Non-cell-autonomous tumor suppression by p53

By A. Lujambio, Leila Akkari, Janelle Simon, Danielle M. Grace, D. Tschaharganeh, Jessica E. Bolden, Zhen Zhao, V. Thapar, J. Joyce, V. Krizhanovsky and 1 more. Cell, 2013

749 citations recorded by the source corpus.

SUMMARY The p53 tumor suppressor can restrict malignant transformation by triggering cell-autonomous programs of cell cycle arrest or apoptosis. p53 also promotes cellular senescence, a tumor suppressive program that involves stable cell cycle arrest and secretion of factors that modify the tissue microenvironment. In the presence of chronic liver damage, we show that ablation of a p53-dependent senescence program in hepatic stellate cells increases liver fibrosis and cirrhosis associated with reduced survival, and enhances the transformation of adjacent epithelial cells into hepatocellular carcinoma. p53-expressing senescent stellate cells release factors that skew macrophage polarization towards a tumor-inhibiting M1-state capable of attacking senescent cells in culture, whereas proliferating p53-deficient stellate cells secrete factors that stimulate polarization of macrophages into a tumor-promoting M2-state and enhance the proliferation of premalignant cells. Hence, p53 can act non-cell autonomously to suppress tumorigenesis by promoting an anti-tumor microenvironment, in part, through secreted factors that modulate macrophage function.

View Paper: https://www.semanticscholar.org/paper/8cf49d4b03127cc637e5c0ea9e660158ee7d9bc8

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Citations in the corpus

• Senescence and the SASP: many therapeutic avenues (2020, background): “2014), and the SASP of senescent hepatic stellate cells (HSCs) participates in fibrotic scar degradation and restores tissue homeostasis in liver fibrosis (Lujambio et al. 2013).”
• Cellular senescence and its effector programs (2014, background): “Furthermore, senescent activated HSCs are eventually eliminated through senescence surveillance, by either NK cells (Krizhanovsky et al. 2008) or macrophages (Lujambio et al. 2013).”
• The senescence-associated secretory phenotype and its physiological and pathological implications (2024, unknown): “Activation or restoration of p53 induces an immunogenic SASP (including, for example, CSF1, CCL2, IL-15, CXCL1, CXCL14 and IGFBP3), which contributes to macrophage-mediated or CD4 + T cell-mediated tumour regression in lymphoma, sarcoma and liver cancer mouse models 71,75,109,173,195,196 .”
• Mechanisms and functions of cellular senescence. (2018, unknown): “Eventually, these HSCs enter into senescence, and the SASP contributes to fibrotic scar degradation, clearance of the senescent cells, and restoration of tissue homeostasis (79).”
• Mechanisms and disease consequences of nonalcoholic fatty liver disease (2021, background): “Finally, senescence of hepatic stellate cells may contribute to an altered immune microenvironment that can affect tumorigenesis associated with obesity (Lujambio et al., 2013; Yoshimoto et al., 2013).”
• Hepatic Stellate Cells and Liver Fibrosis (2013, unknown): “sion by p53 through its impact on the surrounding stromal biology (169).”