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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

Synchronous modulation of proliferation and cancer stem cell marker expression focally in the Ad-ACA transtional zone.Immunostaining in the Ad-ACA transition zones of a primary CRC tumor showing focal loss of PTEN, Ki-67, P53, and EZH2 in the same portion of the gland that shows upregulation of SMAD4 and MGMT. The stretch of cells between the two green arrows (A & B) highlights an exact overlay of PTEN loss and SMAD4 upregulation.
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pone.0131108.g002: Synchronous modulation of proliferation and cancer stem cell marker expression focally in the Ad-ACA transtional zone.Immunostaining in the Ad-ACA transition zones of a primary CRC tumor showing focal loss of PTEN, Ki-67, P53, and EZH2 in the same portion of the gland that shows upregulation of SMAD4 and MGMT. The stretch of cells between the two green arrows (A & B) highlights an exact overlay of PTEN loss and SMAD4 upregulation.

Mentions: We examined the expression pattern of a variety of proliferation markers across the normal-hyperplastic-Ad-ACA morphologic transitions in well-oriented FFPE tumor sections of 735 primary CRC cases. In a subset of tumors, we identified a localized zone that showed striking intraglandular alteration between Ki-67+ proliferative and Ki-67- hypoproliferative stretches of adenomatous epithelium in an area adjacent to invasive carcinoma. These zones of discontinuous Ki-67 expression occurred over a stretch of ten to several hundred tumor cells (Fig 1A). Despite the striking alternating IHC pattern, Ki-67+ and Ki-67 stretches were largely morphologically indistinguishable from each other and were not present at the normal/hyperplastic epithelial transition (Fig 1A) or in the invasive carcinoma (Fig 1A). In a subset of 4 cases examined, we also noted parallel discontinuous expression of multiple cell cycle regulators, including cyclin D1, MYC and P53, in these Ad-ACA transition zones (Fig 2)


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)

Synchronous modulation of proliferation and cancer stem cell marker expression focally in the Ad-ACA transtional zone.Immunostaining in the Ad-ACA transition zones of a primary CRC tumor showing focal loss of PTEN, Ki-67, P53, and EZH2 in the same portion of the gland that shows upregulation of SMAD4 and MGMT. The stretch of cells between the two green arrows (A & B) highlights an exact overlay of PTEN loss and SMAD4 upregulation.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131108.g002: Synchronous modulation of proliferation and cancer stem cell marker expression focally in the Ad-ACA transtional zone.Immunostaining in the Ad-ACA transition zones of a primary CRC tumor showing focal loss of PTEN, Ki-67, P53, and EZH2 in the same portion of the gland that shows upregulation of SMAD4 and MGMT. The stretch of cells between the two green arrows (A & B) highlights an exact overlay of PTEN loss and SMAD4 upregulation.
Mentions: We examined the expression pattern of a variety of proliferation markers across the normal-hyperplastic-Ad-ACA morphologic transitions in well-oriented FFPE tumor sections of 735 primary CRC cases. In a subset of tumors, we identified a localized zone that showed striking intraglandular alteration between Ki-67+ proliferative and Ki-67- hypoproliferative stretches of adenomatous epithelium in an area adjacent to invasive carcinoma. These zones of discontinuous Ki-67 expression occurred over a stretch of ten to several hundred tumor cells (Fig 1A). Despite the striking alternating IHC pattern, Ki-67+ and Ki-67 stretches were largely morphologically indistinguishable from each other and were not present at the normal/hyperplastic epithelial transition (Fig 1A) or in the invasive carcinoma (Fig 1A). In a subset of 4 cases examined, we also noted parallel discontinuous expression of multiple cell cycle regulators, including cyclin D1, MYC and P53, in these Ad-ACA transition zones (Fig 2)

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