Naslov
Associated changes of lipid peroxidation and transforming growth factor b1 levels in human colon cancer during tumour progression

Autori
Biasi, F. ; Tessitore, L. ; Zanetti, D. ; Cutrin, J. C. ; Zingaro, B. ; Chiarpotto, E. ; Žarković, Neven ; Serviddio, G. ; Poli, G.

Izvornik
Gut (0017-5749) 50 (2002), 3; 361-367

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Tgf-beta; Ii receptors; Microsatellite instability; Heterooligomeric complexes; Colorectal-cancer; Gene-expression; Cells; Growth-factor-beta-1; Adenocarcinoma; Proteins

Sažetak
Background: During neoplastic progression, alterations in transforming growth factor b1 (TGF-b1) dependent control of cell growth may be an important mechanism of selective proliferation of transformed cellular clones. Defective regulation of TGF-b1 receptors has been reported to occur in a number of human malignant tumours while little is known of the actual levels of this growth inhibitory cytokine in cancer. On the basis of the demonstrated ability of major lipid peroxidation products such as 4-hydroxynonenal to modulate TGF-b1 expression and synthesis, we speculated that decreased lipid oxidation, as frequently observed in neoplastic tissues, would contribute to the selective promotion of tumour growth through decreased expression of the cytokine within the tumour mass. Aims: To seek a possible association between steady state levels of major aldehydic end products of lipid peroxidation and TGF-b1 content in human colon cancer at different stages of growth. Patients and methods: Tissue biopsies from 15 adult patients with colon adenocarcinoma of different TNM and G stagings were compared with regard to lipid peroxidation aldehydes and net TGF-b1 levels. For a more comprehensive analysis, cytokine type I and II receptors were measured in tumour biopsies. In one set of experiments, to support the conclusions, the apoptotic effect of TGF-b1 was evaluated in a human colon cancer cell line, CaCo-2, retaining receptor changes consistent with those observed in cancer patients. Results: With the exception of two extremely advanced cases (T4/G3) in which tissue levels of lipid peroxidation were within the normal range, 4-hydroxynonenal was significantly decreased in all other cancer specimens. Consistent with lipid peroxidation levels, TGF-b1 protein was markedly decreased or even negligible compared with the corresponding normal tissue surrounding the tumour in all tested biopsies except for the two T4/G3 colon cancers in which cytokine content was again within the normal range. As regards TGF-b1 receptors, both in tumour sections and CaCo-2 cells, downregulation was greater for TGF-b1 receptor I than for receptor II. Of note, in CaCo-2 cells, incubation with appropriate doses of TGF-b1 led to marked nuclear fragmentation and apoptosis. Conclusions: Evasion of human colon cancer cells from TGF-b1 mediated growth inhibition appears to be due not only to downregulation of TGF-b1 receptors, which is inconsistent and unrelated to cancer development, but also to the constant low concentration of this cytokine in the tumour mass. The associated levels of lipid peroxidation aldehydes, much lower than in control tissue, probably represent a lower stimulus for TGF-b1 production in the neoplastic area and thus a favourable condition for neoplastic progression.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti, Kliničke medicinske znanosti

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