The Impact of Obesity, Adipose Tissue, and Tumor Microenvironment on Macrophage Polarization and Metastasis

Abstract

Tumor metastasis is a major cause of death in cancer patients. It involves not only the intrinsic alterations within tumor cells, but also crosstalk between these cells and components of the tumor microenvironment (TME). Tumorigenesis is a complex and dynamic process, involving the following three main stages: initiation, progression, and metastasis. The transition between these stages depends on the changes within the extracellular matrix (ECM), in which tumor and stromal cells reside. This matrix, under the effect of growth factors, cytokines, and adipokines, can be morphologically altered, degraded, or reorganized. Many cancers evolve to form an immunosuppressive TME locally and create a pre-metastatic niche in other tissue sites. TME and pre-metastatic niches include myofibroblasts, immuno-inflammatory cells (macrophages), adipocytes, blood, and lymphatic vascular networks. Several studies have highlighted the adipocyte-macrophage interaction as a key driver of cancer progression and dissemination. The following two main classes of macrophages are distinguished: M1 (pro-inflammatory/anti-tumor) and M2 (anti-inflammatory/pro-tumor). These cells exhibit distinct microenvironment-dependent phenotypes that can promote or inhibit metastasis. On the other hand, obesity in cancer patients has been linked to a poor prognosis. In this regard, tumor-associated adipocytes modulate TME through the secretion of inflammatory mediators, which modulate and recruit tumor-associated macrophages (TAM). Hereby, this review describes the cellular and molecular mechanisms that link inflammation, obesity, and cancer. It provides a comprehensive overview of adipocytes and macrophages in the ECM as they control cancer initiation, progression, and invasion. In addition, it addresses the mechanisms of tumor anchoring and recruitment for M1, M2, and TAM macrophages, specifically highlighting their origin, classification, polarization, and regulatory networks, as well as their roles in the regulation of angiogenesis, invasion, metastasis, and immunosuppression, specifically highlighting the role of adipocytes in this process.

Macrophages in Tumor‐Associated Adipose Microenvironment Accelerate Tumor Progression

“…The M1 macrophages are also involved in the progression of malignancies, through secreting proinflammatory cytokines and increasing cytotoxic activity in antitumor immunity. [ 25 ] Importantly, M2 macrophages can be divided into 4 subtypes according to different surface markers and secreted cytokines. [ 56 ] M2 macrophages could be activated into an M2c phenotype, which has high expression of CD163 and Mer receptor tyrosine kinase, thus giving rise to their efficient phagocytosis of apoptotic cells.…”

“…TAMs facilitated tumor progression including proliferation, extracellular matrix (ECM) remodeling, angiogenesis, and immune escape, either by releasing epidermal growth factor or by degrading ECM proteins. [ 25 ] Hence, macrophage collection in adipose tissue nearby the breast cancer lesion appears to have important clinical implications, particularly regarding macrophage properties; however, it has not been thoroughly investigated.…”

Role of m6A modification and novel circ_0066715/ miR-486-5p/ ETS1 axis in rheumatoid arthritis macrophage polarization progression

“…The functions of macrophages are highly heterogeneous and plastic. Macrophages can be classified into M1 and M2 types [ 7 , 20 , 21 ]. M1 macrophages are stimulated and activated mainly by GM-CSF, LPS, etc., and can secrete a variety of pro-inflammatory cytokines (IL-1beta, IL-23, and TNF-α, etc.…”

Targeting Adiponectin in Breast Cancer

“…In addition, obesity has been shown to be associated with chronic low-grade inflammation and oxidative stress, along with abnormal variations in the level of biologically active adipokines [ 26 ], which could be considered the main mechanisms through which obesity affects breast cancer development. The inflammatory adipose microenvironment of the breast tumor includes more than 600 adipocyte-enriched secretory factors, produced by the adipocytes together with surrounding resident cells such as preadipocytes, fibroblasts, and macrophages, as well as the extracellular matrix, playing a crucial role in cancer development, progression, and metastasis [ 27 ].…”