Prospects & Overviews Inﬂamm-aging of the stem cell niche: Breast cancer as a paradigmatic example Breakdown of the multi-shell cytokine network fuels cancer in aged people Massimiliano Bonafe ` 1)2) , Gianluca Storci 1)2)3) and Claudio Franceschi 1) Inﬂamm-aging is a relatively new terminology used to describe the age-related increase in the systemic pro- inﬂammatory status of humans. Here, we represent inﬂamm-aging as a breakdown in the multi-shell cytokine network, in which stem cells and stromal ﬁbroblasts (referred to as the stem cell niche) become pro-inﬂam- matory cytokine over-expressing cells due to the accumulation of DNA damage. Inﬂamm-aging self-propa- gates owing to the capability of pro-inﬂammatory cyto- kines to ignite the DNA-damage response in other cells surrounding DNA-damaged cells. Macrophages, the major cellular player in inﬂamm-aging, amplify the phenomenon, by broadcasting pro-inﬂammatory signals at both local and systemic levels. On the basis of this, we propose that inﬂamm-aging is a major contributor to the increase in cancer incidence and progression in aged people. Breast cancer will be presented as a para- digmatic example for this relationship. Keywords: .ageing; cancer; DNA damage; inflammation; stem cell; stem cell niche Introduction In this paper we hypothesize that inﬂamm-aging [1–3], the increase in the systemic pro-inﬂammatory status with age, is the major contributor to cancer progression and incidence in aged people [4–6]. On the basis of a literature review, we use breast cancer as a paradigm owing to the crucial role of pro- inﬂammatory cytokines and chemokines (e.g. interleukin-6, tumor necrosis factor alpha, interleukin-8) on the pathogenesis of this age-related malignancy [7, 8–13]. Interleukin-6 is taken as a reference molecule, based on its multi-functional role as an inﬂammatory mediator, but also as a breast cancer stem cell growth factor [8–10], stromal cell ageing inducer [11, 14–16], and systemic tumor marker [17]. In Fig. 1, we depict inﬂamm-aging as the consequence of a breakdown of the multi-shell pro-inﬂam- matory cytokine network. Rather than referring to a strict description of the tissue architecture, the proposed multi-shell model represents a simpliﬁed view aimed at disentangling the contribution of different cell types to inﬂamm-aging. In the inner shell, we represent stem cells that undergo an age-dependent shift toward a cytokine producing phenotype. We deliberately choose the over-simpliﬁed view that normal mam- mary gland stem cells are the target of malignant transformation, being aware that cancer-initiating cells potentially also arise from other normal cell compartments [18–20]. In the intermedi- ate shell, stromal ﬁbroblasts represent the stem cell niche, and we propose several mechanisms that drive such cells to acquire an age-dependent cytokine-producing phenotype. Macrophages, the major cellular actor of inﬂamm-aging [1–3, 21], which amplify local inﬂammatory stimuli and are part of the stem cell niche [22, 23] are represented in the outer shell. At the systemic level, macrophages broadcast pro-inﬂammatory sig- nals that likely depend on age-related changes in other com- partments, such as the intestinal microbiome [7, 24–26] and adipose tissue [27, 28]. Data on hematopoietic tissue are also highlighted, as this tissue represents the body compartment in which the physiologic and pathologic interactions between DOI 10.1002/bies.201100104 1) Department of Experimental Pathology, University of Bologna, Italy 2) CRBA, Center for Applied Biomedical Research, Policlinico S.Orsola Malpighi, University of Bologna, Italy 3) Institute of Oncology and Hematology ‘‘L. & A Seragnoli’’, Policlinico S.Orsola Malpighi, University of Bologna, Italy *Corresponding author: Claudio Franceschi E-mail: claudio.franceschi@unibo.it 40 www.bioessays-journal.com Bioessays 34: 40–49,ß 2011 WILEY Periodicals, Inc. Review essays