Abstract
The importance of inflammation in the pathogenesis of cancer was first proposed by Rudolph Virchow over 150 years ago, and our understanding of its significance has grown over decades of biomedical research. The arachidonic acid pathway of inflammation, including cyclooxygenase (COX) enzymes, PGE2 synthase enzymes, prostaglandin E2 (PGE2) and PGE2 receptors has been extensively studied and has been associated with different diseases and different types of cancers, including oral squamous cell carcinoma (OSCC). In addition to inflammation in the tumour microenvironment, low oxygen levels (hypoxia) within tumours have also been shown to contribute to tumour progression. Understandably, most of our OSCC knowledge comes from study of this aggressive cancer in human patients and in experimental rodent models. However, domestic animals develop OSCC spontaneously and this is an important, and difficult to treat, form of cancer in veterinary medicine. The primary goal of this review article is to explore the available evidence regarding interaction between hypoxia and the arachidonic acid pathway of inflammation during malignant behaviour of OSCC. Overlapping mechanisms in hypoxia and inflammation can contribute to tumour growth, angiogenesis, and, importantly, resistance to therapy. The benefits and controversies of anti-inflammatory and anti-angiogenic therapies for human and animal OSCC patients will be discussed, including conventional pharmaceutical agents as well as natural products.
Highlights
Hypoxia, defined as reduced oxygen levels or deficiencies in oxygen transport, is a common feature of solid tumours, and plays an important role in triggering the development of new blood vessels, which is critical for supporting tumour growth
The purpose of this review is to explore the scientific literature related to the interaction of hypoxia and the arachidonic acid pathway of inflammation, in order to improve our understanding of how these interactions contribute to oropharyngeal squamous cell carcinoma (OSCC) disease progression and treatment resistance
Harris et al [200] showed that vascular and endothelial growth factor (VEGF)-D, VEGF-A and HIF-1a are expressed in Feline OSCC (FOSCC) tissues and cell lines, and they confirmed that FOSCC cells grown in hypoxic conditions express increased levels of VEGF-D. They determined that HIF-1a expression was related to Twist expression, which they proposed could serve as a therapeutic target [200]. These findings demonstrate that, like their human counterparts, feline OSCC cells are capable of hypoxia-induced expression of VEGF, and HIF-1a appears to play a role in epithelial-to-mesenchymal transformation (EMT)
Summary
Hypoxia, defined as reduced oxygen levels or deficiencies in oxygen transport, is a common feature of solid tumours, and plays an important role in triggering the development of new blood vessels (angiogenesis), which is critical for supporting tumour growth. Tumour associated inflammation can lead to activation of hypoxia-inducible factors and pathways that help support tumour progression [2]. One of the key mechanisms of tumour-associated inflammation is activity of the arachidonic acid pathway resulting in generation of prostaglandin E2 (PGE2). Increased PGE2 secretion is usually attributed to increased expression and activity of cyclooxygenases 1 and 2 (COX-1 and COX-2), but there are a number of other points in the arachidonic acid pathway that can influence PGE2 production and there are a variety of PGE2 receptors that are responsible for PGE2-related responses [3]. Areas of chronic hypoxia have been identified in the tumours of patients with oral cancer [4]. Targeting the cycle of inflammation and hypoxia may represent an opportunity to slow tumour progression and improve therapeutic outcomes for patients diagnosed with oral and oropharyngeal squamous cell carcinoma (OSCC)
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