BIOMARKERSAND

CHEMOPREVENTIVES IN ORAL CARCINOGENESIS

Presented by

SHIFAYA NASRIN.S

INTRODUCTION

Oral carcinogenesis is a multi factorial and complex process related

to the sequential occurrence of alterations in genetic structures,

promoting inhibitory or excitatory effects of the tumor on and gene

suppressors, compromising the histophysiology of the division

,differentiation and cell death; and therefore, methods to prevent,

detect, or treat it in the best way is constantly being searched for.

Biomarkers reveal the genetic and molecular changes related to

early, intermediate and late endpoints in the process of oral

carcinogenesis

BIOMARKERS,……

• The national cancer institute defines biomarker as a : A biological

molecule found in blood ,other body fluids or tissues that is a sign of a

normal or abnormal processor of a condition or disease

• A biomarker may be used to how well the body responds to a

treatmentfor a disease or condition

• Also called molecular marker and signature molecule

WHERE DOES THIS TUMOUR MARKERS SEEN…….?

Cells

Tissue

Body fluids

CLASSIFICATION

CONCEPT OF IDEAL TUMOUR MARKER

• Be easy and and inexpensive to measure

• Readily available in body fluids

• Be specific to tumour being studied and commonly

associated with it

• They should change as current state of tumour changes

• Precede and predict recurrence before clinically

detectable

USES OF BIOMARKERS

DIAGNOSTIC

PROGNOSTIC PREDICTIVE

ROLES OF CELLULAR BIOMARKERS

Indicators of deoxyribonucleic acid (DNA) repair

mechanisms

Indicators of programmed cell

death (PCD)

Indicators of tumor

development and growth

Indicators of genetic markers of oral cancer.

INDICATOR OF DNA REPAIR

• Cancer cell require high level of DNA repair

• Repair of the telomeric ends of chromosomes produced

through the action of telomerase and repair of

nucleotide sequences, exemplified by mismatch repair

and nucleotide excision repair (NER).

• In human oral carcinomas, telomerase is elevated in the

proliferative areas of the carcinoma

• DNA repair influence the

progression of oral

carcinogenesis through the

regulation of various growth

factors .e.g; transforming growth

factor -Β3

• Development of DNA repair

defect and development of

mutated TGF-Β3

INDICATOR OF PCD

• PCD gene directed apoptosis- remove unwanted cells

• Plays an important screening role in cancer formation.

• It results in the modification of surviving cell population in

transforming clones by altering the number and type of cell

in a tumor

• Surviving transforming cells :

suppresed PCD

high rate of proliferation

Elevated level of DNA repair

OXIDATION AND EFFECT ON PCD

• ORAL MALIGNANT TRANSFORMATION, a product of

oxidising change

• Oxidative change result in changes in DNA repair and PCD

• Cellular manifestation of this processs :

Loss of cell growth control

modification in cell to cell interaction

enhance tumor metastasis.

CHEMOPREVENTIVE AND PCD

This alter the oxidative state of oral transforming cells as

reducing agent( antioxidant)

Oxidising agent(prooxidant)

These agent induce PCD by there oxygen responding charateristic which

trigger such as

Tumor suppressor gene p53

Modifiers of PCD –BCL2 family,

gene immune derived cytokins( TNF)

Examples of chemopreventive : retinoids , carotinoids, tocopherols,

bioflavonoids , isothia cyanates, indole, poly phenol

INDICATORS OF TUMOR DEVELOPMENT AND GROWTH

• Biomarkers establish the level of risk for individuals in a

target group of patients and provide information

concerning the etiology and the process of

carcinogenesis.

• The primary goal for the use of early, intermediate and

late biomarkers is to identify individuals at risk of

developing malignancy and indicate their level of risk.

INDICATORS OF GENETIC MARKERS OF ORAL CANCER

• A developing solid clone of transforming cells found in an

oral carcinoma arrives at the state of malignancy by

proceeding through stages of transformation

• The transformation rate is dependent on the location of the

clone in the spherical tumor mass and the oxygen states of

the cells

Specific tumourmarkers implicated in oral neoplasms

Alpha-1-antichymotrypsin (1-ACT) & factor XIIIa antibodies:

giant cell lesions of the oral cavity may arise from

precursor cells that express markers for both

macrophages and osteoclasts

BCL2

• Squamous Cell Carcinoma of head and neck.

• The predictive role in terms of pathological response and prognostic role of biomarkers such as

GST-pi,(glutathione-s-transferace)

p53,

bcl-2 and bax expression,

• immune-histochemically detection of the S-phase cell fraction,

Beta 2-Microglobulin

• increase in the level of beta 2- microglobulin -oral submucous fibrosis and oral cancer.

CD44, CD80, CD105 (ENDOGLIN):

• HA and CD44 among different types of salivary gland

tumours,

• In oral SCC’s decreased expression of CD80 may increased

tumourigenicity during early development

• decreased expression of CD44 -decreased survival rate.

• endoglin (CD105) - neovascularization in solid malignancies

• positive CD105 - vessels in Adenoid cystic carcinomas -

increases risk of metastasis.

Cytokeratins:

• useful for evaluation of epithelial differentiation changes in

oral dysplasia’s and oral SCC.

• CK19 and CK8 - premalignant changes in head and neck

carcinogenesis.

• Non expression of CK5 -tobacco-associated

pathological changes in the buccal mucosa.

• CK filaments -reflect the biological behavior and

aggressiveness of tongue SCCs

Cathepsin-d

• promote tumour invasion and metastasis.

• predictor of cervical lymph node metastasis in

Head and Neck SCC.

CEA, CA19-9, CA125, SCC-Ag:

• oral squamous cell carcinoma (OSCC) patients- increase in

Cyfra 21-1, tissue polypeptide antigen, and CA125

Carbohydrate associated antigens

• regarded as markers of glandular differentiation

pattern in salivary gland carcinomas

Calretinin

• Immunohistochemical marker for neoplastic

ameloblastic epithelium

• diagnostic aid in the differential diagnosis of cystic

odontogenic lesions and ameloblastic tumours

Growth factors

• Vascular endothelial growth factor (VEGF) -angiogenic factor

associated with cancer cells and endothelial cells in SCCHN

• VEGF-C or LVD (lymphatic vesseldensity)-lymphatic

metastasis of oral SCC.

• Basic Fibroblast growth factor (FGF) has relevance for

advanced head and neck cancer

cyclins and Mib

• Proliferation markers cyclins and Mib - basal and

superficial cells of premalignant lesions serve as

surrogate end point biomarkers for chemoprevention

trials

P53

• p53 -high risk of developing recurrence of primary disease69 and

second primary tumours of SCCHN who may benefit from

adjuvant therapy and chemoprevention after definitive local

therapy.

• predict radioresistance of the tumours.

• Preoperative serum p53 antibody is a significant

prognostic factor for nodal metastasis of SCCHN

CHEMOPREVENTIVES

• CHEMOPREVENTIVES are chemicals of natural or

synthetic origin which unlike other drugs do not

prevent disease but reduce incidience of disease

such as cancer before clinical syndromes occur

• High dose retinoids- active against oral premalignant

lesions and in prevention of second primary tumor

in head and neck

Rationale for pharmacological prevention of in patients risk

for development of invasive cancer based on

• Field canceirzation

• multi step carcinogenesis.

Field carcinogenesis

Multistep carcinogenesis

CLASSIFICATION OF CHEMOPREVENTIVE AGENTS

1. Antimutagens/Carcinogen Blocking Agents• Phase II metabolic enzyme inducers• N-acetyl L-cysteine• Polyphenols• Curcumin and dehydroepiendrosterone (DHEA).

2. Antiproliferatives• Retinoids/caretinoids: β-carotene, 13-cis-retinoic acid,

vitamin-A• Glucose-6-phosphate dehydrogenase inhibitors• Aspirin.[11]

3. Antioxidants.

COMMONLY TRIED CHEMOPREVENTIVE AGENTS IN ORAL

CANCER• Vitamin A and other retinoids

• β-carotene

• Vitamin E

• Dietary agents

• Other agents

…Β-CAROTENE• carotenoid, acts as an antioxidant,• also act as a pro-oxidant, depending on the oxygen

state of the cell.• β-carotene as well as ellagic acid (from garlic) are

carcinogen-blocking agents that either suppress promotion or act as antioxidants, which are reducing agents.

• mechanism of action - prevent carcinogenic compounds from reacting with critical target sites of DNA by inhibiting the metabolic activation of carcinogens catalyzed by cytochrome P450 (Phase I enzymes

δλ -ALPHA-TOCOPHEROL (VITAMIN E):

• are strong antioxidants that enhance the cellular

detoxification system by increasing the levels of

glutathione-S-transferases (GSTs; Phase II enzymes).

• The activation of these enzymes may also lead to

the trapping of reactive carcinogen metabolites or

the triggering of apoptosis

THE TERPENES,

Inhibit:

• oncogenic expression ,

• cell proliferation,

• reducing dedifferentiation.

INDOMETHACIN,

• an anti-inflammatory drug, blocks prostaglandin

synthesis

• reduces tumor development, resulting in a normal

differentiation pattern.

ENZYMES………

• Cells protect themselves from reactive oxygen substances

(ROSs) by activating antioxidant pathways and molecular

systems that use enzymes

• Examples are superoxide dismutase, which controls the level

of the superoxide anion (e.g., O2−);

• catalase modifies the levels of hydroxyl radicals (e.g., OH−)

• Glutathione- s-transferase (GSTs) alters the level of the

intracellular antioxidant glutathione

PROTEINS…..

• cellular antioxidants are proteins such as Bcl-2 - a family of

proteins that modifies PCD.

• several protein families that function as redox,

antioxidant/pro-oxidant molecules that also regulate PCD

(e.g., p53).

It is thought that patients with head and neck premalignant changes consist of a

diverse population and should be treated differently depending on their

molecular genotype. Patients with minimal genetic changes may be treated with

single-agent retinoids or other agents. Those with more accumulated genetic

changes will require combination of chemoprevention therapies. Lesions that

have advanced genetic changes with mutant p53 may benefi t from targeted p53

therapy and those lesions that express EGFR and COX-2 may require inhibitors of

EFGR and COX-2 However, the challenge today is achieving long-lasting efficacy

with retinoids and/or new agents and determining the optimal dose and duration

of therapy while maintaining acceptable toxicities

conclusion

References

• Journal of Oral and Maxillofacial Pathology: Biomarkers and

chemopreventives in oral carcinogenesis and its prevention

Sonalee Shah, Manpreet Kaur Vol. 18 Issue 1 Jan - Apr 2014

• CA A Cancer Journal for Clinicians Anne S. Tsao, MD; Edward

S. Kim, MD; Waun Ki Hong, MD Volume :54 Number: 3

May/June 2004

• Tumour marker an over view : journal of indian academy of

medicine and radiology, july –september 2010