The Role of Tumor Microenvironment in Genomic Instability of Malignant Tumors

Abstract

Genomic instability is an essential feature of cancer cells. The somatic mutation theory suggests that along with inherited ones, the changes in DNA caused by environmental factors may cause cancer. Although approximately 50-60 mutations per tumor are observed in established cancer tissue, it is known that not all of these mutations occur at the beginning of carcinogenesis but also occur later in the disease progression. The high frequency of somatic mutations referring to genomic instability contributes to the intratumoral genetic heterogeneity and treatment resistance. The contribution of the tumor microenvironment to the mutations observed following the acquirement of essential malignant characteristics of a cancer cell is one of the topics that have been extensively investigated in recent years. The frequency of mutations in hematologic tumors is generally less than solid tumors. Although it is a hematologic tumor, multiple myeloma is more similar to solid tumors in terms of the high number of chromosomal abnormalities and genetic heterogeneity. In multiple myeloma, bone marrow microenvironment also plays a role in genomic instability that occurs in the very early stages of the disease. In this review, we will briefly summarize the role of the tumor microenvironment and bone marrow microenvironment in the genomic instability seen in solid tumors and multiple myeloma.

Keywords: bone marrow; cancer; genomic instability; multiple myeloma; tumor microenvironment.

Figure 1

Hypoxia is the major contributor to genomic instability in the tumor microenvironment. Along with inherited changes and the effect of environmental carcinogens, the factors resulting from tumor microenvironment contribute to genomic instability during tumor progression. DNA changes caused by hypoxia–reoxygenation cycles in the tumor microenvironment are an essential source of genomic instability. Functional genetic changes caused by these mutations lead to inhibition of apoptosis, and induction of angiogenesis and EMT, leading to further progression of tumor tissue and the carcinogenic microenvironment. TME, tumor microenvironment; EMT, epithelial–mesenchymal transition; MMR, mismatch repair; NER, nuclear excision repair; SSB, single-strand break; DSB, double-strand break.