Head and Neck Cancer: Hallmarks of the Inflammation Ecosystem

Introduction to Inflammation Ecosystem in Head and Neck Cancer

Norhafiza Mat Lazim*

Department of Otorhinolaryngology-Head and Neck Surgery, School of Medical Sciences, Universiti Sains Malaysia, Health Campus 16150, Kubang Kerian, Kelantan, Malaysia

Abstract

Head and neck cancer is on the rise around the globe. At present, the disease affects both the elderly and younger patient populations. This type of cancer is significant as it involves crucial anatomic regions of the head and neck, which are vital for breathing, mastication, swallowing, speech, and olfaction. The treatment options for head and neck malignancies are mainly surgery and chemoradiation, depending on the stage of the tumors. Inflammation plays an important role, and it has a strong relationship with the risk factors, assessment, and treatment of head and neck cancer. Multiple risk factors for head and neck squamous cell carcinoma like smoking, alcohol, viruses, chemicals, and foods have some elements of inflammation that play a dominant role in promoting and sustaining carcinogenesis. The inflammation cascades are complex, and multiple factors cohesively interact within the microenvironment that eventually leads to carcinogenesis, tumor recurrence, and metastasis. Recent evidence suggests that numerous anti-inflammatory biomarkers have effective therapeutic roles in the management of head and neck cancer. This chapter highlights the prominent relationship and interaction that exists between head and neck cancer and inflammation, not only in its etiopathogenesis but also in the assessment and overall management approaches. The significant focus is on the role of inflammatory agents that contribute to the process of carcinogenesis, as well as discussion on several significant inflammatory markers and molecules which may serve as a potential effective target for personalized treatment in head and neck cancer management armamentarium in the near future.

Keywords: Anti-inflammation, Carcinogenesis, Chemoradiation, Epstein Barr viruses, Head and neck cancer, Immunomodulation, Loco-regional recurrence, Malignancy, Metastases, Nasopharyngeal carcinoma, Oncogenic viruses, Oncologic surgery.

* Corresponding author Norhafiza Mat Lazim: Department of Otorhinolaryngology-Head and Neck Surgery, School of Medical Sciences, Universiti Sains Malaysia, Health Campus 16150, Kubang Kerian, Kelantan, Malaysia;

Tel: +60199442664, +6097676418, Fax: +6097676424; E-mail: norhafiza@usm.my

INTRODUCTION

At this juncture, the incidence of head and neck malignancy has shown an increasing trend, approaching similar incidence with lung and colon cancers globally. In our practice, we observed that not only the middle-aged and elderly populations are affected by the disease, but also the trend is on the rise in pediatric patients. The types of head and neck malignancy include an oral cavity carcinoma, oropharyngeal carcinoma, salivary glands carcinoma, thyroid carcinoma, sinonasal carcinoma, nasopharyngeal carcinoma, temporal bone tumors, soft tissues sarcomas, and laryngeal carcinoma. The most common histopathology of head and neck cancers is squamous cell carcinoma. Certain types of head and neck squamous cell carcinoma (HNSCC) are prevalent in specific geographic locations. For instance, nasopharyngeal carcinoma is common in China, Taiwan, Hong Kong, and South East Asia region, whereas oral and oropharyngeal carcinoma is prevalent in Europe, India, Middle East, and several other Western countries.

There are multiple identified risk factors for HNSCC, which include smoking, alcohol consumption, viral infections, dietary habits, chemicals, and other environmental pollutants. These so-called inflammation-associated molecules commonly acting in concert with the presence of other environmental and lifestyle-related co-factors promote carcinogenesis. These factors include sedentary lifestyles, stress, home environment, obesity, self-hygiene, and genetics, which together are thought to drive as much as 90% of all cancers [1]. In addition, selected endogenous and exogenous stimuli might lead to various genetic mutations and modulations, which can serve as a possible trigger for the tumor of the head and neck [2]. Certain head and neck cancer only take a short duration, i.e., 5 to 10 years, to develop, whereas others appear in a case with long-standing head and neck masses of more than 20 years.

Clinical presentation of patients with head and neck cancer varies, and it depends on the patient’s age, duration of symptoms, size of the mass, the location involved, presence or absence of distant metastases, and patient’s comorbidities. Generally, a patient will present with a progressive mass or swelling at the head and neck region that causes constant pain or bleeding associated with reduced appetite and significant weight loss. Other associated symptoms will depend on the location of the mass. For instance, suspicious cancerous mass in the nasal cavity may cause epistaxis, mass in the nasopharynx may cause hearing complaints, mass in the oropharynx area may cause dysphagia and odynophagia, and so forth. The other symptoms such as cranial nerve involvement, pulmonary symptoms, or bony tenderness may present in aggressive and late-stage diseases.

Imperatively, the majority of patient presents at late-stage diseases, where the treatment is more challenging, and multimodality therapy is required.

The malignancy around the head and neck region deserves greater attention as it involves important anatomic regions that are crucial for breathing, speech, mastication, swallowing, hearing, olfaction, and vision. Preserving all the structures is paramount to maintain the function of all organs within the head and neck region, to ensure the patient’s daily functioning and quality of life are maintained. To illustrate, for instance, facial nerve paralysis that is caused by malignant infiltrative parotid malignancy can cause significant social embarrassment and affect a patient’s social interaction and integration within the community due to facial disfigurement. Thus, it is equally crucial to understand the true biology of head and neck malignancy and its sequelae in order to provide finesse care for these subsets of patients.

More than a century ago, Rudolf Virchow proposed the connection between inflammation and cancer, who found the infiltration of leukocytes in malignant tissues [3]. He noted leukocytes in the neoplastic tissue and indicated that the lymphocytic infiltrate might represent cancer origin at chronic inflammatory sites. From this evidence and documentation, there was a surge in the literature that reveals the association of inflammation in cancer formation as well as its roles in cancer therapeutics. Numerous studies have been performed to assess in-depth the relation of inflammatory cascades in the etiopathogenesis, risk factors, therapeutic and sequelae of procedures, and overall treatment in head and neck malignancy.

At this juncture, numerous studies include experimental, clinical, and epidemiological studies have revealed that chronic inflammation significantly contributes to carcinogenesis and cancer progression and predisposes to the occurrence of different types of human cancers [3]. Cancer-related inflammation is considered to be the seventh hallmark of cancer, according to Bonomi et al., and numerous scientific researches have shown that the tumors develop and evolve in and from inflammatory diseases [4]. Imperatively, the steps of carcinogenesis always involve an inflammatory process as the initial step. The primary insult results in inflammation at the very beginning before other reactionary cascades coming in and subsequently promote the carcinogenesis and its sequelae.

INFLAMMATION AND CANCER

The strong relationship and interaction that exist between cancer and inflammation are evident not only in the etiopathogenesis of head and neck cancer but also in investigative procedures, assessment tools, and treatment strategies that take place during head and neck cancer management. The process of carcinogenesis and its progression are dependent on multiple important factors involving the tumor microenvironment and surrounding cells that, most of the time, are not cancerous themselves. Multiple inflammatory cascades, mediators, and inflammatory markers are interrelated and highly interactive within a cohesive inflammation ecosystem. Imperatively, these molecules and markers are able to influence, with a switch on and switch off mechanism, and via these, they are able to stimulate or dampen the effects of other tumor microenvironment factors, which finally will result in carcinogenesis.

Chronic inflammation induces different forms of nucleic acid, protein, and lipid damage through the production of reactive oxygen species, which has resulted in tissue damage. Tissue injury can also activate progenitor and stem cells to facilitate regeneration of the tissue. As such, stem cells are damaged by reactive oxygen species that is produced by inflammation, and the resulting mutations can accumulate over time, leading to cancerous stem cells [5]. For instance, in the case of periodontitis where significant inflammation has been shown to have a strong relationship with the development of oral cavity carcinoma. Of note, periodontitis induces a persistent inflow into the saliva of bacterial and inflammatory markers within the oral cavity and the blood to a lesser extent due to the systemic spread of the diseases [6]. Periodontal bacterial and inflammatory cytokines migrate from affected tissues to the neighbouring anatomic regions and distant sites with saliva and blood. Studies from Tezal et al. suggested that oral premalignant tumours, tongue carcinoma, and human papillomavirus (HPV) related tongue base and oropharyngeal tumours may be associated with chronic periodontitis [6, 7]. Additionally, another study by Rezal et al. reported that periodontitis as a chronic inflammatory condition could be associated with HPV positivity of HNSCC. There was a greater strength of this association among patients with oropharyngeal squamous cell carcinoma (OPSCC) than those with laryngeal and oral cavity carcinomas [7]. Currently, it is known that tongue base tumor and other oropharyngeal subsites tumor are strongly associated with HPV [8, 9]. Importantly, the HPV positivity determines the prognosis and treatment outcomes of these subsets of patients.

Another study by Murata et al. examined the stemness markers in human nasopharyngeal carcinoma tissues. They performed an immunohistochemical assessment of cells that were derived from the cancer tissues and revealed that in the positive cancer cells, the development of a nitroguanidine inflammation-specific DNA lesion marker was observed. Further flow cytometric analysis revealed positive cells in a human nasopharyngeal carcinoma cell line population. This highlights the importance of nitroguanidine formation, which is derived from inflammation cascade in nasopharyngeal cancer stem cells [5].

The other important role that we need to consider is immunomodulation. The role of immunomodulation is crucial in carcinogenesis and its progress and advancement. Immune cell infiltration facilitates the tumor progression through multiple factors and substances produced that mitigate carcinogenesis, and importantly it enables the tumors to escape immune response from the host. Interesting molecules like cytokines, chemokines, and growth factors all play key roles in inflammation and cancer through the promotion of proliferation, angiogenesis, and carcinogenesis [4]. Immunomodulation and inflammation are the key elements in therapeutic strategies applied to combat head and neck cancer.

Cancer initiation and growth are also closely related to angiogenesis. In clinical practice, a mass that is highly vascularized is likely to be associated with malignancy. These feeding vessels secrete and produce arrays of substances to maintain the viability of the cancer cells. Such substances include macrophages, peptides, erythrocytes, cytokines, and many more that play multiple crucial roles in the tumor microenvironment. Macrophage infiltration is a dramatic and natural characteristic of inflammation, angiogenesis, and cancer and has been recently emphasized in an effort to establish selected potent new cancer treatment strategies [10]. A reactive stroma with an excess of inflammatory mediators and leukocytes, dysregulated vessels, and proteolytic enzymes characterize the microenvironment of solid tumors [11]. With the technological advancement and refined techniques, multiple arrays of agents, biomarkers, molecules, and extracts can be further assessed and tested as effective, promising roles not only in the application of cancer therapeutics but also in cancer prophylactics. Recently, the emergence of high-quality scientific literature and research have lucidly illustrated the role of anti-inflammatory biomarkers as potential effective antitumorigenic agents.

INFLAMMATION ECOSYSTEM AND CARCINOGENESIS

Generally, as aforementioned, infectious agents, dietary patterns, and environmental factors are responsible for the global cancer burden. This is true not only for head and neck malignancy but also for other significant human malignancies like lung, breast, renal, brain, and gastrointestinal malignancies. Generally, as everybody is aware, inflammation is the major component of these infectious agents and environmental factors that form the initial insults to the mucosa and cause a subsequent chain reaction, the release of mediators and cascades that lead to carcinogenesis. The process involved is complex and requires many factors and co-factors that are derived from systemic circulation or exogenously from the environmental stimuli.

Acute inflammation usually protects against infectious agents, while chronic inflammation exaggerates the mechanism of infection. The chronic inflammation of the tissue and DNA, which includes genetic and epigenetic changes, leads to the formation of cancer, such as squamous cell carcinoma of the head and neck. This chronic infection is associated with the derangement of vital intracellular and cellular processes. Noteworthy, this persistent inflammation may trigger irreparable tissue damage and significant changes in the inflammatory cells and cytokines contained in the tumor microenvironment. For instance, Krüger et al. documented that oral squamous cell carcinoma (OCSCC) is promoted by chronic inflammation either due to traumatic ulceration or periodontitis [12]. Indeed, the trauma and ulceration due to sharp tooth is a well-known risk factor for OCSCC. Premalignant lesion progression to OCSCC is a multi-step process and complicated. In this case, chronic oral cavity species, the microbiota P. gingivalis triggers enzymatic changes that will eventually increase a complex cellular invasion and promote the formation of OCSCC. Sequentially, these changes facilitate the eventual production of tumors into a highly malignant oral cavity carcinoma phenotype.

Chronic inflammation is known to be associated with an increased incidence of human malignancy. This chronic inflammation can be induced by chemical and physical agents, autoimmune state, infectious agents, radiation, and dietary components [13]. The ties between chronic inflammation and cancer in different species can be confirmed by clinical, epidemiological and animal studies. Cervical cancer, colorectal cancer, pancreatic cancer, skin cancer, esophageal cancer, and liver cancer are some of the most significant examples where carcinogenesis is initiate by inflammation [14]. Increased production of pro-inflammatory mediators, like cytokines and chemokines, reactive oxygen intermediates, increased expression of oncogenes, cyclo-oxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and matrix metalloproteinases (MMPs) are the molecular mechanisms by which chronic inflammation drives cancer initiation and promotion. Other important factors involved include nuclear factor κB (NF-κB), activator of transcription 3 (STAT3), and hypoxia-inducible factor1α (HIF-1α) that mediate tumor formation, metastasis, and chemoradioresistance [1].

In carcinogenesis and tumor development, chronic inflammation is a significant occurrence and it has been regarded as the seventh distinctive sign of cancer. Macrophages, dendritic cells, and lymphocytes are established inflammatory cells of a tumor microenvironment. Cancer stem cells are seen as the seed of cancer. Recently, chronic inflammation has been shown to modulate the survival of cancer stem cells. Huang et al., stated that the activation of inflammasome NLP3 was linked with cancer genesis and progression in many cancers, and the role of inflammasome NLRP3 was found to be specific to the tissues of different cancers. Of note, they stressed that head and neck squamous cell carcinoma is inflammation-related cancer [15]. Latest evidence has emerged that showed most tumor formation is associated with dysregulated inflammation. The molecular pathways of inflammation and cancer are uncovered by numerous recent studies. The discovery of transcription factors such as and their gene products has provided the molecular basis for the decisive role of inflammation in carcinogenesis [16]. Cancer-associated inflammation includes leukocyte infiltration and cytokine expression along with active tissue remodeling and neo-angiogenesis [3]. Reactive oxygen species damage biomacromolecules including DNA, proteins, and lipids, in the inflammatory microenvironment. Inflammatory factors recruit inflammatory cells to induce the cytokines. Superoxide is generated by NADH oxidase and inducible nitric oxide synthase (iNOS) in inflammatory and epithelial cells [5]. This superoxide possessed numerous abilities and interfere with the tissue’s inflammatory activity that worsens the carcinogenesis.

The primary component of tumor infiltrates is tumor-associated macrophages (TAMs), and it is derived from circulating monocytic precursors. Chemoattracting cytokines such as chemokines direct associated macrophages into the tumor cells. TAM survivals are prolonged by colony stimulating factors. With specific activation, TAM able to kill the tumor cells or initiate destructive tissues reactions that centered on the endothelium of the involved vessels [13]. Most malignant tumors are known to contain macrophages as major tumor microenvironmental stromal cells. TAMs are modified in the tumor environment, unlike macrophages in normal tissue, with some losing the ability to phagocytize or present tumor antigens to T-cells. TAMs harbor two distinct antitumor activity phenotypes [17]. These multiple roles of macrophages are essential in the malignancy development to sustain a viable cohesive microenvironment.

INFLAMMATION AND ASSOCIATION WITH GENETIC CHANGES

Chronic inflammation promotes cancer initiation and progression. Chronic inflammation, based on recent studies, can increase mutagenic DNA lesions through the generation of ROS/RNS and can promote proliferation for tissue regeneration via stem cell activation. ROS and RNS are able to cause damage to different cellular components, including nucleic acids, proteins, and lipids. Multiple sources generate ROS, including inflammatory cells, carcinogenic chemicals, and their metabolites. ROS can cause formation of oxidative DNA lesion products [18]. ROS may induce the formation of mutagenic DNA oxidative lesion products [19]. This is the stepping-stone that lead to accumulated tissue damages, which persistent leads to malignancy development.

Different studies have shown that epigenetic changes might culminate in an epigenetic translation that transforms premalignant cells into tumor cells or invasive tumor cells and thus, promotes metastasis. An initiating event, which can be inflammation, is required by epigenetic switches. In addition, this switch is induced and maintained by DNA methylation and histone modifications [20]. Accumulating evidence has shown that epigenetic silencing plays an important role in carcinogenesis through the downregulation of tumor suppression genes and microRNAs. Exposure to ROS or pro-inflammatory cytokines like interleukin 6 in the inflammatory microenvironment results in increased DNA methylation of the tumor suppressor and microRNAs [5]. DNA hypermethylation has been associated with multiple head and neck malignancies including salivary glands carcinoma, laryngeal carcinoma, and OCSCC.

INTRATUMOURAL HETEROGENEITY

Significant evidence highlights that intratumoral heterogeneity between malignant and non-malignant cells and their interactions within the microenvironment of the tumor are critical to various aspects of tumor biology. Great advancement has been made in the study of intra-tumoral heterogeneity that can foster the knowledge of cancer and its carcinogenesis. Indeed, intra-tumoral heterogeneity represents a major challenge in oncology. There are various intra-tumoral heterogeneity sources that intermingle and point to its importance in the tumor microenvironment. In a micro-environment, tumor cells consist of stromal cells such as cancer-associated fibroblasts (CAFs), immune cells, and endothelial cells. Each of those cell types plays an active role in the proliferation of tumor cells. CAFs, for example, may release growth factors that are obtained in cancer cells and function to signal them. It is essential that an established malignant tumor's immune compartment is collectively immunosuppressive [21].

Besides common metabolic reprogramming routes in malignant cells, metabolism is also influenced by placement, degree of micronutrient supply, and interactions with other adjacent cells. It is vital to investigate the segment of cellular metabolism that are affected by these humoral factors. In order to identify major players to this metabolic heterogeneity in the malignant cells, many researchers have subsequently demonstrated the pivotal role of selected biomarkers in cancer-related immune response [21]. Among emerging technologies, RNA-sequencing technique has assisted in highlighting the new drug resistance programs, and specific types of immune infiltration that are highly relevant to tumor biology and management inclusive those for diagnostic and therapeutic approach [22].

MACROPHAGES AND ITS ROLES IN INFLAMMATION ECOSYSTEM

TAMs are the principal player that connect inflammation to the development of malignancy. They are the activated macrophages that are recruited to facilitate and promote carcinogenesis process in cancer related ecospheres. Numerous evidences showed that in the tumor ecospheres, TAMs have numerous functions in facilitation of the tumor growth which includes matrix proteases and growth factors expression, adaptive immunity suppression and promoting the angiogenesis [3, 23]. All of these secreted substances play dominant roles in producing desired and controlled effects by cancer cells in a complex manner. A study by Ono et al., reported that macrophages invade the tissue in response to inflammation and release and yield cytokines and angiogenic factors, for instance, matrix metalloproteinases, vascular endothelial growth factor, interleukin-8, and reactive oxygen species. In addition, inflammatory markers including interleukin and cytokines able to enhance tumor proliferation and vascularization with activation and stimulation of macrophages [10].

Another dominant role of TAM is highlighted by a study by Kimura et al., who investigated the roles of macrophages activation in cancer formation and neovascularization in response to interleukin production. Their results showed that recruitment of the macrophages into tumors by monocytes, activated proteins and other chemokines may play a crucial role in promoting tumor formation and neoangiogenesis, through cancer cells interactions which is mediated by inflammatory markers [24]. Angiogenesis is crucial for the restoration of cancer cell viability and survival. Other vital factors and protein also secreted by TAMs that can strongly influence the process of infiltration and metastases. TAMs, neutrophils and mast cells have been shown to produce proteases during experimental carcinogenesis. TAMs also secrete angiogenic and growth factors and enzymic proteases that denuded the extracellular matrix. Subsequently, TAMs can activate tumor cell progression, facilitate angiogenesis and promote invasion, infiltration and metastases [13]. These significant roles of TAMs can be exploited in the quest for novel therapeutic markers in the coming years.

Of note, during the inflammation process, the extracellular matrix is altered which have important sequelae. This altered extracellular matrix provides structural support for the tumor development and progression. In cancers, hypoxia is a common phenomenon and inflamed tissues can result in damage to DNA which sequentially leads to tumorigenic events. In tumor microenvironment, vascularization of tissues plays critical roles by providing nutrients, oxygen, growth factors to the active dividing cells and this serves as a mechanism for metastases [4]. The hypoxia is another promising target that can be used to alter cancer biology and its capacity to spread. In the coming years, with the advancement of the molecular work, productive research and clinical trial, it is highly possible to generate a novel agent as cancer-hypoxia targeting agent that combat cancer progression at the very early phase during its process.

Additionally, another factor such as the migration inhibitory factor (MIF), which is derived from the T-cell, has the ability to inhibit the migration of macrophages. Interestingly, the molecule was proved to be secreted by many cells which includes lymphocytes, eosinophils, and macrophages. Evidences showed that MIF belongs to proinflammatory protein group [25]. Further studies have demonstrated that MIF involves in the carcinogenesis and tumors formation including HNSCC. It has pleiotropic roles in modulating hypoxia and angiogenesis that can regulate the HNSCC cells proliferation, invasion, apoptosis, and metastases. Importantly, MIF levels are found to be higher in HNSCC patients, and the expression of MIF can be used for prediction of clinical outcomes of these selected patient’s category [25]. This is another critical biomarker that can be further explore in tumor microenvironment and future studies will enable the development and expansion of effective therapeutic agents based on these unprecedented findings.

RISK FACTORS OF HEAD AND NECK MALIGNANCY AND ROLE OF INFLAMMATION

The bio-mechanism of the relationship of chronic inflammation with cancer has been extensively discussed but continues to evolve, as both inflammation and cancer are complex processes controlled by a wide range of driving forces. Inflammation is the primary insult that progress and alters the microenvironment and subsequently result in carcinogenesis. Acute inflammation does not relate to the carcinogenesis, but chronic inflammation does. As highlighted previously, many human malignancies have been closely associated with chronic inflammation such as colonic carcinoma with colitis, bronchogenic carcinoma with bronchitis, cervical carcinoma with chronic infection with human papilloma virus (HPV) and so forth. In the surrounding epithelial cells, viruses, pollutants, bacterial products, including endotoxins, enzymes and metabolic byproducts, are able to cause genetic and epigenetic changes. They also have capacity to increase carcinogenic acetaldehydes and nitrosamines. Significant cells for instance monocytes, lymphocytes, fibroblasts, and epithelial cells, produce cytokines, growth factors and prostaglandins in respond to activation by bacteria. All these factors are vital for cell proliferation, angiogenesis and migrations [14]. In addition, the epithelial cells drive the mutation accumulation which flourish under the positive microenvironment influence.

Noteworthy, it is important to understand the process that occurs between chronic inflammation and malignancy development. An association between chronic inflammation and HPV infection is important to be understand as it is critical for cancer progression. The HPV enters through a breach in the mucosa and consequently infects basal cells of the epithelium. Subsequently, basal cell proliferation occurs with the virus replicates simultaneously. These lead to mucosal damage, micro-ulcerations, and consequent epithelial proliferation mediated by inflammatory cytokines released from inflamed sites. Additionally, in this inflammatory environment, the risk of HPV transmission is high as due to increase number of virus particle produced [7]. There have been many studies that validate the association between infection and chronic inflammation that transgress into malignant cervical cancer. Vaccination against HPV has been developed based on the study directed at cervical cancer-related HPV.

Concerning this oncogenic virus, the incidence of head and neck malignancy is equally important. At present, human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) is showing an increasing trend in several countries such as Europe, North America, India, and so forth. Interestingly, there have been records of high variations in the HPV16 viral load and different physical viral status proportions among the HNSCC. HPV positivity was associated with the younger age group and with the oropharyngeal site. Other sites of the head and neck region are also significant in terms of relevance for HPV positivity. This is revealed by a study by Faust et al., who stated that HPV was found in 73 % of tonsillar carcinoma cases, 56 % of the base of tongue cancer cases, 27 % of oral cavity cancers, 14 % of laryngeal cancers [26]. To support the role of inflammation as the etiopathogenesis of malignancy are the study focusing on periodontitis. Tezal et al., stated their study provide the first evidence, of an association between chronic periodontitis and HNSCC especially for the oral cavity, oropharynx and larynx, especially in patients who never used tobacco and alcohol [6]. Imperatively, this study highlights that poorly differentiated tumor is associated with that periodontitis history, which signify role of inflammation in patient’s prognosis. Generally, the poorly differentiated tumor has worse prognosis and outcomes compared to well differentiated tumors (Tables 1 and 2).

Table 1 Specific type of head and neck malignancy and its risk factors and associated inflammatory mediators/markers.

Table 2 List of cancers that are strongly related to inflammation (Balkwill & Mantovani, 2014).

Reciprocal contact between cancer cells and the microenvironment of the tumor helps and allows progression of the cancer. The contribution of stromal cell-secreted factors in cancer development was recognized over the last decade, but the underlying secretory machinery remains mysterious [27]. Among these secreted molecules includes proteins, peptides, chemokines, endothelial growth factors and so forth which are the major players in the inflammatory ecosystem. These molecules are intricately interactive and tend to switch on and off of the other co-factors for different effects to take place. For instance, Kondoh et al. documented that IL-10 and TGF-β have the ability to promote malignant cells immune escape since they are the representative of the immunosuppressive cytokines. IL-10 and TGF-β2 overexpression is associated with poorer prognosis of oral cancers [17].

Other factors are also important in promoting carcinogenesis in tumor microenvironment. Huang et al. documented that NLRP3 inflammasome is a recent critical focus in cancer development and progression, but its role is complicated in tumorigenesis and stimulating antitumor immunity. They stated that recent evidence showed that activated NLRP3 inflammasome contributed to the progression of colon cancer cells, human melanoma cells, and lung cancer cells. In addition, they stated that when gemcitabine and 5-fluorouracil were used to treat cancer cells, the activated NLRP3 inflammasome reduces antitumor efficacy and promote tumor growth [15]. Importantly, IL-10 inhibits antigen-presenting cells i.e., macrophages and dendritic cells and it also confers resistance to the action of cytotoxic T cells. In addition, they documented that hypoxic stress causes immune suppressive molecules such as IL 10 and TGF-β to activate the tumor-associated macrophage division into M2 forms, thus eliminating anti-tumor immunity [17].

Growth Factors and Inflammation Ecosystem

The other major player in the inflammation systems is the growth factors. Such delicate example like transforming growth factor β1 (TGF-β1), which in many types of cancers is over-expressed and correlates with invasion of tumor. Generally, it is known that at an early stage of HNSCC development, TGF-β1 inhibits head and neck malignant cell proliferation. On the other end of the spectrum, TGF-β1 facilitate tumor invasion by its paracrine effects within the tumor microenvironment [28]. These dual effects of a specific molecule in tumor microenvironment is common and mediated by many other molecules, some are secreted by the tumor cells whereas others are secreted in response to tumor cells infiltration. In head and neck cancer tissues, the TGF-β is overexpressed. The study by Lu et al. showed that a transgenic oral epithelium inducible TGF-β1 expression comparable to that seen in human HNSCC patients causes inflammation, epithelial hyper-proliferation and vascularization. They suggested that TGF-β1 has significant tumor promotion role during early stages of HNSCC development [28].

Lu et al. stated that TGF-β1 overexpression may also involves chronic inflammation. Chronic inflammation as we know is a precursor for many human malignancies due to its pro- carcinogenesis effects. TGF-β1 is among the most active chemotactic leukocyte cytokines. Their study data suggested that over-expression of TGF-β1 in the head and neck can be an important mechanism for chronic inflammation, thereby promoting the development of HNSCC [28]. Other supporting evidence of TGF as a major player in inflammation and carcinogenesis are highlighted by Rosenthal et al. They reported that in the tumor-associated stroma, TGFβ1 and IGFII overexpression were substantially over-expressed (3.4-fold) in normal and tumor-associated stromal cells with only TGFβ1. In comparison to normal mucosa, high levels of TGFß1 were identified by immunohistochemical analysis in the stromal compartment of HNSCC tumors [29].

The study reported that the lack of EGF immunological expression in the carcinomatous areas associated with pseudoepitheliomatous hyperplasias and the almost exclusive presence of EGF inflammatory conditions in the hyperplasia lesions [30]. Pseudoepitheliomatous hyperplasia is a lesion that develops as a response to a great diversity of neoplastic, infectious, inflammatory, or traumatic stimuli being associated with different pathologies. It can be grouped according to pseudoepitheliomatous hyperplasia-related etiopathogenic conditions. Infectious, neoplastic, dermatosis with chronic irritation and inflammation, and various other pathological processes are the four major categories [30].

The pseudoepitheliomatous hyperplasia-associated tumor lesions include both benign and malignant entities. The association between pseudoepitheliomatous hyperplasia and granular cell tumour is frequently observed, but lesions of pseudoepitheliomatous hyperplasia associated with spitz nevi have also been described. There are many more malignant tumors associated with pseudoepitheliomatous hyperplasia, including malignant melanoma, lymphoproliferative diseases, basocellular carcinoma, and the malignant variant of clear cell hidradenoma [31]. Other proliferative markers that have been linked to malignancy include MMP, p53, and E-Cadherin. Invasive adenocarcinomas display substantially greater stain of p53 and MMP-1 and less E-cadherin. A related panel consisting of head and neck hyperplasia has shown that p53, MMP-1 and E-cadherin have significant staining patterns of p53 and Ki67 in order to differentiate the carcinoma from reactive epithelial hyperplasia [32].

Chemokines

In spite of therapeutic progress, the survival of patients with squamous cell carcinoma in the head and the neck (HNSCC) remains stagnant. The role of the tumor microenvironment in promoting cancer progression and resistance to therapy has attracted great attention in the past decade. The predominant non-malignant type of cell in the HNSCC microenvironment is cancer-associated fibroblasts (CAFs). Studies have shown that CAFs play a critical role in mediating HNSCC progression. CAFs facilitate HNSCC development by secretion of growth factors, extracellular matrix remodeling, and modulating therapy resistance. HNSCC cells interact symbiotically with CAFs through secreted variables. Recent findings indicate that fibroblasts associated with cancer (CAF) contribute to the tumor progression. The autophagy-dependent secretion by HNSCC-associated CAFs of tumor-promoting factors may explain their role in malignant development [27]. Molecular studies have further demonstrated that inflammatory cytokines, including IL-1, IL-6, and TNF-α, modulate HPV proliferation and expression in the cervical epithelial cells of its oncogenes E6 and E7 [14].

Interaction between Mediators in the Tumor Microenvironments

In a study, the author applied the characterization strategy for primary HNSCC tumors and matched metastatic lymph node. The study analysis highlights a complex cell ecosystem with an active crosstalk between malignant and non-malignant cells. This research represents a significant move in understanding the heterogeneity of intra-tumoral expression in epithelial tumors, which involve most of solid malignancies [22].

A change in cancer cells to a mesenchymal phenotype has been established as a significant contribution to the progression and metastasis of malignant epithelial tumors, including HNSCC. This epithelial-mesenchymal transition (EMT) is a fundamental biological process for wound healing and embryonic development while it plays a role in organ fibrosis and cancer in the pathophysiological context. Growing invasiveness and migration, avoidance of apoptosis, contributions to immunosuppression and immunotherapy resistance in transformed cancer cells, have been documented for EMT. In addition, loss of cell adhesion and epithelial markers, an increase in mesenchymal markers and an alteration of the cytoskeletal structure, are among the features that can be observed in the microenvironment of the tumor [33].

An increase in invasiveness and metastases was associated with a shift toward a mesenchymal phenotype in epithelial tumors. It is assumed that this phenomenon plays a key role in the progression and the prognostication of the disease. In this study, epithelial-mesenchymal transition (EMT) was investigated in human papillomavirus negative pharyngeal squamous cell carcinoma. This study revealed the complex role of EMT in HPV-negative pharyngeal squamous cell carcinoma during the metastasis process. In comparison to lymph node metastases, primary tumor tissue showed surprisingly high stemness characteristics [33]. HNSCC-specific metabolic fingerprints were mainly defined by a staining immunohistochemistry, and serologic examination in the early years. For example, the expression of CRABP in tumor tissue was enriched with its adjacent normal tissue, while further studies have shown that external administration of retinoic acids could modulate the activity of the Epidermal Growth Factor Receptor, which is a critical key in HNSCC progression [2].

ROLE OF INFLAMMATORY MARKERS AND THEIR CRITICAL ACTION

The most important step towards the discovery of effective HNSCC prevention and treatment is to understand the interactions that exist between the risk factors. The fact that carcinogenesis is a multifactorial process is well established and the presence of a single risk factor is usually not adequate to cause cancer. However, the majority of studies focused on the independent effects of particular risk factors [14].

Therapeutics

Tumor angiogenesis and inflammatory angiogenesis can be inhibited by administering either nuclear factor-kappa B-targeting or cyclooxygenase 2 inhibitor drugs or macrophage depletion. Therefore, both inflammatory and angiogenic responses in tumor stroma are the potential targets for the development of therapeutic anticancer drugs [10]. Inflammation contributes to malignant cell survival and proliferation, tumor angiogenesis, metastasis and reduced chemotherapy response. Inflammatory pathways are attractive targets for cancer prevention and therapy given their involvement at different stages of tumor development [16].

The key players that link the inflammation and cancer is TAM. TAM has various functions which includes repression of the adaptive immunity, promoting tumor cell angiogenesis and proliferation and stimulating matrix turnover. These functions have significant effects on the tumor progression. TAM is thus an attractive target of novel biological tumor therapies, together with other myeloid-related cells present at the tumor site [11]. Literature shows that chemotherapeutic and radiation both encourage cytoprotective autophagy in tumor cells. Research