Biomedical subjects

Ernst Reichmann

Publications and source records attributed to Ernst Reichmann.

4 recordsLinked to original sources

PubMed2005

Tumor cell invasiveness correlates with changes in integrin expression and localization.

In nontumorigenic mammary epithelial cells (EpH4), transforming growth factor-beta (TGFbeta1) causes cell cycle arrest/apoptosis, but induces epitheliomesenchymal transition (EMT) in Ha-Ras-transformed EpH4 cells (EpRas). EMT is closely correlated with late-stage tumor progression and results in fibroblastic, migratory cells displaying a mesenchymal gene expression program (FibRas). EpRas and FibRas cells showed strongly increased cell substrate adhesion to fibronectin, collagens I/IV and laminin 1. Furthermore, Ras transformation caused enhanced or de-novo expression of the integrin subunits beta1, alpha2 and alpha3, or alpha5 and alpha6, respectively, the latter subunits being even more strongly expressed in FibRas cells. Importantly, polarized EpRas cells expressed integrin subunits beta1 and alpha6 at distinct (apical and lateral) membrane domains, while FibRas cells coexpressed these integrins and alpha5 at the entire plasma membrane. During EMT, EpRas cells formed an alpha5beta1 complex and deposited its ligand fibronectin into the extracellular matrix. Function-blocking alpha5 antibodies attenuated migration, and caused massive apoptosis in EpRas cells undergoing TGFbeta1-induced EMT in collagen gels, but failed to affect EpRas- or FibRas-derived structures. We conclude that functional alpha5beta1 integrin is centrally implicated in EMT induction. Importantly, FibRas cells also failed to deposit the alpha6beta4 ligand laminin 5, suggesting that alpha6beta4 is no longer functional after EMT and replaced by mesenchymal integrins such as alpha5beta1.

Breast↗

PubMed2002

Transforming growth factor-beta and Ras regulate the VEGF/VEGF-receptor system during tumor angiogenesis.

The formation of new microvasculature by capillary sprouting, or angiogenesis, is a prerequisite for solid tumor growth. The genetic alterations required to activate the angiogenic program in tumor angiogenesis are still only vaguely known, but dominantly acting oncoproteins may have a much greater impact than previously realized. Here we have studied the consequences of oncogenic transformation on tumor angiogenesis in a mouse mammary carcinoma model. We provide evidence that the expression of vascular endothelial growth factor (VEGF) and of the VEGF receptor-2 (Flk-1), a signaling system centrally involved in tumor angiogenesis, occurs efficiently in tumors formed by Ras-transformed mammary epithelial cells and that both TGF-beta1 and hypoxia are potent inducers of VEGF expression in these cells. VEGF induction in the tumor periphery is mainly triggered by TGF-beta1, whereas VEGF expression in perinecrotic areas is regulated by both hypoxia and TGF-beta1. As the Ras-transformed tumor cells convert into migrating, fibroblastoid cells that start to produce TGF-beta during tumor progression, the TGF-beta effect on VEGF expression becomes propagated throughout the tumor tissue. Thus, in progressed tumors, areas of TGF-beta1 activation and hypoxia may overlap and hence cooperate to induce VEGF expression and angiogenesis. Nevertheless, the overexpression of VEGF in non-Ras-transformed mouse mammary epithelial cells was not sufficient to promote vascularization in vivo. Based on these findings, we conclude that amongst the multiple mutations that render a normal cell tumorigenic, oncogenic Ras is a major player that in conjunction with the tumor's micro-environment sets the stage for tumor cell invasion and angiogenesis.

Animals↗

PubMed2002

The biological role of the Fas/FasL system during tumor formation and progression.

The cells of an organism are constantly exposed to conflicting environmental cues that signal cell survival or cell death. Survival signals are delivered by autocrine or paracrine factors that actively suppress a default death pathway. This default death pathway appears to be activated by dedicated death receptors such as Fas, the TRAIL-receptors and other tumor necrosis factor receptor superfamily proteins (TNFR SFPs). Our understanding of how these counteracting receptor systems are modulated during tumorigenesis is only moderate. Nevertheless, there is now broad evidence that susceptibility of tumor cells towards Fas-mediated apoptosis is largely reduced. In addition, tumor cells frequently exhibit de novo expression of Fas-ligand (FasL) which plays a significant role in local tissue destruction, metastatic spread and immune escape of the tumor cells. Restoring the apoptotic potential of cancer cells upon modulating the expression and activity of certain key components of the cell death machinery is an attractive and obvious therapeutic anti-cancer strategy.

Animals↗

PubMed2002

Wnt signaling: a complex issue.

The development of tissues and organs in multicellular organisms is controlled by the interplay of several signaling pathways that cross-talk to provide positional information and induce cell fate specification. Together with other families of secreted factors such as TGF beta s, FGFs, Hedgehog and Notch proteins, Wnt growth factors are crucially implicated in these processes. Here, we will first discuss molecular mechanisms and then consider some biological consequences of Wnt signaling.

Animals↗