Perineural invasion(PNI)in pancreatic cancer is an important cause of local recurrence,but little is known about its mechanism.Pleiotrophin(PTN)is an important neurotrophic factor.It is of interest that our recent exp...Perineural invasion(PNI)in pancreatic cancer is an important cause of local recurrence,but little is known about its mechanism.Pleiotrophin(PTN)is an important neurotrophic factor.It is of interest that our recent experimental data showed its involvement in PNI of pancreatic cancer.PTN strongly presents in the cytoplasm of pancreatic cancer cells,and high expression of PTN and its receptor may contribute to the high PNI of pancreatic cancer.Correspondingly,PNI is prone to happen in PTN-positive tumors.We thus hypothesize that,as a neurite growth-promoting factor,PTN may promote PNI in pancreatic cancer.PTN is released at the time of tumor cell necrosis,and binds with its highaffinity receptor,N-syndecan on pancreatic nerves,to promote neural growth in pancreatic cancer.Furthermore,neural destruction leads to a distorted neural homeostasis.Neurons and Schwann cells produce more N-syndecan in an effort to repair the pancreatic nerves.However,the abundance of N-syndecan attracts further PTN-positive cancer cells to the site of injury,creating a vicious cycle.Ultimately,increased PTN and N-syndecan levels,due to the continuous nerve injury,may promote cancer invasion and propagation along the neural structures.Therefore,it is meaningful to discuss the relationship between PTN/N-syndecan signaling and PNI in pancreatic cancer,which may lead to a better understanding of the mechanism of PNI in pancreatic cancer.展开更多
AIM To detect the expression of pleiotrophin(PTN) and N-syndecan in pancreatic cancer and analyze their association with tumor progression and perineural invasion(PNI).METHODS An orthotopic mouse model of pancreatic c...AIM To detect the expression of pleiotrophin(PTN) and N-syndecan in pancreatic cancer and analyze their association with tumor progression and perineural invasion(PNI).METHODS An orthotopic mouse model of pancreatic cancer was created by injecting tumor cells subcapsularly in a root region of the pancreas beneath the spleen. Pancreatic cancer tissues were taken from 36 mice that survived for more than 90 d. PTN and N-syndecan proteins were detected by immunohistochemistry and analyzed for their correlation with pathological features, PNI, and prognosis.RESULTS The expression rates of PTN and N-syndecan proteinswere 66.7% and 61.1%, respectively, in cancer tissue. PTN and N-syndecan expression was associated with PNI(P = 0.019 and P = 0.032, respectively). High PTN expression was closely associated with large bloody ascites(P = 0.009), liver metastasis(P = 0.035), and decreased survival time(P = 0.022). N-syndecan expression was significantly associated with tumor size(P = 0.025), but not with survival time(P = 0.539). CONCLUSION High PTN and N-syndecan expression was closely associated with metastasis and poor prognosis, suggesting that they may promote tumor progression and PNI in the orthotopic mouse model of pancreatic cancer.展开更多
AIM:To investigate the silencing effects of pAdshRNA-pleiotrophin(PTN) on PTN in pancreatic cancer cells,and to observe the inhibition of pAd-shRNA-PTN on neurite outgrowth from dorsal root ganglion(DRG) neurons in vi...AIM:To investigate the silencing effects of pAdshRNA-pleiotrophin(PTN) on PTN in pancreatic cancer cells,and to observe the inhibition of pAd-shRNA-PTN on neurite outgrowth from dorsal root ganglion(DRG) neurons in vitro.METHODS:PAd-shRNA-PTN was used to infect pancreatic cancer BxPC-3 cells;assays were conducted for knockdown of the PTN gene on the 0th,1st,3rd,5th,7th and 9th d after infection using immunocytochemistry,real-time quantitative polymerase chain reaction(PCR),and Western blotting analysis.The morphologic changes of cultured DRG neurons were observed by mono-culture of DRG neurons and co-culture with BXPC-3 cells in vitro.RESULTS:The real-time quantitative PCR showed that the inhibition rates of PTN mRNA expression in the BxPC-3 cells were 20%,80%,50% and 25% on the 1st,3rd,5th and 7th d after infection.Immunocytochemistry and Western blotting analysis also revealed the same tendency.In contrast to the control,the DRG neurons co-cultured with the infected BxPC-3 cells shrunk;the number and length of neurites were significantly decreased.CONCLUSION:Efficient and specific knockdown of PTN in pancreatic cancer cells and the reduction in PTN expression resulted in the inhibition of neurite outgrowth from DRG neurons.展开更多
The current dogma in neural regeneration research implies that chondroitin sulfate proteoglycans（CSPGs） inhibit plasticity and regeneration in the adult central nervous system（CNS）. We argue that the role of the C...The current dogma in neural regeneration research implies that chondroitin sulfate proteoglycans（CSPGs） inhibit plasticity and regeneration in the adult central nervous system（CNS）. We argue that the role of the CSPGs can be reversed from inhibition to activation by developmentally expressed CSPG-binding factors. Heparin-binding growth-associated molecule（HB-GAM; also designated as pleiotrophin） has been studied as a candidate molecule that might modulate the role of CSPG matrices in plasticity and regeneration. Studies in vitro show that in the presence of soluble HB-GAM chondroitin sulfate（CS） chains of CSPGs display an enhancing effect on neurite outgrowth. Based on the in vitro studies, we suggest a model according to which the HB-GAM/CS complex binds to the neuron surface receptor glypican-2, which induces neurite growth. Furthermore, HB-GAM masks the CS binding sites of the neurite outgrowth inhibiting receptor protein tyrosine phosphatase sigma（PTPσ）, which may contribute to the HB-GAM-induced regenerative effect. In vivo studies using two-photon imaging after local HB-GAM injection into prick-injury of the cerebral cortex reveal regeneration of dendrites that has not been previously demonstrated after injuries of the mammalian nervous system. In the spinal cord, two-photon imaging displays HB-GAM-induced axonal regeneration. Studies on the HB-GAM/CS mechanism in vitro and in vivo are expected to pave the way for drug development for injuries of brain and spinal cord.展开更多
多效生长因子(pleiotrophin,PTN)是分泌型的肝素结合生长因子,具有136个氨基酸,在机体内广泛表达。它能通过特殊的信号通路,即跨膜蛋白酪氨酸磷酸酶(receptor protein tyrosine phosphataseβ/ζ,RPTPβ/ζ)受体转导信号。PTN也是原癌基...多效生长因子(pleiotrophin,PTN)是分泌型的肝素结合生长因子,具有136个氨基酸,在机体内广泛表达。它能通过特殊的信号通路,即跨膜蛋白酪氨酸磷酸酶(receptor protein tyrosine phosphataseβ/ζ,RPTPβ/ζ)受体转导信号。PTN也是原癌基因,它表达在人类肿瘤细胞中,并且来源于肿瘤的细胞链也会表达PTN。不论是不同细胞诱导产生的PTN还是PTN刺激的细胞,它们的相似之处都是高度恶性。此外,将PTN转化到细胞后能使潜在恶性细胞高度恶化。因此,在恶性细胞中PTN不适当的表达能作为肿瘤强有力的启动者。最近确认,在转基因小鼠模型中发现PTN能以乳腺癌病毒为靶向目标诱导乳腺癌更具有侵略性,在表型中更相似于硬癌。另外,PTN能显著增加肿瘤血管生成,重塑肿瘤微环境。展开更多
基金Supported by National Natural Science Foundation of China,No.U1204819Health Science and Technology Innovation Talents Program of Henan Province,China,No.4203
文摘Perineural invasion(PNI)in pancreatic cancer is an important cause of local recurrence,but little is known about its mechanism.Pleiotrophin(PTN)is an important neurotrophic factor.It is of interest that our recent experimental data showed its involvement in PNI of pancreatic cancer.PTN strongly presents in the cytoplasm of pancreatic cancer cells,and high expression of PTN and its receptor may contribute to the high PNI of pancreatic cancer.Correspondingly,PNI is prone to happen in PTN-positive tumors.We thus hypothesize that,as a neurite growth-promoting factor,PTN may promote PNI in pancreatic cancer.PTN is released at the time of tumor cell necrosis,and binds with its highaffinity receptor,N-syndecan on pancreatic nerves,to promote neural growth in pancreatic cancer.Furthermore,neural destruction leads to a distorted neural homeostasis.Neurons and Schwann cells produce more N-syndecan in an effort to repair the pancreatic nerves.However,the abundance of N-syndecan attracts further PTN-positive cancer cells to the site of injury,creating a vicious cycle.Ultimately,increased PTN and N-syndecan levels,due to the continuous nerve injury,may promote cancer invasion and propagation along the neural structures.Therefore,it is meaningful to discuss the relationship between PTN/N-syndecan signaling and PNI in pancreatic cancer,which may lead to a better understanding of the mechanism of PNI in pancreatic cancer.
基金Supported by the National Natural Science Foundation of China,No.U1204819Health Science and Technology Innovation Talents Program of Henan Province,No.4203
文摘AIM To detect the expression of pleiotrophin(PTN) and N-syndecan in pancreatic cancer and analyze their association with tumor progression and perineural invasion(PNI).METHODS An orthotopic mouse model of pancreatic cancer was created by injecting tumor cells subcapsularly in a root region of the pancreas beneath the spleen. Pancreatic cancer tissues were taken from 36 mice that survived for more than 90 d. PTN and N-syndecan proteins were detected by immunohistochemistry and analyzed for their correlation with pathological features, PNI, and prognosis.RESULTS The expression rates of PTN and N-syndecan proteinswere 66.7% and 61.1%, respectively, in cancer tissue. PTN and N-syndecan expression was associated with PNI(P = 0.019 and P = 0.032, respectively). High PTN expression was closely associated with large bloody ascites(P = 0.009), liver metastasis(P = 0.035), and decreased survival time(P = 0.022). N-syndecan expression was significantly associated with tumor size(P = 0.025), but not with survival time(P = 0.539). CONCLUSION High PTN and N-syndecan expression was closely associated with metastasis and poor prognosis, suggesting that they may promote tumor progression and PNI in the orthotopic mouse model of pancreatic cancer.
基金Supported by Health Science and Technology Innovation Talents Program of Henan Province
文摘AIM:To investigate the silencing effects of pAdshRNA-pleiotrophin(PTN) on PTN in pancreatic cancer cells,and to observe the inhibition of pAd-shRNA-PTN on neurite outgrowth from dorsal root ganglion(DRG) neurons in vitro.METHODS:PAd-shRNA-PTN was used to infect pancreatic cancer BxPC-3 cells;assays were conducted for knockdown of the PTN gene on the 0th,1st,3rd,5th,7th and 9th d after infection using immunocytochemistry,real-time quantitative polymerase chain reaction(PCR),and Western blotting analysis.The morphologic changes of cultured DRG neurons were observed by mono-culture of DRG neurons and co-culture with BXPC-3 cells in vitro.RESULTS:The real-time quantitative PCR showed that the inhibition rates of PTN mRNA expression in the BxPC-3 cells were 20%,80%,50% and 25% on the 1st,3rd,5th and 7th d after infection.Immunocytochemistry and Western blotting analysis also revealed the same tendency.In contrast to the control,the DRG neurons co-cultured with the infected BxPC-3 cells shrunk;the number and length of neurites were significantly decreased.CONCLUSION:Efficient and specific knockdown of PTN in pancreatic cancer cells and the reduction in PTN expression resulted in the inhibition of neurite outgrowth from DRG neurons.
基金supported by the Finnish Funding Agency for Innovation Tekes,Academy of FinlandSigrid Jusélius Foundation
文摘The current dogma in neural regeneration research implies that chondroitin sulfate proteoglycans（CSPGs） inhibit plasticity and regeneration in the adult central nervous system（CNS）. We argue that the role of the CSPGs can be reversed from inhibition to activation by developmentally expressed CSPG-binding factors. Heparin-binding growth-associated molecule（HB-GAM; also designated as pleiotrophin） has been studied as a candidate molecule that might modulate the role of CSPG matrices in plasticity and regeneration. Studies in vitro show that in the presence of soluble HB-GAM chondroitin sulfate（CS） chains of CSPGs display an enhancing effect on neurite outgrowth. Based on the in vitro studies, we suggest a model according to which the HB-GAM/CS complex binds to the neuron surface receptor glypican-2, which induces neurite growth. Furthermore, HB-GAM masks the CS binding sites of the neurite outgrowth inhibiting receptor protein tyrosine phosphatase sigma（PTPσ）, which may contribute to the HB-GAM-induced regenerative effect. In vivo studies using two-photon imaging after local HB-GAM injection into prick-injury of the cerebral cortex reveal regeneration of dendrites that has not been previously demonstrated after injuries of the mammalian nervous system. In the spinal cord, two-photon imaging displays HB-GAM-induced axonal regeneration. Studies on the HB-GAM/CS mechanism in vitro and in vivo are expected to pave the way for drug development for injuries of brain and spinal cord.
文摘多效生长因子(pleiotrophin,PTN)是分泌型的肝素结合生长因子,具有136个氨基酸,在机体内广泛表达。它能通过特殊的信号通路,即跨膜蛋白酪氨酸磷酸酶(receptor protein tyrosine phosphataseβ/ζ,RPTPβ/ζ)受体转导信号。PTN也是原癌基因,它表达在人类肿瘤细胞中,并且来源于肿瘤的细胞链也会表达PTN。不论是不同细胞诱导产生的PTN还是PTN刺激的细胞,它们的相似之处都是高度恶性。此外,将PTN转化到细胞后能使潜在恶性细胞高度恶化。因此,在恶性细胞中PTN不适当的表达能作为肿瘤强有力的启动者。最近确认,在转基因小鼠模型中发现PTN能以乳腺癌病毒为靶向目标诱导乳腺癌更具有侵略性,在表型中更相似于硬癌。另外,PTN能显著增加肿瘤血管生成,重塑肿瘤微环境。
