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. 2001 Aug 28;98(18):10356-61.
doi: 10.1073/pnas.171610498.

Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment

T Brabletz  1 , A Jung, S Reu, M Porzner, F Hlubek, L A Kunz-Schughart, R Knuechel, T Kirchner
Affiliations

Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment

T Brabletz et al. Proc Natl Acad Sci U S A. .

Abstract

Invasion and dissemination of well-differentiated carcinomas are often associated with loss of epithelial differentiation and gain of mesenchyme-like capabilities of the tumor cells at the invasive front. However, when comparing central areas of primary colorectal carcinomas and corresponding metastases, we again found the same differentiated epithelial growth patterns. These characteristic phenotypic changes were associated with distinct expression patterns of beta-catenin, the main oncogenic protein in colorectal carcinomas, and E-cadherin. Nuclear beta-catenin was found in dedifferentiated mesenchyme-like tumor cells at the invasive front, but strikingly, as in central areas of the primary tumors, was localized to the membrane and cytoplasm in polarized epithelial tumor cells in the metastases. This expression pattern was accompanied by changes in E-cadherin expression and proliferative activity. On the basis of these data, we postulate that an important driving force for progression of well-differentiated colorectal carcinomas is the specific environment, initiating two transient phenotypic transition processes by modulating intracellular beta-catenin distribution in tumor cells.

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Figures

Figure 1
Figure 1
Correlation of growth and the expression patterns of β-catenin, E-cadherin, and Ki-67 in well-differentiated colorectal adenocarcinomas. Shown are central areas (first column) and invasive front (second column) of the primary tumor and central areas (third column) and invasive front (fourth column) of the corresponding metastasis. Stainings are for CK-18 (first row), β-catenin (second row), E-cadherin (third row), and Ki-67 (fourth row). Boxes indicate magnified regions in stained serial sections. Specific staining is red and nuclear counterstaining is blue [×100 (a–d) and ×400 (e–p)]. CK 18 stainings show a differentiated growth pattern with tubular structures in the centers of primary tumor (a) and metastasis (c) and loss of tubular growth and tumor cell dissemination in the corresponding invasive fronts (b and d). Tumor cells are clearly polarized in the differentiated central areas in both primary tumor and metastasis, and β-catenin is localized distinctly in the apical cytoplasm and membrane of the tumor cells (arrowheads) (e and g). Note that β-catenin is not detectable in the nuclei (arrows). In contrast, tubules at the invasive front break up, and tumor cells lose their polar orientation and dissociate (arrows) (f and h). This morphological change is accompanied by nuclear accumulation of β-catenin (arrows and arrowheads). Correspondingly, tumor cells in differentiated areas of the primary tumor express membranous E-cadherin (arrowheads) (i), which is also expressed in central areas of the metastasis (k). Disseminating tumor cells at the invasive fronts with nuclear β-catenin either completely lost E-cadherin (arrowheads) or showed a cytoplasmic expression (arrows) (j and l). A high Ki-67 ratio indicating strong proliferation is found only in differentiated tubular areas of primary tumors and metastases retaining an epithelial phenotype (m and o). Disseminating, dedifferentiated tumor cells with mesenchymal phenotype did not express Ki-67 (arrows) (n and p).
Figure 2
Figure 2
Weak expression of vimentin in dedifferentiated tumor cells. CK 18 staining of a neoplastic tubulus in the invasive region of a colorectal carcinoma [×100 (a)]. Magnified region of the differentiated (upper square) or dedifferentiated area (lower square) stained in serial section against β-catenin (b and d) or vimentin (c and e). Note that dedifferentiated tumor cells with nuclear β-catenin (d, arrowheads) express vimentin weakly (e, arrowheads) but more strongly than cells in the more differentiated area (c).
Figure 3
Figure 3
Vimentin expression in SW480 and LS174T colon carcinoma cells. Confocal microscopy for expression of vimentin and β-catenin, indicating strong expression of vimentin in SW480 cells and weaker expression in LS174T cells, is shown.
Figure 4
Figure 4
Switch in the expression patterns of β-catenin and E-cadherin in colon carcinoma cell lines. SW480 and LS174T cells are grown at low or high density. Confocal laser scanning microscopy showing staining for β-catenin (green, a–d), E-cadherin (red, e–h) and combination of both (i–f, yellow staining indicates a colocalization of both proteins). At low density, SW480 cells grow fibroblastoid with protruding lammelipodia. Note that β-catenin is nuclear and weakly cytoplasmic (a), E-cadherin shows a granular perinuclear distribution (e), and both proteins do not colocalize (i). With increasing density, SW480 cells acquire a more epithelial growth pattern. β-Catenin translocates from the nucleus to the cytoplasm and membrane (b) and E-cadherin from perinuclear region to the membrane and submembranous cytoplasm (f). Yellow staining (j) indicates a colocalization of β-catenin and E-cadherin at the membrane of the tumor cells. LS174T shows similar features, albeit more rapidly changing towards an epithelial phenotype. However, at low confluency, tumor cells at the rims of clusters show a more mesenchyme-like phenotype (arrowhead) with nuclear β-catenin (c) and cytoplasmic E-cadherin (g), which do not colocalize (k).
Figure 5
Figure 5
Nuclear accumulation of β-catenin in SW480 cells infiltrating fibroblast spheroids. CK-18 (a, c, and e) and β-catenin (b, d, and f) staining of invasive SW480 cells (a and b), less invasive LS174T cells (c and d), and the noninvasive control cell line BT-474 (e and f). Specific staining is brown, and nuclear counter staining is blue. CK 18 staining marks tumor cells surrounding or infiltrating (arrowhead) the fibroblast spheroid (a and c). Note that infiltrating tumor cells accumulate nuclear β-catenin (arrowheads), whereas most surrounding clustered tumor cells lack nuclear β-catenin (arrows) (b and d). The control tumor line expressed not nuclear but only membranous β-catenin (arrow) (f).
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