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Updated: May 8, 2026

A Quantitative Measurement of Reactive Oxygen Species and Senescence-associated Secretory Phenotype in Normal Human Fibroblasts During Oncogene-induced Senescence
13:59

A Quantitative Measurement of Reactive Oxygen Species and Senescence-associated Secretory Phenotype in Normal Human Fibroblasts During Oncogene-induced Senescence

Published on: August 12, 2018

Thrombospondin-1 mediates oncogenic Ras-induced senescence in premalignant lung tumors

Kwan-Hyuck Baek, Dongha Bhang, Alexander Zaslavsky

    The Journal of Clinical Investigation
    |September 11, 2013
    PubMed

    Insights

    Thrombospondin-1 (TSP-1) restrains lung cancer progression by stabilizing p53 and promoting senescence, independent of its antiangiogenic effects. Loss of TSP-1 reduced survival in a Kras-driven lung cancer model.

    Area of Science:

    • Oncology
    • Cell Biology
    • Molecular Biology

    Background:

    • Premalignant lesion progression is inhibited by oncogene-induced senescence.
    • Oncogenic Ras activation triggers senescence in various organs, including the lung.
    • Thrombospondin-1 (TSP-1), an angiogenesis inhibitor, is upregulated in the lung, but its role in tumorigenesis is unclear.

    Purpose of the Study:

    • To investigate the role of TSP-1 in Kras-induced lung tumorigenesis.
    • To determine if TSP-1's function is linked to its antiangiogenic properties.
    • To elucidate the molecular mechanisms by which TSP-1 influences senescence and tumor suppression.

    Main Methods:

    • Utilized a Kras-driven mouse model of lung cancer.
    • Compared tumor progression and survival in wild-type and Tsp-1 knockout mice.
    • Investigated the relationship between Kras, TSP-1, p53, ERK, and senescence pathways.

    Main Results:

    • TSP-1 plays a critical, cell-autonomous role in suppressing Kras-induced lung tumorigenesis, independent of antiangiogenesis.
    • Mice lacking Tsp-1 exhibited decreased survival in a Kras-driven lung cancer model.
    • Oncogenic Kras upregulates TSP-1 in a p53-dependent manner.
    • TSP-1 stabilizes p53 by interacting with activated ERK, sustaining MAPK signaling and senescence.

    Conclusions:

    • TSP-1 is a p53 target that maintains Ras-induced senescence in the lung.
    • TSP-1 acts as a tumor suppressor in Kras-driven lung cancer.
    • The findings reveal a novel feedback loop involving TSP-1, p53, and ERK in senescence regulation.

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