Molecular biology of oral cancer, ppt

Molecular biology of oral cancer

Presented by Raghda ragab Mohamed Hassan

ContentOral cancer Risk factor for oral cancer Hallmarks of cancer  Molecular basis of oral cancer.  Proto – oncogenes, oncogenes. Common gene alteration identified in oral cancer. Cell cycle and dysregulation in oral cancer. Apoptosis and oral cancer. Tumor suppressor genes involved in oral cancer. DNA repair, defects and genome stability. 

Oral cancerOral cancer refers to a subgroup of head and neck

malignanciesthat develop at the lips, tongue, salivary glands, gingiva, floor of the mouth, oropharynx, buccal surfaces and other intra-oral locations.

There are several types of oral cancers.

The majority (>90%) of oral cancers are oral cancer squamous cell carcinoma (OSCC).

The incidence and mortality rates worldwide of OSCC are approximately 5.9 and 3.3 per 100,000 persons per year.

Risk factors for oral cancer

Alcohol consumption

Smoking and tobacco consumption

Family history of cancer

Excessive sun

Exposure

Figure 1: Hallmarks of cancer

Cellular basis of cancer

Cancer charactarized by abnormal and uncontroled cell growth.

In normal tissues, the rate of new cell growth and old cell death are kept in balance.

In cancer cell, this balance is disturbed This disturbtion in cancer result from uncontrolled cell growth.Loss of a cell ability to undergo apoptosis.

There are many differences between cancer cells and normal cells.

Proto-oncogenes, oncogenes and oncoprotein

Protoncogenes are genes whose protein products have been found to be important for normal cell growth signaling and whose overexpression or mutation leads to unchecked cell growth and tumorigenesis.

Oncogenes represent a gain-of-function mutation

Oncogenes can effect a cellular change through mutation of only one of the two gene copies.

Activation of oncogenes

Table 1. Common gene alterations identified in oral cancer

Gene Frequency (%) FunctionProto-oncogenes EGFR  c-myc/N-myc K-ras/N-ras Cyclin D1 STAT-3

  >30%  20–40% 30–40% 30% 80%

  Cell proliferation,

growth 

Cell growth, apoptosis

 Signaling, growth Cell-cycle

regulation Cytokine signaling,

cellproliferation

Tumor-suppressor genes Rb  p53 p16

30– 50% 50–60% 80%

Cell cycle regulation Cell-cycle regulation Senescence, cell-cycleprogression

Classification of oncogenes

1. Growth factors

2. Cell surface receptors (e.g EGFR)

3 .Intracellular signal transduction pathways (e.g RAS gene family).

4. DNA binding nuclear proteins transcription factors (MYC).

5. Cell cycle proteins (cyclins and cyclin dependent protein kinases).

6. Inhibitors of apoptosis (bcl2).

Subcellular localization and functions of major classes of cancer-associated genes

Stimulation of cell division induced by growth factor

TGF-a Transforming growth factor alpha promotes cell

proliferation in oral tissues as well as in other cell types in the body.

TGF-a is overexpressed early and late in oral carcinogenesis.

TGF-a stimulates a target cell by binding to the epidermal growth factor receptor (EGFR) in an autocrine or paracrine fashion.

TGF-a likely serves a tumor-promoting role in epithelial carcinogenesis.

2 .Cell surface receptors (EGFR )

Growth factor receptors are activated in human tumors by several mechanisms. These include mutations, gene rearrangements, and overexpression.

Mutations of genes encoding cell-surface receptors can result in an increased number of receptors or production of a ligand-independent mitogenic signal.

EGFR is frequently found to be overexpressed in human oral cancers.

.

3 .Intracellular signal transduction pathways

Of all the members of the intracellular signaling pathway, only members of the ras gene family (H-ras, K-ras, N-ras) have been examined in human oral cancer.

Ras oncogenes encode for the related protein p21 that has been localized to the cytoplasmic side of the cellular membrane.

Ras proteins bind guanine nucleotides (GDP and GTP) with high affinity and specificity.

Ras proteins transmit mitogenic signals by binding GTP and hydrolysis of GTP to GDP ends the signal.

Action of RAS gene

Mutation in RAS gene

4 .DNA binding nuclear proteins transcription factors

Transcription factors are proteins that regulate the expression of other genes.

E.g: c-myc which helps regulate cell proliferation

and differentiation,

C-myc is frequently overexpressed in oral cancers.

Amplification and over-expression of c-myc has been observed in 20–40% oral cancers.

Tumor suppressor genes involved in oral cancer

1-p53

p53 gene is the most important TSG and has been called the ‘Guardian of the Genome’.

p53 has a role in maintaining genome stability, and an important role in cell cycle progression, cellular differentiation, DNA repair and apoptosis.

p53 is known to be mutated in approximately 70% of oral tumors. The loss of the heterozygosity of the p53 allele has been reported in 20% of oral cancer cases, as well as in 22% of premalignant oral leukoplakia lesions.

Figure : p53 and cellular and genetic stability

p53 gene can be inactivated by several mechanisms, including point mutations, deletion, and binding with cellular and viral proteins.

Point mutations result in a structurally altered protein.

Deletions lead to a reduction and loss of p53 expression and protein function.

p16 gene and its role

5 .Cell cycle proteinscell cycle phases

Figure : Cell cycle checkpoints

Retinoblastoma gene (Rb)

Cyclins, cyclin dependent kinases (CDKs)

Cyclins are a group of proteins known as the cyclins (D= Departure; E= Exit through restriction point; A=Arrival at S Phase; B= Bi or two chromatids ) promote different phases of the cell cycle.

The cyclins and cyclin dependent kinases (CDKs) form the core of cell cycle regulation.

Expression of cyclins is cell cycle phase dependent .

The cyclin family members interact with CDKs, and these complexes are required to pass through specific phases of the cell cycle.

Figure :Regulation of cell cycle processes by CDK– cyclin complexes.

6. Inhibitors of apoptosis (bcl2)Apoptosis ( programmed cell death) Normal cells are either repaired or die (undergo apoptosis) when they are damaged or get old.

APOPTOSIs:

Extracellular:FAS Ligand acting on FASR, FAS receptor

releasingInitiating Intracellular Enzyme Caspases- cell death, thus called

“executioner”Intracellular: pores in mitochondrial inner,

outer membranes releasingInitiating Intracellular Enzyme Caspases- cell death, thus called

“executioner”

DNA repair, Defects and Genomic instability

In normal cell, DNA damage can occur from environmental agents and the DNA of normal dividing cells is susceptible to alterations resulting from errors that occur during DNA replication.

Defects in three types of DNA repair systems, namely, mismatch repair, nucleotide excision repair, and recombination repair.

In oral cancer cells, Such mistakes, if not repaired ,it will push the cells in to neoplastic transformation.

Defects in repair mechanisms are present in human oral cancers and cause genomic instability.

Genomic instability occurs when both copies of these genes are lost as in tumor suppressor genes.

Figure : DNA repair. & genomic stability.

Figure : Mechanism of genome preservation and stability.