Injury in vascular surgery--the intimal hyperplastic response.

Intimal hyperplasia is extensively studied in order to improve arterial reconstruction outcome. The mechanisms leading to stenosis or restenosis may vary according to the technique used for arterial reconstruction. Lesions are mostly made of an accumulation of smooth muscle cells and fibroblasts, with only sparse inflammatory cells. The accumulated material reduces the graft lumen and ultimately induces thrombosis. Intimal hyperplasia with smooth muscle cell and matrix accumulation is the prominent feature in all these situations with evidences of intense cell proliferation and cell death. The purpose of this review is to present the biology of intimal hyperplastic response based on the recently published data. Experiments in the rabbits have shown that the vein wall thickening is mainly regulated by the tangential wall stress which is applied transversely to the vein wall as a blood pressure. Experiments in the rat carotid artery balloon injury suggested that heparin could be used as a treatment to prevent intimal hyperplasia. Treatments for preventing restenosis after angioplasty or stenoses development in bypasses have been disappointing clinical evaluation suffers from insufficient prospective randomized studies. Intimal hyperplasia is the major cause of failure after arterial reconstruction. The biology of intimal hyperplasia is complex, and treatment disappointing. Some types of hyperplasia may need to be preserved in order to prevent functional atrophy and aneurysmal dilatation of vein grafts.

Expression of transforming growth factor beta1 and its receptors in normal human urothelium and human transitional cell carcinomas.

Previous studies indicated that transforming growth factor beta1 (TGFbeta1) is expressed by normal urothelial cells and exerts regulatory autocrine functions in urothelial maintenance and wound healing. However, little is known about the expression patterns of TGFbeta1 and its receptors in bladder tumors. Therefore, we studied the protein and mRNA localization of TGFbeta1 and TGFbeta receptor types I and II (TGFbetaRI and TGFbetaRII) in normal human urothelium and transitional cell carcinomas (TCCs) of different grades and stages. Expression of TGFbeta1 and its receptors was examined by immunocytochemistry and mRNA in situ hybridization in normal urothelium and TCCs using a semiquantitative method. By immunocytochemistry, the expression of TGFbeta1 and TGFbetaRII was higher in superficial and basal cell layers of normal urothelium than in the intermediate layer. A similar localization was seen in superficial TCCs. TGFbetaRI was mainly present in basal and intermediate cell layers of normal urothelium and superficial TCCs. In contrast, in muscle invasive TCCs, all tumor cells stained intensely for all three proteins. No correlation was found between immunostaining and TCC grade. In situ hybridization pointed out that all cell layers in normal urothelium exhibit similar TGFbeta1 mRNA levels. Elevated TGFbeta1 mRNA levels were noted in TCCs irrespective of grade or stage. In conclusion, these data indicate that in normal urothelium TGFbeta1, TGFbetaRI, and TGFbetaRII expression depend on maturation and differentiation. This pattern is particularly lost in muscle invasive TCCs, in which the expression of the three proteins is enhanced. These data suggest autocrine TGFbeta1 mechanisms in human TCC cells that may be more pronounced in muscle invasive TCC cells.

Expression and functions of EGF, FGF and TGFbeta-growth-factor family members and their receptors in invasive human transitional-cell-carcinoma cells.

Studies on epidermal-growth-factor-like-, fibroblast- and transforming growth factors suggested their implication in tumorigenesis involving effects on tumour-cell proliferation and migration. In human transitional-cell carcinomas (TCC), enhanced expression of TGF alpha and EGF receptors correlated with an aggressive phenotype. However, little is known about functions of these growth factors in invasive TCCs. In this study, we performed protein- and RNA-expression studies on a set of growth factors and their receptors on the newly established invasive human TCC cell line designated 1207. The data were correlated with functional proliferation and migration studies. Similar expression patterns of many cellular markers, growth factors and their receptors were noted both in the original TCC tissue and in its derivative cell line, indicating the relevance of this cell line to the investigation of growth factor functions on TCC cells. The proliferation induction by EGF, TGF alpha, amphiregulin, heregulin alpha, FGF-1 and FGF-7 correlated with the presence of EGF receptors, c-erbB4 and FGFR2 (IIIb), respectively. Amphiregulin and heregulin alpha induced the most proliferation. In conformity with the low expression of TGF beta receptors I and II, TGF beta1, barely inhibited proliferation, while TGF alpha induced invasion of 1207 cells into Matrigel. These data support the notion that notably EGF-like proteins mediate TCC growth and invasion through autocrine pathways which can be reinforced by loss of TGF beta1 regulation.

Evaluation of local immune response after intravesical bacille Calmette-Guérin treatment for superficial bladder cancer.

OBJECTIVE: To help define the optimal protocol of Bacille Calmette-Guérin (BCG) treatment for transitional cell carcinoma (TCC) of the bladder by examining cytokine production and antigen presentation to effector cells after instillations of BCG in patients with bladder TCC. PATIENTS AND METHODS: Sixty-four urine samples from 11 patients were tested for the production of interferon gamma (IFN-gamma) using a modified commercial enzyme-linked immunosorbent assay (ELISA) kit. Urine was collected before and at intervals up to 24 h after the intravesical instillation of BCG. Immunohistological studies were also carried out using a two-step alkaline phosphatase technique to explore the expression of tumour-associated antigens (TAAs) (E7, 19A211, T138), major histocompatibility complex (MHC) molecules and lymphocyte subset infiltrates (CD3, CD4, CD8) in bladder biopsies before and 3 weeks after the completion of treatment in seven patients. RESULTS: IFN-gamma was only detected 4, 6 and 8 h after instillation, with a maximum concentration at 6 h (2.9-34.7 IU/mL in 10 patients). During a 6-week course of BCG, IFN-gamma was barely detectable after the first two instillations, but gradually increased from the third instillation onwards. TAA and MHC II antigens, which were absent or faintly expressed on normal urothelial cells before treatment, were expressed strongly in five patients after treatment. The local recruitment of immunocompetent cells was detected in all patients. CONCLUSION: These results suggest that the local immune response after the intravesical instillation of BCG can be quantified using simple ELISA tests and could be useful in defining objective criteria for rationalizing treatment (dose and duration), and in determining the relation between the immune response and anti-tumour activity. There is evidence that antigen presentation is enhanced after BCG instillations, suggesting that a T cell-MHC restricted pathway might be involved in the anti-tumour response. This study supports the search for tumour-rejection antigens in bladder cancer.