Association of changes in the gene expression profile of blood cells with the local tumor inflammatory response in a murine tumor model.

Cancer tissue is frequently associated with the host inflammatory response, which involves blood cells. Using DNA microarrays, we examined the gene expression profiles of blood and tumors in a murine subcutaneous hepatocellular carcinoma model, in which tumors develop during the initial 10 days and then diminish and disappear by day 25 after implantation. Immunohistochemical and gene expression analysis indicated that tumor tissues were associated with an active immune response, particularly the CD4+ T cell-mediated immune response, on day 10. The genes commonly up-regulated in blood and the fraction enriched with tumor-associated inflammatory cells on day 10 also suggested the involvement of CD4+ T cells. Unsupervised hierarchical clustering analysis of gene expression of peripheral blood cells on days 0, 10, 15, 20, and 25 indicated two major clusters: the tumor-existence cluster on days 10, 15, and 20, and the tumor-free cluster on days 0 and 25. Additionally, sub-clusters were detected on each day. These results suggest that the gene expression profile of whole blood cells is affected by the local tumor condition, and is associated with the local host immune response. Its analysis will facilitate exploration of the underlying important features of the host immune response to tumors.

Differential gene expression profiling in blood from patients with digestive system cancers.

To develop a non-invasive and sensitive diagnostic test for cancer using peripheral blood, we evaluated gene expression profiling of blood obtained from patients with cancer of the digestive system and normal subjects. The expression profiles of blood-derived total RNA obtained from 39 cancer patients (11 colon cancer, 14 gastric cancer, and 14 pancreatic cancer) was clearly different from those obtained from 15 normal subjects. By comparing the gene expression profiles of cancer patients and normal subjects, 25 cancer-differentiating genes (p<5.0 x 10(-6) and fold differences >3) were identified and an "expression index" deduced from the expression values of these genes differentiated the validation cohort (11 colon cancer, 8 gastric cancer, 18 pancreatic cancer, and 15 normal subjects) into cancer patients and normal subjects with 100% (37/37) and 87% (13/15) accuracy, respectively. Although, the expression profiles were not clearly different between the cancer patients, some characteristic genes were identified according to the stage and species of the cancer. Interestingly, many immune-related genes such as antigen presenting, cell cycle accelerating, and apoptosis- and stress-inducing genes were up-regulated in cancer patients, reflecting the active turnover of immune regulatory cells in cancer patients. These results showed the potential relevance of peripheral blood gene expression profiling for the development of new diagnostic examination tools for cancer patients.

Common transcriptional signature of tumor-infiltrating mononuclear inflammatory cells and peripheral blood mononuclear cells in hepatocellular carcinoma patients.

Hepatocellular carcinoma (HCC) is frequently associated with infiltrating mononuclear inflammatory cells. We performed laser capture microdissection of HCC-infiltrating and noncancerous liver-infiltrating mononuclear inflammatory cells in patients with chronic hepatitis C (CH-C) and examined gene expression profiles. HCC-infiltrating mononuclear inflammatory cells had an expression profile distinct from noncancerous liver-infiltrating mononuclear inflammatory cells; they differed with regard to genes involved in biological processes, such as antigen presentation, ubiquitin-proteasomal proteolysis, and responses to hypoxia and oxidative stress. Immunohistochemical analysis and gene expression databases suggested that the up-regulated genes involved macrophages and Th1 and Th2 CD4 cells. We next examined the gene expression profile of peripheral blood mononuclear cells (PBMC) obtained from CH-C patients with or without HCC. The expression profiles of PBMCs from patients with HCC differed significantly from those of patients without HCC (P < 0.0005). Many of the up-regulated genes in HCC-infiltrating mononuclear inflammatory cells were also differentially expressed by PBMCs of HCC patients. Analysis of the commonly up-regulated or down-regulated genes in HCC-infiltrating mononuclear inflammatory cells and PBMCs of HCC patients showed networks of nucleophosmin, SMAD3, and proliferating cell nuclear antigen that are involved with redox status, the cell cycle, and the proteasome system, along with immunologic genes, suggesting regulation of anticancer immunity. Thus, exploring the gene expression profile of PBMCs may be a surrogate approach for the assessment of local HCC-infiltrating mononuclear inflammatory cells.