Elsevier

Oral Oncology

Volume 39, Issue 3, April 2003, Pages 213-221
Oral Oncology

Review
Oral cancer: reviewing the present understanding of its molecular mechanism and exploring the future directions for its effective management

https://doi.org/10.1016/S1368-8375(02)00162-8Get rights and content

Abstract

The present review aims to analyze the information available regarding the molecular mechanisms of Oral Carcinogenesis and explore the future directions where the field of Cancer Biology is venturing. Oncologists have excellently followed the proverb “Necessity is the mother of Invention”. The desire to be more precise and comprehensive in their studies has led to the invention of some of the most innovative techniques like laser capture microdissection, comparative genomic hybridization, microarrays, and protein chips etc. Various Biotech companies and Cancer Institutes are on a hunt for anti-cancer drugs and molecular markers for cancers. These revolutionary approaches and the new breed of Oncologists have made the field very exciting and have generated the hope that finally the war against cancer would be won. In the end it is urged that the lead taken in other cancers like colon, breast, leukemia will be emulated in oral cancer. This is expected to provide a molecular blueprint for HNSCC, thus helping to identify suitable markers for the early detection of pre-neoplastic lesions, as well as novel targets for its pharmacological intervention.

Introduction

Oral squamous cell carcinoma (OSCC) is the sixth most common malignancy and is a major cause of cancer morbidity and mortality worldwide. Globally about 500,000 new oral and pharyngeal cancers are diagnosed annually, and three quarters of these are from the developing world [1]. Oral cancer is an epithelial neoplasia generally beginning as a focal clonal overgrowth of altered stem cells near the basement membrane, expanding upward and laterally, replacing the normal epithelium. The neoplastic process is a beginning with normal epithelium progressing through hyperplasia to dysplasia to carcinoma in situ and invasive carcinoma [2]. Oral carcinogenesis is associated with cumulative gene alterations. In neoplasms, cell proliferation is excessive and autonomous, uncoordinated with normal tissues with cell division going on despite DNA damage due to loss of cell cycle check-points. These neoplastic cells ultimately enters lymphatic vessels and metastasize to regional lymph nodes. Age standardized incidence rate of head and neck cancer in males exceeds 30/100,000 in regions of France, Hong Kong, the Indian sub-continent, Central/Eastern/Southern Europe, regions of South America, and among US blacks. High rates (>10/100,000) in females are found in India and Hong Kong [3]. Oral cancers are common in regions with high tobacco and alcohol consumption. In south-east Asian countries people extensively use smokeless tobacco in the form of nass, naswar, khaini, pan masala, gutkha and betel quid (betel leaf coated with slaked line wrapped around areca nut and catechu) or tobacco smoking in the form of cigarette, bidi, chutta, reverse type of smoking and hooka. Hence, in this part of world Buccal Mucosa (cheek) represents the primary site for cancer development as compared with tongue and floor of mouth in Western Countries [4]. Since, carcinogenesis is a multi-step process hence in addition to genetic insult by tobacco-associated intra-oral carcinogens, several additional factors, such as genetic susceptibility of individuals and external agents, such as alcohol, dietary factors and viruses (human papilloma virus, HPV, and Epstein–Barr virus, EBV), may play a synergetic role in oral tumorigenesis [5].

Oral cancer is one of the few cancer types where it is possible to obtain biopsies at all stages of cancer progression. Consequently, it is possible to define a genetic progression model of this disease. The pioneer work characterizing the genetic alterations in colorectal cancer by Fearon and Vogelstein [6] has become a paradigm for other human neoplasias. It is now believed that OSCC follows a similar pattern in its development, and thus is preceeded by premalignant lesions such as leukoplakia, dysplasia, erythroplakia, lichen planus and oral sub-mucous fibrosis (OSMF). The precise nature of the genetic alterations occurring at each step is still unclear, but Califano et al. [7] have described a preliminary HNSCC molecular progression model. Five years survival rates for mouth, tongue, oropharynx and laryngopharyngeal cancers seldom exceed 40%. Involvement of regional lymph nodes is the most important prognostic factor for oral cancer.

Section snippets

Molecular alterations in oral cancer

Cancer evolves in a series of distinct steps, each characterized by the sequential accumulation of additional genetic defects followed by clonal expansion.

Switching to new technologies for systematic identification and cataloguing of genes involved in oral carcinogenesis

The emphasis in oncology during the past decade has been on the incorporation of genomics tool into oncological research and now, in the post genomic era, there is a strong drive to incorporate proteomics technologies into oncology research. With the human genome being sequenced many biotech companies are venturing in the field of Operomics, with the goal of applying this knowledge for anti-cancer drug discovery and molecular diagnosis of cancer. Operomics, an approach that integrates genomics,

Acknowledgements

This work was supported in the form of Research Grants to Professor B.R. Das from Department of Biotechnology (BT/R&D/091/066/96 and BT/PR1347/HRD/15/131/98), Govt. of India; Council of Scientific and Industrial Research, Government of India. The financial support from the Department of Biotechnology, New Delhi and Council of Scientific and Industrial Research, New Delhi to BRD is highly acknowledged. JKN thanks the Council of Scientific and Industrial Research, New Delhi, for a research

References (119)

  • N.L. Simone et al.

    Laser-capture microdissectionopening the microscopic frontier to molecular analysis

    Trends Genet

    (1998)
  • K.K. Jain

    Application of laser capture microdissection to proteomics

    Methods Enzymol.

    (2002)
  • J. Khan et al.

    DNA microarray technology: the anticipated impact on the study of human disease

    Biochim Biophys Acta

    (1999)
  • D. Gerhold et al.

    DNA chipspromising toys have become powerful tools

    Trends Biochem Sci.

    (1999)
  • P.C. Gupta et al.

    Comparison of carcinogenicity of betel quid with and without tobaccoan epidemiologic review

    Ecology of Disease

    (1982)
  • D. Saranath

    Integrated biology and molecular pathology of oral cancer

  • J. Fearlay et al.

    Cancer incidence, mortality and prevalence worldwide, Version 1.0. IARC Cancer Base No.5

    (2001)
  • I.B. Paz et al.

    Human papillomavirus (HPV) in head and neck canceran association of HPV-16 with squamous cell carcinoma of Waldeyer's tonsillar ring

    Cancer

    (1997)
  • D.K. Daftary et al.

    Risk factors and risk markers for oral cancer in high incidence areas of the world

  • J. Califano et al.

    Genetic progression model for head and neck cancer: implications for field cancerization

    Cancer Res.

    (1996)
  • U. Bockmuhl et al.

    Genomic alterations associated with malignancy in head and neck cancer

    Head Neck

    (1998)
  • Y. Jin et al.

    Cytogenetic and fluorescence in situ hybridization characterization chromosome 1 rearrangements in head and neck carcinomas delineate a target region for deletions within 1p11-1p13

    Cancer Res.

    (1998)
  • R.C. Boland et al.

    A national cancer institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer

    Cancer Res.

    (1998)
  • D.J. Lee et al.

    Impact of chromosome 14q loss on survival in primary head and neck squamous cell carcinoma

    Clin Cancer Res.

    (1997)
  • P. Waber et al.

    Genetic alterations of chromosome band 9p21-22 in head and neck cancer are not restricted to p16INK4a

    Oncogene

    (1997)
  • A.K. El-Naggar et al.

    Localization of chromosome 8p regions involved in early tumorigenesis of oral and laryngeal squamous carcinoma

    Oncogene

    (1998)
  • A.D. Lazar et al.

    Loss of hereozygosity at 11q23 in squamous cell carcinoma of the head and neck is associated with recurrent disease

    Clin Cancer Res.

    (1998)
  • E.J. Mao et al.

    Loss of heterozygosity at 5q21-22 (adenomatous polyposis coli gene region) in oral squamous cell carcinoma is common and correlated with advanced disease

    J Oral Pathol Med.

    (1998)
  • K. Ogawara et al.

    Allelic loss of chromosome 13q14.3 in human oral cancer: correlation with lymph node metastasis

    Int J Cancer

    (1998)
  • D.T. Ransom et al.

    Loss of heterozygosity on chromosome 2q: possibly a poor prognostic factor in head and neck cancer

    Head Neck

    (1998)
  • R. Adamson et al.

    Loss of heterozygosity studies on chromosome 17 in head and neck cancer using microsatellite markers

    Oncogene

    (1994)
  • H. Nawroz et al.

    Allelotype of head and neck squamous cell carcinoma

    Cancer Res.

    (1994)
  • A.K. El-Naggar et al.

    Sequential loss of heterozygosity at microsatellite motifs in preinvasive and invasive head and neck squamous carcinoma

    Cancer Res.

    (1995)
  • L. Mao et al.

    Frequent microsatellite alterations at chromosomes 9p21 and 3p14 in oral premalignant lesions and their value in cancer risk assessment

    Nat Med.

    (1996)
  • P.P. Reis et al.

    Quantitative real-time PCR identifies a critical region of deletion on 22q13 related to prognosis in oral cancer

    Oncogene

    (2002)
  • K. Uzawa et al.

    Abnormalities of the adenomatous polyposis coli gene in human oral squamous cell carcinoma

    Int J Cancer

    (1994)
  • M. Sartor et al.

    Role of p16/MTS1, cyclin D1 and RB in primary oral cancer and oral cancer cell lines

    Br J Cancer

    (1999)
  • M.P. Copper et al.

    Role of genetic factors in the etiology of squamous cell carcinoma of the head and neck

    Arch Otolaryngol Head Neck Surg

    (1995)
  • W.D. Foulkes et al.

    Family history is a risk factor for squamous carcinoma of the head and neck in Brazil: a case-control study

    Int J Cancer

    (1995)
  • W.D. Foulkes et al.

    Familial risks of squamous cell carcinoma of the head and neck: a retrospective case-control study

    Br Med J.

    (1996)
  • M.L. Bondy et al.

    Association between family history of cancer and mutagen sensitivity in upper aerodigestive tract cancer patients

    Cancer Epidemiol Biomarkers Prev

    (1993)
  • V. Bongers et al.

    The relation between cancer incidence among relatives and the occurrence of multiple primary carcinomas following head and neck cancer

    Cancer Epidemiol Biomarkers Prev

    (1996)
  • G. Klein et al.

    Evolution of tumors and impact of molecular biolgy

    Nature

    (1985)
  • F.G. Haluska et al.

    Oncogene activation by chromosome translocation in human malignancy

    Annu. Rev. Genet.

    (1987)
  • J.M. Bishop

    Cellular oncogenes and retroviruses

    Ann Rev Biochem.

    (1983)
  • J.R. Grandis et al.

    Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer

    Cancer Res.

    (1993)
  • J.R. Grandis et al.

    Levels of TGE-α and EGFR protein in head and neck squamous cell carcinoma and patient survival

    J Natl Cancer Inst.

    (1998)
  • He Y, Zeng Q, Drenning SD, Melhem MF, Tweardy DJ, Huang L et al. Inhibition of human squamous cell carcinoma growth in...
  • Q. Zeng et al.

    Determination of intermediate biomarker expression levels by quantitative reverse transcription- polymerase chain reaction in oral mucosa of cancer patients treated with liarozole

    Clin. Cancer Res.

    (2000)
  • G.J. Rubin et al.

    Asynchronous modulation of transforming growth factor-α and epidermal growth factor receptor protein expression in progression of premalignant lesions in head and neck squamous cell carcinoma

    Clin Cancer Res.

    (1998)
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