Published in

Wiley Open Access, Molecular Oncology, 8(8), p. 1729-1746, 2014

DOI: 10.1016/j.molonc.2014.07.009

Links

Tools

Export citation

Search in Google Scholar

Senescent stroma promotes prostate cancer progression: The role of miR-210

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

Full text: Download

Green circle
Preprint: archiving allowed
Green circle
Postprint: archiving allowed
Green circle
Published version: archiving allowed
Data provided by SHERPA/RoMEO

Abstract

Senescent fibroblasts lose their proliferation ability and acquire the capacity to produce pro-inflammatory and pro-angiogenic cytokines a process known as senescence-associated secretory phenotype (SASP). To investigate the role of the senescent stroma in the progression of prostate cancer, we focused our interest on replicative senescence (RS) and hydrogen peroxide stress-induced senescence (SIS) of human-derived fibroblasts. Both RS and hydrogen peroxide SIS induce SASP and the secretion of interleukin (IL)-6, IL-8, vascular endothelial growth factor-A (VEGF-A), metalloproteinase-2 and-3 (MMP2-3). Hypoxic senescent fibroblasts can promote prostate cancer aggressiveness by enhancing cancer cell motility, i.e. inducing epithelial to mesenchymal transition (EMT) and by secreting energy-rich compounds, such as lactate and ketone bodies, to support cancer cell growth. Hypoxic senescent fibroblasts additionally modify other components of the tumor microenvironment as they increase: i) the recruitment of monocytes and their M2-macrophage polarization, ii) the recruitment of bone marrow-derived endothelial precursor cells, facilitating their vasculogenic ability and iii) capillary morphogenesis, proliferation and invasion of human mature endothelial cells. In addition, we highlight that overexpression of the hypoxia-induced miR-210 in young fibroblasts increases their senescence-associated features (e.g. SASP and DNA-damage foci) and converts them into cancer associated fibroblast (CAF)-like cells, able to promote cancer cells EMT, to support angiogenesis and to recruit endothelial precursor cells and monocytes/macrophages. Our data shed new light on the ability of senescent stroma to contribute to prostate cancer malignancy, sustaining the development of a favorable microenvironment for cancer progression, by promoting pathological vessels restructuring and sustaining inflammation.