ENO1 expression and PDAC invasion. However, the underlying molecular mechanism was remains unclear.Methods: The relationship between ENO1 expression and clinicopathological characteristics was analyzed in 84 patients with PADC. The effects of CoCl2-induced hypoxia and ENO1 downregulation on the apoptosis, invasion, and proliferation of PDAC cells were evaluated in vitro and in vivo. Hypoxia-and ENO1-induced gene expression was analyzed by transcriptomic sequencing.Results: The prognosis of PDAC with high ENO1 expression was poor(P < 0.05). High ENO1 expression was closely associated with histological differentiation and tumor invasion in 84 PDAC cases(P < 0.05). Hypoxia increased ENO1 expression in PDAC and promoted its migration and invasion. Apoptotic cells and the apoptosis marker caspase-3 in the CoCl_(2)-treated ENO1-sh group were significantly elevated(P < 0.05). Transcriptomic sequencing indicated that CoCl_(2)-induced PDAC cells initiated MAPK signaling. Under hypoxic conditions, PDAC cells upregulated ENO1 expression, thereby accelerating ERK phosphorylation and inhibiting apoptosis(P < 0.05). Consistent results were also observed in a PDAC-bearing mouse hindlimb ischemia model.Conclusions: Hypoxia-induced ENO1 expression promotes ERK phosphorylation and inhibits apoptosis, thus leading to PDAC survival and invasion. These results suggest that ENO1 is a potential therapeutic target for PDAC.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.61874058,51861145301,and 61376023)the National Key Basic Research Program of China(Grant No.2015CB932203)+2 种基金China Postdoctoral Science Foundation(Grant No.2018M642283)the Synergetic Innovation Center for Organic Electronics and Information Displays,Chinathe Priority Academic Program Development Fund of Jiangsu Higher Education Institutions(PAPD)in China
文摘Polarized red, green, and blue light emitting diodes(LEDs) are successfully fabricated using polyfluorene and its derivatives, namely, poly(9,9-dioctylfluorene)(PFO), poly(9,9-dioctylfluorene-co-benzothiadiazole)(F8BT),and poly(triphenylamine-co-4,7-di(thiophen-2-yl)benzo[c][1,2,5]thiadiazole-co-benzo[c]thiadiazole-co-9,9-dioctyl-9 Hfluorene)(Red F).Rubbed hole transport layer poly(3,4-ethylenedioxythiophene): poly(styrene sulfonate)(PEDOT:PSS)is employed in the devices as the alignment layer to achieve fully monodomain alignment in all polymer layers.Red F is blended with F8BT to realize the polarized electroluminescence of red light(dichroic ratio ~3.3), despite having no liquid crystallinity itself.Comparing PFO/F8BT blend to F8BT, higher efficiency of polarized emission is found due to the energy transfer.All the polarized LEDs exhibit pronounced dichroism and efficient polarized emission compared to the non-alignment regular devices.
基金National Natural Science Foundation of China(grants 82272680,82072659,81871978,81772633,82272799,81720108028,81525021,81502067,81302082,81272685,31301151,81172355,31471340,31470957,81472264,and 81401957)National Key R&D Program of China(grants 2020YFA0803704)+1 种基金Tianjin Science Foundation for Distinguished Young Scholars(grants 19JCJQJC63100)NIH grant R01CA233844,R01CA256911(to S.Y.).
文摘VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors.Nevertheless,pancreatic adenocarcinoma(PAAD)cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways,thereby conferring resistance to VEGF inhibitors.Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD.The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth,and worse prognosis.In cells and mice with xenograft tumors,BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent manner.Mechanistically,as an RNA binding protein,BICC1 bounds to the 3’UTR of Lipocalin-2(LCN2)mRNA and post-transcriptionally up-regulated LCN2 expression in PAAD cells.When its level is elevated,LCN2 binds to its receptor 24p3R,which directly phosphorylates JAK2 and activates JAK2/STAT3 signal,leading to increased production of an angiogenic factor CXCL1.Blocking of the BICC1/LCN2 signalling reduced the microvessel density and tumor volume of PAAD cell grafts in mice,and increased the tumor suppressive effect of gemcitabine.In conclusion,BICC1 plays a pivotal role in the process of VEGF-independent angiogenesis in pancreatic cancer,leading to resistance to VEGF inhibitors.BICC1/LCN2 signaling may serve as a promising anti-angiogenic therapeutic target for pancreatic cancer patients.