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A Transition Zone Showing Highly Discontinuous or Alternating Levels of Stem Cell and Proliferation Markers Characterizes the Development of PTEN-Haploinsufficient Colorectal Cancer.

Arvai KJ, Hsu YH, Lee LA, Jones D - PLoS ONE (2015)

Bottom Line: These zones also show parallel alternating levels and/or subcellular localization of multiple cancer stem/progenitor cell (CSC) markers, including β-catenin/CTNNB1, ALDH1, and CD44.There were no significant differences in the levels of KRAS mutation or CTNNB1 mutation in CSC-like tumors as compared to unselected CRC cases.In conclusion, we have identified a distinctive CSC-like pre-invasive transition zone in PTEN-haploinsufficient CRC that shows convergent on-off regulation of the PTEN/AKT, TGF-β/SMAD and Wnt/β-catenin pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Quest Diagnostics Nichols Institute, Chantilly, Virginia, United States of America.

ABSTRACT

Background: Stepwise acquisition of oncogene mutations and deletion/inactivation of tumor suppressor genes characterize the development of colorectal cancer (CRC). These genetic events interact with discrete morphologic transitions from hyperplastic mucosa to adenomatous areas, followed by in situ malignant transformation and finally invasive carcinoma. The goal of this study was to identify tissue markers of the adenoma-carcinoma morphogenetic transitions in CRC.

Methods and findings: We analyzed the patterns of expression of growth regulatory and stem cell markers across these distinct morphologic transition zones in 735 primary CRC tumors. In 202 cases with preserved adenoma-adenocarcinoma transition, we identified, in 37.1% of cases, a zone of adenomatous epithelium, located immediately adjacent to the invasive component, that showed rapidly alternating intraglandular stretches of PTEN+ and PTEN- epithelium. This zone exactly overlapped with similar alternating expression of Ki-67 and inversely with the transforming growth factor-beta (TGF-β) growth regulator SMAD4. These zones also show parallel alternating levels and/or subcellular localization of multiple cancer stem/progenitor cell (CSC) markers, including β-catenin/CTNNB1, ALDH1, and CD44. PTEN was always re-expressed in the invasive tumor in these cases, unlike those with complete loss of PTEN expression. Genomic microarray analysis of CRC with prominent CSC-like expansions demonstrated a high frequency of PTEN genomic deletion/haploinsufficiency in tumors with CSC-like transition zones (62.5%) but not in tumors with downregulated but non-alternating PTEN expression (14.3%). There were no significant differences in the levels of KRAS mutation or CTNNB1 mutation in CSC-like tumors as compared to unselected CRC cases.

Conclusions: In conclusion, we have identified a distinctive CSC-like pre-invasive transition zone in PTEN-haploinsufficient CRC that shows convergent on-off regulation of the PTEN/AKT, TGF-β/SMAD and Wnt/β-catenin pathways. This bottleneck-like zone is usually followed by the emergence of invasive tumors with intact PTEN expression but dysregulated TP53 and uniformly high proliferation rates.

No MeSH data available.


Related in: MedlinePlus

Uniform TP53 dysregulation in colon carcinoma occurring following the CSC-like transition zone.P53 IHC shows only single cell/focal expression in the normal epithelium and most adenomatous areas, alternating expression in pre-invasive/transition zone (inset) and uniformly upregulated P53 protein expression in the later stages of the invasive adenocarcinoma. This tumor is the same as the one illustrated in Fig 1. The common features of each morphologic transition in CRC cases with prominent CSC-like features are shown.
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pone.0131108.g005: Uniform TP53 dysregulation in colon carcinoma occurring following the CSC-like transition zone.P53 IHC shows only single cell/focal expression in the normal epithelium and most adenomatous areas, alternating expression in pre-invasive/transition zone (inset) and uniformly upregulated P53 protein expression in the later stages of the invasive adenocarcinoma. This tumor is the same as the one illustrated in Fig 1. The common features of each morphologic transition in CRC cases with prominent CSC-like features are shown.

Mentions: With the exception of MGMT, which shows more complex variable on/off expression pattern in the majority of tumors, the studied markers that were alternating within the Ad-ACA transition zone were largely uniformly expressed within the invasive ACA away from the transition. As noted above, cases with prominent alternating PTEN expression at the transition always re-expressed the protein in the invasive tumors; a similar pattern was seen for ALDH1 and EZH2. However, SMAD4 and CD44 expression was occasionally completely lost in the invasive tumor. Most striking, however, was P53 expression: TP53 expression showed a high rate of complete loss (50%) or uniform gain (41.7%) in the invasive ACA away from the Ad-ACA transition (Fig 5). In these tumors, the alternating P53 expression seen within the CSC-like transition zones was no longer observed.


A Transition Zone Showing Highly Discontinuous or Alternating Levels of Stem Cell and Proliferation Markers Characterizes the Development of PTEN-Haploinsufficient Colorectal Cancer.

Arvai KJ, Hsu YH, Lee LA, Jones D - PLoS ONE (2015)

Uniform TP53 dysregulation in colon carcinoma occurring following the CSC-like transition zone.P53 IHC shows only single cell/focal expression in the normal epithelium and most adenomatous areas, alternating expression in pre-invasive/transition zone (inset) and uniformly upregulated P53 protein expression in the later stages of the invasive adenocarcinoma. This tumor is the same as the one illustrated in Fig 1. The common features of each morphologic transition in CRC cases with prominent CSC-like features are shown.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476594&req=5

pone.0131108.g005: Uniform TP53 dysregulation in colon carcinoma occurring following the CSC-like transition zone.P53 IHC shows only single cell/focal expression in the normal epithelium and most adenomatous areas, alternating expression in pre-invasive/transition zone (inset) and uniformly upregulated P53 protein expression in the later stages of the invasive adenocarcinoma. This tumor is the same as the one illustrated in Fig 1. The common features of each morphologic transition in CRC cases with prominent CSC-like features are shown.
Mentions: With the exception of MGMT, which shows more complex variable on/off expression pattern in the majority of tumors, the studied markers that were alternating within the Ad-ACA transition zone were largely uniformly expressed within the invasive ACA away from the transition. As noted above, cases with prominent alternating PTEN expression at the transition always re-expressed the protein in the invasive tumors; a similar pattern was seen for ALDH1 and EZH2. However, SMAD4 and CD44 expression was occasionally completely lost in the invasive tumor. Most striking, however, was P53 expression: TP53 expression showed a high rate of complete loss (50%) or uniform gain (41.7%) in the invasive ACA away from the Ad-ACA transition (Fig 5). In these tumors, the alternating P53 expression seen within the CSC-like transition zones was no longer observed.

Bottom Line: These zones also show parallel alternating levels and/or subcellular localization of multiple cancer stem/progenitor cell (CSC) markers, including β-catenin/CTNNB1, ALDH1, and CD44.There were no significant differences in the levels of KRAS mutation or CTNNB1 mutation in CSC-like tumors as compared to unselected CRC cases.In conclusion, we have identified a distinctive CSC-like pre-invasive transition zone in PTEN-haploinsufficient CRC that shows convergent on-off regulation of the PTEN/AKT, TGF-β/SMAD and Wnt/β-catenin pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Quest Diagnostics Nichols Institute, Chantilly, Virginia, United States of America.

ABSTRACT

Background: Stepwise acquisition of oncogene mutations and deletion/inactivation of tumor suppressor genes characterize the development of colorectal cancer (CRC). These genetic events interact with discrete morphologic transitions from hyperplastic mucosa to adenomatous areas, followed by in situ malignant transformation and finally invasive carcinoma. The goal of this study was to identify tissue markers of the adenoma-carcinoma morphogenetic transitions in CRC.

Methods and findings: We analyzed the patterns of expression of growth regulatory and stem cell markers across these distinct morphologic transition zones in 735 primary CRC tumors. In 202 cases with preserved adenoma-adenocarcinoma transition, we identified, in 37.1% of cases, a zone of adenomatous epithelium, located immediately adjacent to the invasive component, that showed rapidly alternating intraglandular stretches of PTEN+ and PTEN- epithelium. This zone exactly overlapped with similar alternating expression of Ki-67 and inversely with the transforming growth factor-beta (TGF-β) growth regulator SMAD4. These zones also show parallel alternating levels and/or subcellular localization of multiple cancer stem/progenitor cell (CSC) markers, including β-catenin/CTNNB1, ALDH1, and CD44. PTEN was always re-expressed in the invasive tumor in these cases, unlike those with complete loss of PTEN expression. Genomic microarray analysis of CRC with prominent CSC-like expansions demonstrated a high frequency of PTEN genomic deletion/haploinsufficiency in tumors with CSC-like transition zones (62.5%) but not in tumors with downregulated but non-alternating PTEN expression (14.3%). There were no significant differences in the levels of KRAS mutation or CTNNB1 mutation in CSC-like tumors as compared to unselected CRC cases.

Conclusions: In conclusion, we have identified a distinctive CSC-like pre-invasive transition zone in PTEN-haploinsufficient CRC that shows convergent on-off regulation of the PTEN/AKT, TGF-β/SMAD and Wnt/β-catenin pathways. This bottleneck-like zone is usually followed by the emergence of invasive tumors with intact PTEN expression but dysregulated TP53 and uniformly high proliferation rates.

No MeSH data available.


Related in: MedlinePlus