CDK inhibitors (p16/p19/p21) induce senescence and autophagy in cancer-associated fibroblasts, “fueling” tumor growth via paracrine interactions, without an increase in neo-angiogenesis

Abstract

Here, we investigated the compartment-specific role of cell cycle arrest and senescence in breast cancer tumor growth. For this purpose, we generated a number of hTERT-immortalized senescent fibroblast cell lines overexpressing CDK inhibitors, such as p16(INK4A), p19(ARF) or p21(WAF1/CIP1). Interestingly, all these senescent fibroblast cell lines showed evidence of increased susceptibility toward the induction of autophagy (either at baseline or after starvation), as well as significant mitochondrial dysfunction. Most importantly, these senescent fibroblasts also dramatically promoted tumor growth (up to ~2-fold), without any comparable increases in tumor angiogenesis. Conversely, we generated human breast cancer cells (MDA-MB-231 cells) overexpressing CDK inhibitors, namely p16(INK4A) or p21(WAF1/CIP1). Senescent MDA-MB-231 cells also showed increased expression of markers of cell cycle arrest and autophagy, including β-galactosidase, as predicted. Senescent MDA-MB-231 cells had retarded tumor growth, with up to a near 2-fold reduction in tumor volume. Thus, the effects of CDK inhibitors are compartment-specific and are related to their metabolic effects, which results in the induction of autophagy and mitochondrial dysfunction. Finally, induction of cell cycle arrest with specific inhibitors (PD0332991) or cellular stressors [hydrogen peroxide (H₂O₂) or starvation] indicated that the onset of autophagy and senescence are inextricably linked biological processes. The compartment-specific induction of senescence (and hence autophagy) may be a new therapeutic target that could be exploited for the successful treatment of human breast cancer patients.

Cellular senescence and autophagy of myoepithelial cells are involved in the progression of in situ areas of carcinoma ex-pleomorphic adenoma to invasive carcinoma. An in vitro model

“…Furthermore, the autophagic-senescent phenotype of stromal cells result in the production of high-energy mitochondrial fuels transferred to epithelial cancer cells to satisfy their high-energy demands, driving anabolic tumor growth (Capparelli et al 2012a, b).…”

Effects of ginsenoside Rg1 on the senescence of vascular smooth muscle cells

“…p16, p21, and p53 are involved in regulating the cell cycle and, therefore, have important roles in the process of cellular senescence (Capparelli et al, 2012). p16 inhibits the binding of CDK4/6 and cyclinD, thus preventing the activation of CDK4/6, phosphorylation of Rb, and the subsequent activation of the transcription factor E2F.…”

Mitochondria “fuel” breast cancer metabolism: Fifteen markers of mitochondrial biogenesis label epithelial cancer cells, but are excluded from adjacent stromal cells

“…In direct support of this hypothesis, genetic induction of mitochondrial dysfunction in cancer-associated fibroblasts dramatically promotes both local tumor growth and distant cancer cell metastasis. [12][13][14][15][16][17][18][19][20][21][22][23][24] Conversely, genetic amplification of mitochondrial biogenesis in epithelial cancer cells also promotes tumor growth, independently of neo-angiogenesis. 23,[25][26][27][28] Consistent with these pre-clinical findings, we have identified a series of new stromal biomarkers and related gene signatures that are characteristic of this type of lethal cancer metabolism.…”