Abstract
Emerging evidence reveals that adipose tissue-associated inflammation is a main mechanism whereby obesity promotes colorectal cancer risk and progression. Increased inflammasome activity in adipose tissue has been proposed as an important mediator of obesity-induced inflammation and insulin resistance development. Chronic inflammation in tumor microenvironments has a great impact on tumor development and immunity, representing a key factor in the response to therapy. In this context, the inflammasomes, main components of the innate immune system, play an important role in cancer development showing tumor promoting or tumor suppressive actions depending on the type of tumor, the specific inflammasome involved, and the downstream effector molecules. The inflammasomes are large multiprotein complexes with the capacity to regulate the activation of caspase-1. In turn, caspase-1 enhances the proteolytic cleavage and the secretion of the inflammatory cytokines interleukin (IL)-1β and IL-18, leading to infiltration of more immune cells and resulting in the generation and maintenance of an inflammatory microenvironment surrounding cancer cells. The inflammasomes also regulate pyroptosis, a rapid and inflammation-associated form of cell death. Recent studies indicate that the inflammasomes can be activated by fatty acids and high glucose levels linking metabolic danger signals to the activation of inflammation and cancer development. These data suggest that activation of the inflammasomes may represent a crucial step in the obesity-associated cancer development. This review will also focus on the potential of inflammasome-activated pathways to develop new therapeutic strategies for the prevention and treatment of obesity-associated colorectal cancer development.
Highlights
During the past decades, colorectal cancer (CRC) has become a major public health problem constituting the second most common type of cancer in females and the third most common in males, with its incidence being expected to continue increasing in the coming years [1, 2]
It is crucial to distinguish between the different anatomical distribution of the fat depots, rather than focusing exclusively on the body mass index (BMI), given that abdominal obesity characterized by an accumulation of visceral fat is associated with metabolic risk whereas the peripheral subcutaneous fat depot confers protective effects on energy homeostasis [20, 21]
Previous studies demonstrated the dual regulation between nuclear factor κ B (NF-κB) and hypoxia-inducible factor 1 (HIF-1) in cellular cultures [82, 83] Hypoxia potentiates the NF-κB signaling by modulating the expression of toll like receptors (TLRs), which are known for their functional roles in the inflammatory response in both, infectious and non-infectious diseases and in the production of IL-1β, a main pro-inflammatory cytokine [55, 84]
Summary
Colorectal cancer (CRC) has become a major public health problem constituting the second most common type of cancer in females and the third most common in males, with its incidence being expected to continue increasing in the coming years [1, 2]. Growing evidence indicates that obesity-associated low grade chronic inflammation is a central mechanism whereby obesity promotes CRC risk and progression [30, 31] In this sense, multiple clinical studies have evaluated the role of inflammation as a possible mechanism linking adipose tissue excess with increased risk of CRC development [6]. Adipose tissue depots become hypoxic as tissue mass expands, restricting the availability of oxygen in clusters of adipocytes that are distant from the vasculature [56] This imbalance between the O2 supply and demand in adipocytes promotes the release of proinflammatory mediators, an inhibition of the anti-inflammatory adipokine adiponectin, macrophage infiltration and adipocyte death. Previous studies demonstrated the dual regulation between NF-κB and HIF-1 in cellular cultures [82, 83] Hypoxia potentiates the NF-κB signaling by modulating the expression of toll like receptors (TLRs), which are known for their functional roles in the inflammatory response in both, infectious and non-infectious diseases and in the production of IL-1β, a main pro-inflammatory cytokine [55, 84]
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