Prospective identification and characterization of breast cancer stem cells

Abstract

A small percentage of cells within an established solid tumor have the properties of stem cells. These solid tumor stem cells give rise both to more tumor stem cells and to the majority of cells in the tumor that have lost the capacity for extensive proliferation and the ability to give rise to new tumors. Thus, solid tumor heterogeneity reflects the presence of tumor cell progeny arising from a solid tumor stem cell. We have developed a xenograft model in which we have been able to establish tumors from primary tumors via injection of tumors in the mammary glad of severely immunodeficient mice. These xenograft assays have allowed us to do biological and molecular assays to characterize clonogenic solid tumor stem cells. We have also developed evidence that strongly implicates the Notch pathway, especially Notch 4, as playing a central pathway in carcinogenesis. This discovery is the basis for solid tumor stem cell compositions, methods for distinguishing functionally different populations of tumor cells, methods for using these tumor cell populations for studying the effects of therapeutic agents on tumor growth, and methods for identifying and testing novel anti-cancer therapies directed to solid tumor stem cells.

1 - 31 . (canceled) 
     
     
         32 - 55 . (canceled) 
     
     
         56 . A method of killing or inhibiting the proliferation of solid tumor stem cells in a solid tumor comprising solid tumor stem cells, said method comprising contacting the solid tumor stem cells with an effective amount of an inhibitor of Notch signaling, wherein the inhibitor is an antibody against a Notch receptor. 
     
     
         57 . The method of  claim 56 , wherein the effective amount is an amount sufficient to kill the solid tumor stem cells. 
     
     
         58 . The method of  claim 56 , wherein the effective amount is an amount sufficient to cause cell death of cells in the solid tumor. 
     
     
         59 . The method of  claim 56 , wherein the Notch receptor is Notch4. 
     
     
         60 . The method of  claim 56 , wherein the Notch receptor is Notch1. 
     
     
         61 . The method of  claim 56 , wherein the Notch receptor is Notch2. 
     
     
         62 . The method of  claim 56 , wherein the solid tumor stem cells express the cell surface marker CD44. 
     
     
         63 . The method of  claim 56 , wherein the solid tumor stem cells do not express CD24 or express low levels of CD24. 
     
     
         64 . The method of  claim 56 , wherein the solid tumor is an epithelial cancer. 
     
     
         65 . The method of  claim 64 , wherein the epithelial cancer is a breast cancer. 
     
     
         66 . The method of  claim 64 , wherein the epithelial cancer is an ovarian cancer. 
     
     
         67 . The method of  claim 56 , wherein the solid tumor is a sarcoma. 
     
     
         68 . The method of  claim 56 , further comprising determining the death or inhibition of proliferation of solid tumor stem cells in the solid tumor following contact with the antibody. 
     
     
         69 . A method of targeting solid tumor stem cells in a solid tumor comprising solid tumor stem cells, said method comprising contacting the solid tumor stem cells with an antibody against a Notch receptor. 
     
     
         70 . The method of  claim 69 , wherein the Notch receptor is Notch4. 
     
     
         71 . The method of  claim 69 , wherein the Notch receptor is Notch1. 
     
     
         72 . The method of  claim 69 , wherein the Notch receptor is Notch2.