Role of morphogenetic factors in metastasis of mammary carcinoma cells

Abstract

We have analysed the role of the morphogenetic factors hepatocyte growth factor/scatter factor (HGF), neuregulin and E-cadherin in the process of metastasis and morphogenesis of mammary carcinoma cells. The cDNAs for HGF, neuregulin and E-cadherin were stably expressed in anaplastic human MDA MB 435 carcinoma cells. The altered cells were then injected into the mammary fat pads of nude mice, where they form tumors which can spontaneously metastasize to the lungs. We found that expression of HGF or neuregulin promoted metastasis whereas expression of the cell adhesion molecule E-cadherin was inhibitory. Moreover, expression of E-cadherin reconstituted the ability of the cells to form morphogenetic structures in matrigel cultures in response to HGF. These data demonstrate that HGF and neuregulin, which control branching or lobulo-alveolar morphogenesis of normal breast epithelium, do have metastasis-promoting eects on breast carcinoma cells. Moreover, our results suggest that the dierential activities of the two factors can be explained by the degree of epithelial dierentiation: induction of morphogenesis requires an intact epithelial adhesion and dierentiation system, whereas induction of metastasis is observed when the cells have lost their epithelial characteristics.

Distinct tyrosine autophosphorylation sites mediate induction of epithelial mesenchymal like transition by an activated ErbB-2/Neu receptor

“…Consistent with their dispersed phenotype, extensive membrane extensions and lamellipodia are visible in NT-expressing cells (Figure 3) and these cells show enhanced cell motility in Transwell assays, comparable to cells stimulated with HGF (Figure 4). These data are similar to the cytoskeletal changes and enhanced cell motility observed following stimulation of some breast cancer cell lines with heregulin, a ligand (Chausovsky et al, 1998;Adam et al, 1998;Meiners et al, 1998). However many breast tumor cell lines lack functional adherens junctions through genetic alterations that lead to loss of expression of E-cadherin (Ji et al, 1997) and a role for Her2/Neu in the breakdown of epithelial junctions had not been addressed.…”

“…Epithelial-mesenchymal transition (EMT) is characterized by the conversion of epithelial cells into ®broblast- (Boyer et al, 1996;Meiners et al, 1998). ErbB-2/Neu ampli®cation and overexpression has been implicated in the etiology of breast and ovarian carcinomas and correlates with poor clinical prognosis (Pegram et al, 1998).…”

“…In some breast tumor cell lines, ErbB-2 enhances cell migration and invasion in response to neuregulins or heregulin, ligands that indirectly activate ErbB-2 (Meiners et al, 1998;Brandt et al, 1999), whereas in others, activation of ErbB-2 promotes a remodeling of epithelial cell junctions consistent with a morphogenic response (Chausovsky et al, 1998). Hence the biological consequence of an ErbB-2 activation signal to promote epithelial cell dispersal versus reorganization, may depend on signals altered in the various tumor cells assayed.…”

Biologic effects of heregulin/neu differentiation factor on normal and malignant human breast and ovarian epithelial cells

“…In the ®rst, NDF expression induced formation of adenocarcinomas (Krane and Leder, 1996). In the second, transfection of the human breast cancer cell line MDA-MB-435 with either scatter factor (HGF) or HRG/NDF increased tumor size at the primary site and induced metastasis of transfected cells to the lungs (Meiners et al, 1998).…”

Loss of E-cadherin Expression in Melanoma Cells Involves Up-regulation of the Transcriptional Repressor Snail

“…Transfection of E-cadherin cDNA into invasive carcinoma cells led to significant reduction of their invasive capacity in vitro (11,12), and activation of E-cadherin resulted in growth retardation of tumor cell lines (13,14). Subsequently, results obtained from in vivo tumor models provided consistent evidence for a role of E-cadherin as a potent tumor suppressor (12,(15)(16)(17). Further, the tumor suppressor gene fat in Drosophila melanogaster was revealed as a member of the cadherin gene family (18).…”