Overview on Molecular Biomarkers for Laryngeal Cancer: Looking for New Answers to an Old Problem

Abstract

Laryngeal squamous cell cancer (LSCC) accounts for almost 25-30% of all head and neck squamous cell cancers and is clustered according to the affected districts, as this determines distinct tendency to recur and metastasize. A major role for numerous genetic alterations in driving the onset and progression of this neoplasm is emerging. However, major efforts are still required for the identification of molecular markers useful for both early diagnosis and prognostic definition of LSCC that is still characterized by significant morbidity and mortality. Non-coding RNAs appear the most promising as they circulate in all the biological fluids allowing liquid biopsy determination, as well as due to their quick and characteristic modulation useful for non-invasive detection and monitoring of cancer. Other critical aspects are related to recent progress in circulating tumor cells and DNA detection, in metastatic status and chemo-refractoriness prediction, and in the functional interaction of LSCC with chronic inflammation and innate immunity. We review all these aspects taking into account the progress of the technologies in the field of next generation sequencing.

Keywords: CTC; LSCC (laryngeal squamous cell carcinoma); TME (tumor microenvironment); biomarkers; ctDNA; epigenetic modifications; inflammatory markers; lncRNA; miRNA.

Figure 1

DNA methyltransferases (DNMT)-dependent regulation of miRNA expression. Promoter hypermethylation inhibits the expression of tumor suppressor genes, thus hindering their translational inhibitory function which results in neoplastic transformation.

Figure 2

miRNA-dependent target-gene expression through DNMT regulation. (A) In normal cells, tumor suppressor miRNAs inhibit DNMT allowing target gene expression. (B) In cancer cells, the downregulation of tumor suppressor miRNAs activates DNMT-dependent silencing of target genes.

Figure 3

Schematic representation of multilevel interactions between extracellular molecular mediators of LSCC. Both extrinsic and intrinsic pathways contribute to triggering immune response and inflammation in LSCC, promoting EMT process, cell proliferation, motility, and chemo-resistance. The delivery of siRNA towards specific targets can improve the drug response or opportunely alter the miRNA expression profile improving patients’ prognosis.