COMPOSITION FOR THE DIAGNOSIS, PREVENTION OR TREATMENT OF DISEASES RELATED TO CELLS EXPRESSING IL-8 OR GRO-ALPHA, COMPRISING UCB-MSCs

Abstract

Provided is a gene therapy composition for transferring one of a therapeutical gene, a maker gene, or a mixture thereof to a cell that expresses interleukin-8(IL-8) or GRO-α and induces tropism of mesenchymal stem cells isolated from umbilical cord blood and/or the mesenchymal stem cells expanded from said mesenchymal stem cells (UCB-MSCs), wherein the cell-treating composition includes UCB-MSCs. Provided is a composition for treating disease related to a cell expressing IL-8 or GRO-α, that is, a brain tumor in gene therapy, by using UCB-MSCs. Provided is a composition or kit for diagnosing brain tumors, preventing brain tumors, treating brain tumors, or monitoring brain tumor treatment progression by using UCB-MSCs.

1 . A method of preventing or treating a tumor comprising administering to a subject an effective dose of a composition comprising mesenchymal stem cells derived from umbilical cord blood (UCB-MSC). 
     
     
         2 . The method of  claim 1 , wherein a cell of the tumor expresses at least one gene selected from a group of a gene encoding IL-8 and a gene encoding GRO-α. 
     
     
         3 . The method of  claim 1 , wherein the tumor is selected from the group consisting of a brain tumor, a liver hepatoma, a breast cancer, a colon cancer and a B-cell neoplasm. 
     
     
         4 . The method of  claim 1 , wherein an anti-tumor agent gene is introduced into the UCB-MSC. 
     
     
         5 . The method of  claim 4 , wherein the anti-tumor agent gene is selected from the group consisting of a tumor suppressor gene, an apoptosis-inducing factor gene, a cell cycle regulatory factor gene and an angiogenesis inhibitor gene. 
     
     
         6 . The method of  claim 5 , wherein the tumor suppressor gene is selected from the group consisting of a gene encoding phosphatase and tensin homolog (PTEN), a gene encoding Maspin, a gene encoding RUNX3, a gene encoding Caveolin-1, a gene encoding nm23, a gene encoding Rb protein, a gene encoding Brush-1, a gene encoding inhibitor of tumor growth (ING-4), a gene encoding survivin, a gene encoding X chromosome linked inhibitor apoptosis protein (XIAP), a gene encoding neural apoptosis inhibitory protein (NAIP) and genes encoding proteins related to regulation of said genes. 
     
     
         7 . The method of  claim 5 , wherein the apoptosis inducing factor gene is selected from the group consisting of a gene encoding cytokine, a gene encoding interleukin, a gene encoding a tumor necrosis factor (TNF), a gene encoding interferon (INF-α, INF-β, INF-γ), a gene encoding a colony stimulating factor (CSFs), a gene encoding p53, a gene encoding Apaf-1, a gene encoding TRAIL, a gene encoding Caspase, a gene encoding Bax, a gene encoding Bad, a gene encoding FADD, a gene encoding JNK, a gene encoding p38 kinase and genes encoding proteins related to regulation of said genes. 
     
     
         8 . The method of  claim 7 , wherein the cell cycle regulatory factor gene is selected from the group consisting of a gene encoding cdc2, a gene encoding Cyclin (Cyclin A, Cyclin D, Cyclin E), a gene encoding cdc25C, a gene encoding WAF, a gene encoding INK4, a gene encoding CDK (CDK1, CDK2, CDK4, CDK6), a gene encoding Rb protein, a gene encoding E2F, an antisense or siRNA thereof and genes encoding proteins related to the regulation of said genes. 
     
     
         9 . The method of  claim 5 , wherein the angiogenesis inhibitor gene is selected from the group consisting of a gene encoding thrombospondin-1, a gene encoding endostatin, a gene encoding tumstatin, a gene encoding canstatin, a gene encoding vastatin, a gene encoding restin, a gene encoding a vascular endothelial growth factor inhibitor, a gene encoding maspin, a gene encoding angiopoietins, a gene encoding 16-kd prolactin fragment and a gene encoding endorepellin. 
     
     
         10 . The method of  claim 1 , wherein a prodrug converting enzyme gene is introduced to the UCB-MSC. 
     
     
         11 . The method of  claim 10 , wherein the method further comprises administering a prodrug of an anticancer drug. 
     
     
         12 . The method of  claim 10 , wherein the prodrug converting enzyme gene is selected from cytosine deaminase gene and CYP2B 1 gene. 
     
     
         13 . The method of  claim 1 , wherein an antisense or siRNA of a gene related to brain tumor is introduced to the UCB-MSC. 
     
     
         14 . The method of  claim 13 , wherein the gene related to brain tumor is selected from the group consisting of a gene encoding a Ras family protein, a gene encoding c-myc, a gene encoding abl, a gene encoding erbB-1, a gene encoding EGFR, a gene encoding Bax, a gene encoding Apaf-1 interacting protein (APIP), a gene encoding Wnt-1-induced secreted protein 1 (WISP-1), a gene encoding Wnt, a gene encoding Raf-1, a gene encoding Src, a gene encoding Akt, a gene encoding Erk-1, 2 and a gene encoding BcL-2. 
     
     
         15 . The method of  claim 1 , wherein an oncolytic virus is introduced to the UCB-MSC. 
     
     
         16 . The method of  claim 15 , wherein the oncolytic virus is selected from Herpes simplex virus and Reovirus type 3. 
     
     
         17 . The method of  claim 3 , wherein the brain tumor is selected from the group consisting of astrocytoma, pilocytic astrocytoma, low-grade astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, brain stem cell glioma, ependymoma, subependymoma, ganglioneuroma, mixed glioma, oligodendroglioma, optic nerve glioma, acoustic neuroma, chordoma, CNS lymphoma, craniopharyngioma, hemangioblastoma, medulloblastoma, meningioma, pineal tumors, pituitary tumors, primitive neuroectodermal tumors, rhabdoid tumors, schwannoma, cysts, neurofibromatosis, pseudotumor cerebri and tuberous sclerosis. 
     
     
         18 . The method of  claim 1 , further comprises enhancing the expression level of at least one gene selected from the group consisting of a gene encoding IL-8 receptor and a gene encoding GRO-α receptor at the USC-MSC. 
     
     
         19 . The method of  claim 18 , wherein the IL-8 receptor is selected from a group consisting of CXCR1 and CXCR2. 
     
     
         20 . The method of  claim 18 , wherein the GRO-α receptor CXCR2. 
     
     
         21 . The method of  claim 18 , wherein the enhancement of the expression is achieved by at least one selected from the group consisting of activating the endogenous gene and introducing an exogenous gene. 
     
     
         22 . A kit for identifying the location and the size of a brain tumor, comprising UCB-MSC, said UCB-MSC being labeled with a detectable marker. 
     
     
         23 . The kit of  claim 22 , wherein the detectable marker is selected from luciferase-containing enzyme-based fluorescent detector and Tat peptide-derivatized magnetic nanoparticles. 
     
     
         24 . A method of identifying the location and the size of a brain tumor of a subject, wherein the method comprises:
 (a) administering to the subject UCB-MSC;   (b) identifying the location and the size of the distribution of the administered UCB-MSC.   
     
     
         25 . The method of  claim 24 , wherein the UCB-MSC are labeled with a detectable marker. 
     
     
         26 . The method of  claim 24 , wherein the detectable marker is selected from luciferase-containing enzyme-based fluorescent detector and Tat peptide-derivatized magnetic nanoparticles. 
     
     
         27 . A method of monitoring a progression of a tumor treatment in a subject who is received the brain tumor treatment, wherein the method comprises:
 (a) first administering to the subject UCB-MSC;   (b) identifying the location and the size of the distribution of the first administered UCB-MSC in the subject;   (c) second administering to the subject UCB-MSC;   (d) identifying the location and the size of the distribution of the second administered UCB-MSC in the subject;   (e) comparing the location and the size of the distribution identified by (b) and (d),
 wherein the subject receives a treatment of the tumor during the period starting from the first administration of the UCB-MSC to the second administration of the UCB-MSC. 
   
     
     
         28 . The method of  claim 27 , wherein the UCB-MSC are labeled with a detectable marker. 
     
     
         29 . The method of  claim 28 , wherein the detectable marker is selected from luciferase-containing enzyme-based fluorescent detector and Tat peptide-derivatized magnetic nanoparticles. 
     
     
         30 . A method for delivering a therapeutic gene to a site of a subject, the site comprising cells expressing at least one selected from the group consisting of IL-8 and GRO-α and inducing tropism of UCB-MSC toward the cells, wherein the method comprises the step of administering to the subject an effective dose of the UCB-MSC. 
     
     
         31 . The method of  claim 30 , wherein the therapeutic gene is introduced into the UCB-MSC. 
     
     
         32 . The method of  claim 30 , wherein the therapeutic gene is selected from the group consisting of a tumor suppressor gene, an apoptosis-inducing factor gene, a cell cycle regulatory gene and an angiogenesis inhibitor gene. 
     
     
         33 . The method of  claim 32 , wherein the tumor suppressor gene is selected from the group consisting of a gene encoding phosphatase and tensin homolog (PTEN), a gene encoding Maspin, a gene encoding RUNX3, a gene encoding Caveolin-1, a gene encoding nm23, a gene encoding Rb protein, a gene encoding Brush-1, a gene encoding inhibitor of tumor growth (ING-4), a gene encoding survivin, a gene encoding X chromosome linked inhibitor apoptosis protein (XIAP), a gene encoding neural apoptosis inhibitory protein (NAIP), and genes encoding proteins related to the regulation of said genes. 
     
     
         34 . The method of  claim 32 , wherein the apoptosis-inducing factor gene is selected from the group consisting of a gene encoding cytokine, a gene encoding interleukin, a gene encoding a tumor necrosis factor (TNF), a gene encoding interferon (INF-α, INF-β, INF-γ), a gene encoding a colony stimulating factor (CSFs), a gene encoding p53, a gene encoding Apaf-1, a gene encoding TRAIL, a gene encoding Caspase, a gene encoding Bax, a gene encoding Bad, a gene encoding FADD, a gene encoding JNK, a gene encoding p38 kinase, and genes encoding proteins related to the regulation of said genes. 
     
     
         35 . The method of  claim 32 , wherein the cell cycle regulatory factor gene is selected from the group consisting of a gene encoding cdc2, a gene encoding Cyclin Cyclin A, Cyclin D, Cyclin E), a gene encoding cdc25C, a gene encoding WAF, a gene encoding INK4, a gene encoding CDK (CDK1, CDK2, CDK4, CDK6), a gene encoding Rb protein, a gene encoding E2F, an antisense or SiRNA thereof, and genes encoding proteins related to the regulation of said genes. 
     
     
         36 . The method of  claim 32 , wherein the angiogenesis inhibitor gene is selected from the group consisting of a gene encoding thrombospondin-1, a gene encoding endostatin, a gene encoding tumstatin, a gene encoding canstatin, a gene encoding vastatin, a gene encoding restin, a gene encoding a vascular endothelial growth factor inhibitor, a gene encoding maspin, a gene encoding angiopoietins, a gene encoding 16-kd prolactin fragment and a gene encoding endorepellin. 
     
     
         37 . The method of  claim 30 , wherein a prodrug converting enzyme gene is introduced to the UCB-MSC. 
     
     
         38 . The method of  claim 30 , wherein the method further comprises administering a prodrug of an anticancer drug. 
     
     
         39 . The method of  claim 37 , wherein the prodrug converting enzyme gene is selected from the group consisting of cytosine deaminase gene and a CYP2B 1 gene. 
     
     
         40 . The method of  claim 30 , wherein an antisense or siRNA of a gene related to tumor is introduced to the UCB-MSC. 
     
     
         41 . The method of  claim 40 , wherein the gene related to tumor is selected from the group consisting of a gene encoding Ras family protein, a gene encoding c-myc, a gene encoding abl, a gene encoding erbB-1, a gene encoding EGF-R, a gene encoding Bax, a gene encoding an Apaf-1 interacting protein (APIP), a gene encoding Wnt-1-induced secreted protein 1 (WISP-1), a gene encoding Wnt, a gene encoding Raf-1, a gene encoding Src, a gene encoding Akt, a gene encoding Erk-1,2 and a gene encoding BcL-2. 
     
     
         42 . The method of  claim 30 , wherein an oncolytic virus is introduced to the UCB-MSC. 
     
     
         43 . The method of  claim 42 , wherein the oncolytic virus is selected from the group consisting of Herpes simplex virus and Reovirus type 3. 
     
     
         44 . The method of  claim 30 , wherein the cell expressing at least one selected from the group consisting of IL-8 and GRO-α is selected from the group consisting of a brain tumor cell, a hepatoma cell, a breast cancer cell, a lung cell with an acute respiratory distress syndrome, a colon cancer cell and a B-cell neoplasm cell. 
     
     
         45 . The method of  claim 44 , wherein the B-cell neoplasm cell is selected from the group consisting of a common B acute lymphoblastic leukemia cell, a precursor B acute lymphoblastic leukemia cell, a B-cell chronic lymphocytic leukemia cell, a mantle cell lymphoma cell, a Burkitt's lymphoma cell and a Follicular lymphoma cell. 
     
     
         46 . A kit for identifying the location and the size of a site of a subject, the site comprising cells expressing at least one selected from the group consisting of IL-8 and GRO-α and inducing tropism of UCB-MSC toward the cells, wherein the kit comprises UCB-MSC, the UCB-MSC are labeled with a detectable marker. 
     
     
         47 . The kit of  claim 46 , wherein the detectable marker is selected from luciferase-containing enzyme-based fluorescent detector and Tat peptide-derivatized magnetic nanoparticles. 
     
     
         48 . The kit of  claim 46 , wherein the cell expressing at least one selected from the group consisting of IL-8 and GRO-α is selected from the group consisting of a brain tumor cell, a hepatoma cell, a breast cancer cell, a lung cell with an acute respiratory distress syndrome, a colon cancer cell and a B-cell neoplasm cell. 
     
     
         49 . The kit of  claim 48 , wherein the B-cell neoplasm cell is selected from the group consisting of a common B acute lymphoblastic leukemia cell, a precursor B acute lymphoblastic leukemia cell, a B-cell chronic lymphocytic leukemia cell, a mantle cell lymphoma cell, a Burkitt's lymphoma cell and a Follicular lymphoma cell. 
     
     
         50 . A method of identifying the location and the size of a site of a subject, the site comprising cells expressing at least one selected from the group consisting of IL-8 and GRO-α and inducing tropism of UCB-MSC toward the cells, wherein the method comprises:
 (a) administering to the subject UCB-MSC; 
 (b) identifying the location and the size of the distribution of the administered UCB-MSC. 
 
     
     
         51 . The method of  claim 50 , wherein the UCB-MSC are labeled with a detectable marker. 
     
     
         52 . The method of  claim 51 , wherein the detectable marker is selected from luciferase-containing enzyme-based fluorescent detector and Tat peptide-derivatized magnetic nanoparticles. 
     
     
         53 . The method of  claim 50 , wherein the cell expressing at least one selected from the group consisting of IL-8 and GRO-α is selected from the group consisting of a brain tumor cell, a hepatoma cell, a breast cancer cell, a lung cell with an acute respiratory distress syndrome, a colon cancer cell and a B-cell neoplasm cell. 
     
     
         54 . The method of  claim 53 , wherein the B-cell neoplasm cell is selected from the group consisting of a common B acute lymphoblastic leukemia cell, a precursor B acute lymphoblastic leukemia cell, a B-cell chronic lymphocytic leukemia cell, a mantle cell lymphoma cell, a Burkitt's lymphoma cell and a Follicular lymphoma cell. 
     
     
         55 . A method of monitoring treatment progression of a disease occurred in a site of a subject, the site comprising cells expressing at least one selected from groups consisting of IL-8 and GRO-α and inducing tropism of UCB-MSC, wherein the method comprises:
 (a) first administering to the subject UCB-MSC; 
 (b) identifying the location and the size of the distribution of the first administered UCB-MSC in the subject; 
 (a) second administering to the subject UCB-MSC; 
 (b) identifying the location and the size of the distribution of the second administered UCB-MSC in the subject; and 
 (c) comparing the location and the size of the distribution identified by (b) and (d), 
 wherein the subject receives a treatment of the tumor during the period starting from the first administration of the UCB-MSC to the second administration of the UCB-MSC. 
 
     
     
         56 . The method of  claim 55 , wherein the UCB-MSC are labelled with a detectable marker. 
     
     
         57 . The method of  claim 56 , wherein the detectable marker is selected from luciferase-containing enzyme-based fluorescent detector and Tat peptide-derivatized magnetic nanoparticles. 
     
     
         58 . The method of  claim 55 , wherein the cell expressing at least one selected from the group consisting of IL-8 and GRO-α is selected from the group consisting of a brain tumor cell, a hepatoma cell, a breast cancer cell, a lung cell with an acute respiratory distress syndrome, a colon cancer cell and a B-cell neoplasm cell. 
     
     
         59 . The method of  claim 56 , wherein the B-cell neoplasm cell is selected from the group consisting of a common B acute lymphoblastic leukemia cell, a precursor B acute lymphoblastic leukemia cell, a B-cell chronic lymphocytic leukemia cell, a mantle cell lymphoma cell, a Burkitt's lymphoma cell and a Follicular lymphoma cell. 
     
     
         60 . A method of delivering an anti-tumor agent to a site of a tumor in a subject, which comprises administering mesenchymal stem cells together with the anti-tumor agent to the site, wherein the mesenchymal stem cells (MSCs) are umbilical cord blood-derived MSCs (“UCB-MSC”). 
     
     
         61 . The method according to  claim 60 , wherein the MSCs are used in an amount of 1×10 4 -1×10 7  cells/kg body weight. 
     
     
         62 . The method according to  claim 60 , wherein the anti-tumor agent is selected from the group consisting of a tumor suppressor gene, an apoptosis-inducing factor gene, a cell cycle regulatory factor gene and an angiogenesis inhibitor gene. 
     
     
         63 . The method according to  claim 60 , wherein the anti-tumor agent is admixed with the UCB-MSCs. 
     
     
         64 . The method according to  claim 60 , wherein the anti-tumor agent is carried within the UCB-MSCs. 
     
     
         65 . The method according to  claim 60 , wherein the tumor is a brain tumor. 
     
     
         66 . The method according to  claim 62 , wherein the tumor suppressor gene is selected from the group consisting of phosphatase and tensin homolog gene (PTEN), Maspin gene, RUNX3 gene, Caveolin-1 gene, nm23 gene, Rb protein gene, Brush-1 gene, a gene encoding an inhibitor of tumor growth (ING-4), surviving gene, X chromosome linked inhibitor apoptosis protein (XIAP) gene, neural apoptosis inhibitory protein (NAIP) gene and genes encoding a protein related to regulating said genes. 
     
     
         67 . The method according to  claim 62 , wherein the apoptosis inducing factor gene is selected from the group consisting of a gene encoding cytokine, a gene encoding interleukin, a gene encoding a tumor necrosis factor (TNF), a gene encoding interferon (INF-α, INF-β, INF-γ), a gene encoding a colony stimulating factor (CSFs), a gene encoding p53, a gene encoding Apaf-1, a gene encoding TRAIL, a gene encoding Caspase, a gene encoding Bax, a gene encoding Bad, a gene encoding FADD, a gene encoding JNK, a gene encoding p38 kinase and genes encoding proteins related to regulating said genes. 
     
     
         68 . The method according to  claim 62 , wherein the cell cycle regulatory factor gene is selected from the group consisting of a gene encoding cdc2, a gene encoding Cyclin (Cyclin A, Cyclin D, Cyclin E), a gene encoding cdc25C, a gene encoding WAF, a gene encoding INK4, a gene encoding CDK (CDK1, CDK2, CDK4, CDK6), a gene encoding Rb protein, a gene encoding E2F, an antisense or siRNA thereof and genes encoding proteins related to regulating said genes. 
     
     
         69 . The method according to  claim 62 , wherein the angiogenesis inhibitor gene is selected from the group consisting of a gene encoding thrombospondin-1, a gene encoding endostatin, a gene encoding tumstatin, a gene encoding canstatin, a gene encoding vastatin, a gene encoding restin, a gene encoding a vascular endothelial growth factor inhibitor, a gene encoding maspin, a gene encoding angiopoietins, a gene encoding 16-kd prolactin fragment and a gene encoding endorepellin. 
     
     
         70 . The method according to  claim 60 , wherein the anti-tumor agent is a prodrug converting enzyme gene. 
     
     
         71 . The method according to  claim 60 , wherein the anti-tumor agent is an antisense or siRNA of a gene related to a brain tumor. 
     
     
         72 . The method according to  claim 71 , wherein the gene related to brain tumor is selected from the group consisting of a gene encoding Ras family, a gene encoding c-myc, a gene encoding abl, a gene encoding erbB-1, a gene encoding EGF-R, a gene encoding Bax, a gene encoding Apaf-1 interacting protein (APIP), a gene encoding Wnt-1-induced secreted protein 1 (WISP-1), a gene encoding Wnt, a gene encoding Raf-1, a gene encoding Src, a gene encoding Akt, a gene encoding Erk-1,2 and a gene encoding BcL-2. 
     
     
         73 . The method according to  claim 60 , wherein the anti-tumor agent is an oncolytic virus. 
     
     
         74 . The method according to  claim 73 , wherein the oncolytic virus is selected from Herpes simplex virus and Reovirus type 3. 
     
     
         75 . The method according to  claim 74 , wherein the brain tumor is selected from the group consisting of astrocytoma, pilocytic astrocytoma, low-grade astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, brain stem glioma, ependymoma, subependymoma, ganglioneuroma, mixed glioma, oligodendroglioma, optic nerve glioma, acoustic neuroma, chordoma, CNS lymphoma, craniopharyngioma, hemangioblastoma, medulloblastoma, meningioma, pineal tumors, pituitary tumors, primitive neuroectodermal tumors, rhabdoid tumors, schwannoma, cysts, neurofibromatosis, pseudotumor cerebri and tuberous sclerosis.