Thrombospondin-1 mediates oncogenic Ras–induced senescence in premalignant lung tumors
Kwan-Hyuck Baek, … , Gerard I. Evan, Sandra Ryeom
Kwan-Hyuck Baek, … , Gerard I. Evan, Sandra Ryeom
Published September 9, 2013
Citation Information: J Clin Invest. 2013;123(10):4375-4389. https://doi.org/10.1172/JCI67465.
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Thrombospondin-1 mediates oncogenic Ras–induced senescence in premalignant lung tumors

Abstract

Progression of premalignant lesions is restrained by oncogene-induced senescence. Oncogenic Ras triggers senescence in many organs, including the lung, which exhibits high levels of the angiogenesis inhibitor thrombospondin-1 (TSP-1). The contribution of TSP-1 upregulation to the modulation of tumorigenesis in the lung is unclear. Using a mouse model of lung cancer, we have shown that TSP-1 plays a critical and cell-autonomous role in suppressing Kras-induced lung tumorigenesis independent of its antiangiogenic function. Overall survival was decreased in a Kras-driven mouse model of lung cancer on a Tsp-1–/– background. We found that oncogenic Kras–induced TSP-1 upregulation in a p53-dependent manner. TSP-1 functioned in a positive feedback loop to stabilize p53 by interacting directly with activated ERK. TSP-1 tethering of ERK in the cytoplasm promoted a level of MAPK signaling that was sufficient to sustain p53 expression and a senescence response. Our data identify TSP-1 as a p53 target that contributes to maintaining Ras-induced senescence in the lung.

Authors

Kwan-Hyuck Baek, Dongha Bhang, Alexander Zaslavsky, Liang-Chuan Wang, Anil Vachani, Carla F. Kim, Steven M. Albelda, Gerard I. Evan, Sandra Ryeom

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Figure 2

KrasG12D-induced senescence during lung tumor progression is compromised in the absence of TSP-1.

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KrasG12D-induced senescence during lung tumor progression is compromise...
(A) Microvessel density in large lung adenomas of similar size from KrasG12D×Tsp-1+/+ and KrasG12D×Tsp-1–/– mice 21 weeks after oncogenic Kras activation. Tumor microvessels were visualized by immunostaining for CD31 and quantified by measuring microvessel density per high-powered field (MVD/hpf). Arrows indicate representative tumor microvessels. (B) Hyperplastic lesions in lungs 4 weeks after Ad-Cre inhalation. Lungs were isolated (n = 4 per group), and the number of lesions with atypical adenomatous hyperplasia or epithelial hyperplasia (EH) was counted after H&E staining. Arrows indicate hyperplastic lesions. (C) H&E staining, BrdU uptake, and SA–β-gal staining of serial sections from lung tumors harvested 21 weeks after Ad-Cre infection. (D) Proliferation in lung tumor lesions, as assessed by immunostaining for Ki-67, 21 weeks after Ad-Cre infection. (E) KrasG12D-induced senescence of primary adult lung epithelial cells isolated in vitro, as assessed by SA–β-gal positivity, at the indicated times after oncogenic Kras activation. (F) PML expression 21 days after oncogenic Kras activation in primary adult lung epithelial cells, determined by immunostaining. (G) Proliferation of primary adult lung fibroblasts isolated in vitro at the indicated times after oncogenic Kras activation. (H) KrasG12D-induced senescence of primary adult lung fibroblasts in vitro, measured by SA–β-gal positivity, at the indicated times after oncogenic Kras activation. SA–β-gal staining was quantified 35 days after Kras activation. Scale bars: 50 μm (A; B, insets; C; and D); 1 mm (B); 200 μm (E and H); 100 μm (F). Data represent mean ± SEM.