Potential oncogenic roles of mutant-p53-derived exosomes in the tumor-host interaction of head and neck cancers

Abstract

The wide-ranging collection of malignancies arising at the upper aerodigestive tract is categorized as head and neck cancer (HNC), the sixth most prevalent cancer worldwide. Infection with human papillomavirus (HPV) or exposure to carcinogens is the leading causes of HPV+ and HPV- HNCs development, respectively. HPV+ and HPV- HNCs are different in clinical and molecular aspects. Specifically, HPV- HNCs tightly associate with missense mutants of the TP53 gene (encoding for the p53 protein), suggesting a central role for mutant p53 gain-of-function (GOF) in driving tumorigenesis. In contrast, in HPV + HNC, the sequence of TP53 typically remains intact, while the protein is degraded. In tumor cells, the status of the TP53 gene affects the cargo of secreted exosomes. In this review, we describe the accumulated knowledge regarding the involvement of exosomes and p53 on cellular interactions between HPV+ and HPV- HNC cells, and the surrounding tumor microenvironment (TME). Moreover, we envision how TP53 status may determine exosomes cargo in HNC, and, consequently, modify the TME. The potential roles of exosomes described herein are based on both our studies and the studies of others on mutant p53-derived exosomes. Specifically, we showed how exosomes are shed by cancer cells harboring mutant p53 communicate with tumor-associated macrophages in the colon as well as with cancer-associated fibroblasts in the lung, creating immunosuppressive conditions and promoting invasiveness. Altogether, exosomes in HNC in the context of TP53 status are understudied and extensive research is required to shed light on the biology of HPV+ and HPV- HNC.

Keywords: CITIM 2019; Exosomes; Head and neck; Human papillomavirus; Mutant p53; Tumor microenvironment.

Fig. 1

p53 mutation rate and frequency in HNC. Analysis of the AACR Project GENIE Consortium: Powering Precision Medicine Through An International Consortium [38], showing the frequency and mutation types of TP53 in HNC sites. Left panel: rates of TP53 mutation in different anatomic sites. Middle panel: mutational distribution in the TP53 gene. Right panel: pie analysis of the TP53 mutation types

Fig. 2

Exosomes originating from ^mutp53 cancer cells promote cancer progression. Cancer cells harboring ^mutp53 interact with TME cells via unique subsets of exosomes. In the colon, ^mutp53 cancer cells release exosomes enriched with miR-1246, taken up by TAMs, reprogramming their inflammatory phenotype, thus promoting immunosuppression and metastasis. In the lung, ^mutp53 exosomes drive invasiveness by targeting CAFs. Increased integrin recycling governed by low levels of Podocalyxin in exosomes was associated with the modulation of the invasive front

Fig. 3

Prospected oncogenic mechanisms of exosomes released by HNC cells, dependent on HPV infection and p53 status. Exosomes shed by HPV+ cancer cells carry viral oncogenic proteins (E6 and E7), while exosomes from HNC HPV−, mostly p53 mutated, carry different molecular cargo, including complement proteins and mucosal proteins