The Role of Chronic Inflammation in Pediatric Cancer

Abstract

Inflammation plays a crucial role in wound healing and the host immune response following pathogenic invasion. However, unresolved chronic inflammation can result in tissue fibrosis and genetic alterations that contribute to the pathogenesis of human diseases such as cancer. Recent scientific advancements exploring the underlying mechanisms of malignant cellular transformations and cancer progression have exposed significant disparities between pediatric and adult-onset cancers. For instance, pediatric cancers tend to have lower mutational burdens and arise in actively developing tissues, where cell-cycle dysregulation leads to gene, chromosomal, and fusion gene development not seen in adult-onset counterparts. As such, scientific findings in adult cancers cannot be directly applied to pediatric cancers, where unique mutations and inherent etiologies remain poorly understood. Here, we review the role of chronic inflammation in processes of genetic and chromosomal instability, the tumor microenvironment, and immune response that result in pediatric tumorigenesis transformation and explore current and developing therapeutic interventions to maintain and/or restore inflammatory homeostasis.

Keywords: cancer; epigenetics; immunology; inflammation; therapeutics.

Figure 1

Chronic inflammation in pediatric cancer. Chronic inflammation plays a unique role in pediatric cancer, targeting differentiating cells and tissues. Alterations in the normal regulation of DNA repair, and abnormal epigenetic and chromosomal regulation alter the tumor microenvironment, promoting malignant transformation and tumor progression. The undeveloped and weakened pediatric immune system is limited in its ability to recognize and counter malignant cells contributing to cancer onset.

Figure 2

Chronic inflammation contributes to DNA and chromosomal instability. Chronic inflammation impairs the DNA damage response machinery resulting in the maintenance of oncogenic DNA breaks, splicing errors, and gene fusions. Exposure to chronic inflammation also contributes to the chromosomal abnormalities associated with pediatric cancer.

Figure 3

Chronic inflammation contributes to oncogenic genetic and epigenetic alterations. Exposure to chronic inflammation results in abnormal DNA and promoter methylation patterns that promote tumor growth and progression. Abnormal histone methylation and acetylation in malignant cells contribute to altered gene expression patterns affecting prognosis and drug response. Non-coding RNA alterations inhibit normal cell-cycle regulation and promote cancer cell migration.

Figure 4

Chronic inflammation alters the tissue microenvironment and immune recruitment to promote tumor onset, progression, and metastasis. Chronic inflammation promotes de-differentiation and/or malignant transformation of cells within the microenvironment, increased angiogenesis, and proinflammatory cytokine release. Conditions within the tumor microenvironment (TME) promote metastasis and inhibit immune cell recognition and targeting of malignantly transformed cancer cells. Arrows indicate an increase.