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Colorectal cancers mimic structural organization of normal colonic crypts.

Cernat L, Blaj C, Jackstadt R, Brandl L, Engel J, Hermeking H, Jung A, Kirchner T, Horst D - PLoS ONE (2014)

Bottom Line: Colonic crypts are stereotypical structures with distinct stem cell, proliferating, and differentiating compartments.Our findings suggest that full activation of preserved intestinal morphogenetic programs in colon cancer requires in vivo growth environments.Furthermore, crypt-like architecture was linked with less aggressive tumor biology, and may be useful to improve current colon cancer grading schemes.

View Article: PubMed Central - PubMed

Affiliation: Pathologisches Institut, Ludwig-Maximilians-Universität, München, Germany; Victor Babes University of Medicine and Pharmacy, Timisoara, Romania.

ABSTRACT
Colonic crypts are stereotypical structures with distinct stem cell, proliferating, and differentiating compartments. Colorectal cancers derive from colonic crypt epithelia but, in contrast, form morphologically disarrayed glands. In this study, we investigated to which extent colorectal cancers phenocopy colonic crypt architecture and thus preserve structural organization of the normal intestinal epithelium. A subset of colon cancers showed crypt-like compartments with high WNT activity and nuclear β-Catenin at the leading tumor edge, adjacent proliferation, and enhanced Cytokeratin 20 expression in most differentiated tumor epithelia of the tumor center. This architecture strongly depended on growth conditions, and was fully reproducible in mouse xenografts of cultured and primary colon cancer cells. Full crypt-like organization was associated with low tumor grade and was an independent prognostic marker of better survival in a collection of 221 colorectal cancers. Our findings suggest that full activation of preserved intestinal morphogenetic programs in colon cancer requires in vivo growth environments. Furthermore, crypt-like architecture was linked with less aggressive tumor biology, and may be useful to improve current colon cancer grading schemes.

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Types of colorectal cancer as defined by nuclear β-Catenin and CK20 expression.Double immune staining for β-Catenin (brown) and CK20 (red). (Type A) Full structural organization with nuclear β-Catenin at the tumor edge (arrowhead) and CK20 within the tumor center (arrow). (Type B) Absence of nuclear β-Catenin. (Type C) Absence of central CK20. (Type D) Absence of decreased nuclear β-Catenin in the tumor center. (Type E) Absence of both nuclear β-Catenin and CK20. Frequencies of these types are given in the table.
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pone-0104284-g003: Types of colorectal cancer as defined by nuclear β-Catenin and CK20 expression.Double immune staining for β-Catenin (brown) and CK20 (red). (Type A) Full structural organization with nuclear β-Catenin at the tumor edge (arrowhead) and CK20 within the tumor center (arrow). (Type B) Absence of nuclear β-Catenin. (Type C) Absence of central CK20. (Type D) Absence of decreased nuclear β-Catenin in the tumor center. (Type E) Absence of both nuclear β-Catenin and CK20. Frequencies of these types are given in the table.

Mentions: To determine the frequency of crypt-like organization in CRCs, we used a case collection of 221 primary tumors and applied double immune staining for β-Catenin and CK20, marking both extremes of normal colonic crypt compartments. Analyses of these cases revealed 5 different types of colon cancers: The largest group (type A) showed organized expression of nuclear β-Catenin at the leading tumor edge and enhanced CK20 within the tumor center (Figure 3). Of note however, when examining cases of this type on serial sections, we observed additional enhanced CK20 expression in most infiltrative tumor cells at the leading tumor edge, overlapping with nuclear β-Catenin in most of these cases (Figure S2). The other tumors lacked this organization to some degree (Figure 3), either by absence of nuclear β-Catenin (type B), absence of enhanced CK20 in the tumor center (type C), absence of decreased nuclear β-Catenin in the tumor center (type D), or absence of both nuclear β-Catenin and CK20 expression (type E). We then examined these types for associations with tumor specific survival. Interestingly, Kaplan-Meier plots revealed best outcome for CRCs with full crypt-like structural organization, based on nuclear β-Catenin and CK20 expression (type A) that was significantly better, when statistically tested against all other types combined (Figure 4). We then examined type A tumors for associations with other clinical variables and found a significant correlation with low tumor grade, while there was no significant association with other variables such as age, gender and T category (Table 1). Finally, when testing type A tumors against others for survival prediction in multivariate analyses, full structural organization proved to be an independent prognostic marker for better cancer specific survival (Table 2). These findings demonstrate that CRCs mimic crypt-like compartments and axis formation to varying degrees and implicate that high structural similarity to normal colonic crypts may be associated with less aggressive tumor behavior.


Colorectal cancers mimic structural organization of normal colonic crypts.

Cernat L, Blaj C, Jackstadt R, Brandl L, Engel J, Hermeking H, Jung A, Kirchner T, Horst D - PLoS ONE (2014)

Types of colorectal cancer as defined by nuclear β-Catenin and CK20 expression.Double immune staining for β-Catenin (brown) and CK20 (red). (Type A) Full structural organization with nuclear β-Catenin at the tumor edge (arrowhead) and CK20 within the tumor center (arrow). (Type B) Absence of nuclear β-Catenin. (Type C) Absence of central CK20. (Type D) Absence of decreased nuclear β-Catenin in the tumor center. (Type E) Absence of both nuclear β-Catenin and CK20. Frequencies of these types are given in the table.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4128715&req=5

pone-0104284-g003: Types of colorectal cancer as defined by nuclear β-Catenin and CK20 expression.Double immune staining for β-Catenin (brown) and CK20 (red). (Type A) Full structural organization with nuclear β-Catenin at the tumor edge (arrowhead) and CK20 within the tumor center (arrow). (Type B) Absence of nuclear β-Catenin. (Type C) Absence of central CK20. (Type D) Absence of decreased nuclear β-Catenin in the tumor center. (Type E) Absence of both nuclear β-Catenin and CK20. Frequencies of these types are given in the table.
Mentions: To determine the frequency of crypt-like organization in CRCs, we used a case collection of 221 primary tumors and applied double immune staining for β-Catenin and CK20, marking both extremes of normal colonic crypt compartments. Analyses of these cases revealed 5 different types of colon cancers: The largest group (type A) showed organized expression of nuclear β-Catenin at the leading tumor edge and enhanced CK20 within the tumor center (Figure 3). Of note however, when examining cases of this type on serial sections, we observed additional enhanced CK20 expression in most infiltrative tumor cells at the leading tumor edge, overlapping with nuclear β-Catenin in most of these cases (Figure S2). The other tumors lacked this organization to some degree (Figure 3), either by absence of nuclear β-Catenin (type B), absence of enhanced CK20 in the tumor center (type C), absence of decreased nuclear β-Catenin in the tumor center (type D), or absence of both nuclear β-Catenin and CK20 expression (type E). We then examined these types for associations with tumor specific survival. Interestingly, Kaplan-Meier plots revealed best outcome for CRCs with full crypt-like structural organization, based on nuclear β-Catenin and CK20 expression (type A) that was significantly better, when statistically tested against all other types combined (Figure 4). We then examined type A tumors for associations with other clinical variables and found a significant correlation with low tumor grade, while there was no significant association with other variables such as age, gender and T category (Table 1). Finally, when testing type A tumors against others for survival prediction in multivariate analyses, full structural organization proved to be an independent prognostic marker for better cancer specific survival (Table 2). These findings demonstrate that CRCs mimic crypt-like compartments and axis formation to varying degrees and implicate that high structural similarity to normal colonic crypts may be associated with less aggressive tumor behavior.

Bottom Line: Colonic crypts are stereotypical structures with distinct stem cell, proliferating, and differentiating compartments.Our findings suggest that full activation of preserved intestinal morphogenetic programs in colon cancer requires in vivo growth environments.Furthermore, crypt-like architecture was linked with less aggressive tumor biology, and may be useful to improve current colon cancer grading schemes.

View Article: PubMed Central - PubMed

Affiliation: Pathologisches Institut, Ludwig-Maximilians-Universität, München, Germany; Victor Babes University of Medicine and Pharmacy, Timisoara, Romania.

ABSTRACT
Colonic crypts are stereotypical structures with distinct stem cell, proliferating, and differentiating compartments. Colorectal cancers derive from colonic crypt epithelia but, in contrast, form morphologically disarrayed glands. In this study, we investigated to which extent colorectal cancers phenocopy colonic crypt architecture and thus preserve structural organization of the normal intestinal epithelium. A subset of colon cancers showed crypt-like compartments with high WNT activity and nuclear β-Catenin at the leading tumor edge, adjacent proliferation, and enhanced Cytokeratin 20 expression in most differentiated tumor epithelia of the tumor center. This architecture strongly depended on growth conditions, and was fully reproducible in mouse xenografts of cultured and primary colon cancer cells. Full crypt-like organization was associated with low tumor grade and was an independent prognostic marker of better survival in a collection of 221 colorectal cancers. Our findings suggest that full activation of preserved intestinal morphogenetic programs in colon cancer requires in vivo growth environments. Furthermore, crypt-like architecture was linked with less aggressive tumor biology, and may be useful to improve current colon cancer grading schemes.

Show MeSH
Related in: MedlinePlus