SummaryMany colorectal cancer cells are resistant to the anti-proliferative effects of transforming growth factor-β (TGF-β). TGF-β also acts as paracrine factor from cancer cells on their mesenchymal cells. The aim of this study was to examine the expression of TGF-β and its receptors in human colorectal cancer tissue and determine any relationship with cancer growth. In situ hybridization and Northern blot hybridization detection of TGF-β 1 , type I and type II receptor mRNA and immunohistochemical staining of TGF-β 1 were performed using 11 human colorectal adenomas, 22 colorectal cancers and ten normal colorectal mucosas as control. TGF-β receptor mRNAs were expressed mainly by normal colorectal epithelial cells and adenoma. However, mRNAs for TGF-β receptors were only faintly, if at all, expressed in eight of 22 human colorectal cancers. In addition, intense signals of TGF-β 1 mRNA and the protein were detected in all colorectal cancers. TGF-β receptor mRNAs and TGF-β 1 protein were also distributed in fibroblasts and endothelial cells in the interstitium. Moreover, Smad 4 protein was translocated to nucleus in primarily cultured adenoma cells, but not in cancer cells after TGF-β stimulation. The escape of human colon cancer from TGF-β -mediated growth inhibition by down-regulation of TGF-β receptors as well as the effects of TGF-β on stroma formation and angiogenesis indicate a possible role for TGF-β in the progression of colon cancer in an intact host.Keywords: TGF-β; TGF-β receptor; Smad, colorectal cancer; colorectal adenoma 194British Journal of Cancer (1999) 80(1/2), 194-205 © 1999 Cancer Research Campaign Article no. bjoc.1998 Received 30 receptors, and alterations in post-receptor pathways. Several reports indicate that elevated levels of TGF-β mRNA and protein in colorectal cancer are associated with cancer progression (Tsushima et al, 1996). If TGF-β is indeed an inhibitor for epithelial cells, how then do colorectal cancer cells manage to proliferate despite elevated TGF-β production by tumour cells? Concerning the mechanisms of resistance to the anti-proliferative effects of TGF-β in colorectal cancer, Markowitz et al (1995) identified a specific TGF-β RII mutation that is associated with defective DNA mismatch repair in colon cancer cells. However, numerous reports also indicate that transcriptional regulation makes an important contribution to determination of the expression level of TGF-β receptors (Birchenall-Roberts et al, 1995;Kim et al, 1997). Accordingly, to clarify the mechanisms of resistance to the antiproliferative effects of TGF-β in vivo, we estimated the transcriptional level of TGF-β receptors in colorectal cancer using in situ hybridization and Northern blot hybridization as the standard for those in normal colorectal epithelial cells.In addition, no studies of human colorectal tumour to date have compared in situ levels of TGF-β 1 with those of its receptors as a presumptive target gene, and with the presence of ligand protein.To ascertain if TGF-β from colorectal cancer act...

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A 51-year-old man with osteomyelitis developed acute renal failure and superior mesenteric venous (SMV)thrombosis after piperacillin (PIPC) treatment. Coagulation profile disclosed disseminated intravascular coagulation (DIC). The serum levels of IgE and eosinophil cationic protein showed significant increases, while a lymphocyte stimulation test with PIPC also demonstrated an extremely high index. These observations suggest that hypersensitivity to PIPC might play a role in the pathogenesis of acute renal failure and SMVthrombosis due to hypercoagulopathy. Withdrawal of PIPC and anticoagulation therapy resulted in clinical improvementand normalization of the affected laboratory data. This is the first report to describe PIPCinduced hypercoagulopathy.

The induction of metallothionein (MT) isoforms (MT-1, -2) by anticancer drugs was investigated in cultured rat hepatoma H4 II E C3 cells. The steady-state expression of MT-1 mRNAs was higher than that of MT-2 mRNAs. During incubation of the cells with various anticancer drugs, namely, adriamycin, epirubicin, cis-diamminedichloroplatinum(II) (CDDP), and cis-diammine(1, 1-cyclobutyldicarboxylato)platinum(II), both MT-1 and MT-2 mRNAs were coordinately inducible: the levels of isoMT mRNA reached a maxim of approximate by 6-fold at 3 h. Immunofluorescent studies revealed that the cytosolic fluorescence in the cells exposed to 1 microM CDDP for 48 h was more intensified than that in the untreated cells. Transfer of antisense oligonucleotides resulted in marked reduction of isoMT mRNA, and upon exposure to 5 microM CDDP for 48 h, the viabilities of these cells dropped to 25.8% of the controls. These results indicate that anticancer drugs are potent inducers of MT isoforms in hepatoma cells and that a decrease in cellular MTs enhances the susceptibility of hepatoma cells to CDDP. Thus, we conclude that endogenous MTs play a role in determining the sensitivity or resistance of cancer cells to clinically important anticancer agents.