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Von Hippel-Lindau status influences phenotype of liver cancers arising from PTEN loss.

Sendor AB, Hacker KE, Chen S, Corona AL, Sen O, Chiang DY, Snavely A, Rogers AB, Montgomery SA, Rathmell WK, McRee AJ - Gastrointest Cancer (2015)

Bottom Line: The factors that influence the penetrance of these conditions are unclear.Pten deletion alone led to large hepatic tumors with widespread hepatosteatosis.Co-deletion of Vhl and Pten results in lower tumor burden with gene expression profiling suggesting a switch from a profile of lipid deposition to an expression profile more consistent with upregulation of the hypoxia response pathway.

View Article: PubMed Central - PubMed

Affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.

ABSTRACT

Background: PTEN loss contributes to the development of liver diseases including hepatic steatosis and both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). The factors that influence the penetrance of these conditions are unclear. We explored the influence of sustained hypoxia signaling through co-deletion of Pten and Vhl in a murine model.

Methods: We used a CreER-linked Keratin 18 mouse model to conditionally delete Pten, Vhl or both in somatic cells of adult mice, evaluating the resultant tumors by histology and gene expression microarray. Existing sets of gene expression data for human HCC and CC were examined for pathways related to those observed in the murine tumors, and a cohort of human CC samples was evaluated for relationships between HIF-1α expression and clinical outcomes.

Results: Both Pten deletion genotypes developed liver tumors, but with differing phenotypes. Pten deletion alone led to large hepatic tumors with widespread hepatosteatosis. Co-deletion of Pten and Vhl with the Keratin 18 promoter resulted in reduced steatosis and a reduced tumor burden that was characterized by a trabecular architecture similar to CC. Genes associated with hepatic steatosis were coordinately expressed in the human HCC dataset, while genes involved in hypoxia response were upregulated in tumors from the human CC dataset. HIF-1α expression and overall survival were examined in an independent cohort of human CC tumors with no statistical differences uncovered.

Conclusion: Pten deletion in Keratin 18 expressing cells leads to aggressive tumor formation and widespread steatosis in mouse livers. Co-deletion of Vhl and Pten results in lower tumor burden with gene expression profiling suggesting a switch from a profile of lipid deposition to an expression profile more consistent with upregulation of the hypoxia response pathway. A relationship between tumor hypoxia signaling and altered hepatic steatotic response suggests that competing influences may alter tumor phenotypes.

No MeSH data available.


Related in: MedlinePlus

HIF-1α is variably expressed in a UNC cohort of human CC and may influence disease severity.Notes: (A and B) human CC tumors were stained for HIF-1α expression, demonstrating an example of high expression (A) and low expression (B). Human tumors were also stained for phosphor-S6, with all tumors displaying positive expression of this marker, example shown in (C). (D) Kaplan–Meier curve demonstrates survival data from a cohort of 27 human CC patients based on HIF-1α expression.Abbreviations: UNC, University of North Carolina; CC, cholangiocarcinoma.
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Figure 5: HIF-1α is variably expressed in a UNC cohort of human CC and may influence disease severity.Notes: (A and B) human CC tumors were stained for HIF-1α expression, demonstrating an example of high expression (A) and low expression (B). Human tumors were also stained for phosphor-S6, with all tumors displaying positive expression of this marker, example shown in (C). (D) Kaplan–Meier curve demonstrates survival data from a cohort of 27 human CC patients based on HIF-1α expression.Abbreviations: UNC, University of North Carolina; CC, cholangiocarcinoma.

Mentions: To more directly examine the role of HIF expression in influencing tumor phenotype, we identified a cohort of CC cases at UNC for protein analysis. The clinicopathologic characteristics of 27 CC patients and their tumors are summarized in Table 1. Via IHC, 56% of these tumors expressed HIF-1α. Univariate analysis of OS in these patients based on HIF-1α expression was not statistically significant (60 versus 30.9 months, P=0.402) (Figure 5). In comparing the clinicopathologic variables of these two groups, patients whose tumors displayed positive HIF-1α expression were more likely to have resectable tumors with only 13% being unresectable compared to 50% of the HIF-1α negative tumors (P=0.053; Table 2). The small sample size and exploratory nature of this study begs for future studies aimed at determining whether targeting the HIF pathway has any bearing on clinical outcomes.


Von Hippel-Lindau status influences phenotype of liver cancers arising from PTEN loss.

Sendor AB, Hacker KE, Chen S, Corona AL, Sen O, Chiang DY, Snavely A, Rogers AB, Montgomery SA, Rathmell WK, McRee AJ - Gastrointest Cancer (2015)

HIF-1α is variably expressed in a UNC cohort of human CC and may influence disease severity.Notes: (A and B) human CC tumors were stained for HIF-1α expression, demonstrating an example of high expression (A) and low expression (B). Human tumors were also stained for phosphor-S6, with all tumors displaying positive expression of this marker, example shown in (C). (D) Kaplan–Meier curve demonstrates survival data from a cohort of 27 human CC patients based on HIF-1α expression.Abbreviations: UNC, University of North Carolina; CC, cholangiocarcinoma.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2 - License 3
Show All Figures
getmorefigures.php?uid=PMC4383253&req=5

Figure 5: HIF-1α is variably expressed in a UNC cohort of human CC and may influence disease severity.Notes: (A and B) human CC tumors were stained for HIF-1α expression, demonstrating an example of high expression (A) and low expression (B). Human tumors were also stained for phosphor-S6, with all tumors displaying positive expression of this marker, example shown in (C). (D) Kaplan–Meier curve demonstrates survival data from a cohort of 27 human CC patients based on HIF-1α expression.Abbreviations: UNC, University of North Carolina; CC, cholangiocarcinoma.
Mentions: To more directly examine the role of HIF expression in influencing tumor phenotype, we identified a cohort of CC cases at UNC for protein analysis. The clinicopathologic characteristics of 27 CC patients and their tumors are summarized in Table 1. Via IHC, 56% of these tumors expressed HIF-1α. Univariate analysis of OS in these patients based on HIF-1α expression was not statistically significant (60 versus 30.9 months, P=0.402) (Figure 5). In comparing the clinicopathologic variables of these two groups, patients whose tumors displayed positive HIF-1α expression were more likely to have resectable tumors with only 13% being unresectable compared to 50% of the HIF-1α negative tumors (P=0.053; Table 2). The small sample size and exploratory nature of this study begs for future studies aimed at determining whether targeting the HIF pathway has any bearing on clinical outcomes.

Bottom Line: The factors that influence the penetrance of these conditions are unclear.Pten deletion alone led to large hepatic tumors with widespread hepatosteatosis.Co-deletion of Vhl and Pten results in lower tumor burden with gene expression profiling suggesting a switch from a profile of lipid deposition to an expression profile more consistent with upregulation of the hypoxia response pathway.

View Article: PubMed Central - PubMed

Affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.

ABSTRACT

Background: PTEN loss contributes to the development of liver diseases including hepatic steatosis and both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). The factors that influence the penetrance of these conditions are unclear. We explored the influence of sustained hypoxia signaling through co-deletion of Pten and Vhl in a murine model.

Methods: We used a CreER-linked Keratin 18 mouse model to conditionally delete Pten, Vhl or both in somatic cells of adult mice, evaluating the resultant tumors by histology and gene expression microarray. Existing sets of gene expression data for human HCC and CC were examined for pathways related to those observed in the murine tumors, and a cohort of human CC samples was evaluated for relationships between HIF-1α expression and clinical outcomes.

Results: Both Pten deletion genotypes developed liver tumors, but with differing phenotypes. Pten deletion alone led to large hepatic tumors with widespread hepatosteatosis. Co-deletion of Pten and Vhl with the Keratin 18 promoter resulted in reduced steatosis and a reduced tumor burden that was characterized by a trabecular architecture similar to CC. Genes associated with hepatic steatosis were coordinately expressed in the human HCC dataset, while genes involved in hypoxia response were upregulated in tumors from the human CC dataset. HIF-1α expression and overall survival were examined in an independent cohort of human CC tumors with no statistical differences uncovered.

Conclusion: Pten deletion in Keratin 18 expressing cells leads to aggressive tumor formation and widespread steatosis in mouse livers. Co-deletion of Vhl and Pten results in lower tumor burden with gene expression profiling suggesting a switch from a profile of lipid deposition to an expression profile more consistent with upregulation of the hypoxia response pathway. A relationship between tumor hypoxia signaling and altered hepatic steatotic response suggests that competing influences may alter tumor phenotypes.

No MeSH data available.


Related in: MedlinePlus