The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also influenced by signals from the environment. In multiple myeloma (MM), the factors and signals coming from the bone marrow microenvironment are possibly even essential for the growth of the tumor cells. As targets for intervention, these signals may be equally important as mutated oncogenes. Given their oncogenic potential, WNT signals form a class of paracrine growth factors that could act to influence MM cell growth. In this paper, we report that MM cells have hallmarks of active WNT signaling, whereas the cells have not undergone detectable mutations in WNT signaling genes such as adenomatous polyposis coli and ␤-catenin (CTNNB1). We show that the malignant MM plasma cells overexpress ␤-catenin, including its N-terminally unphosphorylated form, suggesting active ␤-catenin͞T cell factor-mediated transcription. Further accumulation and nuclear localization of ␤-catenin, and͞or increased cell proliferation, was achieved by stimulation of WNT signaling with either Wnt3a, LiCl, or the constitutively active S33Y mutant of ␤-catenin. In contrast, by blocking WNT signaling by dominant-negative T cell factor, we can interfere with the growth of MM cells. We therefore suggest that MM cells are dependent on an active WNT signal, which may have important implications for the management of this incurable form of cancer.␤-catenin ͉ T cell factor ͉ lymphoma ͉ plasma cell

Integrins are heterodimeric transmembrane glycoproteins which are engaged in a variety of cellular functions, such as adhesion, migration and differentiation1. The integrin alpha 6 beta 4 is expressed on squamous epithelia, on subsets of endothelial cells, immature thymocytes and on Schwann cells and fibroblasts in the peripheral nervous system. In stratified epithelia, alpha 6 beta 4 is concentrated in specialised adhesion structures, called hemidesmosomes, which are implicated in the stable attachment of the basal cells to the underlying basement membrane by connecting the intermediate filaments with the extracellular matrix. The nature of the interactions between the various hemidesmosomal proteins, that lead to the formation of hemidesmosome is poorly understood. To study the contribution of the integrin alpha 6 beta 4 in hemidesmosome formation and their anchoring properties, we inactivated the beta 4 gene in mice by targeted gene disruption. Homozygous beta 4 null mice died shortly after birth and displayed extensive detachment of the epidermis and other squamous epithelia. The dramatically reduced adhesive properties of the skin was accompanied by the absence of hemidesmosomes at the basal surface of keratinocytes. No evidence was found for impaired T-cell development, nor for defects in myelination in the peripheral nervous system.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive potential against colorectal carcinomas (CRCs). Inhibition of cyclooxygenase (COX)-2 underlies part of this effect, although COX-2-independent mechanisms may also exist. Nonsteroidal antiinflammatory drugs appear to inhibit the initial stages of the adenoma -carcinoma sequence, suggesting a link to the APC/b-catenin/ TCF pathway (Wnt-signalling pathway). Therefore, the effect of the NSAID sulindac on nuclear (nonphosphorylated) b-catenin and b-catenin/TCF-mediated transcription was investigated. Nuclear b-catenin expression was assessed in pretreatment colorectal adenomas and in adenomas after treatment with sulindac from five patients with familial adenomatous polyposis (FAP). Also, the effect of sulindac sulphide on b-catenin/TCF-mediated transcription was studied. Adenomas of FAP patients collected after treatment with sulindac for up to 6 months showed less nuclear b-catenin expression compared to pretreatment adenomas of the same patients. Sulindac sulphide abrogated b-catenin/TCF-mediated transcription in the CRC cell lines DLD1 and SW480, and decreased the levels of nonphosphorylated b-catenin. As a result, the protein levels of the positively regulated TCF targets Met and cyclin D1 were downregulated after sulindac treatment. This study provides in vivo and in vitro evidence that nuclear b-catenin localisation and b-catenin/TCF-regulated transcription of target genes can be inhibited by sulindac. The inhibition of Wnt-signalling provides an explanation for the COX-2-independent mechanism of chemoprevention by NSAIDs. . Also, in patients with familial adenomatous polyposis (FAP), an autosomal dominantly inherited disorder characterised by the development of numerous colorectal adenomas at a young age, the NSAIDs sulindac and indomethacin can cause regression of adenomas (Giardiello et al, 1993;Nugent et al, 1993;Spagnesi et al, 1994;Hirota et al, 1996;Winde et al, 1997;Picariello et al, 1998). The chemopreventive effect of NSAIDs appears mediated by the induction of apoptosis and cell cycle arrest (Pasricha et al, 1995;DuBois and Smalley, 1996;Piazza et al, 1997;Keller et al, 1999;Shiff and Rigas, 1999). The molecular mechanisms underlying these biological effects are not completely understood. Nonsteroidal anti-inflammatory drugs inhibit the enzymatic activity of cyclooxygenase (COX)-1 and -2, enzymes that convert arachidonic acid into prostaglandins (Shiff and Rigas, 1999). However, COX-independent mechanisms may also play a role, since NSAIDs inhibit the growth of colon cancer cell lines lacking COX-2 expression (Hanif et al, 1996;Zhang et al, 1999;Smith et al, 2000).Oncogenic activation of the Wnt-signalling pathway by mutations in Adenomatous polyposis coli (APC) or b-catenin, which results in the accumulation and nuclear translocation of b-catenin and in b-catenin/TCF4-regulated transcription of TCF target genes, is mandatory for the initial neoplastic transformation of intestinal epithelium (reviewed in Kinzler and Vogelstein, 1996...

Abstract. CD44 is a glycoprotein involved in inflammation and cell-cell/cell-matrix interactions. CD44 is upregulated in the kidney upon injury; however, its role in the pathogenesis of renal damage and fibrosis remains largely unknown. The authors show that mice lacking CD44 developed more tubular damage, associated with decreased proliferation and increased apoptosis of tubular epithelial cells, but less renal fibrosis after unilateral ureteral obstruction. In addition, impaired influx of macrophages and decreased accumulation of myofibroblasts was observed in the obstructed kidney of CD44