Alteration in chromatin remodeler in cancer. Chromatin remodelers are complexes that utilize ATP to shape the chromatin structure by moving, evicting, and exchanging histones. They act in response to the epigenetic modifications of chromatin and DNA generated by various epigenetic writers. There are four main families of chromatin remodelers: switch defective/sucrose non-fermenting (SWI/SNF), imitation switch (ISWI), nucleosome remodeling deacetylase/Mi-2/chromodomain helicase family (NuRD/Mi-2/CHD), and inositol requiring 80 (INO80) family
. Chromatin remodeling complexes play a crucial role in granting access to condensed genomic DNA to regulatory transcription, thereby functioning in opposition to polycomb complexes, which repress the chromatin structure. Alterations and mutations in chromatin remodeler complexes can lead to an imbalance in the chromatin structure, which can promote tumor malignancy by disrupting the balance between cell self-renewal and differentiation genes and upregulating the expression of genes involved in cell cycle progression, cell motility, and nuclear hormone signaling
Epigenetic regulation of innate immune cells. The function of dendritic cells, which are essential for T-cell-mediated immunity, is altered in the TME. The epigenetic changes in the TME impede the maturation of dendritic cells, leading to immunotolerant phenotypes with a low expression of the major histocompatibility complex (MHC, a key component in antigen-presenting machinery) and co-stimulatory molecules
[189]. In pancreatic and colon cancer, FOXM1 overexpression, a transcription factor that suppresses DC maturation and function, is due to increased H3K79me2 methylation caused by dysregulated DOT1L methyltransferase activity
[190]. In the TME, KLF4 activation in dendritic cells inhibits their maturation by promoting IL-6 release, a dendritic maturation inhibitor, through hyperacetylation of histones in the IL-6 promoter
[191][192].
Epigenetic regulation of adaptive immune cells. CD8
+ T cells are crucial in limiting tumor growth and preventing its progression. The differentiation of T-naive cells into T-effector cells, central memory cells, effector memory cells, and exhausted T cells depends on epigenetic mechanisms. However, the tumor and tumor microenvironment manipulate these mechanisms to render T cells dysfunctional and exhausted. T-cell exhaustion is characterized by an augmentation of transcriptional activity in genes associated with exhaustion, which is attributed to chromatin remodeling and relaxation. The expression of exhaustion markers, such as Tim-3, HMG box transcription factor Tox, and Tox2, is closely tied to the demethylation of their respective promoter regions
[198]. The lack of memory T cells in the tumor immune infiltration is due to specific demethylation at tissue-resident effector gene loci, such as CD39 and CD103
[199]. In pancreatic cancer, tumor-associated macrophages (TAMs) have the potential to impact the epigenetic landscape of tumor-infiltrating lymphocytes (TILs).
6.4. Nutrition and Cancer
Nutrition and diet have recently received considerable attention because of their potential impact on the development of neoplasms and as a complementary therapy to enhance the effectiveness of anti-tumor treatments. Despite numerous epidemiological studies assessing the effects of different dietary habits on health and cancer incidence, the results remain inconclusive. These studies found statistical differences among various dietary patterns, but the differences were small and difficult to reproduce
[200][201][202]. Confounding factors, such as socioeconomic status, age, physical activity, food quality, and cooking methods, may also influence the observed benefits of different dietary habits.
Nutrition can affect tumorigenesis in several ways, including modulating the immune system and inflammatory state; regulating endocrine factors, such as circulating insulin, insulin-like growth factor, leptin, and adiponectin
[203]; and influencing the gut microbiota
[204]. Although the mechanisms by which dietary macronutrients and micronutrients affect the inflammatory state are not yet fully understood, vitamin deficiencies, excessive food intake, and food deprivation have been shown to modulate the immune system and inflammatory processes
[205].
Overnutrition refers to the intake of excessive amounts of both macro- and micronutrients, which are then stored in the body’s tissues, especially adipose tissue. When there is no longer any space to store these excess nutrients, adipocytes swell and undergo changes that result in chronic inflammation, which can lead to noncommunicable diseases, such as diabetes mellitus, coronary artery disease, and stroke.
The overconsumption of food can lead to obesity, hyperlipidemia, and metabolic syndrome, which can cause chronic inflammation and predispose one to cancer
[206]. These conditions are associated with an increase in pro-inflammatory macrophage M1 and a decrease in anti-inflammatory M2 macrophages in adipose tissue, as well as an imbalance in the intestinal microbiota that leads to an accumulation of bacteria that produce procarcinogenic metabolites
[203][207]. Additionally, free fatty acids can activate Toll-like receptors, leading to the activation of the pro-inflammatory NF-κB and JNK1 pathways
[208]. Overnutrition also leads to an increase in acetyl-CoA, overactivation of mTOR, and reduction in the autophagic protein ATG7, all of which cooperate in blocking autophagy
[209]. The inhibition of autophagy can lead to the accumulation of damaged organelles that favor the aging process, activation of the NLRP3 inflammasome
[210], and accumulation of oncogenic P62
[211].
An unbalanced diet (excess or deficiency of macro- or micronutrients) may increase the risk of developing metabolic syndrome, which is characterized by elevated levels of various markers, such as C-reactive protein, glucose, IL-6, insulin, leptin, triglycerides, and low adiponectin. These changes can lead to inflammation and impair the immune system, increasing the risk of certain types of cancer.
Micronutrients, such as vitamin B6 and 25-hydroxyvitamin D, have been found to exhibit anti-tumor activity and to enhance anti-tumor immunosurveillance by preventing DNA damage and inflammation. High consumption of vitamin B6 and elevated plasma concentrations of its metabolite, pyridoxal-5′-phosphate (PLP), have been linked to a reduced risk of cancer, including gastrointestinal tumors
[212]. Increased levels of 25-hydroxyvitamin D in serum have also been associated with a decrease in pro-inflammatory markers and favorable prognosis in patients with breast cancer, prostate cancer, or colorectal cancer
[213][214][215].