Mast Cells, microRNAs and Others: The Role of Translational Research on Colorectal Cancer in the Forthcoming Era of Precision Medicine

Abstract

Colorectal cancer (CRC) is a heterogeneous disease, molecularly and anatomically, that develops in a multi-step process requiring the accumulation of several genetic or epigenetic mutations that lead to the gradual transformation of normal mucosa into cancer. In fact, tumorigenesis is extremely complex, with many immunologic and non-immunologic factors present in the tumor microenvironment that can influence tumorigenesis. In the last few years, a role for mast cells (MCs), microRNAs (miRNAs), Kirsten rat sarcoma (KRAS) and v-raf murine sarcoma viral oncogene homologue B (BRAF) in cancer development and progression has been suggested, and numerous efforts have been made to thoroughly assess their correlation with CRC to improve patient survival and quality of life. The identification of easily measurable, non-invasive and cost-effective biomarkers, the so-called "ideal biomarkers", for CRC screening and treatment remains a high priority. The aim of this review is to discuss the emerging role of mast cells (MCs), microRNAs (miRNAs), KRAS and BRAF as diagnostic and prognostic biomarkers for CRC, evaluating their influence as potential therapy targets in the forthcoming era of precision medicine.

Keywords: BRAF; KRAS; colorectal cancer; mast cells; microRNAs; precision medicine; translational research.

Figure 1

The close relationship between mast cells (MCs) and tumor progression angiogenesis-mediated. Reproduced with permission from Marech et al. [35].

Figure 2

Schematic of the selected miRNA–mRNA networks involved in colorectal cancer (CRC). Red indicates a higher level in CRC and green represents a lower level compared with controls. The triangle refers to miRNAs, and the circle refers to target genes. Yellow refers to MARKER genes related to CRC that are recruited in the Comparative Toxicogenomics Database (CTD) database. In tumors, miR-1260b possesses 53 target genes that are significantly down-regulated, whereas miR-425-5p and miR-144-3p possess 159 and 162 target genes, respectively, that were significantly upregulated. A total of nine MARKER-related genes are found in CRC, including ATP-binding Cassette Transporter A1 (ABCA1), ATP-binding Cassette Transporter A8 (ABCA8), EGF Containing Fibulin Extracellular Matrix Protein 1 (EFEMP1), Monoamine Oxidase B (MAOB), REarranged during Transfection (RET), StAR Related Lipid Transfer Domain Containing 8 (STARD8), ATP-binding Cassette Transporter A10 (ABCA10), Leucine Rich Repeat Containing 3B (LRRC3B), and Secreted Frizzled Related Protein 1 (SFRP1). Reproduced with permission from Tan et al. [61].

Figure 3

MicroRNAs control colorectal carcinoma progression through modulating anti-tumor immune responses in the tumor microenvironment. For example, miR-20b and miR-130b repress the expression of Phosphatase and tensin homolog (PTEN) and increase the activity of Phosphoinositide 3-kinase (PI3K), leading to the increased viability of CRC cells. MiR-21 promotes CRC invasion and metastasis by directly targeting Programmed Cell Death 4 (PDCD4). Furthermore, miR-34a enhances cluster of differentiation 8 (CD8+) T cells cytotoxicity by repressing the expression of programmed death-ligand 1 (PD-L1), contributing to the elimination of CRC cells by cytotoxic T lymphocytes (CTLs). Reproduced with permission from [68].