Host-Related Factors in the Interplay among Inflammation, Immunity and Dormancy in Breast Cancer Recurrence and Prognosis: An Overview for Clinicians

Abstract

A significant proportion of patients treated for early breast cancer develop medium-term and late distant recurrence. The delayed manifestation of metastatic disease is defined as "dormancy". This model describes the aspects of the clinical latency of isolated metastatic cancer cells. Dormancy is regulated by extremely complex interactions between disseminated cancer cells and the microenvironment where they reside, the latter in turn influenced directly by the host. Among these entangled mechanisms, inflammation and immunity may play leading roles. This review is divided into two parts: the first describes the biological underpinnings of cancer dormancy and the role of the immune response, in particular, for breast cancer; the second provides an overview of the host-related factors that may influence systemic inflammation and immune response, subsequently impacting the dynamics of breast cancer dormancy. The aim of this review is to provide physicians and medical oncologists a useful tool to understand the clinical implications of this relevant topic.

Keywords: breast cancer; dormancy; dormant; host-related factors; immune escape; inflammation; lifestyle.

Figure 1

The life cycle of dormant cancer cells and their interactions with the niche ecosystem. An endosteal-perivascular niche is schematically represented above. The endosteal surface is placed below (cell lining below, ENC: endosteal cell or bone lining cell, OC: osteoclast, OB: osteoblast). Extracellular matrix (ECM) is the pink or blue space in the middle (pink: hypoxic environment, blue: oxygenated environment, fibrils: ECM protein structure, CAF: cancer-associated fibroblast, TAM: tumor-associated macrophage, DCC: dormant cancer cells). Blood vessels are above in the figure (PC: pericyte, EC: endothelial cell). (a) Niche invasion: DCCs anchor to ECM protein structure, establish a hypoxic microenvironment and interact with niche-resident cells that stimulate survival signals in the DCCs. (b) Quiescence: DCCs upregulate transcription factors that maintain a mesenchymal, quiescent phenotype and inhibit immune response with a direct interplay with T-lymphocytes and other immune-competent cells. (c) Reactivation: at some point, soluble factors secreted by the niche-resident cells and immune-competent cells and signals stimulated directly by DCCs induce angiogenesis and promitotic signals with subsequent reactivation of DCCs and manifestation as clinically detectable metastasis. (TCR: T-cell receptor, MHC: major histocompatibility complex, IRF7: interferon regulatory factor 7, TAP: transporter associated with antigen processing, CXCL5: C-X-C motif chemokine ligand 5, TGFβ: transforming growth factor β, GAS6: growth arrest-specific 6, NR2F1: nuclear receptor subfamily 2 group F member 1, ZFP281: zinc finger protein 281, POSTN: periostin, FA: fatty acid, BMP4: bone morphogenetic protein 4.

Figure 2

Host-related factors that influence the reactivation of DCCs through the modulation of systemic inflammation. (a) Insulin-resistance and hyperinsulinemia: elevated levels of insulin could affect the systemic inflammation, either directly, by activating immune cells, or indirectly, through the induction of proinflammatory cytokines (i.e., interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) also secreted by adipose tissue) that, in turn, boost local inflammation. (b) Prostaglandin-mediated inflammation: cancerous and normal cells from neoplastic tissue could express cyclo-oxigenase-2 (COX-2) enzyme. It converts arachidonic acid into prostaglandins, thus inducing local inflammatory response and acting on vascular compartment. (c) Lifestyle: particular types of lifestyles could affect levels of pro- and anti-inflammatory cytokines. Mediterranean diet and physical activity have the potential to reduce the levels of systemic inflammation. Conversely, a high-fat/high-sugar diet directly stimulates the release of factors that sustain inflammation (as insulin-like growth factor-1 (IGF-1)) and increases the risk of obesity. Vitamin D deficiency correlates with increased IGF-1 receptor (IGF-1R) activity, further promoting inflammation. (d) Obesity: adipose tissue could actively secrete inflammatory cytokines and sustain systemic inflammation through leptin production, which foster radical oxygen species (ROS) formation and lipid peroxidation. These processes increase the risk of steatohepatitis, which exacerbates systemic inflammatory response. SHBG: sexual hormone binding globulin, T cell: T-lymphocyte, B-cell: B-lymphocyte, NK cell: natural killer cell.