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. 2009 Jan 29;28(4):509-17.
doi: 10.1038/onc.2008.407. Epub 2008 Nov 10.

PTEN deficiency accelerates tumour progression in a mouse model of thyroid cancer

C J Guigon  1 , L Zhao, M C Willingham, S-Y Cheng
Affiliations

PTEN deficiency accelerates tumour progression in a mouse model of thyroid cancer

C J Guigon et al. Oncogene. .

Abstract

Inactivation and silencing of PTEN have been observed in multiple cancers, including follicular thyroid carcinoma. PTEN (phosphatase and tensin homologue deleted from chromosome 10) functions as a tumour suppressor by opposing the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway. Despite correlative data, how deregulated PTEN signalling leads to thyroid carcinogenesis is not known. Mice harbouring a dominant-negative mutant thyroid hormone receptor beta (TRbeta(PV/PV) mice) spontaneously develop follicular thyroid carcinoma and distant metastases similar to human cancer. To elucidate the role of PTEN in thyroid carcinogenesis, we generated TRbeta(PV/PV) mice haploinsufficient for Pten (TRbeta(PV/PV)Pten(+/-) mouse). PTEN deficiency accelerated the progression of thyroid tumour and increased the occurrence of metastasis spread to the lung in TRbeta(PV/PV)Pten(+/-) mice, thereby significantly reducing their survival as compared with TRbeta(PV/PV)Pten(+/+) mice. AKT activation was further increased by two-fold in TRbeta(PV/PV)Pten(+/-) mice thyroids, leading to increased activity of the downstream mammalian _target of rapamycin (mTOR)-p70S6K signalling and decreased activity of the forkhead family member FOXO3a. Consistently, cyclin D1 expression was increased. Apoptosis was decreased as indicated by increased expression of nuclear factor-kappaB (NF-kappaB) and decreased caspase-3 activity in the thyroids of TRbeta(PV/PV)Pten(+/-) mice. Our results indicate that PTEN deficiency resulted in increased cell proliferation and survival in the thyroids of TRbeta(PV/PV)Pten(+/-) mice. Altogether, our study provides direct evidence to indicate that in vivo, PTEN is a critical regulator in the follicular thyroid cancer progression and invasiveness.

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Figures

Figure 1
Figure 1
(A) The Kaplan–Meier survival curves for TRβ+/+Pten+/+, TRβ+/+Pten+/−, TRβPV/PVPten+/+ and TRβPV/PVPten+/− mice up to 15 months of age. The Kaplan–Meier cumulative survival analysis was performed using StatView 5.0. Survival rates of TRβ+/+Pten+/− (n = 33) and TRβ+/+Pten+/+ wild-type (n = 16) mice are significantly different (P < 0.01); survival rates of TRβPV/PVPten+/+ (n = 25) and TRβPV/PVPten+/− (n = 33) are significantly different (P < 0.01) and survival rates of TRβ+/+Pten+/− and TRβPV/PVPten+/− are significantly different (P < 0.01). (B) Thyroid glands of TRβ+/+Pten+/+ (n = 3–4), TRβ+/+Pten+/− (n = 4–10), TRβPV/PVPten+/+ (n = 4–10) and TRβPV/PVPten+/− (n = 9–26) mice were dissected and compared in the same age groups. The data are presented as the ratios of thyroid weight to body weight. The difference in the thyroid weight between TRβPV/PV mice with and without deletion of one Pten allele is significant at 5–7 months (P < 0.01), as determined by analysis of variance (ANOVA). (C) H&E staining of thyroids and lungs from (a) TRβ+/+Pten+/− (b) TRβPV/PVPten+/+ and (c–f) TRβPV/PVPten+/− mice. (a) Normal thyroid of a TRβ+/+Pten+/− mouse aged 7 months. (b) Hyperplastic TRβPV/PVPten+/+ thyroid at 7 months of age showing an onset of capsular invasion (arrow). (c) Hyperplastic TRβPV/PVPten+/− thyroid at 5 months of age displaying extensive capsular invasion (arrow), (d) vascular invasion (arrow) or (e) spindle cell anaplasia. (f) Lung metastases (arrow) in TRβPV/PVPten+/− mouse. (D) Accelerated pathological progression of thyroid cancer in TRβPV/PVPten+/− mice as compared with TRβPV/PVPten+/+ mice. Sections of thyroids and lungs from TRβPV/PVPten+/+ (n = 23) and TRβPV/PVPten+/− (n = 34) mice were stained with H&E and analysed for age-dependent pathological progression of (a) capsular invasion, (b) vascular invasion, (c) anaplasia and (d) metastases in the lung. The data are expressed as the percentage of occurrence of total mutant mice examined. # indicates 0% occurrence.
Figure 2
Figure 2
No significant differences in thyroid function tests between TRβPV/PVPten+/+ and TRβPV/PVPten+/− mice at different ages. Serum total T4 (a), total T3 (b) and TSH (c) of TRβPV/PVPten+/+ (n = 9–12) mice, and TRβPV/PVPten+/− (n = 6–18) mice were determined at the ages indicated, as described in Materials and methods.
Figure 3
Figure 3
Reduced abundance of PTEN protein and increased activation of AKT in TRβPV/PVPten+/− thyroids. Total protein extracts were prepared from thyroids of TRβ+/+Pten+/+, TRβ+/+Pten+/− and thyroid tumours of TRβPV/PVPten+/+ and TRβPV/PVPten+/− mice aged 2–3 months (a and b) and 5–6 months (c–f). Western blot analyses for PTEN (a and c), phosphorylated AKT (p-AKT) (d), total AKT (e) and dynactin-2 (b and f) as loading controls were carried out as described in Materials and methods. Representative results from two to three mice are shown and the genotypes are marked. The ratios of phosphorylated protein to total protein levels after quantification of the band intensities for each sample are indicated.
Figure 4
Figure 4
Increased alteration in the AKT downstream signalling pathways in TRβPV/PV mice induced by PTEN deficiency. Total protein extracts were prepared from thyroids of TRβ+/+Pten+/+ and TRβ+/+Pten+/− and from thyroid tumours of TRβPV/PVPten+/+ and TRβPV/PVPten+/− mice, aged 5–6 months. Western blot analysis was carried out for (a) phosphorylated mTOR (p-mTOR), (b) total mTOR, (c) Dynactin-2, (d) phosphorylated p70S6K (p-p70S6K), (e) total p70S6K, (f) Dynactin-2, (g) phosphorylated FOXO3a (p-FOXO3a), (h) total FOXO3a and (i) Dynactin-2, as described in Materials and methods. The littermates with different genotypes were used in the analysis. Representative results from two to three mice are shown and the genotypes marked. The ratios of phosphorylated protein to total protein levels after quantification of the band intensities for each sample are indicated.
Figure 5
Figure 5
Increased cell-cycle progression and cell survival in TRβPV/PV mice with PTEN deficiency. Total protein extracts were prepared from thyroids of TRβ+/+Pten+/+ and TRβ+/+Pten+/−, and from thyroid tumours of TRβPV/PVPten+/+ and TRβPV/PVPten+/− mice. Western blot analysis was carried out for (Aa) Cyclin D1, (Ab) Dynactin-2, (Ba) NF-κB and (Bb) GAPDH. The littermates with different genotypes were used in the analysis. (C) Reduced apoptotic activity of thyroid tumour cells of TRβPV/PVPten+/− (c and d) mice as compared with TRβPV/PVPten+/+ (a and b). Immunostaining of cleaved caspase-3 was carried as described in Materials and methods. In the thyroid of TRβPV/PVPten+/− mice, very few thyroid cells show cleaved caspase-3 labelling (arrow) as compared with TRβPV/PVPten+/+ thyroids.
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