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Table of Contents   
REVIEW ARTICLE  
Year : 2015  |  Volume : 8  |  Issue : 4  |  Page : 88-93
Understanding oral cancer at molecular level: The new frontier


1 Department of Public Health Dentistry, Government Dental College and Hospital, Shimla, Himachal Pradesh, India
2 Department of Oral and Maxillofacial Surgery, Gurunanak Institute of Dental Science Research, Kolkata, West Bengal, India
3 Department of Oral Pathology and Microbiology, Government Dental College and Hospital, Shimla, Himachal Pradesh, India
4 Department of Conservative and Endodontic, Government Dental College and Hospital, Shimla, Himachal Pradesh, India
5 Department of Radiation Oncology, Regional Cancer Centre, IGMC, Shimla, Himachal Pradesh, India

Click here for correspondence address and email

Date of Web Publication7-Aug-2015
 

   Abstract 

Oral cancer is one of the major threats to public health in developed as well as developing countries. Despite the current therapeutic modalities, which include the use of nonselective treatments (surgery, radiation, and chemotherapy), the mortality and morbidity rates still remain high due to delays in diagnosis and treatment. Thus, it is important to completely understand the molecular mechanism in the development of oral cancer to further develop more selective treatment. This review attempts to identify and understand the deregulated molecular pathways and related genes in oral carcinogenesis.

Keywords: Cancer, genetics, hallmarks, molecular biology, oral cancer, squamous cell carcinoma (SCC)

How to cite this article:
Manchanda K, Sarkar AD, Chauhan I, Sharma N, Fotedar S, Fotedar V. Understanding oral cancer at molecular level: The new frontier. Ann Trop Med Public Health 2015;8:88-93

How to cite this URL:
Manchanda K, Sarkar AD, Chauhan I, Sharma N, Fotedar S, Fotedar V. Understanding oral cancer at molecular level: The new frontier. Ann Trop Med Public Health [serial online] 2015 [cited 2020 Apr 1];8:88-93. Available from: http://www.atmph.org/text.asp?2015/8/4/88/162314

   Introduction Top


Oral and pharyngeal cancer, grouped together, is the sixth-most common cancer in the world. [1] Although there has been a reduction in total mortality over the past two decades, the 5-year relative cancer survival rate for oral cancer is one of the lowest, far below the rate for many other cancers, including skin melanoma and cancers of the testis, breast, colon, rectum, and kidney. [2]

Oral squamous cell carcinoma (OSCC) is among the most frequently seen of all oral cancers. [3] Tobacco and alcohol remain the most important risk factors for squamous cell carcinomas (SCCs) of the oral cavity, [3] but a genetic predisposition has also been suggested, due to the fact that the majority of the population exposed to these risk factors do not develop oral cancer and the fact that sporadic cases of oral tumors occur in young adults and nonusers of tobacco and alcohol. [4] Oral cancers are characterized by a multitude of these genetic alterations [5] and have a remarkable incidence with fairly poor prognosis, which has encouraged the setting up of many studies to explore the underlying mechanism of its development. [6] In the following review, we address the information currently available for several genetic and molecular aspects of oral cancer and the metastatic process, as it will help in recognizing the population at risk and in enabling prompt treatment due to early diagnosis.


   Basic Concept of Tumor Biology Top


Clonal evolution [7]

The dominant theory of tumor development over the past 30 years has been the clonal evolution theory, first proposed in 1976 by Nowell. In this model, repeated carcinogenic insults, or "events," occur within a cell, usually at the genetic or epigenetic level. When enough events occur, a selective growth advantage is conferred on the affected cell. As this cell proliferates, mutant progeny arise as a result of further insults and genomic instability. Most of the offspring do not survive because of immunologic surveillance, apoptosis, or metabolic derangement. Eventually, however, a dominant clonal population of cells is produced that not only survives, but flourishes. As evolution occurs within this clonal population, new clones are produced with acquired additional characteristics, such as the capacity for invasion, that define cancer.

Molecular progression model [8]

Over the past 20 years, investigators have identified a number of acquired alterations in oncogenes and tumor suppressor genes and have tried to coordinate these genotypic changes with the phenotypic changes seen clinically. Initial work by van der Riet et al. has assembled these genetic events, whether they result from cytogenetic alterations, interaction with viral products, or damage from radiation or chemical carcinogens, into an "allelotype" for head and neck carcinoma. This has led to the development of a molecular progression model for head and neck cancer. Again, it is the accumulation of genetic events and not the specific ordering of the events that appears to be associated with phenotypic progression. This model is important not only for understanding the pathogenesis of head and neck cancer, but also for developing new diagnostic, staging, and therapeutic techniques.

Field carcinogenesis [9]

Clear evidence exists that exposure to the carcinogens in tobacco is responsible for the vast majority of squamous cell carcinoma of the head and neck (SCCHN). Slaughter hypothesized that because of constant carcinogenic pressure, the entire upper aerodigestive tract is at increased risk of developing multiple primary tumors. The original hypothesis was that multiple genetic events occurred throughout the involved mucosa, allowing the development of multiple, molecularly distinct lesions. Recently, however, an alternative hypothesis has been postulated to explain field carcinogenesis. According to it, a single lesion is thought to form multiple upper aerodigestive tract lesions through the process of intraepithelial migration.

SCC arising in nonsmokers

Though SCCHN has been strongly linked to tobacco, a disturbing trend has been observed recently: An increase in incidence among nonsmokers.[10] In the absence of carcinogenic pressure from tobacco, several causative agents have been theorized to play a role in the pathogenesis of these cancers. These include the consumption of alcohol, human papillomavirus (HPV) infection, exposure to secondhand smoke, imbalance of vitamins, immunosuppression, and genetic susceptibility. [8],[11] Lindel et al. [12] showed that oral cancers in nonsmokers were more likely to be associated with HPV-positive cancers compared to smokers. Currently, sequences for more than 100 different serotypes of HPV have been identified. They are subdivided on the basis of cutaneous and mucosal site of involvement as high-, intermediate-, and low-risk, depending on their association with malignancy. The transforming potential of high-risk HPVs is largely a result of the function of two viral oncoproteins, namely E6 and E7. [10],[13]


   Hallmarks of Oral Cancer Top


Acquisition of autonomous proliferative signaling

Epidermal growth factor (EGF) axis

The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor that belongs to the HER/erbB family and is overexpressed in up to 90% of SCCHN. A high EGFR gene copy number has been reported in 10-58% of SCCHN. In SCCHN, in contrast to lung cancer, activating EGFR mutations are rare and overexpressions of EGFR and high EGFR gene copy number are also associated with poor prognosis and radioresistance. The EGFR is a relevant target in SCCHN, as cetuximab, an immunoglobulin G1 (IgG1) monoclonal antibody that targets the EGFR, improves overall survival when combined with radiotherapy (RT) or chemotherapy. However, only a minority of patients will benefit from anti-EGFR monoclonal antibodies, and the objective response rate in monotherapy is 6-13%. [14]

Signal transducers and activators of transcription proteins

The transcription factor signal transducers and activators of transcription 3 (STAT3), which has been detected in many types of cancer, plays an important role in tumor cell survival, proliferation, self-renewal, and invasion. [15] The activation of STAT3 causes a significant decrease in apoptosis, inhibition of cell cycle progression by activation of caspase 3, and decreased expression of B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-XL), Myeloid cell leukemia 1 (Mcl-1), cyclin D3 (CCND3), and Myc myelocytomatosis oncogene (c-myc). It appears that this downregulation is due to elevated levels of the antiapoptotic protein Bcl-XL. [16],[17],[18] In one of the studies conducted by Tatsuhito Nagumo, it was seen that treatment with JSI-124, which is a specific inhibitor of STAT3, resulted in a decrease of phosphorylated STAT3 and a downregulated expression of survivin, a downstream molecule of the STAT3 signaling cascade. He suggests that the inhibition of STAT3 signaling by JSI-124 might be promising as a molecular therapy strategy against OSCC. [19]

Nuclear factor-kappa B (NF-kB)

NF-kB may promote tumor progression of SCC through the enhancement of tumor survival and expression of cytokines and other genes. [20],[21] In this study, 85% of tumors showed increase in the nuclear localization of NF-kB with stronger immunostaining, and was associated with worst prognosis. [22]

Fibroblast growth factors [23]

The expression of fibroblast growth factors (FGFs) FGF-1 and FGF-2 is elevated compared with the levels of those in normal mucosa, which was seen by investigators studying cell lines as well as primary tumors of SCC.

Hepatocyte growth factor (HGF) axis [24]

The HGF receptor has been found to be coded by the c-Met proto-oncogene. Invasion and metastasis of oral cavity cancer cell lines has implicated both HGF and c-Met in recent studies. This increase in invasiveness may be due to HGF's ability to upregulate both matrix metalloproteinase-1 (MMP-1) and MMP-9. [25] In addition, Dong et al. have shown that a role may be played by HGF in angiogenesis in SCCHN via upregulation of the proangiogenic cytokine interleukin 8 (IL-8) and the vascular endothelial growth factor (VEGF). [26]

Inhibition of growth inhibitory signals

TP53

The TP53 gene that encodes the p53 protein is an important tumor suppressor. [26] It is estimated that of over 50% of human tumors that harbor mutations in the TP53 gene have dysfunctional p53 signaling. Thus, p53 is also an important candidate target for cancer gene therapy as it participates in all steps of tumor initiation and development by regulating the expression of many downstream genes. [27] Boyle et al. found that TP53 mutations were there in 19% of premalignant lesions and 43% of malignant lesions. [28]

INK4 gene family

The INK4 (inhibitors of CDK4) family of genes consists of several proteins - pl5INK4B, pl6INK4A, pl8 INK4C, pl9 INK4D - that appear to act mainly on the G1 phase in the cell cycle. P16 activity was lost in the wide number of primary tumors. [8] The frequent finding of pl6 gene mutations or the loss of its expression in dysplastic as well as neoplastic oral lesions indicates that this may be an early step in oral carcinogenesis. [29]

Cyclin D1

In a study conducted in a Taiwanese population, it was seen that OSCC showed overexpression of cyclin D1 protein, which was significantly associated with lymph node metastasis, and tumor cell differentiation and stage. [30],[31] Overexpression of cyclin D1 when compared to normal mucosa showed a direct positive correlation with poor prognosis. [32]

P21 family

An important role is played by p21 by inhibiting cell apoptosis or resistance to therapy. Patients with a high p21 expression level must be administered intensive combined therapy and provided with follow-ups at an increased frequency to improve overall survival rates. [33]

Evasion of programmed cell death (apoptosis)

The balance between the proliferation and death of tumor cells depicts the rate of tumor growth. It is known that the Bcl-2 protein is a death antagonist, whereas the Bax, caspase-3, and p53 proteins are death-promoting factors. [34]

Immortalization

A small amount of telomeric DNA that acts as a protective cap is lost with each replicative cycle. Cell death occurs once enough has been lost.[35] Telomerase activity was found in 100% of cell lines and 90% of invasive cancers but was not detected in any normal tissues in an analysis of 16 SCCHN cell lines and 29 tumor specimens.[36]

Acquisition of a nutrient blood supply (angiogenesis)

The formation of new blood vessels is critical as the tumors grow, invade, and metastasize. Tumors larger than 1 mm 3 may undergo necrosis without adequate vascularization. This process is a multistep process, which appears to be regulated by factors that are both stimulatory and inhibitory. [37]

Microvessel density

Conflicting results have been shown by several studies that looked at microvessel density in relation to the clinical outcome of patients with SCCHN. A correlation between elevated microvessel density, as determined by factor VIII staining, and the development of cervical metastases was shown in one study of 25 patients with stage 2 lesions of the oral cavity. [38] Another study found that patients who had SCCHN with low microvessel density had a worse prognosis, with a median survival of 10 months, than did patients with increased microvessel density, with a median survival of 69 months. [39]

Regulators of angiogenesis

A few of these molecules and their purported roles in the angiogenic pathway, with special reference to SCCHN, are discussed below:

Positive regulators of angiogenesis

i. VEGF

Various studies have identified that VEGF acts as the most significant predictor of poor prognosis in patients with oral or oropharyngeal carcinoma. [40]

ii. Platelet-derived endothelial cell growth factor (PD-ECGF)

PD-ECGF was found to be overexpressed in a high percentage of tumor cells, in 58 patients with oral or oropharyngeal cancers. Those patients with lower percentages of tumor cells expressing PD-ECGF had lower rates of relapse and death from their disease than did those with a higher degree of staining. [41]

Negative regulators of angiogenesis

i. Interferons (IFNs)

Studies of IFNs have shown that the members of this family of cytokines have potent antiangiogenic activity. [42] Decreased IFN-P expression has been inversely correlated with microvessel density and new blood vessel formation [43]

ii. Thrombospondins (TSPs)

Two members of the TSP family - TSP-1 and TSP-2 - are also naturally occurring inhibitors of angiogenesis. [44] Evidence shows that TSP-1 inhibits angiogenesis by inducing endothelial cell apoptosis. [45]

Tissue invasion and metastasis [8]

The three steps critical to epithelial tumor cell invasion are the attachment of tumor cells to the basement membrane, proteolysis of the extracellular matrix, and migration of the tumor cell.

Tumor adhesion

Integrins

Integrins are a family of cell adhesion molecules, and the α6β4 integrin is also known to bind specifically to laminin. [46] The initial loss of α6β4 is associated with tumor growth in SCC. The expression of α6β4 is frequently enhanced in SCCs and correlates with poor prognosis in patients. [47]

E-cadherin

It plays an important role in maintaining cell-to-cell contacts; increased tumor burden and nodal metastasis seen in the late clinical stage was associated with a significant loss of E-cadherin membranous expression, which was observed in hyperplasia as compared to the normal oral tissues. [48]

Catenins

The results from this study indicate that reduced β-catenin protein in OSCC may disrupt stability and integrity of the E-cadherin/catenin complex and disturb cellular adherens junctions. This results in the dissociation of the tumor cells from primary sites, thereby allowing metastases. Invasive growth is the other main characteristic of malignant tumors. Downregulation of β-catenin expression is associated with increased invasiveness. [49]

Proteolysis and migration

MMPs

In patients with oral cavity tumors, the expression of this group of enzymes has been correlated with the development of cervical lymph node metastases and lymphatic and vascular invasion. [50]

Urokinase-type plasminogen activator (uPA)

Patients with uPA receptor (uPAR)-negative tumors had a higher life expectancy than those with uPAR-positive tumors. [51] The Kaplan-Meier correlation curve showed that there is a statistical correlation that subjects with grade 1 had a shorter overall survival rate, for uPAR-positive patients, while no correlation was found with grades 2 and 3. This may be potentially relevant for the implementation of closer follow-up protocols and/or alternative therapeutic regimens, especially for patients diagnosed with grade 1 tumors. [52]

Serpins

Immunohistochemical techniques have shown that patients with oral SCC tumors having high maspin (mammary serine protease inhibitor, a member of the serpin family) expression had lower rates of regional metastases and better overall survival rates, but this indicated that invasive OSCC showed overexpression of SerpinB1 compared to normal oral mucosa. [53],[54]


   Conclusion Top


The past decade has brought about an explosion of information about the pathogenesis of cancer in general and of SCCHN specifically. As more studies correlating clinical outcome with specific molecular aberrations are completed, molecular diagnosis will play an increasingly important role in determining the prognosis and need for specific treatments for patients with SCCHN.

 
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Correspondence Address:
Kavita Manchanda
Manchanda Medical Stores, 65, The Mall, Shimla - 171 001, Himachal Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1755-6783.162314

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