Downregulation in vivo of the invasion-suppressor molecule E-cadherin in experimental and clinical cancer.
The invasion-suppressor molecule E-cadherin (E-CAD) can be regulated at multiple levels: synthesis, processing and stability of mRNA; synthesis, processing and stability of protein; localization and posttranslational modification of protein; binding to catenins (E-CAD-associated proteins); and size and charge of cell surface glycosaminoglycans. Loss of E-CAD antigen and of E-CAD function in vivo has been observed with cell lines that homogeneously expressed functional E-CAD in vitro. These observations led to the idea that factors in the host may downmodulate E-CAD on the cancer cells, thereby promoting cell invasion. Nude mouse cancers that were homogeneously E-CAD-positive and noninvasive in vitro, formed by epithelioid MDCK or NMuMG cells, stained heterogeneously for E-CAD; such cancers were invasive and metastatic. The in vivo downmodulation appeared to be transient. Ex vivo cultures from primary cancers, as well as from metastases, produced homogeneously E-CAD-positive and noninvasive cells. Downmodulation did not occur when cells were micro-encapsulated and then implanted in the mouse, suggesting a role for immediate cancer cell-host cell contact. Similar in vitro/in vivo/ex vivo experiments with mouse MO4 fibrosarcoma cells, transfected with E-CAD cDNA under the control of a b-actin promotor, showed downregulation at the transcriptional or mRNA stability level. This downregulation was rapidly reversible upon ex vivo culture of the tumor cells. TGF-bl and IGF-I were found, respectively, to downregulate and upregulate the expression or the function of E-CAD. We speculate that IGF-1 restores the function of E-CAD through interaction of the IGF-I tyrosine kinase receptor with the catenin-actin cytoskeletal complex. In human cancers, immunohistochemistry has revealed changes in E-cadherin that agree with the experimental data on transient downmodulation of the invasion-suppressor function of E-cadherin by host factors.
Mareel
M
M
Laboratory of Experimental Cancerology, University of Gent, Belgium.
Vleminckx
K
K
Vermeulen
S
S
Yan
G
G
Bracke
M
M
van Roy
F
F
D000818:Animals; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D015534:Trans-Activators; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D051178:alpha Catenin; D051176:beta Catenin
C495273:CTNNA1 protein, human; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D015820:Cadherins; C495272:Ctnna1 protein, mouse; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D051178:alpha Catenin; D051176:beta Catenin; D007334:Insulin-Like Growth Factor I; D011494:Protein Kinases