Tumor Biology in Head and Neck Tumors
Introduction:
Most head and neck cancers result from multistep accumulation of genetic alterations resulting in clonal outgrowth of transformed cells. These genetic alterations include a variety of changes in the structure and sequence of cellular DNA within the offending clonal population. These changes result in activation of proto-oncogenes and inactivation of tumor suppressor genes. These DNA changes are caused by a variety of mechanisms like endogenous mutation and exogenous mutation. Exogenous mutations are caused by potent environmental carcinogens.
These genetic mutations cause changes in the biologic characteristics of any neoplasm like cell growth, death, motility and invasion. These mutations also influence the host’s defense mechanism and immunological status. Another important aspect of tumor biology in head and neck cancers is the role played by Circadian rhythm. Circadian rhythm enables humans to adapt to daily environmental changes and also manages to synchronize various biochemical and physiologic processes with each other. These circadian clocks have known to interfere with cell cycle. An intact circadian rhythm is necessary for normal cell growth and cell death. It is hence necessary to study the role played by circadian rhythm in the tumorogenesis.
Chromosome region 9p21 loss is the most common aberration detected in patients with head and neck cancers. It has been demonstrated that 9p21 loss is one of the earliest detectable events in head and neck cancer patients. This chromosomal region loss is also commonly seen in patients with squamous hyperplastic lesions (benign) of head and neck.
Inhibition of gene p16: This gene is a critical inhibitor of cyclin CDK complexes. Inactivation of this gene permits inappropriate progression through critical G1/S cell cycle check points allowing cell division to occur unimpeded and relentlessly. This gene can be inhibited by complete deletion or by methylation of the promoter region.
Deletion of several discrete regions in chromosome 3p: This has been identified in 60% of head and neck cancer patients. The precise nature of function of this gene is still unknown.
Loss of chromosome 17p: This has been shown to occur in more than 50% of head and neck malignancies. It also correlates with p53 inactivation.
Mutation / inactivation of p53 genes: This is a tumor suppressor gene. It is of course the most extensively studied of all genes. This gene is known to suppress cell division. It induces G1 arrest till genetic repair is effected. If genetic repair is not possible it directs the cell into apoptotic pathway. It has been shown that Human papilloma virus E6 gene interacts with p53 protein causing it to degrade thus essentially inactivating it. Carcinogenesis of HPV is due to this action.
Loss of chromosome 13q: Is seen in about 60% of patients with tumors of head and neck. This portion of the chromosome is supposed to contain the RB gene. Human papilloma virus E7 another oncogenic protein is known to deactivate this RB gene. This gene has been known to negatively modulate transcription factor E2F.
Amplification of 11q13: This has commonly been implicated in 40% of head and neck cancer patients. This chromosomal area is responsible for the production of cyclin D1. Cyclin D1 is considered to be an important oncogene in the tumorogenesis of head and neck malignant tumors. Cyclin D1 is known to activate cell cycle progression.
Squamous cell carcinoma related onco-gene: This gene is activated by amplification of 3q26.3 gene. This onco-gene has been identified as one of the important initiator of squamous cell carcinoma of head and neck.
Role of growth factors in tumorogenesis of head and neck malignancies:
It is the presence of Growth factors and their receptors signals stimulus to cell division and growth in normal cells under physiologic conditions. Over expression of growth factors and their receptors can cause pathologic proliferation of cells and hence considered as products of proto-oncogenes. More than 90% of head and neck cancers over express epidermal growth factor receptor. This growth factor is encoded by c-erb
The HER-2/neu gene encodes transmembrane receptor called tyrosine kinase. Tyrosine kinase belongs to epidermal growth factor receptor group. Hence HER -2/neu gene amplification plays a role in tumor genesis.
Clinical applications: ? possible
It has been shown that nearly 50% of tumors arising from oropharynx contain oncogenic human papilloma virus DNA. As described above the tumorogenecity of HPV is due to the action of this protein on p53 chromosome. It has also been shown that patients with antibodies to HPV showed overall better survival rates. Recently the antiviral agent cidofovir when used in combination with tumor irradiation resulted in increased radio sensitivity of tumor cells.
The concept of molecular staging has been introduced. This procedure makes use of these commonly present tumor markers described above. These elements can also be used in early diagnosis of malignancies / potential malignancies. Recently therapeutic strategies have been evolved to target thee p53 mutant tumors. This is done by developing adenovirus with E1b 55 kd gene deleted. This virus is known to selectively replicate and lyse p53 deficient cells.
Cyclidin D1 has been found to be commonly over expressed in patients with head and neck cancers. Flavopiridol a CDK inhibitor has been used to repress transcription of cyclin D. This causes a cellular arrest at G2 and G1 phases of cell division. This chemical is also found to promote p53 independent cellular apoptosis. It is also known to increase the chemo / radio sensitivity of tumor cells.
Over expression of epidermal growth factor in head and neck tumors is associated with poorer prognosis. Various EGFR blockers have been devised in order to improve the prognosis. These blockers include antibodies, tyrosine kinase etc.
