BACKGROUND The actions of the extracellular‐matrix degrading enzymes, matrix metalloproteinases (MMPs), are implicated in tumorigenesis. The cellular localization of MMP‐2, MMP‐9, membrane type 1 (MT1)‐MMP, tissue inhibitors of metalloproteinases (TIMPs) 1‐3, and the presence of active gelatinases were investigated in endometrial carcinoma. METHODS Endometrial carcinomas were grouped according to histologic grade (Grades 1‐3), depth of myometrial invasion (0, < 50%, > 50%) and the presence of vascular/lymphatic invasion. Twenty‐nine endometrial carcinoma biopsies were investigated immunohistochemically to determine the tissue localization of MMP‐2 (gelatinase A), MMP‐9 (gelatinase B), MT1‐MMP, and TIMPs 1‐3. In situ hybridization was performed to localize MMP‐2 and MMP‐9 mRNA. The presence of active gelatinases was assessed using in situ zymography. RESULTS Epithelial tumor cells were the main site of MMP‐2, MMP‐9, and MT1‐MMP protein. Variable stromal cell localization was also observed, particularly in areas adjacent to tumor nests. Semiquantitative analysis revealed increases in MMP‐9 and MMP‐2 but not MT1‐MMP staining scores in tumor epithelial cells in the transition from histologic Grade 1 to Grades 2 and 3. Matrix metalloproteinase‐9 and MT1‐MMP staining scores in tumor cells were significantly associated with the presence of myometrial invasion and vascular/lymphatic invasion, while MMP‐2 did not correlate with these factors. In addition, MT1‐MMP was co‐localized with MMP‐2, supporting its role in the activation of proMMP‐2. Tumor cells from all histologic grades stained intensely for TIMP‐2 and TIMP‐3 proteins, while variable stromal staining was observed. In Grade 1 carcinomas TIMP‐1 was predominantly immunolocalized to the stromal compartment with variable tumor cell localization being observed in Grades 2 and 3 carcinomas. Matrix metalloproteinase‐9 and MMP‐2 mRNAs were predominantly observed in tumor epithelial cells as well as in the stroma to varying degrees. In situ zymography revealed active forms of gelatinases at the cellular surface and in association with tumor epithelial cells within endometrial carcinoma tissues. CONCLUSIONS These data suggest that increasing expression of MMPs and endometrial carcinoma progression are closely related. Active gelatinases are present in endometrial carcinoma, resulting in alterations to the microenvironment that promote tumor invasion and metastasis. Cancer 2002;94:1466–75. © 2002 American Cancer Society. DOI 10.1002/cncr.10355

Prostaglandins play a critical role in gastric mucosal cytoprotection and decrease progressively with age. Cyclooxygenase (COX), the rate-limiting enzyme for prostaglandin synthesis, exists in two isoforms, COX-1 and COX-2. The rat COX-1 gene expresses an alternatively spliced mRNA COX-1 splice variant (SV) that may, at best, code for a truncated COX-1 protein. With the use of competitive PCR, we determined whether COX gene expression was altered in the stomach with increasing age and after gastric ulcer induction. COX-1 mRNA was significantly reduced in the aged, and COX-1SV mRNA was significantly higher in the adults compared with the young and aged stomach. Levels of COX-1 and COX-2 were similarly expressed in the normal stomach. In acute gastric ulcers, only COX-2 mRNA levels were significantly elevated. When ulcers were undergoing healing and repair, COX-1 and COX-2 mRNA levels were significantly elevated. Age-related changes in COX-1 and COX-1SV but not COX-2 mRNA may alter gastric mucosal cytoprotection. Furthermore, COX-1 and COX-2 may both contribute to the healing of a gastric ulcer.

The ability of 5-aminosalicylic acid and olsalazine to inhibit colonic aberrant crypts and tumors was investigated in 1,2-dimethylhydrazine-treated rats. The effect of these drugs on the rates of tumor apoptosis and proliferation was studied as potential mechanisms for their action. 5-Aminosalicylic acid reduced the number of aberrant crypt foci by over one third, while olsalazine had no effect on this parameter. However, both agents effectively reduced tumor number and load, increased the rate of tumor apoptosis, and reduced the rate of tumor cell proliferation. In conclusion, 5-aminosalicylic acid and olsalazine are both ultimately effective chemopreventive agents in this model; however, only 5-aminosalicylic acid inhibited the formation of aberrant crypt foci. The inhibitory effect of these agents in tumors is related to the inhibition of proliferation and the induction of apoptosis.

Cyclooxygenase-2 inhibitors are potentially ideal chemopreventive agents as they inhibit ACF and are not gastrotoxic.

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We investigated aromatization and the mechanism of action of epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha) on oestradiol biosynthesis in freshly prepared granulosa cells from polycystic ovaries. Freshly prepared granulosa cells from polycystic ovaries incubated for only 3 h under basal conditions secreted significantly (P< 0.001) greater amounts of oestradiol-17beta than that of granulosa cells from normal ovaries. 8-Bromo-cyclic adenosine monophosphate (8-Br-cAMP), but not follicle stimulating hormone (FSH) or luteinizing hormone (LH), further enhanced this activity. Both EGF and TGFalpha inhibited gonadotrophinor 8-Br-cAMP-stimulated, but not basal, oestradiol production. LH receptor (LHR) binding, estimated by immunolabelling the bound LH, was significantly (P< 0.001) reduced in granulosa cells from polycystic ovaries when compared with cells from normal ovaries. EGF or TGFalpha significantly reduced the binding in cultured cells from all patient groups (P< 0.05). More interestingly, a further increase of the inhibitory effect was seen in granulosa cells from polycystic ovaries (P < 0.001). In conclusion, granulosa cells from polycystic ovaries contain high levels of basal aromatase activity in vitro, which is probably inherited from the in-vivo condition. EGF and TGFalpha suppress oestradiol synthesis at a step beyond the production of cAMP and also LHR binding with more effect in granulosa cells from polycystic ovaries.

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