Compositions and methods for treating and diagnosing cancer

Abstract

The present invention relates to compositions and methods for treating, characterizing, and diagnosing cancer. In particular, the present invention provides gene expression profiles and signatures associated with solid tumor stem cells, as well as novel stem cell cancer markers useful for the diagnosis, characterization, prognosis and treatment of solid tumor stem cells. More particularly, the present invention identifies two profiles of cancer stem cells useful for the diagnosis, characterization, and treatment of cancer and cancer metastases. The invention also provides a variety of reagents such as stem cell gene signatures for use in the diagnosis and management of cancer.

1 . An enriched population of solid tumor stem cells obtained from a solid tumor of epithelial origin, wherein the population comprises solid tumor stem cells and solid tumor cells, wherein the solid tumor stem cells: 
 are enriched at least two-fold compared to unfractionated tumor cells;    are tumorigenic; and    express undetectable levels or low levels of alpha-catenin or e-cadherin.    
     
     
         2 . The enriched population of solid tumor stem cells of  claim 1 , wherein the solid tumor stem cells: 
 express undetectable levels or low levels of e-cadherin; and,    express undetectable levels or low levels of one or more of MMP7, Nov, FOSL1, IL1R2, SFRP1, KRT6B, G0S2, IL8, B3GNT5, and FGFBP1.    
     
     
         3 . The enriched population of solid tumor stem cells of  claim 1 , wherein the solid tumor stem cells: 
 express undetectable levels or low levels of e-cadherin; and,    express undetectable levels or low levels of one or more of MMP7, Nov, FOSL1, and IL1R2.    
     
     
         4 . The enriched population of solid tumor stem cells of  claim 1 , wherein the solid tumor stem cells: 
 express undetectable levels or low levels of e-cadherin; and,    express elevated levels of one or more of SHC1, FLJ20152, ARNT, CYFIP2, C17orf27, TAP1, RNASEL, and LOC57168.    
     
     
         5 . The enriched population of solid tumor stem of  claim 1 , wherein the solid tumor stem cells: 
 express undetectable levels or low levels of e-cadherin; and,    express elevated levels of one or more of SHC1 and FLJ20152.    
     
     
         6 . An enriched population of solid tumor stem cells obtained from a solid tumor of epithelial origin, wherein the population comprises solid tumor stem cells and solid tumor cells, wherein the solid tumor stem cells: 
 are enriched at least two-fold compared to unfractionated tumor cells;    are tumorigenic; and    express undetectable levels or low levels of two or more of e-cadherin, MMP7, Nov, FOSL1, IL1R2, SFRP1, KRT6B, G0S2, IL8, B3GNT5, and FGFBP1.    
     
     
         7 . The enriched population of solid tumor stem cells of  claim 6 , wherein the solid tumor stem cells: 
 express undetectable levels or low levels of two or more of e-cadherin, MMP7, Nov, FOSL1, and IL1R2.    
     
     
         8 . An enriched population of solid tumor stem cells obtained from a solid tumor of epithelial origin, wherein the population comprises solid tumor stem cells and solid tumor cells, wherein the solid tumor stem cells: 
 are enriched at least two-fold compared to unfractionated tumor cells;    are tumorigenic; and,    express elevated levels of two or more of SHC1, FLJ20152, ARNT, CYFIP2, C17orf27, TAP1, RNASEL, and LOC57168.    
     
     
         9 . The enriched population of solid tumor stem cells of  claim 8 , wherein the solid tumor stem cells: 
 express elevated levels of SHC1 and FLJ20152.    
     
     
         10 . An enriched population of solid tumor stem cells obtained from a solid tumor of epithelial origin, wherein the population comprises solid tumor stem cells and solid tumor cells, wherein the solid tumor stem cells: 
 are enriched at least two-fold compared to unfractionated tumor cells;    are tumorigenic;    express undetectable levels or low levels of one or more of e-cadherin, MMP7, Nov, FOSL1, IL1R2, SFRP1, KRT6B, G0S2, IL8, B3GNT5, and FGFBP1; and    express elevated levels of one or more of SHC1, FLJ20152, ARNT, CYFIP2, C17orf27, TAP1, RNASEL, and LOC57168.    
     
     
         11 . An enriched population of solid tumor stem cells obtained from a solid tumor of epithelial origin, wherein the population comprises solid tumor stem cells and solid tumor cells, wherein the solid tumor stem cells: 
 are enriched at least two-fold compared to unfractionated tumor cells;    are tumorigenic;    express undetectable levels or low levels of alpha-catenin; and,    express undetectable levels or low levels of one or more of NCSTN, LNX, ARMCX3, D2S448, TUSC1, GLUL, RB1, BEX2, SLC12A2, GALC, NGFRAP1, FGF13, KIAA1102, SLC1A4, and DNAJD1.    
     
     
         12 . The enriched population of solid tumor stem cells of  claim 11 , wherein the solid tumor stem cells: 
 express undetectable levels or low levels of one or more of NCSTN, LNX, ARMCX3, D2S448, GLUL, and RB1.    
     
     
         13 . An enriched population of solid tumor stem cells obtained from a solid tumor of epithelial origin, wherein the population comprises solid tumor stem cells and solid tumor cells, wherein the solid tumor stem cells: 
 are enriched at least two-fold compared to unfractionated tumor cells;    are tumorigenic;    express undetectable levels or low levels of alpha-catenin; and, express elevated levels of one or more of EDG2, CAV1, CAV2, DCBLD2, IGFBP3, S100A2, CXCL5, MET, FOXQ1, CDKN2A, MFHAS1, IL27RA, KLRF1, PKCA, UPP1, CTSL2, SLC7A5, ARNTL2, PRSS1, PRSS2, PRSS3, VNN1, RAB38, ZBED2, MYEOV, MAL, IMP-3, and DHRS9.    
     
     
         14 . The enriched population of solid tumor stem cells of  claim 13 , wherein the solid tumor stem cells: 
 express elevated levels of one or more of EDG2, CAV1, CAV2, DCBLD2, IGFBP3, S100A2, CXCL5, MET, FOXQ1, CDKN2A, CTSL2, and MFHAS1.    
     
     
         15 . An enriched population of solid tumor stem cells obtained from a solid tumor of epithelial origin, wherein the population comprises solid tumor stem cells and solid tumor cells, wherein the solid tumor stem cells: 
 are enriched at least two-fold compared to unfractionated tumor cells;    are tumorigenic;    express undetectable levels or low levels of two or more of alpha-catenin, NCSTN, LNX, ARMCX3, D2S448, TUSC1, GLUL, RB1, BEX2, SLC12A2, GALC, NGFRAP1, FGF13, KIAA1102, SLC1A4, and DNAJD1.    
     
     
         16 . The enriched population of solid tumor stem cells of  claim 15 , wherein the solid tumor stem cells: 
 express undetectable levels or low levels of two or more of alpha-catenin, NCSTN, LNX, ARMCX3, D2S448, GLUL, and RB1.    
     
     
         17 . An enriched population of solid tumor stem cells obtained from a solid tumor of epithelial origin, wherein the population comprises solid tumor stem cells and solid tumor cells, wherein the solid tumor stem cells: 
 are enriched at least two-fold compared to unfractionated tumor cells;    are tumorigenic; and,    express elevated levels of two or more of EDG2, CAV1, CAV2, DCBLD2, IGFBP3, S100A2, CXCL5, MET, FOXQ1, CDKN2A, MFHAS1, IL27RA, KLRF1, PKCA, UPP1, CTSL2, SLC7A5, ARNTL2, PRSS1, PRSS2, PRSS3, VNN1, RAB38, ZBED2, MYEOV, MAL, IMP-3, and DHRS9.    
     
     
         18 . The enriched population of solid tumor stem cells of  claim 17 , wherein the solid tumor stem cells: 
 express elevated levels of EDG2, CAV1, CAV2, DCBLD2, IGFBP3, S100A2, CXCL5, MET, FOXQ1, CDKN2A, CTSL2, and MFHAS1.    
     
     
         19 . An enriched population of solid tumor stem cells obtained from a solid tumor of epithelial origin, wherein the population comprises solid tumor stem cells and solid tumor cells, wherein the solid tumor stem cells: 
 are enriched at least two-fold compared to unfractionated tumor cells;    are tumorigenic;    express undetectable levels or low levels of one or more of alpha-catenin, NCSTN, LNX, ARMCX3, D2S448, GLUL, and RB1; and    express elevated levels of one or more of EDG2, CAV1, CAV2, DCBLD2, IGFBP3, S100A2, CXCL5, MET, FOXQ1, CDKN2A, MFHAS1, IL27RA, KLRF1, PKCA, UPP1, CTSL2, SLC7A5, ARNTL2, PRSS1, PRSS2, PRSS3, VNN1, RAB38, ZBED2, MYEOV, MAL, IMP-3, and DHRS9.    
     
     
         20 . An enriched population of solid tumor stem cells obtained from a solid tumor of epithelial origin, wherein the population comprises solid tumor stem cells and solid tumor cells, wherein the solid tumor stem cells: 
 are enriched at least two-fold compared to unfractionated tumor cells;    are tumorigenic;    express undetectable levels or low levels of alpha-catenin; and,    express elevated levels of MET.    
     
     
         21 . A method of classifying a cancer comprising: 
 (a) determining expression levels of one or more genes comprising alpha-catenin signature 2 in a cancer sample;    (b) comparing the expression levels of the genes in the cancer sample to alpha-catenin signature 2; and,    (c) classifying the cancer sample to either a high risk or low risk group based on the comparison in (b).    
     
     
         22 . The method of  claim 21  wherein determining the expression levels of one or more genes comprising alpha catenin signature 2 is by measuring the expression of a corresponding protein or polypeptide.  
     
     
         23 . The method of  claim 22  wherein the protein or polypeptide is detected by immunohistochemical analysis of the cancer sample using an antibody that binds to the protein or polypeptide.  
     
     
         24 . The method of  claim 23 , wherein said antibody comprises an anti-CD44 antibody.  
     
     
         25 . The method of  claim 23 , wherein said antibody comprises an anti-beta cantenin antibody.  
     
     
         26 . The method of  claim 22  wherein the protein or polypeptide is detected by ELISA assay using an antibody that binds to the protein or polypeptide.  
     
     
         27 . The method of  claim 26 , wherein said antibody comprises an anti-CD44 antibody.  
     
     
         28 . The method of  claim 26 , wherein said antibody comprises an anti-beta cantenin antibody.  
     
     
         29 . The method of  claim 22  wherein the protein or polypeptide is detected using a protein array comprising an antibody that binds to the protein or polypeptide.  
     
     
         30 . The method of  claim 29 , wherein said antibody comprises an anti-CD44 antibody.  
     
     
         31 . The method of  claim 29 , wherein said antibody comprises an anti-beta cantenin antibody.  
     
     
         32 . The method of  claim 21  wherein determining the expression levels of one or more genes comprising alpha catenin signature 2 is by measuring the expression of corresponding mRNA.  
     
     
         33 . The method of  claim 32  wherein the mRNA is detected using a polynucleotide array comprising a polynucleotide that hybridizes to the mRNA.  
     
     
         34 . The method of  claim 32  wherein the mRNA is detected using polymerase chain reaction comprising polynucleotide primers to amplify the mRNA.  
     
     
         35 . The method of  claim 21  further comprising; providing diagnostic, prognostic, or predictive information based on the classifying in (d).  
     
     
         36 . A method of classifying a cancer comprising: 
 (a) determining expression levels of one or more genes comprising alpha-catenin signature 3 in a cancer sample;    (b) comparing the expression levels of the genes in the cancer sample to alpha-catenin signature 3; and,    (c) classifying the cancer sample to either a high risk or low risk group based on the comparison in (b).    
     
     
         37 . The method of  claim 36  wherein determining the expression levels of one or more genes comprising alpha catenin signature 3 is by measuring expression of the corresponding protein or polypeptide.  
     
     
         38 . The method of  claim 37  wherein the protein or polypeptide is detected by immunohistochemical analysis on the cancer sample using an antibody that binds to the protein or polypeptide.  
     
     
         39 . The method of  claim 38 , wherein said antibody comprises an anti-CD44 antibody.  
     
     
         40 . The method of  claim 38 , wherein said antibody comprises an anti-beta cantenin antibody.  
     
     
         41 . The method of  claim 37  wherein the protein or polypeptide is detected by ELISA assay using an antibody that binds to the protein or polypeptide.  
     
     
         42 . The method of  claim 41 , wherein said antibody comprises an anti-CD44 antibody.  
     
     
         43 . The method of  claim 41 , wherein said antibody comprises an anti-beta cantenin antibody.  
     
     
         44 . The method of  claim 37  wherein the protein or polypeptide is detected using a protein array comprising an antibody that binds to the protein or polypeptide.  
     
     
         45 . The method of  claim 44 , wherein said antibody comprises an anti-CD44 antibody.  
     
     
         46 . The method of  claim 44 , wherein said antibody comprises an anti-beta cantenin antibody.  
     
     
         47 . The method of  claim 36  wherein determining the expression levels of one or more genes comprising alpha catenin signature 3 is by measuring the expression of corresponding mRNA.  
     
     
         48 . The method of  claim 47  wherein the mRNA is detected using a DNA array comprising a polynucleotide that hybridizes to the mRNA.  
     
     
         49 . The method of  claim 47  wherein the mRNA is detected using polymerase chain reaction comprising polynucleotide primers that specifically amplify the mRNA.  
     
     
         50 . The method of  claim 36  further comprising; 
 providing diagnostic, prognostic, or predictive information based on the classifying in (d).