Abstract
Head and neck squamous cell carcinomas (HNSCCs) are the eighth most common cancers worldwide. While promising new therapies are emerging, cisplatin-based chemotherapy remains the gold standard for advanced HNSCCs, although most of the patients relapse due to the development of resistance. This review aims to condense the different mechanisms involved in the development of cisplatin resistance in HNSCCs and highlight future perspectives intended to overcome its related complications. Classical resistance mechanisms include drug import and export, DNA repair and oxidative stress control. Emerging research identified the prevalence of these mechanisms in populations of cancer stem cells (CSC), which are the cells mainly contributing to cisplatin resistance. The use of old and new CSC markers has enabled the identification of the characteristics within HNSCC CSCs predisposing them to treatment resistance, such as cell quiescence, increased self-renewal capacity, low reactive oxygen species levels or the acquisition of epithelial to mesenchymal transcriptional programs. In the present review, we will discuss how cell intrinsic and extrinsic cues alter the phenotype of CSCs and how they influence resistance to cisplatin treatment. In addition, we will assess how the stromal composition and the tumor microenvironment affect drug resistance and the acquisition of CSCs’ characteristics through a complex interplay between extracellular matrix content as well as immune and non-immune cell characteristics. Finally, we will describe how alterations in epigenetic modifiers or other signaling pathways can alter tumor behavior and cell plasticity to induce chemotherapy resistance. The data generated in recent years open up a wide range of promising strategies to optimize cisplatin therapy, with the potential to personalize HNSCC patient treatment strategies.
Highlights
HPV-positive and negative cancers have been considered two different clinical entities by the World Health Organization (WHO) since 2017 [4]
Still is, the standard choice of treatment for advanced Head and neck squamous cell carcinomas (HNSCCs), we will focus this review on describing the main mechanisms of resistance to cisplatin, including both intrinsic mechanisms and adaptative tumoral mechanisms, as well as the composition of the tumor microenvironment (TME) and how it affects the response to chemotherapy
A complementary study showed that cancer-associated fibroblasts (CAFs) producing higher levels of hyaluronan help to support tumor growth and tumor invasion. Another population of CAFs producing high levels of TGFβ were critical in promoting tumor invasion, but did so with slightly less efficiency than hyaluronan-dependent CAFs [152]. These results demonstrate that different CAF phenotypes can support complementary tumor promoting mechanisms, while others can act by diminishing tumor aggressiveness
Summary
They include inactivating mutations of the tumor suppressor TP53 (altered in 84% of the patients) and loss of function and deletion of CDKN2A (p16/p14, 58%), which both contribute to increased cell proliferation and apoptosis evasion [9]. Gain of function mutations or amplifications affecting classical oncogenes such as PIK3CA (34%), MYC (14%), and CCND1 (31%) often result in increased cell proliferation and survival cues. Gain of function mutations and amplifications occur in multiple receptor tyrosine kinases such as EGFR, FGFR1, and IGFR, converging on the activation of PI3K and MAPK signaling pathways, again boosting tumor proliferation and survival. Increased cellular detoxification is driven by alterations in the NRF2/KEAP1 pathway [17]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.