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REVIEW ARTICLE
Year : 2017  |  Volume : 6  |  Issue : 1  |  Page : 1-7

Molecular biology of head and neck cancer


Department of Oral Pathology and Microbiology, SIBAR Institute of Dental Sciences, Guntur, Andhra Pradesh, India

Date of Web Publication20-Mar-2017

Correspondence Address:
Swetha Gudiseva
Department of Oral Pathology and Microbiology, SIBAR Institute of Dental Sciences, Guntur, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2277-8632.202584

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  Abstract 

The term molecular biology of head and neck cancer includes two terms “molecules” and” biology.” Molecules are made of atoms and biology includes study of life. Hence, the study of molecular biology of cancer is very essential in understanding the atoms involved, their effect on life in cancer, and the factors controlling its growth, extension, and the process of metastasis. Even though it is an old concept, new molecules were being discovered which have been involved actively in the carcinogenesis. It is a complex process to understand because it involves numerous factors, few involved in halting the process of cancer and few involved in progression of cancer. In normal cells, these both are in a balanced state, and any imbalance in these two results in abnormal growth which becomes persistent. Hence, new treatment modalities by targeting atoms, molecules, receptors, and signal transduction pathways, abnormal, or mutated genes can be invented to decrease the mortality rate and increase the prognosis of patients suffering from head and neck cancer. This review mainly focuses on the molecules involved in head and cancer, their clinical implications, and their role in inventing new therapies.

Keywords: Cancer, genes, molecules, pathways, signals


How to cite this article:
Gudiseva S, Katappagari KK, Kantheti LP, Poosarla C, Gontu SR, Baddam VR. Molecular biology of head and neck cancer. J NTR Univ Health Sci 2017;6:1-7

How to cite this URL:
Gudiseva S, Katappagari KK, Kantheti LP, Poosarla C, Gontu SR, Baddam VR. Molecular biology of head and neck cancer. J NTR Univ Health Sci [serial online] 2017 [cited 2017 Oct 23];6:1-7. Available from: http://www.jdrntruhs.org/text.asp?2017/6/1/1/202584


  Introduction Top


Molecular biology is the division of biology that pacts with the molecular basis of biological commotion. Interfaces among various types of nucleic acids, synthesis of proteins, and indulging the interactions between various systems of the cell, as well as learning how these interactions are curbed is a part of molecular biology. In the same manner, molecular biology of head and neck cancer covenants with the study of genetic molecules, mutated genes, onco proteins, extracellular matrix proteins, enzymes, certain hormones, and limited other related elements liable for initiating cancer and its advancement.[1] Tumors repeatedly grow within preneoplastic turfs of genetically rehabilitated cells. The perseverance of these fields after handling grants a key challenge because it might lead to native recurrences and second primary tumors that are accountable for a large percentage of deaths.[2] We as clinicians are also required to ponder a new set of disputes, the so-called molecular bases of head and neck cancer.[3]


  Genetic Analysis in Cancer Top


Genetic analysis is the study of genetics, molecular biology, and the global route of exploring the grounds of science, which embrace the detection of genetic alterations, mutations, genes, and DNA deviations. Various genetic changes accumulate and fail to revert to normal leading to cancer. Cancer instigates when genes in a cell turn out to be irregular and the cell twitches to grow and crack out of control.[4] The general idea of genetic analysis consist of the point study of changes in proto-oncogenes, tumor suppressor genes, genetic susceptibility, cytogenic alterations, and suppressive growth regulation. These genetic alterations mainly contain initiation of proto-oncogenes and inactivation of tumor suppressor genes [Figure 1].[4]
Figure 1: Basic molecular involvement in the transformation of normal cell to cancer cell

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Proto-oncogenes

Proto-oncogene is a gene that has the capacity to alter in to an oncogene to cause cancer. In tumor cells, they are often mutated or expressed at high levels.[5] The word “oncogene” was invented in 1969 by National Cancer Institute Scientists, George Todaro and Robert Heubner. Proto-oncogene is a standard gene that has the chance to convert in to an oncogene due to mutations or augmented expression. The ensuing protein can be labelled as oncoprotein. Proto-oncogenes program for proteins that support to adjust cell growth and differentiation.[6],[7],[8] They are repeatedly associated with signal transduction and implementation of mitogenic signals, typically through their protein products. Upon stimulation, a proto-oncogene befits a tumor-inducing agent, an oncogene. Example of proto-oncogenes includes Rat associated sarcoma gene (RAS), Wingless type (WNT), Myelocytomatosis virus (MYC), and Tyrokinases (TRK).[9] The proto-oncogene can turn into an oncogene by a fairly small alteration of its unique function. A boom in the total protein caused by increase in protein stability, extending its existence and thus its action in the cell, subsequently increases the amount of protein in the cell. The oncogenes responsible for the process of oncogenesis are growth factors and receptors, signal transduction proteins, nuclear regulatory proteins, and mediators of cell cycle.[10]

Growth factors

Growth factors (GFs) may be defined as “polypeptides that stimulate cell growth by binding to specific high-affinity cell membrane receptors.”[11] These GFs diverge from the other known hormones in the reaction type and in the style of distribution. GFs include epidermal growth factor and receptor (EGF R), fibroblast growth factor and receptor (FGFR), platelet derived growth factor and receptor (PDGFR), transforming growth factor and receptor (TGF), insulin like growth factor and receptor (IGF), nerve growth factor and receptor (NGFR), and colony stimulating factor (CSF).[11] Epidermal growth factor (EGF) is a principal member of the EGF-family of proteins. Associates of this protein family have vastly parallel functional and structural individualities. They are heparin-binding EGF-like growth factor (HB-EGF), transforming growth factor-α (TGFα), neuregulin-1 (NRG1), aAmphiregulin (AR), neuregulin-2 (NRG2), epiregulin (EPR), epigen, betacellulin (BTC), neuregulin-3 (NRG3), neuregulin-4(NRG4).[12] EGF arouses cellular differentiation, cell growth, proliferation by sbinding to its receptor EGFR.

This excites ligand-induced dimerization, activating the intrinsic protein-tyrosine kinase activity of the receptor. The tyrosine kinase activity pathway in turn stimulates a signal transduction cascade that results in a variety of biochemical changes within the cells that eventually lead to DNA synthesis and cell proliferation.[13] This highly preserved signaling molecule theatres a vital role in the morphogenesis of organisms and has also been involved in the growth and development of countless types of human tumor cells.[14] EGF is mitogenic for fibroblasts and keratinocytes, stimulating their migration and production of the granulation tissue.

Increased amount of the proto-oncogenes is absolute than being mutated in cancer.[9] The factor designated as endothelial cell growth factor is related to the FGF family. The family consists of 4 receptors, namely FGFR1, FGFR2, FGFR3, and FGFR 4. In neoplasia, it becomes augmented or overexpressed. FGFs are multifunctional proteins with a varied variety of effects; they are most communal mitogens but also have governing, morphological, and endocrine effects.[15]

In neoplasm they stimulate VEGF and EGF causing angiogenesis and act as a mitogenic signal for the growth of tumor cells.[16] PDGF is one of the plentiful growth factors or proteins that control cell growth and division and plays a momentous role in angiogenesis.[17] The PDGFs fix to the protein tyrosine kinase receptors PDGF receptor-α and -β. PDGF is a major mitogen in serum; furthermore, it provokes a chemotactic retort in the fibroblast and smooth muscle cells.[18]

Transforming growth factor (TGF) is one of the numerous proteins effectively produced by transformed cells that can motivate the growth of normal cells. There are two categories of polypeptide growth factors, namely TGFα and TGFβ. The two classes of TGFs are not anatomically or hereditarily related to one another, and they turn through diverse receptor mechanisms. As an associate of the EGF family, TGF-α is one of the mitogenic polypeptide. This gene has been linked with many types of cancers, and it may also be implicated in some cases of cleft lip palate.[19]

Transforming growth factor β (TGFβ or TGF-B) is seen in hematopoietic (blood-forming) tissue. It has a central role in regulation of the immune system, tissue regeneration, cell differentiation, embryonic development, and even initiates a signaling pathway that overwhelms the early expansion of cancer cells.[20] Insulin or insulin-like growth factor was (IGF-I and IGF-II) first labelled as a “sulfation factor” by Salmon and Daughaday in 1970.[21] IGF-I matches to human somatomedin C and IGF-II matches to human somatomedin. It arouses cell division so that cell unremittingly splits and proliferate and aids in tumor growth.[22]

Signal transducing proteins

Signal transduction ensues when an extracellular signaling molecule triggers a specific receptor which is present on the cell surface or inside the cell. Consecutively, it triggers a response by creating a chain of biochemical actions within the cell.[23] Receptors aimed at signal transduction are generally distributed into two major types, i.e., intracellular receptors and extracellular receptors. It happens as a consequence of a ligand binding to the receptor present on the membrane, and the molecule cannot pass across the membrane.[24] Examples are the tyrosine kinases and phosphatases. They generate second messengers such as cyclic AMP and IP3, controlling the production of intracellular calcium stores into the cytoplasm, leading to formation of ATP, and enabling the cell to continue its growth.[25] EGFR-TK is a transmembrane receptor TK that is overexpressed or abnormally activated in most of the solid tumors of the head and neck, helping in tumor growth and malignant progression.[26] Because angiogenesis is a foremost event in cancer development, growth, and proliferation, tyrosine kinase inhibitors act as a goal for antiangiogenesis and can be pertinently applied as a new mode of cancer therapy.[27]

Cyclins and cyclin dependent kinases

Cyclins are a group of proteins that regulate the advancement of cells through the cell cycle, triggering cyclin-dependent kinase (Cdk) enzymes. The final outcome of growth promoting signals is to shove the inactive cell in to cell cycle, which in turn is organized by cyclins and cyclin-dependent kinases. Cyclins were formerly named as their concentration varies in a cyclic manner during the cell cycle. The undulations of the cyclins, namely fluctuations in cyclin gene expression and devastation by the ubiquitin-mediated proteasome pathway stimulate Cdk activity to drive the cell cycle.[28] Cyclins themselves do not have enzymatic activity but they have sites for some substrates to bind and target the Cdks to appropriate subcellular locations. Cancer develops in a tissue in which the genes that derive the cell cycle are mutated or amplified, or make certain proteins to pass through phosphorylation, which are accountable for specific events in cycle division such as microtubule materialization and chromatin renovation.[29]

Telomerase

Telomerase is an RNA-based reverse transcriptase, which acts as a prototype and adds DNA sequence repeats to the 3′ end of DNA strands in the telomere regions averting constant harm to important DNA segments from ends of the chromosome.[30] It comprises three molecules each of human telomerase reverse transcriptase (TERT), telomerase RNA (TR orTERC), and dyskerin (DKC1).[31] During cell division, progeny cells subsequently reach the terminal stages in normal conditions due to surplus telomerase.[32] When cells miss their senesce, they become immortal and the company of telomerase activates uninhibited proliferation of cells, and hence dividing cell can substitute the mislaid piece of DNA.[33]

Tumor suppressor genes

A tumor suppressor gene, or antioncogene, defends a cell from cancer. When it undergoes mutation, the cell headway to cancer with other genetic changes. The loss of these genes plays an important role than proto-oncogene/oncogene activation for the establishment of various kinds of cancer cells. Contrasting oncogenes, tumor suppressor genes usually follow the “two-hit hypothesis,” which infers that both of the alleles coding for a precise protein must be altered. These are the proteins that cipher or have a dulling or suppressive effect on the cell cycle or initiate apoptosis or may cause both. Certain proteins in cell adhesion avoid tumor cells from diffusing in to the process of metastasis. These proteins are called metastatic suppressors, e.g., cadherins. These are “calcium-reliant adhesion molecules” a type of type-1 transmembrane proteins. They play an imperative role in cell adhesion, making adherent junctions to bind cells within tissues together. They need calcium (Ca 2+) ions to function. The cadherin superfamily comprises cadherins, protocadherins, desmogleins, and desmocollins etc., Types of cadherins hinge on their location and functional tissue as epithelial cadherin (e cadherin), neural cadherin (N cadherin), and placental cadherin (p cadherin).[34] In epithelial cells, e-cadherin-encompassing cell-to-cell junctions are often end-to-end to actin-filaments of the cytoskeleton.[35] E-cadherin functional loss or expression has been concerned in ensuing increase in invasion. In neoplasms, the cadherins decline, and hence beta-catenins cannot bind to cadherins and get translocated to the nucleus and endure the process of transcription, leading to progression of the tumor.[36]

P53 a decisive protein labelled as “the guardian of the genome.”[37] P53 plays role in apoptosis, genomic constancy, and modulating angiogenesis. In cancer, p53 works through several mechanisms: It can motivate DNA repair proteins in sustained DNA damage; halt growth by controlling the cell cycle at the G1/S regulation point; and can recruit apoptosis if DNA damage proves to be irreversible.[38] Definite pathogens such as human papillomavirus (HPV) can affect the p53 protein, such as it codes a protein E6 which binds to the p53 protein and disables it. Furthermore, the mutant p53 protein can constrain normal p53 protein levels. In certain cases, sole missense mutations in p53 have been revealed to disrupt p53 function and stability.[39]

Retinoblastoma gene (RB) is a tumor suppressor gene located on 13q14.1q14.2., encoding a protein called retinoblastoma protein (Rb), which is a tumor suppressor protein. One function of Rb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. Rb is phosphorylated to where it becomes inactive and allows cell cycle progression.[40] In normal cells, Rb restricts the cell's ability to replicate DNA by preventing its progression from the G1 (gap phase) to S (synthesis phase). Rb binds and inhibits transcription factors of the E2F family. When Rb is bound to E2F, the complex acts as a growth suppressor and prevents progression through the cell cycle.[41]

Another tumor suppressor gene is adenomatous polyposis coli (APC). It is positioned on the chromosome 5q22.2. It comprises an internal ribosome entry site. The important function of APC protein is to act as a bad supervisor that reins beta-catenin concentrations and interrelates with e-cadherin, which are tangled in cell adhesion. It controls a cell to divide, its attachment with other cells within a tissue, or its mode of travel within or away from a tissue. The action of beta-catenin is specific and is well-ordered by the APC protein.[42] Mutations in APC lead to damage of β-catenin regulation, transformed cell migration, and chromosome instability.[43],[44]

Breast carcinoma geneis a human tumor suppressor gene, accountable for fixing DNA.[45]BRCA1 and BRCA2 are customarily stated in the tissue of breast and other tissues, where they aid to renovate damaged DNA or destroy cells if DNA cannot be repaired.[46] Hence, it plays a role in transcription, DNA healing of double-strand breaks, transcriptional regulation, and ubiquitination. As an end result, mutations shape up and can root cells to split in an unrestrained manner to form a tumor.[47]

Cytogenic alterations

The accretion of genetic variations drives the normal cells through hyperplastic and dysplastic phases to invasive cancer, and lastly, metastatic disease.[48] Mutational and gene analysis of tumor suppressors and oncogenes in the framework of early tumor genesis has provided insight into the part of these genes in cancer development. Furthermore, high quantity, genome-wide methods, and the broad sequencing of the human genome have enhanced the huge-scale discovery of cancer-linked genes and pathways.[49] Genetic adjustments in tumors are very difficult to understand and changes noticed in premalignant stages are fundamental events initiating and promoting cancer. Up to now, genomic and proteomic exertions have been principally focused to study tumors.[50]

Genetic susceptibility

Trivial difference in gene segments make selected individuals more liable to develop cancer, acknowledged as “genetic susceptibility.” Genetic predilection is a distinctive process, which powers the phenotypic development of an individual under the effect of environmental circumstances. Intrinsic susceptibility and acquaintance to carcinogens can act in a recital manner to modulate cancer risk. In this association, fragile site identification may be an appropriate marker for predilection to cancer development.[51],[52]

Suppressive growth regulation

The growth factors which emphasis mainly on overwhelming the tumor growth is TGF β. Some head and neck cancers yield mutations of TGF β receptors whose communications leads to adverse regulation of the cell cycle.[53] Retinoic acid receptors have been concerned in negative development of head and neck squamous cell carcinoma.[4]


  Molecular Basis of Risk Factors Top


Head and neck cancer mainly comprises oral cavity, oropharynx, larynx, and hypopharynx, which are in a straight line exposure to tobacco smoke and have comparatively high risk of cancer development than other regions.[50] Tobacco-related compounds comprise a varied array of chemical carcinogens that cause cancers of numerous types.[52] Sixty different known carcinogens have been detected in smokeless tobacco and in cigarette smoke. Among these, tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons, and aromatic amines seem to have an imperative role in cancer. Tobacco commences metabolic stimulation by a procedure started by chemical carcinogen cytochrome p450 enzymes, which sorts the carcinogens form DNA adducts causing mutations. Tobacco would be just extra factor, instead of the lone cause of death. Nicotine is one of the factor which is addictive and toxic but not carcinogenic.[43]

A pivotal association among the betel quid chewing habit and leukoplakia, oral submucous fibrosis, lichen planus, and oral cancer has been intensely established. Keratinocyte inflammation is thought to be a serious step in tumor promotion. Arecanut contents makes the prostaglandin E2 and 6-keto PGF1-alpha assembly by oral keratinocytes. It also increases the production of COX-2 mRNA and protein, forms conjugates with carcinogens to form reactive oxygen species, sister chromatid exchange, chromosomal aberrations, DNA strand breakage, DNA protein cross linkage, inhibits the DNA repair process and incurable differentiation of buccal keratinocytes.[40]

Several DNA viruses have been linked with the etiology of cancer. Among the many human DNA viruses, four are of particular interest because they have been implicated in causing cancer. Approximately 70 genetically types of HPV have been identified. HPV 16 and 18 are found in approximately 85% of squamous cell carcinoma patients. The viral DNA gets incorporated in to the host genome and is responsible for malignant transformation. E1 and E2 open reading frames will be interrupted and can lead to overexpression of E6 and E7 proteins. This E7 protein binds to underphosphorylated form of retinoblastoma and displaces E2F transcription factor. E6 protein degrades p53 protein. Epstein Barr virus gains entry in to B cells via CD21 molecule. In B lymphocytes, the linear genome of the virus circularizers to form an episome in the nucleus. The LMP-1 prevents apoptosis of B cells by upregulating the expression of bcl-2 and activating growth promoting pathways. EBV encodes EBNA 2 gene which activates cyclin D and src family. It also activates LMP 1. RNA viruses such as human T Cell Leukemia Virus Type 1 has tropism for CD4 T cells similar to HIV virus. The genomic structure of HTLV 1 gene contains tax protein which activates the process of transcription of several genes in the host.

Helicobacter pylori was declared as type I carcinogen by IARC in 1994. There are three supposed pathways of H. pylori carcinogenic action. H. pylori act as a direct mutagen through interactions of intercellular signaling molecules and Cag A, which predispose the cells to accumulate multiple genetic and epigenetic changes that promote multistep carcinogenesis. H. pylori induced Vac A can cause immunosuppression by blocking proliferation of T cells. It can include cell proliferation by increasing the levels of several cytokines and regulatory molecules, which are involved in tumor formation and cell transformation. H. pylori stimulates lymphocytic infiltration of the mucosal stroma, which may act as a focus for cellular alterations and proliferations, ultimately resulting in neoplastic transformation to lymphoma.[7]


  Conclusion Top


Treatment for innovative head and neck squamous cell carcinoma is uninterruptedly attuned to current scientific knowledge. It is frequently alleged that there is no treatment of choice for head and neck squamous cell carcinoma, but relatively a choice of treatments is accessible. Therefore, finding the markers that predict response to chemoradiation protocols to personalize the mode of treatment facilities in each individual patient is supreme. Countenance of these markers in diagnostics can act as supplementary tool. Thus, the study of the molecular mechanisms can help to identify the possible pathways for development of new treatment modalities in the process of carcinogenesis and metastasis.

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Conflicts of interest

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