The identification of novel biomarkers for early prostate cancer diagnosis is highly important because early detection and treatment are critical for the medical management of patients. Disruption in the continuity of...The identification of novel biomarkers for early prostate cancer diagnosis is highly important because early detection and treatment are critical for the medical management of patients. Disruption in the continuity of both the basal cell layer and basement membrane is essential for the progression of high-grade prostatic intraepithelial neoplasia （HGPIN） to invasive adenocarcinoma in human prostate. The molecules involved in the conversion to an invasive phenotype are the subject of intense scrutiny. We have previously reported that matrix metalloproteinase-26 （MMP-26） promotes the invasion of human prostate cancer cells via the cleavage of basement membrane proteins and by activating the zymogen form of MMP-9. Furthermore, we have found that tissue inhibitor of metalloproteinases-4 （TIMP-4） is the most potent endogenous inhibitor of MMP-26. Here we demonstrate higher （p〈0.0001） MMP-26 and TIMP-4 expression in HGPIN and cancer, compared to non-neoplastic acini. Their expression levels are highest in HGPIN, but decline in invasive cancer （p〈0.001 for each） in the same tissues. Immunohistochemical staining of serial prostate cancer tissue sections suggests colocalization of MMP-26 and TIMP-4. The present study indicates that MMP-26 and TIMP-4 may play an integral role during the conversion of HGPIN to invasive cancer and may also serve as markers for early prostate cancer diagnosis.展开更多
Natural killer(NK)cells are cytotoxic immune cells that can eliminate target cells without prior stimulation.Human induced pluripotent stem cells(iPSCs)provide a robust source of NK cells for safe and effective cell-b...Natural killer(NK)cells are cytotoxic immune cells that can eliminate target cells without prior stimulation.Human induced pluripotent stem cells(iPSCs)provide a robust source of NK cells for safe and effective cell-based immunotherapy against aggressive cancers.In this in vitro study,a feeder-free iPSC differentiation was performed to obtain iPSC-NK cells,and distinct maturational stages of iPSC-NK were characterized.Mature cells of CD56^(bright)CD16^(bright)phenotype showed upregulation of CD56,CD16,and NK cell activation markers NKG2D and NKp46 upon IL-15 exposure,while exposure to aggressive atypical teratoid/rhabdoid tumor(ATRT)cell lines enhanced NKG2D and NKp46 expression.Malignant cell exposure also increased CD107a degranulation markers and stimulated IFN-γsecretion in activated NK cells.CD56^(bright)CD16^(bright)iPSC-NK cells showed a ratio-dependent killing of ATRT cells,and the percentage lysis of CHLA-05-ATRT was higher than that of CHLA-02-ATRT.The iPSC-NK cells were also cytotoxic against other brain,kidney,and lung cancer cell lines.Further NK maturation yielded CD56^(-ve) CD16^(bright)cells,which lacked activation markers even after exposure to interleukins or ATRT cells-indicating diminished cytotoxicity.Generation and characterization of different NK phenotypes from iPSCs,coupled with their promising anti-tumor activity against ATRT in vitro,offer valuable insights into potential immunotherapeutic strategies for brain tumors.展开更多
Matrix metalloproteinase-26 (MMP-26, endo-metase and matrilysin-2), a novel member of the MMPs family, is detected not only in the placenta and uterus, but is widely expressed in malignant tumors from different source...Matrix metalloproteinase-26 (MMP-26, endo-metase and matrilysin-2), a novel member of the MMPs family, is detected not only in the placenta and uterus, but is widely expressed in malignant tumors from different sources as well as in diverse tumor cell lines. However, the function of MMP-26 in the reproductive system has never been reported. Expression of MMP-26 in mouse embryos and the function of the MMP-26 antibody during mouse embryo implantation was examined for the first time by injecting the uterine horn, immunohistochemistry, in situ hybridization, co-culture of mouse blastocysts and uterine monolayer epithelial cells, Western blot, RT-PCR, Northern blot and zymography. Our results show that there is strong expression of MMP-26 niRNA and protein in the mouse embryo. Furthermore, the MMP-26 antibody dramatically inhibited mouse embryo implantation and significantly inhibited adhesion and outgrowth of mouse blastocysts on in vitro uterine monolayer epithelial cells. At the same time, the MMP-26展开更多
Human primary brain cancer is one of the most lethal and clinically challenging malignancies.The failure of conventional therapies to alleviate its poor outcome has prompted efforts to find innovative treatments.Recen...Human primary brain cancer is one of the most lethal and clinically challenging malignancies.The failure of conventional therapies to alleviate its poor outcome has prompted efforts to find innovative treatments.Recent breakthroughs in immunotherapy across a variety of solid tumors have set immune-based therapeutics as a pillar for brain cancer treatment.However,the unique features of brain malignancies including intratumoral heterogeneity,immunosuppressive microenvironment,and impervious blood-brain barrier,thwart the success of immunotherapeutic approaches.Yet,seminal findings regarding tumor-driven enrichment of specific immune cells granted the field novel insights to harness the immune cells to fight cancer.This review discusses the anatomical,microenvironmental,and immunobiological features of the human brain and presents an overview of immunotherapies tested for primary brain cancer patients with a special emphasis on registered phase 2,3,and combinatorial clinical trials.Immune checkpoint inhibitors,immune cell-based therapies,cancer vaccines,oncolytic viral therapy,and combination therapies are investigated in clinical settings for the treatment of human brain tumors.Despite their occasional adverse effects,immune-targeted therapies provide a promising opportunity for primary brain cancer patients to enhance survival and improve prognosis.展开更多
Atypical teratoid/rhabdoid tumor(ATRT)is a rare childhood malignancy that originates in the central nervous system.Over ninety-five percent of ATRT patients have biallelic inactivation of the tumor suppressor gene SMA...Atypical teratoid/rhabdoid tumor(ATRT)is a rare childhood malignancy that originates in the central nervous system.Over ninety-five percent of ATRT patients have biallelic inactivation of the tumor suppressor gene SMARCB1.ATRT has no standard treatment,and a major limiting factor in therapeutic development is the lack of reliable ATRT models.We employed CRISPR/Cas9 gene-editing technology to knock out SMARCB1 and TP53 genes in human episomal induced pluripotent stem cells(Epi-iPSCs),followed by brief neural induction,to generate an ATRT-like model.The dual knockout Epi-iPSCs retained their stemness with the capacity to differentiate into three germ layers.High expression of OCT4 and NANOG in neurally induced knockout spheroids was comparable to that in two ATRT cell lines.Beta-catenin protein expression was higher in SMARCB1-deficient cells and spheroids than in normal Epi-iPSC-derived spheroids.Nucleophosmin,Osteopontin,and Ki-67 proteins were also expressed by the SMARCB1-deficient spheroids.In summary,the tumor model resembled embryonal features of ATRT and expressed ATRT biomarkers at mRNA and protein levels.Ribociclib,PTC-209,and the combination of clofilium tosylate and pazopanib decreased the viability of the ATRT-like cells.This disease modeling scheme may enable the establishment of individualized tumor models with patient-specific mutations and facilitate high-throughput drug testing.展开更多
文摘The identification of novel biomarkers for early prostate cancer diagnosis is highly important because early detection and treatment are critical for the medical management of patients. Disruption in the continuity of both the basal cell layer and basement membrane is essential for the progression of high-grade prostatic intraepithelial neoplasia （HGPIN） to invasive adenocarcinoma in human prostate. The molecules involved in the conversion to an invasive phenotype are the subject of intense scrutiny. We have previously reported that matrix metalloproteinase-26 （MMP-26） promotes the invasion of human prostate cancer cells via the cleavage of basement membrane proteins and by activating the zymogen form of MMP-9. Furthermore, we have found that tissue inhibitor of metalloproteinases-4 （TIMP-4） is the most potent endogenous inhibitor of MMP-26. Here we demonstrate higher （p〈0.0001） MMP-26 and TIMP-4 expression in HGPIN and cancer, compared to non-neoplastic acini. Their expression levels are highest in HGPIN, but decline in invasive cancer （p〈0.001 for each） in the same tissues. Immunohistochemical staining of serial prostate cancer tissue sections suggests colocalization of MMP-26 and TIMP-4. The present study indicates that MMP-26 and TIMP-4 may play an integral role during the conversion of HGPIN to invasive cancer and may also serve as markers for early prostate cancer diagnosis.
基金supported by the National Science Foundation(CBET-1652992 and CBET-1917618 to Y.L.).
文摘Natural killer(NK)cells are cytotoxic immune cells that can eliminate target cells without prior stimulation.Human induced pluripotent stem cells(iPSCs)provide a robust source of NK cells for safe and effective cell-based immunotherapy against aggressive cancers.In this in vitro study,a feeder-free iPSC differentiation was performed to obtain iPSC-NK cells,and distinct maturational stages of iPSC-NK were characterized.Mature cells of CD56^(bright)CD16^(bright)phenotype showed upregulation of CD56,CD16,and NK cell activation markers NKG2D and NKp46 upon IL-15 exposure,while exposure to aggressive atypical teratoid/rhabdoid tumor(ATRT)cell lines enhanced NKG2D and NKp46 expression.Malignant cell exposure also increased CD107a degranulation markers and stimulated IFN-γsecretion in activated NK cells.CD56^(bright)CD16^(bright)iPSC-NK cells showed a ratio-dependent killing of ATRT cells,and the percentage lysis of CHLA-05-ATRT was higher than that of CHLA-02-ATRT.The iPSC-NK cells were also cytotoxic against other brain,kidney,and lung cancer cell lines.Further NK maturation yielded CD56^(-ve) CD16^(bright)cells,which lacked activation markers even after exposure to interleukins or ATRT cells-indicating diminished cytotoxicity.Generation and characterization of different NK phenotypes from iPSCs,coupled with their promising anti-tumor activity against ATRT in vitro,offer valuable insights into potential immunotherapeutic strategies for brain tumors.
基金This work was supported in part by the Special Fund for the State Key Basic Research Projects (Grant No. G1999055903)the National Natural Science Foundation of China (Grant No. 30170357)the 100-Scientist-Program of the Chinese Academy of Sciences
文摘Matrix metalloproteinase-26 (MMP-26, endo-metase and matrilysin-2), a novel member of the MMPs family, is detected not only in the placenta and uterus, but is widely expressed in malignant tumors from different sources as well as in diverse tumor cell lines. However, the function of MMP-26 in the reproductive system has never been reported. Expression of MMP-26 in mouse embryos and the function of the MMP-26 antibody during mouse embryo implantation was examined for the first time by injecting the uterine horn, immunohistochemistry, in situ hybridization, co-culture of mouse blastocysts and uterine monolayer epithelial cells, Western blot, RT-PCR, Northern blot and zymography. Our results show that there is strong expression of MMP-26 niRNA and protein in the mouse embryo. Furthermore, the MMP-26 antibody dramatically inhibited mouse embryo implantation and significantly inhibited adhesion and outgrowth of mouse blastocysts on in vitro uterine monolayer epithelial cells. At the same time, the MMP-26
基金in part supported by Florida Department of Health(FDOH)Live Like Bella award(9LA01)funded in part by the Florida State University+1 种基金funded by an Endowed Chair Professorship in Cancer Research from anonymous donorsa Lebanese grant
文摘Human primary brain cancer is one of the most lethal and clinically challenging malignancies.The failure of conventional therapies to alleviate its poor outcome has prompted efforts to find innovative treatments.Recent breakthroughs in immunotherapy across a variety of solid tumors have set immune-based therapeutics as a pillar for brain cancer treatment.However,the unique features of brain malignancies including intratumoral heterogeneity,immunosuppressive microenvironment,and impervious blood-brain barrier,thwart the success of immunotherapeutic approaches.Yet,seminal findings regarding tumor-driven enrichment of specific immune cells granted the field novel insights to harness the immune cells to fight cancer.This review discusses the anatomical,microenvironmental,and immunobiological features of the human brain and presents an overview of immunotherapies tested for primary brain cancer patients with a special emphasis on registered phase 2,3,and combinatorial clinical trials.Immune checkpoint inhibitors,immune cell-based therapies,cancer vaccines,oncolytic viral therapy,and combination therapies are investigated in clinical settings for the treatment of human brain tumors.Despite their occasional adverse effects,immune-targeted therapies provide a promising opportunity for primary brain cancer patients to enhance survival and improve prognosis.
文摘Atypical teratoid/rhabdoid tumor(ATRT)is a rare childhood malignancy that originates in the central nervous system.Over ninety-five percent of ATRT patients have biallelic inactivation of the tumor suppressor gene SMARCB1.ATRT has no standard treatment,and a major limiting factor in therapeutic development is the lack of reliable ATRT models.We employed CRISPR/Cas9 gene-editing technology to knock out SMARCB1 and TP53 genes in human episomal induced pluripotent stem cells(Epi-iPSCs),followed by brief neural induction,to generate an ATRT-like model.The dual knockout Epi-iPSCs retained their stemness with the capacity to differentiate into three germ layers.High expression of OCT4 and NANOG in neurally induced knockout spheroids was comparable to that in two ATRT cell lines.Beta-catenin protein expression was higher in SMARCB1-deficient cells and spheroids than in normal Epi-iPSC-derived spheroids.Nucleophosmin,Osteopontin,and Ki-67 proteins were also expressed by the SMARCB1-deficient spheroids.In summary,the tumor model resembled embryonal features of ATRT and expressed ATRT biomarkers at mRNA and protein levels.Ribociclib,PTC-209,and the combination of clofilium tosylate and pazopanib decreased the viability of the ATRT-like cells.This disease modeling scheme may enable the establishment of individualized tumor models with patient-specific mutations and facilitate high-throughput drug testing.
