Cancer is known as a globally serious health concern, and among various characterized types, head and neck cancer (HNC) is identified as the seventh most common in the world, with approximately 890,000 new cases worldwide. HNC refers to a group of tumors in the head and neck area, exclusive of the brain, eye, ear, and esophagus. Tumors of the oral cavity, maxillofacial, otolaryngological (e.g., laryngeal cancer and nasopharyngeal carcinoma), and neck regions (e.g., thyroid cancer) are considered HNCs. Among characterized HNCs, squamous cell carcinoma (SCC) has the highest frequency of occurrence and arises from epithelial cells in the mucosa [1]. Surgery, chemo-, radio-, immune-, and/or targeted-therapy consist the common therapeutic approaches for HNC treatment. Even with employing the aggressive treatment methods, the relapse rate could be more than 50% in patients [2]. Therefore, despite all the advances, HNC treatment is still challenging. This emphasizes the need for introducing methods for prediction, noninvasive tumor detection, and prognostic markers [3].

Formation of new blood vessels from existing conduits known as angiogenesis, is essential for cancer cell proliferation, differentiation, and migration. Considering the influence of angiogenic factors on tumor growth and metastasis [4], focusing on angiogenic regulation appears to be promising for introducing novel cancer treatment strategies. Aberrant expression of non-coding RNAs (ncRNAs), a large and diverse class of RNAs, have established to promote abnormal angiogenesis [5], [6]. Unable to encode any protein, ncRNAs are key players in biological and pathological functions in various diseases, such as cancer and inflammation [7]. ncRNAs are compartmentalized into microRNA (miRNA), circular RNA (circRNA), long non-coding RNA (lncRNA), Piwi-interacting RNAs, small nuclear RNAs (snRNAs), and small nucleolar RNAs, according to the relative molecular weight, morphology and function [8]. Many processes in cancer cells, including proliferation, apoptosis, angiogenesis, and metastasis, are known to be mediated by ncRNAs which occur through transcriptional regulation and signaling pathways [9], [10]. In that regard, ncRNAs can be considered as oncogenes or tumor suppressor genes, and thereby, as therapeutic targets in various malignancies.

In tumorigenesis, transformation and communication of tumor cells with each other and with normal cells are pivotal for elevating tumor cell survival, growth, progress, angiogenesis, and metastasis [11].

Exosomes are saclike, double-layered structures, and estimated to have diameter of 30–100 nm [12]. Secreted by cancerous and various other cell types, exosomes are able to mediate local and systemic cell communications. The role of exosomes in tumor cell communication is manifested by transferring a variety of biomolecules such as lipids, proteins, DNA, RNA, and ncRNAs which are easy to transfer from the donor to the recipient cells in active form [13], [14], [15], [16]. Through fusion with the plasma membrane of target cells, exosomes are able to deliver genetic information, as well tumor cell-derived exosomes contribute to diverse pathological stages of angiogenesis [17], immunosuppression [18], and tumor deterioration [19]. Therefore, in this review, we focus on the critical role of ncRNAs including miRNA, lncRNA, and circRNA in the regulation of HNC angiogenesis to the controlling or promote HNC development. Besides, we will discuss the importance of tumor-derived exosomes, and exosomal ncRNAs in the regulation angiogenesis pathway in HNC.