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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

Liver and tumor tissue from mice with different genotypes show differing phenotypes on histological examination.Notes: Livers from Vhl−/− mice had no evidence of tumor or fatty liver formation, but did show a mildly expanded vasculature, magnified in the inset (A and B). Tumors were found in Pten−/−;Vhl−/− and Pten−/− mouse livers and had different phenotypes and varying levels of fatty liver. Pten−/−;Vhl−/− tumors had a poorly demarcated, trabecular morphology and only occasional lipid vesicles (yellow arrow) (C–E), while Pten−/− tumors had mixed glandular and solid morphologies (black arrow) and widespread lipid deposition (yellow arrow) (F–H). Large pictures are 10× magnification, inset pictures, 20×. Sizing measurements are indicated in each panel.
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Figure 1: Liver and tumor tissue from mice with different genotypes show differing phenotypes on histological examination.Notes: Livers from Vhl−/− mice had no evidence of tumor or fatty liver formation, but did show a mildly expanded vasculature, magnified in the inset (A and B). Tumors were found in Pten−/−;Vhl−/− and Pten−/− mouse livers and had different phenotypes and varying levels of fatty liver. Pten−/−;Vhl−/− tumors had a poorly demarcated, trabecular morphology and only occasional lipid vesicles (yellow arrow) (C–E), while Pten−/− tumors had mixed glandular and solid morphologies (black arrow) and widespread lipid deposition (yellow arrow) (F–H). Large pictures are 10× magnification, inset pictures, 20×. Sizing measurements are indicated in each panel.

Mentions: No tumor formation or evidence of hepatic injury was observed in Vhl−/− mice aged 12 months, although some expansion of vascular sinusoids was appreciated (Figure 1A and B). However, both Pten−/− and Pten−/−;Vhl−/− mouse populations formed tumors located exclusively in the liver with overt tumor phenotype onset (palpable mass, weight loss, ruffed coat) at approximately 9–12 months. No abnormalities were observed in other tissues. Tumors were detectable only on histologic evaluation in the majority of Pten−/−;Vhl−/− animals, but were grossly visible as numerous massive tumors in Pten−/− mice. Pten−/−;Vhl−/− mouse tumors were small and widely dispersed (Figure 1C–E), and displayed a trabecular morphology (Figure 1D and E, white arrows) with large, unencapsulated, expansile and partially infiltrative masses of neoplastic cells replacing and compressing normal remaining hepatocytes, consistent with histologic findings of a CC. Tumors from Pten−/− mice, however, histologically showed highly variable neoplastic cells that typically arose within foci of hepatic alteration (Figure 1F–H). The phenotype was indicative of a poorly-differentiated carcinoma with mixed glandular and solid morphologies (Figure 1F, black arrows), and may represent a hepatocellular or mixed cell neoplasm.


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)

Liver and tumor tissue from mice with different genotypes show differing phenotypes on histological examination.Notes: Livers from Vhl−/− mice had no evidence of tumor or fatty liver formation, but did show a mildly expanded vasculature, magnified in the inset (A and B). Tumors were found in Pten−/−;Vhl−/− and Pten−/− mouse livers and had different phenotypes and varying levels of fatty liver. Pten−/−;Vhl−/− tumors had a poorly demarcated, trabecular morphology and only occasional lipid vesicles (yellow arrow) (C–E), while Pten−/− tumors had mixed glandular and solid morphologies (black arrow) and widespread lipid deposition (yellow arrow) (F–H). Large pictures are 10× magnification, inset pictures, 20×. Sizing measurements are indicated in each panel.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Liver and tumor tissue from mice with different genotypes show differing phenotypes on histological examination.Notes: Livers from Vhl−/− mice had no evidence of tumor or fatty liver formation, but did show a mildly expanded vasculature, magnified in the inset (A and B). Tumors were found in Pten−/−;Vhl−/− and Pten−/− mouse livers and had different phenotypes and varying levels of fatty liver. Pten−/−;Vhl−/− tumors had a poorly demarcated, trabecular morphology and only occasional lipid vesicles (yellow arrow) (C–E), while Pten−/− tumors had mixed glandular and solid morphologies (black arrow) and widespread lipid deposition (yellow arrow) (F–H). Large pictures are 10× magnification, inset pictures, 20×. Sizing measurements are indicated in each panel.
Mentions: No tumor formation or evidence of hepatic injury was observed in Vhl−/− mice aged 12 months, although some expansion of vascular sinusoids was appreciated (Figure 1A and B). However, both Pten−/− and Pten−/−;Vhl−/− mouse populations formed tumors located exclusively in the liver with overt tumor phenotype onset (palpable mass, weight loss, ruffed coat) at approximately 9–12 months. No abnormalities were observed in other tissues. Tumors were detectable only on histologic evaluation in the majority of Pten−/−;Vhl−/− animals, but were grossly visible as numerous massive tumors in Pten−/− mice. Pten−/−;Vhl−/− mouse tumors were small and widely dispersed (Figure 1C–E), and displayed a trabecular morphology (Figure 1D and E, white arrows) with large, unencapsulated, expansile and partially infiltrative masses of neoplastic cells replacing and compressing normal remaining hepatocytes, consistent with histologic findings of a CC. Tumors from Pten−/− mice, however, histologically showed highly variable neoplastic cells that typically arose within foci of hepatic alteration (Figure 1F–H). The phenotype was indicative of a poorly-differentiated carcinoma with mixed glandular and solid morphologies (Figure 1F, black arrows), and may represent a hepatocellular or mixed cell neoplasm.

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