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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

Mulitfocal alternating proliferation and cancer stem cell marker expression in a tumor with a prominent CSC-like Ad-ACA transtional zone.(A-D) Adenomatous epithelium adjacent to the invasive tumor shows prominent multifocal zones of PTEN loss and decreased Ki-67, with nuclear localization of β -catenin and decreased levels and basal membrane relocalization of CD44. (E,F) The Ad-ACA transition in another tumor shows multifocal stretches of adenomatous epithelium with loss of EZH2 and ALDH1 expression. The green arrows highlight areas where out-of-phase alternating patterns of CSC-like markers are occurring.
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pone.0131108.g003: Mulitfocal alternating proliferation and cancer stem cell marker expression in a tumor with a prominent CSC-like Ad-ACA transtional zone.(A-D) Adenomatous epithelium adjacent to the invasive tumor shows prominent multifocal zones of PTEN loss and decreased Ki-67, with nuclear localization of β -catenin and decreased levels and basal membrane relocalization of CD44. (E,F) The Ad-ACA transition in another tumor shows multifocal stretches of adenomatous epithelium with loss of EZH2 and ALDH1 expression. The green arrows highlight areas where out-of-phase alternating patterns of CSC-like markers are occurring.

Mentions: Given the role of PTEN/AKT signaling in mediating ISC cycling [4,15,16], we examined the level and subcellular localization of CSC markers in 21 CRC cases with PTEN/SMAD4/Ki-67 alternating transition zones. These same proliferative-hypoproliferative zones also showed dramatic discontinuity in the expression of ALDH1, EZH2, and MGMT, as well as levels and localization of CD44, and shifts in cytoplasmic/membrane and nuclear localization of β-catenin (Figs 2 and 3). In the stretches of cells with low-to-absent PTEN and Ki-67 positivity, β-catenin was shifted to the nucleus (Fig 3C). Away from the Ad-ACA transition zones, β-catenin was either fully translocated to the nucleus or present in membrane/cytoplasmic locations in nearly all cells, with only scattered single cells or small clusters of cells with nuclear-localized protein. CD44 was both downregulated and redistributed to the basal epithelium border in PTEN- areas (Fig 3D). MGMT was upregulated in areas that showed downregulation/absence of EZH2 and ALDH1 staining (Fig 2E and 2F) (Fig 3E and 3F).


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)

Mulitfocal alternating proliferation and cancer stem cell marker expression in a tumor with a prominent CSC-like Ad-ACA transtional zone.(A-D) Adenomatous epithelium adjacent to the invasive tumor shows prominent multifocal zones of PTEN loss and decreased Ki-67, with nuclear localization of β -catenin and decreased levels and basal membrane relocalization of CD44. (E,F) The Ad-ACA transition in another tumor shows multifocal stretches of adenomatous epithelium with loss of EZH2 and ALDH1 expression. The green arrows highlight areas where out-of-phase alternating patterns of CSC-like markers are occurring.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131108.g003: Mulitfocal alternating proliferation and cancer stem cell marker expression in a tumor with a prominent CSC-like Ad-ACA transtional zone.(A-D) Adenomatous epithelium adjacent to the invasive tumor shows prominent multifocal zones of PTEN loss and decreased Ki-67, with nuclear localization of β -catenin and decreased levels and basal membrane relocalization of CD44. (E,F) The Ad-ACA transition in another tumor shows multifocal stretches of adenomatous epithelium with loss of EZH2 and ALDH1 expression. The green arrows highlight areas where out-of-phase alternating patterns of CSC-like markers are occurring.
Mentions: Given the role of PTEN/AKT signaling in mediating ISC cycling [4,15,16], we examined the level and subcellular localization of CSC markers in 21 CRC cases with PTEN/SMAD4/Ki-67 alternating transition zones. These same proliferative-hypoproliferative zones also showed dramatic discontinuity in the expression of ALDH1, EZH2, and MGMT, as well as levels and localization of CD44, and shifts in cytoplasmic/membrane and nuclear localization of β-catenin (Figs 2 and 3). In the stretches of cells with low-to-absent PTEN and Ki-67 positivity, β-catenin was shifted to the nucleus (Fig 3C). Away from the Ad-ACA transition zones, β-catenin was either fully translocated to the nucleus or present in membrane/cytoplasmic locations in nearly all cells, with only scattered single cells or small clusters of cells with nuclear-localized protein. CD44 was both downregulated and redistributed to the basal epithelium border in PTEN- areas (Fig 3D). MGMT was upregulated in areas that showed downregulation/absence of EZH2 and ALDH1 staining (Fig 2E and 2F) (Fig 3E and 3F).

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