p16^Ink4a and p21^Cip1/Waf1 promote tumour growth
by enhancing myeloid-derived suppressor cells chemotaxis

Atsushi Okuma, Aki Hanyu, Sugiko Watanabe & Eiji Hara

Nat Commun. 2017 Dec 12; 8: 2050

Speaker: Wan-Yu Lee (李婉瑜)                            Time: 15:00~16:00, Mar 28^th, 2018

Commentator: Dr. Li-Jin Hsu (徐麗君老師)     Place: Room 601

Abstract:

The p16^Ink4a and p21^Waf1/Cip1 genes encode cyclin-dependent kinase (CDK) inhibitors and are upregulated upon various oncogenic stimuli to induce cellular senescence. The results of cellular senescence, a state of irreversible growth arrest, caused by these genes may act as the tumor suppressors. Indeed, mice lacking p16^Ink4a and/or p21^Waf1/Cip1 exhibit early onset of cancer.¹ However, another study revealed that p16^Ink4a expression was strikingly induced in the stroma of developing neoplasia and was important in establishing the tumor microenvironment.² As stromal elements of the tumor microenvironment can influence tumor growth and metastasis, it may illustrate the importance of understanding the role of p16^Ink4-expressed stroma cells in tumorigenesis. To date, it remains unclear which cell types are able to express p16^Ink4a in the stroma and the role of p16^Ink4a in these cancer stromal cells. Here, the author found the senescence-independent role of p16^Ink4a and p21^Waf1/Cip1 in the stromal cells of cancer. First, they found that both p16^Ink4a and p21^Waf1/Cip1 are highly expressed in monocytic myeloid-derived suppressor cells (Mo-MDSCs) without senescence phenotypes. Furthermore, they demonstrated that the expression of p16^Ink4a and p21^Waf1/Cip1 in Mo-MDSCs facilitates the infiltration of them into tumor microenvironment by upregulating the CX3CR1 chemokine receptor. The increase of Mo-MDSCs led to local immunosuppression and promoted tumor growth. This stimulation of CX3CR1 expression was triggered by preventing CDK-mediated phosphorylation and inactivation of SMAD3. Besides, blockade of CX3CL1-CX3CR1 axis suppressed the tumor growth whereas using CDK inhibitors resulted in acceleration of tumor development. These findings reveal a novel function of p16^Ink4a and p21^Waf1/Cip1 in regulating the chemotaxis of  Mo-MDSCs and provide a potential strategy to control tumorigenesis.

References:

1. Takeuchi, S. et al. Intrinsic cooperation between p16^INK4a and p21^Waf1/Cip1 in the onset of cellular senescence and tumor suppression in vivo. Cancer Res.70, 9381–9390 (2010).
2. Burd, C. E. et al. Monitoring tumorigenesis and senescence (INK4a)-luciferase model. Cell 152, 340–351 (2013).