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. 2005 Aug 1;19(15):1773-8.
doi: 10.1101/gad.1314605. Epub 2005 Jul 18.

Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2

Brendan D Manning  1 , M Nicole Logsdon, Alex I Lipovsky, Derek Abbott, David J Kwiatkowski, Lewis C Cantley
Affiliations

Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2

Brendan D Manning et al. Genes Dev. .

Abstract

The PTEN and TSC2 tumor suppressors inhibit mammalian target of rapamycin (mTOR) signaling and are defective in distinct hamartoma syndromes. Using mouse genetics, we find that Pten and Tsc2 act synergistically to suppress the severity of a subset of tumors specific to loss of each of these genes. Interestingly, we find that the slow-growing tumors specific to Tsc2+/- mice exhibit defects in signaling downstream of Akt. However, Pten haploinsufficiency restores Akt signaling in these tumors and dramatically enhances their severity. This study demonstrates that attenuation of the PI3K-Akt pathway in tumors lacking TSC2 contributes to their benign nature.

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Figures

Figure 1.
Figure 1.
Reduced survival and early development of lymph node hyperplasia in Tsc2+/- Pten+/- double-heterozygous mice. (a) One-year Kaplan-Meier survival analyses for a cohort of 248 offspring from crosses between Tsc2+/- and Pten+/- mice (N = 70 wild type [WT], 59 Tsc2+/-, 69 Pten+/-, and 50 Tsc2+/- Pten+/- [Dbl Het]). P = 0.0003 for comparison of Pten+/- and Dbl Het survival curves. (b) Kaplan-Meier analyses of lymph node hyperplasia detection in the same cohort from a. P = 0.0003 for comparison of Pten+/- and Dbl Het curves. (c) Presence of TSC2 and PTEN protein and elevated mTOR signaling in the hyperplastic lymph nodes of Tsc2+/- PTEN+/- mice. Protein extracts from normal (wild-type and Tsc2+/- [T+/-]) and hyperplastic (Pten+/- and Dbl Het) lymph nodes were prepared from six 15-wk-old mice of each genotype as indicated (representative samples for each are shown), normalized for protein concentration (100 μg/lane), and analyzed by immunoblotting, as indicated.
Figure 2.
Figure 2.
Enhanced angiosarcomas and liver hemangiomas in Tsc2+/- Pten+/- mice. (a) Summary graph of the incidence of TSC-related tumors in Tsc2+/- and Tsc2+/- Pten+/- mice. See text for details. (b) Macroscopic view of a typical angiosarcoma on the paw of a Tsc2+/- Pten+/- mouse at 40 wk. (c) A section from the tumor in b. (d) An angiosarcoma found adjacent to the spine of a Tsc2+/- Pten+/- mouse. (SkM) Skeletal muscle; (Sp) spine. The boxed region is shown at high magnification in the inset. (e) Kidney adenoma from a Tsc2+/- Pten+/- mouse at 6 mo. (f,g) Typical liver hemangioma from a 12-mo-old Tsc2+/- mouse (f) compared with an example of the lesions found in Tsc2+/- Pten+/- mice (g). (c-g) H&E-stained tumors. (c-e) Arrowheads point to tumor borders. (h) Anti-TSC2 staining of a Tsc2+/- Pten+/- liver hemangioma and adjacent normal liver (NL). The staining within the vascular lesion is blood (bl). (i) High-magnification view of the box from h, demonstrating loss of TSC2 staining within the endothelial cells comprising the liver hemangioma. (j) Maintenance of PTEN expression in a Tsc2+/- Pten+/- liver hemangioma. Bars: b, 1 cm; c-g, 1 mm; d, inset, 100 μm; h, 200 μm; i,j, 40 μm.
Figure 3.
Figure 3.
High phospho-S6 levels and differential FOXO1 localization in liver hemangiomas from Tsc2+/- and Tsc2+/- Pten+/- mice. (a,b) A representative example of high phospho-S6 staining within a Tsc2+/- liver hemangioma (a) and a Tsc2+/- Pten+/- liver hemangioma (b), both from mice aged 12 mo. (c-e) Differential localization of FOXO1 in the endothelial cells of Tsc2+/- and Tsc2+/- Pten+/- liver hemangiomas. A representative example of the nuclear localization of FOXO1 in lesions from Tsc2+/- mice (c), in contrast to the predominantly cytoplasmic localization in those from age-matched (12 mo) Tsc2+/- Pten+/- mice (d) (arrowheads point to examples of this localization; insets, 1000× magnification). Bars: a-d, 40 μm. (e) Quantification of endothelial cells from liver hemangiomas showing more cytoplasmic FOXO1 than nuclear. Three hemangiomas per liver for two different Tsc2+/- (T1 and T2) and Tsc2+/- Pten+/- (TP1 and TP2) mice (all aged 12 mo) were examined. Nuclear/cytoplasmic localization in each endothelial cell positive for FOXO1 staining was scored within these lesions (>100 positive cells counted per lesion). Data are graphed as the mean percentage of cells per lesion exhibiting greater cytoplasmic than nuclear FOXO1 staining (error bars indicate standard deviation). P < 0.0001 for all comparisons between Pten+/- and Tsc2+/- Pten+/- data sets. As a control, cytoplasmic phospho-S6 (pS6) staining from adjacent sections of the same lesions was scored. (f) Crude lysates were prepared from liver hemangioma tissue and were analyzed by immunoblotting, as indicated. The total Akt blot was performed after stripping of the phospho-Akt (S473) blot. Representative samples from two of each genotype are shown.
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