In vivo and in vitro invasiveness of a rat colon‐cancer cell line maintaining E‐cadherin expression: An enhancing role of tumor‐associated myofibroblasts
Abstract:In various cell systems, an inverse relationship was found between expression of E-cadherin, a molecule involved in the Ca(2+)-dependent homophylic cell-to-cell attachment of epithelial cells, and the capacity to invade extracellular matrix gels or normal tissues in vitro. DHD/K12/TRb (PROb) cells, maintained as a cell line derived from a rat colon carcinoma, homogeneously expressed in vitro immunoreactive E-cadherin, which was functional as shown in cell dissociation-reassociation assays. PROb cells were foun… Show more
“…that the uPAR and the C4.4A on BSp73ASML cells are occupied by uPA and/or the not yet de®ned proper ligand of C4.4A. Finally, as also described for the uPAR, it could well be that C4.4A transfected BSp73AS cells can recruit in vivo uPA and/ or related molecules from host cells (Dimanche-Boitrel et al, 1994). Taking into account this possibility it becomes comprehensible that C4.4A transfected cells degrade in vivo e ciently surrounding tissue, but hardly a layer of matrigel in vitro.…”
We have described recently a panel of metastasisassociated antigens expressed on a rat pancreatic tumor. One of these molecules, recognized by the monoclonal antibody C4.4 and named accordingly C4.4A, was under physiological conditions expressed only in the gravid uterus and on epithelial of the upper gastrointestinal tract. The cDNA of the antigen has been isolated and cloned. The 1,637 b cDNA codes for a 352 amino acid long glycosylphosphatidyl-inositol (GP) anchored molecule, whose molecular weight varies in di erent cells between 94 ± 98 kD according to the degree of N-and Oglycosylation. Data base searches have revealed a low degree of homology to the receptor for the plasminogen activator (uPAR). After intrafootpad and intravenous application of C4.4A transfected and mocktransfected tumor cells, an increased number of lung nodules was detected with the former, whereby the individual metastatic nodules amalgamated without any encapsulation of the tumor tissue. Furthermore, C4.4A is involved in adhesion to laminin and, although transfection of a non-metastasizing tumor line with the molecule was not su cient, constitutively C4.4A-positive tumor cells penetrated through matrigel. This process could be completely prevented by C4.4. Finally, we could demonstrate that uPA, albeit weakly, bound to the C4.4A molecule. In view of the observed in¯uence of C4.4A on metastasis formation and matrix penetration it is tempting to speculate that this newly described metastasis-associated molecule may exert functional activity similar to the uPAR, i.e. via activation of matrix degrading enzymes. By the very restricted expression of the molecule in the adult organism, modulation of C4.4A could well be of therapeutic interest.
“…that the uPAR and the C4.4A on BSp73ASML cells are occupied by uPA and/or the not yet de®ned proper ligand of C4.4A. Finally, as also described for the uPAR, it could well be that C4.4A transfected BSp73AS cells can recruit in vivo uPA and/ or related molecules from host cells (Dimanche-Boitrel et al, 1994). Taking into account this possibility it becomes comprehensible that C4.4A transfected cells degrade in vivo e ciently surrounding tissue, but hardly a layer of matrigel in vitro.…”
We have described recently a panel of metastasisassociated antigens expressed on a rat pancreatic tumor. One of these molecules, recognized by the monoclonal antibody C4.4 and named accordingly C4.4A, was under physiological conditions expressed only in the gravid uterus and on epithelial of the upper gastrointestinal tract. The cDNA of the antigen has been isolated and cloned. The 1,637 b cDNA codes for a 352 amino acid long glycosylphosphatidyl-inositol (GP) anchored molecule, whose molecular weight varies in di erent cells between 94 ± 98 kD according to the degree of N-and Oglycosylation. Data base searches have revealed a low degree of homology to the receptor for the plasminogen activator (uPAR). After intrafootpad and intravenous application of C4.4A transfected and mocktransfected tumor cells, an increased number of lung nodules was detected with the former, whereby the individual metastatic nodules amalgamated without any encapsulation of the tumor tissue. Furthermore, C4.4A is involved in adhesion to laminin and, although transfection of a non-metastasizing tumor line with the molecule was not su cient, constitutively C4.4A-positive tumor cells penetrated through matrigel. This process could be completely prevented by C4.4. Finally, we could demonstrate that uPA, albeit weakly, bound to the C4.4A molecule. In view of the observed in¯uence of C4.4A on metastasis formation and matrix penetration it is tempting to speculate that this newly described metastasis-associated molecule may exert functional activity similar to the uPAR, i.e. via activation of matrix degrading enzymes. By the very restricted expression of the molecule in the adult organism, modulation of C4.4A could well be of therapeutic interest.
“…Stromal cells of interest are myofibroblasts, as suggested by our previous experiments [18]. During epithelial carcinogenesis, the efferent signalling changes (dotted thick arrow) and this causes cancer-associated changes in the stroma.…”
Maintenance of epithelial tissues needs the stroma. When the epithelium changes, the stroma inevitably follows. In cancer, changes in the stroma drive invasion and metastasis, the hallmarks of malignancy. Stromal changes at the invasion front include the appearance of myofibroblasts, cells sharing characteristics with fibroblasts and smooth muscle cells
“…Through specific communication with cancer cells, CAFs can directly promote tumor initiation, progression and metastasis (Dimanche-Boitrel et al, 1994;Olaso et al, 1997;Olumi et al, 1999;Bhowmick et al, 2004;Kuperwasser et al, 2004;Grum-Schwensen et al, 2005;Orimo et al, 2005). CAFs secrete growth factors and ECM-degrading proteases to promote tumor growth and invasiveness.…”
Emerging evidence has suggested that glycolysis is enhanced in cancer-associated fibroblasts (CAF), and miR-186 is downregulated during the CAF formation. However, it is not clear whether miR-186 is involved in the regulation of glycolysis and what the role of miR-186 plays during the CAF formation. In this study, quantitative PCR analysises show miR-186 is downregulated during the CAF formation. Moreover, miR-186 targets the 3' UTR of Glut1, and its overexpression results in the degradation of Glut1 mRNA, which eventually reduces the level of Glut1 protein. On the other hand, knockdown of miR-186 increased the expression of Glut1. Both time course and dose response experiments also demonstrated that the protein and mRNA levels of Glut1 increase during CAF formation, according to Western blot and quantitative PCR analyses, respectively. Most importantly, besides the regulation on cell cycle progression, miR-186 regulates glucose uptake and lactate production which is mediated by Glut1. These observations suggest that miR-186 plays important roles in glycolysis regulation as well as cell cycle checkpoint activation.
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