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2.
Gut ; 59(11): 1501-10, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20947885

ABSTRACT

OBJECTIVE: There are currently no biomarkers in routine clinical use for determining prognosis in rectal cancer. In a preliminary proteomic study, variation in the levels of heat shock protein 27 (HSP27) in colorectal cancer samples was observed. The expression of HSP27 in a cohort of 404 patients with colorectal cancer with a predominantly poor prognosis was characterised and an investigation was undertaken of whether the differences were related to clinical outcome. HSP27 levels in diagnostic rectal biopsies were compared with matched surgical samples to determine whether changes in expression occurred in the time between biopsy and surgery and to investigate whether preoperative radiotherapy affected expression. Finally, the relationship between HSP27 expression and outcome was examined in an independent cohort of 315 patients with a predominantly good prognosis. METHODS: HSP27 levels were determined using combined two-dimensional gel electrophoresis and tandem mass spectrometry (12 cases) and by immunohistochemistry using tissue microarrays of colorectal cancers sampled at surgery and 80 diagnostic rectal biopsies. RESULTS: HSP27 overexpression was strongly associated with poor cancer-specific survival in rectal cancer (n=205, p=0.0063) but not colon cancer (n=199, p=0.7385) in the cohort with a poor prognosis. Multivariate Cox regression confirmed nodal metastases (p=0.0001) and HSP27 expression (p=0.0233) as independent markers of survival in rectal cancer. HSP27 levels remained unchanged in the majority of cases (65/80, 81%) between diagnostic biopsies and matched surgical samples, regardless of whether patients had undergone preoperative radiotherapy. In the cohort with a good prognosis the association between HSP27 and survival was not observed in patients with either rectal (n=115; p=0.308) or colon cancer (n=200; p=0.713). CONCLUSION: In a large cohort of patients with a poor prognosis, HSP27 is an independent marker of poor outcome in rectal cancer; its expression is not altered by neoadjuvant radiotherapy. This finding requires validation in an independent similar cohort of patients with rectal cancer. HSP27 levels merit evaluation as a stratification factor for treatment of rectal cancer.


Subject(s)
Biomarkers, Tumor/metabolism , Colonic Neoplasms/metabolism , HSP27 Heat-Shock Proteins/metabolism , Rectal Neoplasms/metabolism , Aged , Cohort Studies , Colonic Neoplasms/pathology , Colonic Neoplasms/therapy , Female , Humans , Male , Middle Aged , Molecular Weight , Neoadjuvant Therapy , Neoplasm Proteins/metabolism , Prognosis , Proteomics/methods , Radiotherapy, Adjuvant , Rectal Neoplasms/pathology , Rectal Neoplasms/therapy , Survival Analysis , Treatment Outcome
3.
Carcinogenesis ; 31(9): 1541-51, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20622003

ABSTRACT

S100A8 and its dimerization partner S100A9 are emerging as important chemokines in cancer. We previously reported that Smad4-negative pancreatic tumors contain fewer stromal S100A8-positive monocytes than their Smad4-positive counterparts. Here, we studied S100A8/A9-expressing cells in colorectal tumors relating their presence to clinicopathological parameters and Smad4 status. Two-dimensional gel electrophoresis (n = 12) revealed variation in the levels of S100A8 protein in colorectal cancer tumors, whereas immunohistochemical analysis (n = 313) showed variation in the numbers of stromal S100A8-positive and S100A9-positive cells. Loss of Smad4 expression was observed in 42/304 (14%) colorectal tumors and was associated with reduced numbers of S100A8-positive (P = 0.03) but not S100A9-positive stromal cells (P = 0.26). High S100A9 cell counts were associated with large tumor sizes (P = 0.0006) and poor differentiation grade (P = 0.036). However, neither S100A8 nor S100A9 cell counts predicted poor survival, except for patients with Smad4-negative tumors (P = 0.02). To address the impact of environmental S100A8/A9 chemokines on tumor cells, we examined the effects of exogenously added S100A8 and S100A9 proteins on cellular migration and proliferation of colorectal and pancreatic cancer cells. S100A8 and S100A9 enhanced migration and proliferation in Smad4-positive and Smad4-negative cancer cells. However, transient depletion of Smad4 resulted in loss of responsiveness to exogenous S100A8, but not S100A9. S100A8 and S100A9 activated Smad4 signaling as evidenced by phosphorylation of Smad2/3; blockade of the receptor for the advanced glycation end products inhibited this response. In conclusion, Smad4 loss alters the tumor's interaction with stromal myeloid cells and the tumor cells' response to the stromal chemokine, S100A8.


Subject(s)
Calgranulin A/metabolism , Colorectal Neoplasms/metabolism , Monocytes/metabolism , Pancreatic Neoplasms/metabolism , Smad4 Protein/metabolism , Aged , Blotting, Western , Calgranulin B/metabolism , Cell Adhesion , Cell Line, Tumor , Cell Movement , Cell Proliferation , Colorectal Neoplasms/pathology , Dimerization , Electrophoresis, Gel, Two-Dimensional , Female , Fluorescent Antibody Technique , Glycation End Products, Advanced/antagonists & inhibitors , Glycation End Products, Advanced/immunology , Glycation End Products, Advanced/metabolism , Humans , Male , Middle Aged , Monocytes/cytology , Pancreatic Neoplasms/pathology , RNA, Small Interfering/pharmacology , Signal Transduction , Smad4 Protein/antagonists & inhibitors , Smad4 Protein/genetics , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Stromal Cells/metabolism , Stromal Cells/pathology
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