Clusterin Expression in Normal Mucosa and Colorectal Cancer

The gene Clusterin is a target for cancer therapy in clinical trials. The indication for intervention is up-regulated Clusterin expression. Clusterin has been reported to be deregulated in multiple cancer types, including colorectal cancer (CRC). However, for CRC the studies have disagreed on whether Clusterin is up- or down-regulated by neoplastic cells. In the present study we sought to clarify the expression and distribution of Clusterin mRNAs and proteins in normal and neoplastic colorectal tissue through laser microdissection, variant-specific real time RT-PCR, immunohistochemistry, immunofluorescence, Western blotting, and array-based transcriptional profiling. At the transcript level we demonstrated the expression of two novel Clusterin transcripts in addition to the known transcript, and at the protein level we demonstrated two Clusterin isoforms. Our analysis of normal epithelial cells revealed that among these, Clusterin was only expressed by rare neuroendocrine subtype. Furthermore our analysis showed that in the normal mucosa the majority of the observed Clusterin protein originated from the stromal compartment. In tumors we found that Clusterin was de novo synthesized by non-neuroendocrine cancer cells in ∼25% of cases. Moreover we found that the overall Clusterin level in tumors often appeared to be lower than in normal mucosa due to the stromal compartment often being suppressed in tumors. Although Clusterin in normal neuroendocrine cells showed a basal localization, the localization in cancer cells was often apical and in some cases associated with apical secretion. Collectively our results indicate that Clusterin expression is very complex. We conclude that Clusterin expression is associated with neuroendocrine differentiation in normal epithelia and that the Clusterin observed in neoplastic cells is de novo synthesized. The cases with de novo synthesized Clusterin define a distinct subgroup of CRC that may be of clinical importance as anti-Clusterin therapeutics are now in clinical trials. The gene Clusterin is a target for cancer therapy in clinical trials. The indication for intervention is up-regulated Clusterin expression. Clusterin has been reported to be deregulated in multiple cancer types, including colorectal cancer (CRC). However, for CRC the studies have disagreed on whether Clusterin is up- or down-regulated by neoplastic cells. In the present study we sought to clarify the expression and distribution of Clusterin mRNAs and proteins in normal and neoplastic colorectal tissue through laser microdissection, variant-specific real time RT-PCR, immunohistochemistry, immunofluorescence, Western blotting, and array-based transcriptional profiling. At the transcript level we demonstrated the expression of two novel Clusterin transcripts in addition to the known transcript, and at the protein level we demonstrated two Clusterin isoforms. Our analysis of normal epithelial cells revealed that among these, Clusterin was only expressed by rare neuroendocrine subtype. Furthermore our analysis showed that in the normal mucosa the majority of the observed Clusterin protein originated from the stromal compartment. In tumors we found that Clusterin was de novo synthesized by non-neuroendocrine cancer cells in ∼25% of cases. Moreover we found that the overall Clusterin level in tumors often appeared to be lower than in normal mucosa due to the stromal compartment often being suppressed in tumors. Although Clusterin in normal neuroendocrine cells showed a basal localization, the localization in cancer cells was often apical and in some cases associated with apical secretion. Collectively our results indicate that Clusterin expression is very complex. We conclude that Clusterin expression is associated with neuroendocrine differentiation in normal epithelia and that the Clusterin observed in neoplastic cells is de novo synthesized. The cases with de novo synthesized Clusterin define a distinct subgroup of CRC that may be of clinical importance as anti-Clusterin therapeutics are now in clinical trials. Over the recent years it has become increasingly clear that the gene Clusterin (CLU) 1The abbreviations used are: CLU, Clusterin; CgA, Chromogranin A; CRC, colorectal cancer; DAPI, 4,6-diamidino-2-phen yl in dole; IF, immunofluorescence; IHC, immunohistochemistry; LOH, loss of heterozygosity; SNP, single nucleotide polymorphism; UBC, Ubiquitin C; TMA, tissue microarray; EST, expressed sequence tag. and the proteins encoded by it are involved in carcinogenesis, tumor growth, and resistance to therapy (1Shannan B. Seifert M. Leskov K. Willis J. Boothman D. Tilgen W. Reichrath J. Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer.Cell Death Differ. 2006; 13: 12-19Crossref PubMed Scopus (282) Google Scholar). CLU has been reported to be involved in numerous physiological processes important for carcinogenesis and tumor growth, including apo pto tic cell death, cell cycle regulation, DNA repair, cell adhesion, tissue remodeling, lipid transportation, membrane recycling, and immune system regulation (1Shannan B. Seifert M. Leskov K. Willis J. Boothman D. Tilgen W. Reichrath J. Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer.Cell Death Differ. 2006; 13: 12-19Crossref PubMed Scopus (282) Google Scholar, 2Trougakos I.P. Gonos E.S. Clusterin/apolipoprotein J in human aging and cancer.Int. J. Biochem. Cell Biol. 2002; 34: 1430-1448Crossref PubMed Scopus (320) Google Scholar). In the literature the dominating view states that increased CLU expression confers cytoprotective capabilities to the tumor (1Shannan B. Seifert M. Leskov K. Willis J. Boothman D. Tilgen W. Reichrath J. Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer.Cell Death Differ. 2006; 13: 12-19Crossref PubMed Scopus (282) Google Scholar). The mechanisms for this are not fully understood; however, a recent study showed that intracellular CLU can inhibit apo pto sis by interfering with Bax activation in mitochondria (3Zhang H. Kim J.K. Edwards C.A. Xu Z. Taichman R. Wang C.Y. Clusterin inhibits apo pto sis by interacting with activated Bax.Nat. Cell Biol. 2005; 7: 909-915Crossref PubMed Scopus (379) Google Scholar). It is generally accepted that CLU is a stress-inducible gene, induced for example by ionizing radiation and several chemotherapeutics (1Shannan B. Seifert M. Leskov K. Willis J. Boothman D. Tilgen W. Reichrath J. Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer.Cell Death Differ. 2006; 13: 12-19Crossref PubMed Scopus (282) Google Scholar). Increased CLU levels lead to inhibition of apo pto sis and promote cancer cell survival in the face of therapeutic stimuli (1Shannan B. Seifert M. Leskov K. Willis J. Boothman D. Tilgen W. Reichrath J. Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer.Cell Death Differ. 2006; 13: 12-19Crossref PubMed Scopus (282) Google Scholar, 4Miyake H. Hara I. Gleave M.E. Antisense oligodeoxynucleotide therapy targeting clusterin gene for prostate cancer: Vancouver experience from discovery to clinic.Int. J. 2005; PubMed Scopus Google Scholar). and clinical studies have demonstrated that inhibition of CLU expression the apo pto sis induced by several (1Shannan B. Seifert M. Leskov K. Willis J. Boothman D. Tilgen W. Reichrath J. Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer.Cell Death Differ. 2006; 13: 12-19Crossref PubMed Scopus (282) Google Scholar, 4Miyake H. Hara I. Gleave M.E. Antisense oligodeoxynucleotide therapy targeting clusterin gene for prostate cancer: Vancouver experience from discovery to clinic.Int. J. 2005; PubMed Scopus Google Scholar, D. M. of clusterin in colorectal and J. 2005; PubMed Scopus Google Scholar, M. H. of targeting the cytoprotective gene, to and in prostate J. 2005; PubMed Scopus Google Scholar). CLU has been reported to be a gene protein with distinct and (1Shannan B. Seifert M. Leskov K. Willis J. Boothman D. Tilgen W. Reichrath J. Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer.Cell Death Differ. 2006; 13: 12-19Crossref PubMed Scopus (282) Google Scholar, of clusterin in human PubMed Scopus Google Scholar, Leskov K. K. Boothman protein that cell PubMed Scopus Google a of H. Gleave M.E. of by of the pto tic gene prostate in prostate cancer Google Scholar, J. of cancer cells to by of clusterin in PubMed Scopus Google Scholar, M. B. B. of the pto tic gene J by Biol. PubMed Scopus Google a of (3Zhang H. Kim J.K. Edwards C.A. Xu Z. Taichman R. Wang C.Y. Clusterin inhibits apo pto sis by interacting with activated Bax.Nat. Cell Biol. 2005; 7: 909-915Crossref PubMed Scopus (379) Google and a pto tic of J. Boothman and of a cell Biol. PubMed Scopus Google Scholar). It is the protein are from the CLU gene, and this a of on or of the protein for J. Boothman and of a cell Biol. PubMed Scopus Google Scholar, localization of in epithelial PubMed Scopus Google Scholar). from several indicate the of CLU the for sequence two CLU has and the multiple CLU B. the PubMed Scopus Google Scholar). CLU transcripts be for the observed CLU the the of multiple novel CLU the of the for transcripts and to expression has not been of CLU transcripts is of importance for CLU the novel therapeutic CLU is of for the of that CLU, including and colorectal cancer (1Shannan B. Seifert M. Leskov K. Willis J. Boothman D. Tilgen W. Reichrath J. Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer.Cell Death Differ. 2006; 13: 12-19Crossref PubMed Scopus (282) Google Scholar). However, studies on CLU expression in CRC have disagreed on whether CLU is up-regulated of clusterin in human PubMed Scopus Google Scholar, D. M. of clusterin in colorectal and J. 2005; PubMed Scopus Google or down-regulated by the cancer cells J. M. apo pto sis is by and is PubMed Scopus Google Scholar). are for the analysis of CLU by the of or by targeting isoforms. be the of of the cell the observed CLU The importance of the was in a recent study of prostate cancer M. M. D. Clusterin expression is in and human prostate cancer.Int. J. PubMed Scopus Google analysis revealed CLU to be in cells being expressed in a to have been by as Western or real time is the regulation of CLU expression. In a known of gene regulation of the of the CLU is are observed in CRC M. M. of in colorectal PubMed Scopus Google and the reported CLU The of the present study the and as to CLU and expression in colorectal to the expression levels of CLU transcripts in normal epithelia and cancer to the the expression of CLU by neoplastic colorectal and H. Hara I. Gleave M.E. Antisense oligodeoxynucleotide therapy targeting clusterin gene for prostate cancer: Vancouver experience from discovery to clinic.Int. J. 2005; PubMed Scopus Google to whether loss of at the CLU is associated with the of CLU observed in normal mucosa and two used to the expression of CLU by was on of and a of normal colorectal mucosa and from and and colorectal normal and in a human tissue The system was used for of the and from two of the of normal and used for used for tissue from of normal mucosa and to laser by cell of normal epithelial and cancer cells DNA from cell was used for single nucleotide analysis M. M. of in colorectal PubMed Scopus Google and for of the CLU was from of the of and used for real time Furthermore of the by Western of normal mucosa and used for transcriptional as M. R. D. K. H. M. expression for colorectal cancer and J. 2005; PubMed Scopus Google Scholar). the expression of CLU transcript in colorectal was synthesized from of from of normal mucosa and two cancer The was the the as the by in the or with a in and are in The from the and the The used as for the and was the as used for human CLU a CLU a CLU a CLU and a CLU can be found in a of neuroendocrine we used a Chromogranin from for Western blotting, we used a was as K. W. H. B. is a novel for neuroendocrine 2005; PubMed Scopus Google Scholar). In was by of and to at the CLU CLU CLU CLU and Chromogranin was the system the with The and by two and K. The of and CLU was from for of CLU as the epithelial cells of the normal mucosa only the cancer cells in the tumor was in or of the target cells and in for of CLU as was was in or of the and in was as W. J. B. W. M. W. The with PubMed Scopus Google Scholar). with a of CLU and is a known of neuroendocrine differentiation K. W. H. B. is a novel for neuroendocrine 2005; PubMed Scopus Google Scholar). with and DNA was by 4,6-diamidino-2-phen yl in a on a with and Western analysis was as K. W. H. B. is a novel for neuroendocrine 2005; PubMed Scopus Google Scholar). of and normal mucosa of protein on and to with CLU protein was at the and a to was real time for the CLU was on the or the gene Ubiquitin was We have demonstrated the of as a gene for analysis of normal mucosa and colorectal cancer of a to for to and cancer PubMed Scopus Google Scholar). We laser to normal epithelial and cancer cell from tumor and normal mucosa of CRC two and cells was from the of normal epithelia and cancer cells the including was by analysis with two clear The of the CLU variant-specific The overall CLU level of was a targeting the and to The of and can be found in The of was by and D. The human at 2002; PubMed Scopus Google Scholar). Furthermore the to only a single of the The gene was a The for the have been of a to for to and cancer PubMed Scopus Google Scholar). was in and for expression a of The was a of of the we have of and CRC by M. M. of in colorectal PubMed Scopus Google Scholar). cancer and DNA was the DNA system The to the and was to the of and DNA was from the as M. M. of in colorectal PubMed Scopus Google Scholar). The of the CLU was by the and the and the by The and for of the used for can be found in the of in the sequence and in The transcriptional used in the present study have been by our M. R. D. K. H. M. expression for colorectal cancer and J. 2005; PubMed Scopus Google Scholar). In from normal mucosa and colorectal and The expression novel CLU we the CLU in the B. the PubMed Scopus Google the sequence for the we the in the CLU and as of revealed multiple CLU of by sequence than the We and a and the and to the two CLU transcript by the and The of are as we found sequence in the for the of observed in from the cancer cell by Leskov J. Boothman and of a cell Biol. PubMed Scopus Google Scholar). protein on the the localization of was K. a for in proteins and Biochem. PubMed Scopus Google Scholar). and the in in of localization the proteins to be on the was to be to the by of the the expression of in normal colorectal mucosa and cancer We not in the variant-specific we found of a of have in a the expression of the CLU in cancer cells to normal variant-specific real time was on of normal epithelial cells and cancer cells from CRC The analysis was on from cell of normal epithelial cells and cancer cells. the at from the normal mucosa and tumor tissue not have been as the of the was very stromal tissue in the normal than in the tumor The real time showed in the expression of In some the expression level was in the cancer cells than in normal in it was lower or In was in cancer and the level of to be associated with cancer was expressed at levels in the normal epithelial cells and cancer cells that the was The overall CLU expression level of a very to that of that the the majority of the CLU transcripts found in colorectal that the expression of the CLU is by or mechanisms and that only the expression of to be associated with cancer was used to study CLU protein expression in normal colorectal mucosa and two The analysis revealed the majority of CLU proteins to be in the stromal and not in the epithelia a very of epithelial cells expressed CLU and cells observed the with to a basal The localization of the CLU protein was CLU protein was observed in the basal of in a that appeared to be protein It is not clear cells CLU protein was found in the of the cells appeared to and CLU protein the of the expressed CLU protein cells of expressed CLU, and CLU protein observed the of it is not clear cells that the observed CLU expression was not a of a targeting a CLU protein the analysis was CLU and targeting of the CLU results that the observed expression was and and distribution the with the localization of the CLU protein that the epithelial cells neuroendocrine epithelial cells. this we with CLU and CgA, often used of neuroendocrine differentiation K. W. H. B. is a novel for neuroendocrine 2005; PubMed Scopus Google on of normal mucosa from two and The results that CLU was expressed by a of the neuroendocrine cells. CLU is expressed by neuroendocrine CLU be to be expressed by with neuroendocrine we CLU on a and we found it to of CLU with a distribution to that observed in normal epithelial cells our we used to CLU and in normal mucosa from two The analysis that CLU was expressed by a of the neuroendocrine cells We conclude that CLU protein is expressed only by a of the epithelial cells in the normal mucosa and that cells a of the neuroendocrine cells. We CLU protein expression by in neoplastic and the of the and We found CLU expressed in of the of Clusterin in normal colorectal mucosa and in and colorectal tumors with CLU CLU expression in the tumors was for the cancer cells only and in normal mucosa for epithelial cells was and a CLU normal mucosa was as of the epithelial cells of the normal mucosa Furthermore the normal epithelial cells neuroendocrine a cell not present in the tumors. normal mucosa was as of the epithelial cells of the normal mucosa Furthermore the normal epithelial cells neuroendocrine a cell not present in the The CLU expression in the tumors was for the cancer cells only and in normal mucosa for epithelial cells was and a CLU The normal mucosa was as of the epithelial cells of the normal mucosa Furthermore the normal epithelial cells neuroendocrine a cell not present in the tumors. in a In the tumors of the cancer cells expressed The of CLU protein was in to the normal in the of a In of the a apical of CLU was observed and tumors with neuroendocrine are rare in the and and of the tumors as of neuroendocrine that CLU was de novo synthesized by the neoplastic cells. with epithelia of normal mucosa the of CLU expression in and was increased at the stromal level was a in CLU expression the neoplastic and normal the stromal that in normal mucosa showed CLU and only the in observed in tumors. in to the normal mucosa only a very CLU expression was observed in the of the tumors. on this of the stromal we that the overall CLU protein level of CLU in and cancer in the majority of tumors of tumors cancer was lower than in normal mucosa Western analysis of tumor and normal mucosa this at the transcriptional level the overall of CLU transcripts was often lower in tumors than in normal mucosa Collectively the indicate that in a of and CLU is de novo synthesized by neoplastic cells neuroendocrine In the of the tumors the overall CLU protein level is often lower than in normal mucosa due to of the stromal compartment. The subgroup of colorectal CLU may a the is to the transcriptional regulation of and tumor of We to the of the CLU in a of colorectal by LOH, DNA and used to and DNA from of and cancer of the CLU at from the of to the human revealed tumors and DNA loss of CLU in tumors. in the we the CLU in and cancer from the The and cancer with the analysis revealed two a in the of and a in of the for or and in cases the cancer We conclude that colorectal often CLU the of the In the present we have for the of CLU transcript and of the two are We demonstrated that expressed by normal and neoplastic human colorectal The have of has a to the CLU reported in the CLU it the CLU protein (1Shannan B. Seifert M. Leskov K. Willis J. Boothman D. Tilgen W. Reichrath J. Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer.Cell Death Differ. 2006; 13: 12-19Crossref PubMed Scopus (282) Google Scholar, J. Boothman and of a cell Biol. PubMed Scopus Google Scholar, M. Leskov K. Boothman activation of clusterin a Biol. 2005; PubMed Scopus Google Scholar, J. J. D. J. Wang M. and expression of the gene, a gene in apo pto Biol. PubMed Google Scholar). The two transcript are novel in to the CLU In the of has been to of the of the CLU protein to the J. Boothman and of a cell Biol. PubMed Scopus Google Scholar). We found for this of in the or in our of the in the CLU Moreover our for CLU expressed in colorectal in showed of a of this is not expressed by colorectal or it be of the cancer cell it was J. Boothman and of a cell Biol. PubMed Scopus Google Scholar). sequence analysis of the and to and the CLU Although on our we whether the and to the our real time indicate that expression levels are by that have our real time we that and are expressed the cells or expressed by epithelial cell In with the it is to that of expression with of cells with neuroendocrine the is expressed by neuroendocrine cells. analysis of the localization to be the our real time analysis very expression levels of this in normal epithelia and cancer or at very levels of CLU was we observed by Although some have CLU to be up-regulated in neoplastic colorectal of clusterin in human PubMed Scopus Google Scholar, D. M. of clusterin in colorectal and J. 2005; PubMed Scopus Google have J. M. apo pto sis is by and is PubMed Scopus Google Scholar). is not for studies CLU expression in CRC as it has been reported for prostate cancer (1Shannan B. Seifert M. Leskov K. Willis J. Boothman D. Tilgen W. Reichrath J. Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer.Cell Death Differ. 2006; 13: 12-19Crossref PubMed Scopus (282) Google Scholar). of the and protein at in a of the Our novel of transcript to this We our variant-specific real time on normal epithelia and cancer cell by laser we not only that we the of that we in the cell has only been in studies on CLU expression. only of the showed a in cancer was down-regulated in cancer on we that of is for the cancer or the in is by the of the cell CLU expression in the normal mucosa we to of the CLU we to the CLU protein in Western analysis two of and However, important of the analysis was that the majority of cells in the normal mucosa in the stromal compartment. CLU was observed in and cells and as protein in the basal of and the of we found that only a of the epithelial cells expressed was in to a study on CLU expression in colorectal that expression of CLU in normal epithelial cells and a in localization to the in tumors of clusterin in human PubMed Scopus Google Scholar). our analysis the CLU and in the we observed expression in normal epithelial cells. this we have however, our are by study of CLU expression in normal and neoplastic colorectal tissue in the not CLU D. M. of clusterin in colorectal and J. 2005; PubMed Scopus Google Scholar). Our of the of the epithelial cells to conclude of novel that the cells a of the rare neuroendocrine cells. is very as studies have CLU to be in of neuroendocrine and J. J. M. in the and intracellular of clusterin in cells apo pto Death Differ. PubMed Scopus Google Scholar, D. R. of a protein for apical in the in the cell J. Cell Biol. Google Scholar, The of from with human and cell Biol. PubMed Google Scholar). the that the CLU protein we often observed in the basal of the was by the neuroendocrine cells. studies have that CLU is a protein induced by including ionizing and (1Shannan B. Seifert M. Leskov K. Willis J. Boothman D. Tilgen W. Reichrath J. Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer.Cell Death Differ. 2006; 13: 12-19Crossref PubMed Scopus (282) Google Scholar, 2Trougakos I.P. Gonos E.S. Clusterin/apolipoprotein J in human aging and cancer.Int. J. Biochem. Cell Biol. 2002; 34: 1430-1448Crossref PubMed Scopus (320) Google Scholar). be the the neuroendocrine cells to CLU the We a of tumors by tumors the of CRC pathogenesis, including and In the majority of tumors the cancer cells not In the we found CLU de novo synthesized by non-neuroendocrine cancer cells. of cases may for the tumors that have expression in the of normal cells as in The de novo CLU was observed in tumors of CRC from the to the de novo synthesized CLU was often the stromal of the tumor often suppressed with normal in of the tumor cancer the overall level of CLU appeared lower than in normal was at the protein and level by Western and array-based transcriptional of is a of the among the studies on CLU expression in colorectal Collectively our indicate that CLU expression is involved in and progression of ∼25% of CLU expression is in normal colorectal epithelial cells and in cancer cells is However, a to the transcriptional regulation of and tumor of the of the CLU we and DNA analysis on a of CRC on the CLU protein expression levels revealed by our we the majority of tumors to have two CLU and to of tumors to a to our we a that the majority of tumors showed loss of CLU whether of the CLU was the for CLU not being expressed in of we the of the by In cases the of the was our not the and of the tumors. However, our revealed that tumors at CLU and the to from a clinical the that CLU is de novo synthesized in of is very It is accepted that CLU confers cytoprotective and to the cancer cells and that this in tumor progression (1Shannan B. Seifert M. Leskov K. Willis J. Boothman D. Tilgen W. Reichrath J. Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer.Cell Death Differ. 2006; 13: 12-19Crossref PubMed Scopus (282) Google Scholar). we that the CRC with de novo CLU expression be for with the novel CLU therapy in with is in with a recent of the clinical of CLU expression that of CLU expression in that CLU (1Shannan B. Seifert M. Leskov K. Willis J. Boothman D. Tilgen W. Reichrath J. Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer.Cell Death Differ. 2006; 13: 12-19Crossref PubMed Scopus (282) Google and the multiple and clinical that have CLU therapy to and cancer cells to chemotherapeutics (1Shannan B. Seifert M. Leskov K. Willis J. Boothman D. Tilgen W. Reichrath J. Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer.Cell Death Differ. 2006; 13: 12-19Crossref PubMed Scopus (282) Google Scholar, 4Miyake H. Hara I. Gleave M.E. Antisense oligodeoxynucleotide therapy targeting clusterin gene for prostate cancer: Vancouver experience from discovery to clinic.Int. J. 2005; PubMed Scopus Google Scholar, M.E. Antisense therapy for 2005; PubMed Scopus (320) Google Scholar, M. H. of targeting the cytoprotective gene, to and in prostate J. 2005; PubMed Scopus Google Scholar). recent CLU has for not to target the pto tic CLU CLU therapy (1Shannan B. Seifert M. Leskov K. Willis J. Boothman D. Tilgen W. Reichrath J. Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer.Cell Death Differ. 2006; 13: 12-19Crossref PubMed Scopus (282) Google Scholar). Our indicate that this is not a for the of CRC as we not CLU expression. important of is to the to from the In the present study we that CRC can be to CLU expression level the to from the In we and the expression of CLU transcript in colorectal these, the was to be down-regulated by cancer cells. Furthermore we demonstrated that in the normal epithelia CLU protein was only expressed by neuroendocrine in ∼25% of CLU protein was de novo synthesized by non-neuroendocrine cancer cells. Collectively the indicate that therapy may as as of CRC We are to and for We of for the array-based transcriptional Furthermore we of for with the and of for with the analysis of the with

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