Abstract
Simple SummaryThe inflammatory adipose microenvironment in obesity plays a crucial role in cancer development and metastases. By focusing on adipocytes and macrophages, as well as the extracellular matrix, the cellular and molecular mechanisms that link inflammation, obesity, and cancer will be addressed by this review. After describing the tumor microenvironment and extracellular matrix, the influence of M1, M2, and tumor-associated macrophages will be explored through their origin, classification, polarization, and regulatory networks, including their potential role in angiogenesis, invasion, metastasis, and immunosuppression, with a specific focus on the roles of adipocytes in this process.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.
Highlights
Cancer is typically associated with neo-angiogenesis, tumor-enhanced inflammation, and the uncontrolled growth of abnormal cells
Macrophages and tumor cells secrete various cytokines, chemokines, hormones, matrix metalloproteinase (MMP), Lysyl Oxidases (LOX: enzymes secreted by primary tumor cells for linear cross-linking of collagen) and growth factor (GF), which are initially interstitial
Immunotherapy strategies targeting nonmalignant cells have been developed, including the following: (a) antiangiogenic drugs [340–343], (b) drugs targeting tumor-associated macrophages (TAM), which contribute to chemoresistance by inducing prosurvival and antiapoptotic signals in cancer cells [344,345], (c) anti-cachexia drugs [346], (d) adoptive cellular immunotherapy [347], (e) antibodies [348,349], (f) small-molecule inhibitors [350], (g) immune checkpoint inhibitors [351] and (h) multiple agents targeting Th2 cytokines and their receptors [352,353]
Summary
Cancer is typically associated with neo-angiogenesis, tumor-enhanced inflammation, and the uncontrolled growth of abnormal cells. Invasive tumor cells gain access to blood vessels by leaving the primary tumor site and invading the surrounding tissues, reaching the blood and lymphatic vessels where they disseminate to remote organs [4–7] The metastasis of these cancers accounts for approximately 90% of cancer-related deaths [8,9]. Leek and Harris described macrophages as the “Swiss Army knife” of the immune system [22], as they are involved in the regulation of tissue homeostasis, the inflammatory response to pathogens, and wound healing [23,24] These cells show high phenotypic heterogeneity (different subpopulations) depending on the microenvironment [25,26]. Macrophages can stimulate angiogenesis and improve tumor cell motility and infiltration During metastasis, they initiate the pre-metastatic site, promoting extravasation, survival, and the sustained growth of tumor cells. Obesity/overweight (adipocytes), inflammation (macrophages), and tumors (transformed cells) form an important triangle that is proven to regulate TME [35–37]
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