cells Review Impacts of Environmental Factors on Head and Neck Cancer Pathogenesis and Progression Marisol Miranda-Galvis 1, Reid Loveless 1 , Luiz Paulo Kowalski 2,3 and Yong Teng 1,4,5,* 1 Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA; [email protected] (M.M.-G.); [email protected] (R.L.) 2 Department of Head and Neck Surgery and Otorhinolaryngology, A.C. Camargo Cancer Center, São Paulo 01509, Brazil; [email protected] 3 Head and Neck Surgery Department, Medical School, University of São Paulo, São Paulo 01509, Brazil 4 Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA 5 Department of Medical Laboratory, Imaging and Radiologic Sciences, College of Allied Health, Augusta University, Augusta, GA 30912, USA * Correspondence: [email protected]; Tel.: +1-70-6446-5611; Fax: +1-70-6721-9415 Abstract: Epidemiological and clinical studies over the past two decades have provided strong evidence that genetic elements interacting with environmental components can individually and collectively influence one’s susceptibility to cancer. In addition to tumorigenic properties, numerous environmental factors, such as nutrition, chemical carcinogens, and tobacco/alcohol consumption, possess pro-invasive and pro-metastatic cancer features. In contrast to traditional cancer treatment, modern therapeutics not only take into account an individual’s genetic makeup but also consider gene–environment interactions. The current review sharpens the focus by elaborating on the impact that environmental factors have on the pathogenesis and progression of head and neck cancer and the underlying molecular mechanisms involved. Recent advances, challenges, and future perspectives in Citation: Miranda-Galvis, M.; this area of research are also discussed. Inhibiting key environmental drivers of tumor progression Loveless, R.; Kowalski, L.P.; Teng, Y. should yield survival benefits for patients at any stage of head and neck cancer. Impacts of Environmental Factors on Head and Neck Cancer Pathogenesis Keywords: environmental factors; head and neck cancer; metastasis; anticancer; modern therapy and Progression. Cells 2021, 10, 389. https://doi.org/10.3390/cells10020389 Academic Editor: Gianpaolo Papaccio 1. Introduction Each year, 450,000 global deaths are attributed to head and neck cancers [1]. Of these, Received: 16 January 2021 head and neck squamous cell carcinoma (HNSCC), arising from mucosal surfaces of the oral Accepted: 10 February 2021 Published: 13 February 2021 cavity, oropharynx, larynx, and hypopharynx, represents the most common histological subtype [2]. Although these tumors originate from the same squamous epithelium, HNSCC Publisher’s Note: MDPI stays neutral is nevertheless a biologically and clinically heterogeneous disease involving different risk with regard to jurisdictional claims in factors, molecular pathogeneses, treatment responses, and prognoses [3,4]. published maps and institutional affil- The alarming rates of mortality reported in HNSCC are, at least in part, due to the high iations. prevalence of loco-regional recurrence and/or metastatic disease [5]. Indeed, while patients affected with locally advanced HNSCC present 5-year overall survival rates under 50%, subjects with early stages of the disease carry a markedly improved prognosis, with survival rates closer to 80% [6]. Ever since initial descriptions of HNSCC metastasis were reported in the early 19th century, researchers have abandoned the concept of passive drainage Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. of tumor cells into regional lymph nodes [7]. Instead, metastasis has been recognized as This article is an open access article a complex, multi-step process that is orchestrated by tumor biology and supported by distributed under the terms and the internal tumor microenvironment, as well as external environmental factors that are conditions of the Creative Commons involved in tumor cell invasion, intravasation, circulation, extravasation, and metastatic Attribution (CC BY) license (https:// colonization [8]. creativecommons.org/licenses/by/ While the role of the tumor microenvironment has been the subject of intensive 4.0/). research in recent years, far less is known regarding the participation of external factors Cells 2021, 10, 389. https://doi.org/10.3390/cells10020389 https://www.mdpi.com/journal/cells Cells 2021, 10, x 2 of 16 Cells 2021, 10, 389 2 of 16 While the role of the tumor microenvironment has been the subject of intensive re- search in recent years, far less is known regarding the participation of external factors in in metastasis. Besides the two greatest risk factors, tobacco and alcohol consumption, metastasis. Besides the two greatest risk factors, tobacco and alcohol consumption, onco- oncogenic viruses (e.g., human papillomavirus (HPV)), the microbiome, and diet have also genic viruses (e.g., human papillomavirus (HPV)), the microbiome, and diet have also been established in recent decades as contributing factors (Figure1). The current review been established in recent decades as contributing factors (Figure 1). The current review provides a comprehensive summary of the environmental factors involved in HNSCC and provides a comprehensive summary of the environmental factors involved in HNSCC highlights the recently reported mechanisms involved in environmental factor-associated and highlights the recently reported mechanisms involved in environmental factor-asso- HNSCC progression. Evidence supporting the further development of a precision-based ciatedmodel HNSCC of cancer progression. prevention hingedEvidence on supporting modifiable the risk further factors development is also provided. of a precision- based model of cancer prevention hinged on modifiable risk factors is also provided. Figure 1. Environmental factors support metastasis of head and neck cancer. Metastasis is a complex and multi-step pro- Figurecess that 1. isEnvironmental orchestrated by factors tumor supportbiology metastasisand supported of head by external and neck environmental cancer. Metastasis factors, is such a complex as tobacco and and multi-step alcohol processconsumption, that is orchestratedhuman papillomavirus by tumor biology (HPV) andinfection, supported the microbiome, by external environmental and diet, which factors, are involved such as tobaccoin tumor and cell alcohol inva- consumption,sion, intravasation, human circulation, papillomavirus extravasation, (HPV) infection, and metastatic the microbiome, colonization. and A diet, precision which- arebased involved model inof tumor metastasi cells invasion, preven- intravasation,tion centered around circulation, modifiable extravasation, risk factors and involves metastatic smoking colonization. and alcohol A precision-based cessation, HPV model vaccination, of metastasis and a preventiondiet that is centeredhigh in fruits around and modifiable vegetables risk and factors low in involves processed smoking and red and meats. alcohol cessation, HPV vaccination, and a diet that is high in fruits and vegetables and low in processed and red meats. 2. Tobacco Smoking 2. TobaccoA sudden Smoking spike in deaths related to lung carcinoma in 1950 led R. Doll and B. Hill to identifyA sudden an increased spike inrisk deaths of cancer related among to lung tobacco carcinoma-smoking in 1950 patients led R. [9]. Doll Afterward, and B. Hill data to fromidentify several an increased studies extended risk of cancer the association among tobacco-smoking of tobacco consumption patients [9]. with Afterward, carcinomas data affectingfrom several the head studies and extended neck, esophagu the associations, pancreas, of tobacco bladder, consumption kidney, cervix, with and carcinomas stomach, asaffecting well as the with head cardiovascular and neck, esophagus, and respiratory pancreas, disease. bladder, kidney, cervix, and stomach, as well asCigarettes, with cardiovascular the most common and respiratory form of tobacco, disease. contain over 7000 chemicals and toxic substances,Cigarettes, including the most more common than 60 form recognized of tobacco, carcinogens contain over[10]. Di 7000rect chemicals evidence andbased toxic on experimentalsubstances, including animal models more than shows 60 recognizedN′-nitrosonornicotine carcinogens (NNN), [10]. Direct a tobacco evidence-specific based ni- trosamineon experimental (TSNA), animal to be the models major shows tobaccoN0 -nitrosonornicotinecomponent driving head (NNN), and a neck tobacco-specific carcinogen- esisnitrosamine [11]. Alongside (TSNA), NNN, to be other the major TSNAs tobacco and tobacco component constituents, driving headsuch andas polycyclic neck carcino- aro- maticgenesis hydrocarbons [11]. Alongside (PAHs), NNN, aromatic other TSNAs amines, and and tobacco certain constituents, volatile organic such asagents, polycyclic con- tributearomatic to hydrocarbonstumorigenesis (PAHs), and tumor aromatic development amines, and [10]. certain Underlying volatile tobacco organic’s agents, pro-tumor con- tribute to tumorigenesis and tumor development [10]. Underlying tobacco’s pro-tumor Cells 2021, 10, 389 3 of 16 contributions is the creation of an imbalance between the metabolic activation and detoxifi- cation of carcinogens that directly leads to DNA damage. Metabolic activation is primarily achieved through cytochrome P450 enzymes (CYPs), while metabolic detoxification