We found that prostaglandin (PG) D 2 , the most abundant PG in the central nervous system, stimulates food intake after intracerebroventricular administration in mice. The orexigenic effect of PGD 2 was mimicked by a selective agonist for the DP 1 receptor among two receptor subtypes for PGD 2 , and abolished by its antagonist. Central administration of an antagonist or antisense oligodeoxynucleotide for the DP 1 receptor remarkably decreased food intake, body weight and fat mass. Hypothalamic mRNA levels of lipocalin-type PGD synthase were up-regulated after fasting. The orexigenic activity of PGD 2 was also abolished by an antagonist for neuropeptide Y (NPY) Y 1 receptor. Taken together, PGD 2 may stimulate food intake through central DP 1 receptor coupled to the NPY system.

Expression of matrix metalloproteinase 7 (MMP7) is increased in the human colorectal carcinomas, and correlates with malignant progression. However, its contribution to colon cancer pathogenesis is not understood thoroughly. To investigate the roles of MMP7 in colon cancer progression, we introduced an Mmp7 knockout mutation into the cis-Apc/Smad4 mutant mouse, a model of invasive colon cancer in which SMAD4-dependent TGF-b family signaling is inactivated. We demonstrate here that lack of MMP7 reduces the number and size of tumors in the cis-Apc/Smad4 mice. On the other hand, MMP7-deficiency does not affect the depth of tumor invasion, number of stromal fibroblasts or levels of extracellular matrix components in the tumors. These results indicate that MMP7 is required for tumor formation, but not for the invasion or fibrosis of the colon cancer whose SMAD4-dependent TGF-b family signaling is blocked. Accumulating evidence suggest that most colorectal adenomas are initiated by the inactivation of APC gene, and progress into adenocarcinomas through additional genetic alterations in KRAS (for KRAS), TP53 (P53), SMAD4, TGFBR2 (TGF-b type-II receptor), etc. 1 In colorectal carcinomas, marked tumor invasion and expansion of the stroma are well-known features associated with metastasis and poor prognosis. [2][3][4] As a mouse model for colorectal adenocarcinomas, we previously constructed cis-Apc þ /D716 Smad4 þ /À compound mutant (hereafter cis-Apc/Smad4 mice) carrying a knockout allele of the Smad4 gene on the same chromatid as that of Apc. 5 Using these mice, we demonstrated that loss of SMAD4-dependent TGF-b family signaling converts intestinal adenomas to adenocarcinomas. Namely, the cis-Apc/ Smad4 mice develop tumors that show marked invasion and stromal expansion, although the simple Apc mutant (Apc D716 ) mice form only benign adenomas. 5,6 To examine the mechanisms underlying such malignant changes in the cis-Apc/Smad4 tumors, we recently performed DNA microarray analyses and found that the adenocarcinomas expressed much higher levels of CC-chemokine ligand 9 (CCL9) than the Apc D716 adenomas. Further studies revealed that CCL9 released from the cis-Apc/Smad4 tumor epithelia recruits immature myeloid cells (iMCs) that carry its CC-chemokine receptor (CCR1) and express matrix metalloproteinase (MMP) 2 and 9 to help tumor invasion. 7 Although it is the tumor stromal cells that produce most MMPs whose levels are increased in the colon cancer (eg MMP2 and MMP9), the tumor epithelial cells can express another MMP, MMP7. 8 Interestingly, our microarray data 7 showed increased expression of MMP7 in the cis-Apc/Smad4 adenocarcinomas compared with the Apc D716 adenomas. In human colorectal cancer, it has been reported that the level of MMP7 correlates with advanced Dukes stages, poor outcome, invasion and metastasis to the liver. 9-11 Several studies have shown that overexpression of MMP7 increases the invasive ability and metastasis to the liver in some colon cancer cell lines, 9,12,13 although another study suggests ...

No abstract

The expression level of inhibitor of DNA binding 2 (Id2) is increased in colorectal carcinomas and is positively correlated with poor prognosis. However, the functional significance of Id2 in intestinal tumorigenesis has not been fully defined using genetic approaches. Here, we show that Id2 promotes ileal tumor initiation in Apc-deficient mice. Expression of Id2 was stimulated by Wnt signaling through the enhancer region of the Id2 promoter at the early stage of tumorigenesis in Apc+/Δ716 (ApcΔ716) mice. Genetic depletion of Id2 in ApcΔ716 mice caused ∼80% reduction in the number of ileal polyps, but had little effect on tumor size. Notably, the lack of Id2 increased the number of apoptotic cells in the normal crypt epithelium of the mice. Furthermore, DNA microarray analysis revealed that the expression level of Max dimerization protein 1 (Mxd1), known as a c-Myc antagonist, was specifically increased by Id2 deletion in the ileal intestinal epithelium of ApcΔ716 mice. In contrast, the protein level of c-Myc, but not the mRNA level, was decreased by loss of Id2 in these mice. These results indicate that loss of Id2 inhibits tumor initiation by up-regulation of Mxd1 and down-regulation of c-Myc in ApcΔ716 mice.

Tenosynovial giant cell tumor (TSGCT) of localized type is a common disease occurring mostly in the hands. Diagnosis of this tumor is relatively easy to render with hematoxylin-eosin–stained sections as compared with that of TSGCT of diffuse type. However, very rare cases with chondroid metaplasia that have recently been reported mainly in diffuse type can make pathological differentiation from soft tissue cartilaginous tumors extremely difficult. In this article, the authors present the second reported case of TSGCT of localized type showing extensive chondroid metaplasia. Pathological interpretation was difficult without utilizing immunohistochemistry and fluorescence in situ hybridization. One must be careful not to misdiagnose this lesion as cartilaginous tumors of soft tissue, and we suspect at least some chondroblastoma-like chondroma could be reclassified as TSGCT of localized type with extensive chondroid metaplasia. Morphological, immunohistochemical, and molecular genetic characteristics are presented and discussed.