Improvement of cancer immunotherapy by combining molecular targeted therapy.

In human cancer cells, a constitutive activation of MAPK, STAT3, β-catenin, and various other signaling pathways triggers multiple immunosuppressive cascades. These cascades result in the production of immunosuppressive molecules (e.g.

Activation of epidermal growth factor receptor signaling by the prostaglandin E(2) receptor EP4 pathway during gastric tumorigenesis.

Cyclooxygenase-2 (COX-2) plays an important role in tumorigenesis through prostaglandin E(2) (PGE(2)) biosynthesis. It has been shown by in vitro studies that PGE(2) signaling transactivates epidermal growth factor receptor (EGFR) through an intracellular mechanism. However, the mechanisms underlying PGE(2)-induced EGFR activation in in vivo tumors are still not fully understood.

Tumor Necrosis Factor (TNF) and Chemokines in Colitis-Associated Cancer.

The connection between inflammation and tumorigenesis has been well established, based on a great deal of supporting evidence obtained from epidemiological, pharmacological, and genetic studies. One representative example is inflammatory bowel disease, because it is an important risk factor for the development of colon cancer. Moreover, intratumoral infiltration of inflammatory cells suggests the involvement of inflammatory responses also in other forms of sporadic as well as heritable colon cancer.

Prostaglandin E₂ signaling and bacterial infection recruit tumor-promoting macrophages to mouse gastric tumors.

Background & Aims: Helicobacter pylori infection induces an inflammatory response, which can contribute to gastric tumorigenesis. Induction of cyclooxygenase-2 (COX-2) results in production of prostaglandin E(2) (PGE(2)), which mediates inflammation. We investigated the roles of bacterial infection and PGE(2) signaling in gastric tumorigenesis in mice.

Crucial involvement of the CX3CR1-CX3CL1 axis in dextran sulfate sodium-mediated acute colitis in mice.

Ingestion of DSS solution can induce in rodents acute colitis with a massive infiltration of neutrophils and macropahges, mimicking pathological changes observed in the acute phase of UC patients. Concomitantly, DSS ingestion enhanced the expression of a potent macrophage-tropic chemokine, CX3CL1/fractalkine, and its receptor, CX3CR1, in the colon. WT but not CX3CR1-deficient mice exhibited marked body weight loss and shortening of the colon after DSS ingestion.

Blockade of a chemokine, CCL2, reduces chronic colitis-associated carcinogenesis in mice.

Accumulating evidence indicates the crucial contribution of chronic inflammation to various types of carcinogenesis, including colon carcinoma associated with ulcerative colitis and asbestosis-induced malignant mesothelioma. Ulcerative colitis-associated colon carcinogenesis can be recapitulated in mice by azoxymethane administration followed by repetitive dextran sulfate sodium ingestion. In the course of this carcinogenesis process, the expression of a macrophage-tropic chemokine, CCL2, was enhanced together with intracolonic massive infiltration of macrophages, which were a major source of cyclooxygenase (COX)-2, a crucial mediator of colon carcinogenesis.

Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis.

The inflammatory bowel disease ulcerative colitis (UC) frequently progresses to colon cancer. To understand the mechanisms by which UC patients develop colon carcinomas, we used a mouse model of the disease whereby administration of azoxymethane (AOM) followed by repeated dextran sulfate sodium (DSS) ingestion causes severe colonic inflammation and the subsequent development of multiple tumors. We found that treating WT mice with AOM and DSS increased TNF-alpha expression and the number of infiltrating leukocytes expressing its major receptor, p55 (TNF-Rp55), in the lamina propria and submucosal regions of the colon.

Aberrant Pim-3 expression is involved in gastric adenoma-adenocarcinoma sequence and cancer progression.

Purpose: Pim-3, a member of the proto-oncogene Pim family with serine/threonine kinase activity was aberrantly expressed in cancerous lesions of endoderm-derived organs such as liver, pancreas, and colon. The aim of this study was to clarify the role of Pim-3 expression in the tumorigenesis and the development of gastric carcinomas.

Methods: Pim-3 expression was immunohistochemically examined on the tissue microarrays containing primary (n = 285) and metastastic (n = 37) sites of gastric carcinomas, in comparison with adenoma (n = 48) and non-cancerous mucosa (n = 84).

Proto-oncogene, Pim-3 with serine/threonine kinase activity, is aberrantly expressed in human colon cancer cells and can prevent Bad-mediated apoptosis.

We previously observed that Pim-3 with serine/threonine kinase activity, was aberrantly expressed in malignant lesions of endoderm-derived organs, liver and pancreas. Because Pim-3 protein was not detected in normal colon mucosal tissues, we evaluated Pim-3 expression in malignant lesions of human colon, another endoderm-derived organ. Pim-3 was detected immunohistochemically in well-differentiated (43/68 cases) and moderately differentiated (23/41 cases) but not poorly differentiated colon adenocarcinomas (0/5 cases).

Implication of "Down syndrome cell adhesion molecule" in the hippocampal neurogenesis of ischemic monkeys.

Molecular signals regulating adult neurogenesis in primates are largely unknown. Here the authors used differential display to analyze gene expression changes that occur in dentate gyrus of adult monkeys after transient global cerebral ischemia. Among 14 genes upregulated, the authors focused on Down syndrome cell adhesion molecule (DSCAM) known to play crucial role during neuronal development, and characterized its expression pattern at the protein level.

Pim-3, a proto-oncogene with serine/threonine kinase activity, is aberrantly expressed in human pancreatic cancer and phosphorylates bad to block bad-mediated apoptosis in human pancreatic cancer cell lines.

Pancreatic cancer still remains a serious health problem with <5% 5-year survival rate for all stages. To develop an effective treatment, it is necessary to identify a target molecule that is crucially involved in pancreatic tumor growth. We previously observed that Pim-3, a member of the proto-oncogene Pim family that expresses serine/threonine kinase activity, was aberrantly expressed in human and mouse hepatomas but not in normal liver.

Aberrant expression of serine/threonine kinase Pim-3 in hepatocellular carcinoma development and its role in the proliferation of human hepatoma cell lines.

Most cases of human hepatocellular carcinoma develop after persistent chronic infection with human hepatitis B virus or hepatitis C virus, and host responses are presumed to have major roles in this process. To recapitulate this process, we have developed the mouse model of hepatocellular carcinoma using hepatitis B virus surface antigen transgenic mice. To identify the genes associated with hepatocarcinogenesis in this model, we compared the gene expression patterns between pre-malignant lesions surrounded by hepatocellular carcinoma tissues and control liver tissues by using a fluorescent differential display analysis.

Vascular adventitia generates neuronal progenitors in the monkey hippocampus after ischemia.

In the adult hippocampus, neurogenesis proceeds in the subgranular zone (SGZ) of the dentate gyrus (DG), but not in the cornu Ammonis (CA). Recently, we demonstrated in monkeys that transient brain ischemia induces an increase of the neuronal progenitor cells in the SGZ, but not in CA1, in the second week after the insult. To identify the origin of primary neuronal progenitors in vivo, we compared the postischemic monkey DG and CA1, using light and electron microscopy, focusing on specific phenotype markers, as well as the expression of neurotrophic factors.

Accumulation of microglial cells expressing ELR motif-positive CXC chemokines and their receptor CXCR2 in monkey hippocampus after ischemia-reperfusion.

ELR(+) CXC chemokines including IL-8 are known to be involved in the ischemia-reperfusion injuries in various organs including rodent brain. However, the roles of these chemokines during the ischemia-reperfusion injuries of the primate brain still remain unknown. Here, we studied expressions of CXC chemokines and their receptor CXCR2 in monkey hippocampus known to develop total CA1 neuronal loss on day 5 after 20-min ischemia and reperfusion.