Determination of p185 and adenylosuccinate lyase (ASL) activity in preneoplastic colon lesions and intestinal mucosa of human subjects.

OBJECTIVES: The HER2 gene has been found amplified in a number of human adenocarcinoma leading to elevated levels of expression of its encoded product, p185 protein. Because little information is available on the tissue and tumor specificity of this gene product, we studied the expression of p185 protein in preneoplastic colon lesions. Adenylosuccinate lyase (ASL, EC 4.3.2.2) is known to increase in malignancies such as colorectal, breast, and prostate cancer. In order to evaluate the potential of ASL as a tumor marker, its activity was determined and compared with the expression of p185. DESIGN AND METHODS: p185 was determined by an immunohistochemical procedure in patients with the preneoplastic lesions. ASL activity was evaluated in intestinal mucosa adjacent to colorectal cancers (patient group A) and in preneoplastic colorectal lesions (group B). The enzyme activity was evaluated in dialyzed supernatants, following the disappearance of substrate (adenylosuccinate AMP-S) and the formation of product (adenosine 5'-monophosphate-AMP), separated by high performance liquid chromatography. RESULTS AND CONCLUSIONS: Increased expression of p185 and elevated ASL activity were observed in tubular and tubulo-villous adenoma and may, therefore, be associated with the early stages of colorectal cancer.

Development of inflammatory angiogenesis by local stimulation of Fas in vivo.

Fas-Fas ligand interaction is thought to be a crucial mechanism in controlling lymphocyte expansion by inducing lymphocyte apoptosis. However, Fas is also broadly expressed on nonlymphoid cells, where its function in vivo remains to be determined. In this study, we describe the development of inflammatory angiogenesis induced by agonistic anti-Fas mAb Jo2 in a murine model where Matrigel is used as a vehicle for the delivery of mediators. The subcutaneous implants in mice of Matrigel containing mAb Jo2 became rapidly infiltrated by endothelial cells and by scattered monocytes and macrophages. After formation and canalization of new vessels, marked intravascular accumulation and extravasation of neutrophils were observed. Several mast cells were also detected in the inflammatory infiltrate. The phenomenon was dose and time dependent and required the presence of heparin. The dependency on activation of Fas is suggested by the observation that the inflammatory angiogenesis was restricted to the agonistic anti-Fas mAb and it was absent in lpr Fas-mutant mice. Apoptotic cells were not detectable at any time inside the implant or in the surrounding tissue, suggesting that angiogenesis and cell infiltration did not result from recruitment of phagocytes by apoptotic cells but rather by a stimulatory signal through Fas-engagement. These findings suggest a role for Fas-Fas ligand interaction in promoting local angiogenesis and inflammation.