Monitoring and modulating HGF/HGFR activity

Abstract

Provided are methods and compositions for the modulation of hepatocyte growth factor activity to regulate lymphatic vessel development and function. Methods and composition for the monitoring and treatment of skin disorders, lymphedema, and metastatic cancers are disclosed. Also described are methods of identifying inhibitors of hepatocyte growth factor dependent lymphangiogenesis.

1 . A method of treating a subject having an unwanted skin condition comprising increasing hepatocyte growth factor activity to thereby treat the disorder.  
   
   
       2 . The method of  claim 1 , wherein the unwanted skin condition is a condition that affects the structure of the skin.  
   
   
       3 . The method of  claim 1 , wherein the condition can be caused by a genetic factor.  
   
   
       4 . The method of  claim 3 , wherein the genetic factor is epidermolysis.  
   
   
       5 . The method of  claim 1 , wherein the condition is caused by an environmental factor.  
   
   
       6 . The method of  claim 5 , wherein the environmental factor is ultraviolet radiation.  
   
   
       7 . The method of  claim 1 , wherein the unwanted condition is aged skin.  
   
   
       8 . The method of  claim 1 , wherein the unwanted condition is psoriasis.  
   
   
       9 . The method of  claim 1 , wherein the unwanted condition is rosacea dermatosis.  
   
   
       10 . The method of  claim 1 , wherein the unwanted condition is skin damage caused by photoradiation.  
   
   
       11 . The method of  claim 1 , wherein increasing hepatocyte growth factor activity comprises administering to the subject an agonist of hepatocyte growth factor activity.  
   
   
       12 . The method of  claim 11 , wherein the agonist of hepatocyte growth factor activity is selected from the group consisting of: a hepatocyte growth factor polypeptide or a biologically active fragment or analog thereof, a nucleic acid encoding a hepatocyte growth factor or a biologically active fragment or analog thereof, and an agonist of hepatocyte growth factor.  
   
   
       13 . The method of  claim 11 , wherein the agonist of hepatocyte growth factor activity is an agent effective to increase the endogenous level of hepatocyte growth factor.  
   
   
       14 . A method of treating a subject having lymphedema comprising increasing hepatocyte growth factor activity to thereby treat the lymphedema.  
   
   
       15 . The method of  claim 14 , wherein increasing hepatocyte growth factor activity comprises administering to the subject an agonist of hepatocyte growth factor activity.  
   
   
       16 . The method of  claim 15 , wherein the agonist of hepatocyte growth factor activity is selected from the group consisting of: a hepatocyte growth factor polypeptide or a biologically active fragment or analog thereof, a nucleic acid encoding a hepatocyte growth factor or a biologically active fragment or analog thereof, and an agonist of hepatocyte growth factor.  
   
   
       17 . The method of  claim 15 , wherein the agonist of hepatocyte growth factor activity is an agent effective to increase the endogenous level of hepatocyte growth factor.  
   
   
       18 . A method of treating a subject having or at risk for a neoplastic disorder comprising inhibiting hepatocyte growth factor activity to thereby treat or reduce the risk of the neoplastic disorder.  
   
   
       19 . The method of  claim 18 , wherein the neoplastic disorder is a cancer.  
   
   
       20 . The method of  claim 19 , wherein the cancer is characterized by a risk of metastasis to a lymph node.  
   
   
       21 . The method of  claim 18 , wherein inhibiting hepatocyte growth factor activity comprises administering to the subject an antagonist of hepatocyte growth factor activity.  
   
   
       22 . The method of  claim 21 , wherein the antagonist of hepatocyte growth factor activity is selected from the group consisting of: a hepatocyte growth factor nucleic acid molecule that can bind to cellular hepatocyte growth factor mRNA and inhibit expression of the protein, an antibody that specifically binds to a hepatocyte growth factor protein, a soluble hepatocyte growth factor receptor, a dominant negative hepatocyte growth factor protein or fragment thereof, and an agent that decreases hepatocyte growth factor nucleic acid expression.  
   
   
       23 . The method of  claim 21 , wherein the antagonist of hepatocyte growth factor activity is an agent effective to decrease the endogenous level of hepatocyte growth factor.  
   
   
       24 . A method of treating a subject having or at risk for a neoplastic disorder comprising inhibiting α9 integrin activity to thereby treat or reduce the risk of the neoplastic disorder.  
   
   
       25 . The method of  claim 24 , wherein inhibiting α9 integrin activity comprises administering to the subject an antagonist of α9 integrin activity.  
   
   
       26 . The method of  claim 25 , wherein the antagonist of α9 integrin activity is selected from the group consisting of: an α9 integrin nucleic acid molecule that can bind to cellular α9 integrin mRNA and inhibit expression of the protein, an antibody that specifically binds to an α9 integrin, a soluble α9 integrin receptor, a dominant negative α9 integrin protein or fragment thereof, and an agent that decreases α9 integrin nucleic acid expression.  
   
   
       27 . A method of identifying a compound that inhibits hepatocyte growth factor-dependent lymphatic endothelial cell proliferation or migration, comprising: 
 providing a lymphatic endothelial cell expressing the hepatocyte growth factor receptor;    contacting the lymphatic endothelial cell with hepatocyte growth factor and a test compound; and    determining whether proliferation of the lymphatic endothelial cell is decreased in the presence of the test compound, a decrease in the proliferation being an indication that the test compound inhibits hepatocyte growth factor-dependent lymphatic endothelial cell proliferation.    
   
   
       28 . The method of  claim 27 , wherein the lymphatic endothelial cell is a mammalian cell selected from the group consisting of: mouse, rat, rabbit, hamster, and human.  
   
   
       29 . The method of  claim 28 , wherein the mammalian cell expresses Prox1 and the hyaluronan receptor LYVE-1.  
   
   
       30 . The method of  claim 27 , wherein the test compound is a peptide or an antibody.  
   
   
       31 . The method of  claim 27 , wherein the lymphatic endothelial cell expresses a recombinant hepatocyte growth factor receptor or a mutant thereof.  
   
   
       32 . A method of identifying a compound that inhibits hepatocyte growth factor-dependent lymphangiogenesis comprising: 
 providing lymphatic endothelial cells expressing the hepatocyte growth factor receptor;    contacting the lymphatic endothelial cells with hepatocyte growth factor and a test compound; and    determining if lymphangiogenesis is decreased, wherein a decrease in lymphangiogenesis is an indication that the compound inhibits hepatocyte growth factor-dependent lymphangiogenesis.    
   
   
       33 . The method of  claim 32 , wherein the lymphatic endothelial cells are mammalian cells selected from the group consisting of: mouse, rat, rabbit, hamster, and human.  
   
   
       34 . The method of  claim 33 , wherein the mammalians cell express Prox1 and the hyaluronan receptor LYVE-1.  
   
   
       35 . The method of  claim 32 , wherein the test compound is a peptide or an antibody.