Oncogenesis and Tumor markers

Define cancer

A state of abnormal, uncontrolled and excessive proliferation or growth of a cell or tissue invading other tissues.

What are the 2 types of tumors and explain them

• Benign:- grows by expansion but remains encapsulated in layer of connective tissue.Not life threatening e.g moles, warts

• Malignant:- exhibit uncontrolled proliferation and spread to distant places or different tissues (Metastasis) in the body. Life threatening e.g lung cancer, leukemia

Tumors of epithelial origin are called as

Carcinoma

Tumors of connective tissue are called as

Sarcoma

Tumors of lymph nodes are called as

Lymphoma

Tumors of stem cells of haematopoeotic tissue are called as

Leukemia

What are the predisposing factors for cancer

• Age ( can happen at any age but more common over age of 55 )

• Heredity

• Environmental factors

Occupation: Benzene, Asbestos- skin cancer

Diet: - Long term intake of a diet rich in trans-fats, cholesterol

      - Food infected with fungus like Aspergillus- Aflatoxin B-Hepatoma

      - Pesticides

Life Style:   Cigarette smoke: Ca lung

                     Alcohol: Ca Liver, Ca Pancreas

         Tobacco: Ca Oral cavity

Iatrogenic: Certain drugs, exposure to radiations

What are the morphological changes in cancer cells?

• Shape : Loses original shape, receptors and transforms the cell to larger size with irregular nucleus, distinct nucleoli, scarce cytoplasm.

  
  

• Motility & Growth:

1. Loss of contact inhibition thus grow in multilayer, over one another to form a mass.

2. Cell cycle changes, 2-5 times increase in mitotic phase

3. Loss of Anchorage dependence and tissue adherence - can grow without attachment to surface

4. Loss of Apoptosis (programmed cell death) - thus retain ability to survive & proliferate.

• Metastasis: loss of adhesion and increased collagenase, proteinases facilitate migration into other tissues

What are the Biochemical changes in cancer cells?

1.Increased synthesis of DNA & RNA

2.Changes in composition and structures of glycoproteins & glycolipids receptors on surface of cancer cells may cause metastasis.

3.Appearance of new antigens & loss of certain antigens.

4.Inappropriate synthesis of certain hormones and growth factors.

5.Decreased requirement for nutrition - Rapid growth --- high rate of glycolysis --- leads to accumulation of lactic acid.

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What are mutagens

• substances which increase rate of mutation & enhance incidence of cancer.

• all mutagens are carcinogenic.

• e.g. Radiations, free radical generators, environmental & dietary factors, chemical carcinogens, oncogenic viruses, certain bacteria & parasites.

What are antimutagens

• substances which have the ability to inhibit tumor promotion.

• e.g. vitamin A & carotenoids, vitamin E & C, leafy vegetables, curcumin, resvasterol, flavinoids

What are carcinogens

A cancer causing agent is called a carcinogen

What are the 3 types of carcinogens?

• Physical : radiation

• Chemical: variety of chemical compounds.

• Biological : oncogenic viruses

Physical carcinogens (radiation) can cause cancer by 2 ways -

• Direct effect

• Indirect effect

Explain them

Direct effect:-

- Damages DNA by:

Breaking of double strand

Deletion of purine/pyrimidine bases,

Thymin dimers

Cross linking of strands

Indirect effect:

Excessive radiations by γ-rays & X-rays produce free radicals, which interact with DNA & other macromolecules - increased lipid peroxidation and oxidative stress causing molecular damage.

What are direct acting and indirect acting chemical carcinogens

• Direct-acting: interact directly with target molecules.

• Indirect-acting : require prior metabolism / activation to become carcinogenic (procarcinogens)

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What is the mechanism of action of chemical carcinogens

Mechanism of action of chemical carcinogens:

• Ultimate carcinogens are electrophilic (electron deficient),so they attack nucleophilic (electron rich) group of DNA.

• May bind  to N2, N3 &N7 of guanine (highly prone)

• These changes leads DNA alterations à increases probability of mutation.

What are some dna and rna common oncogenic viruses

DNA Viruses:

i) Human papillomaviruses(HPV)-  Uterine cervical cancer

ii) Hepatitis B virus (HBV)- Hepatoma

iii) Human herpes virus 8 (HHV8)-Oral cancer

RNA viruses: (Retro- virus)

i) Leukemia virus – Leukemia, lymphoma.

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What are oncogenes

•Genes capable of causing cancer.

•They were first identified in tumour causing viruses e.g. Rous sarcoma virus

what are proto-oncogenes

•Genes of normal cells, which play role in cell growth and division

•Proto-oncogenes are important regulatory genes of the cells. More than 100 human proto-oncogenes are known.

Proto-oncogenes are activated to oncogenes by which mechanisms

1) promoter & enhancer insertion

  2) chromosomal translocation

  3) gene amplification and

  4) point mutation

What is promoter and enhancer insertion

What is chromosomal translocation

What is gene amplification

What is point mutation

• What are growth factors ? Give some examples also

• Growth Factors are polypeptide or protein molecules responsible for differentiation, remodeling, migration and growth of targeted normal cell.

• Generally cause mitosis/ differentiation of target cells.

• They regulate cell division by signal transduction across the cell membrane to the interior.

• Growth factors are products of oncogenes

• Play a key role in carcinogenesis

  
  

• Examples of growth factors

    - Epidermal growth factor (EGF)

    - Platelet derived growth factor (PDGF)

    - Nerve growth factor (NGF)

What are anti oncogenes or tumor suppressor genes , give some examples also

• Genes that normally protect the cell from developing  cancer.

• Mutations in these genes à Inactivation of tumor suppressor gene  à loss of growth control

  
  

• Few widely studied tumor suppressor genes are:

  - Retinoblastoma (RB) gene –Retinoblastoma

  - p53gene – Lung cancer

  - DCC – Colon cancer,

  - BRCA: Familial Breast Cancer

What is Mechanism of action of Tumor Suppressor Gene ?

• Tumour suppressor gene, p53  encodes a phosphoprotein.

• It blocks the cell division of those cells that have damaged DNA until the damage is repaired.

• If the DNA damage is severe, the p53 directs the cell to commit suicide by triggering apoptosis.

• It is also seen that p53 activates the expression of genes that suppress cell proliferation.

• Most tumours have a complete absence of p53, whereas others show mutant non functional p53.

What is apoptosis

• Definition: Genetically programmed series of events leading to cell damage that follows cell death.

• The events involve cell shrinking, membrane blebbing, absence of inflammation.

• Many Caspases (Proteinases) are involved.

• Apoptosis is regulated by balance between factors that inhibit and activate the process.

• Mutations found in cancer cells enable them to evade apoptosis leading to cell proliferation.

What are tumor markers and what are they used for

• Tumor cells produce certain  biological substances whose detection in the blood indicates the presence of tumour in the body.

• They mainly include enzymes, hormones and tumor antigens.

Tumor markers are  used for:

-Screening

  -Diagnosis

  -Monitoring treatment

  -Prognosis & staging of cancer

  -Detecting recurrence

Ideal characteristics of a tumor marker

It should:

1. only specifically increase in malignant cancer.

2. be at minimum level in healthy subjects & benign conditions.

3. increase in early stage, thereby enabling early detection and initiating appropriate therapy.

4. be present in or produced by tumor itself-should not be produced by healthy tissues.

5. be easy for analysis in routine lab investigation & economical to measure.

6. Tumor markers can be: Serum based (better) or Tissue based.

What is metastasis

• The cancer cells can spread to distinct tissues through blood or lymph. Such spread of cancer cells and colonization of distinct tissues is called metastasis.

• On reaching other tissues , the cancer cell invades other tissue and form secondary tumor.

• It is the major cause of cancer related morbidity & mortality.

• Also shows poor adherence to surface & loss of contact inhibition.

Tell abt treatment of cancer

1)Surgical removal:

Removes as much as tumor as possible.

2) Radiotherapies.

Radiation delivers energy to the tissues causing  ionization  and excitation of atoms and molecules. This causes damage to DNA and promote apoptosis.

Surgery and radiotherapy are most effective to reduce the initial tumour load.

These are the prime modalities of treatment in solid tumours.

3) Chemotherapy:

Anticancer Drugs that are used to kill cancer cells which are in dividing phase.

a)DNA damaging agents

b)Antimetabolites (interfere with DNA synthesis)

Tell some precautionary measures to reduce occurrence or prevalence of cancer:

•Life Style Changes: Daily exercise, control over Body weight

• Avoid smoking or Tobacco chewing

• Minimal exposure to industrial pollutants and radiations.

• Diet: Low fat diet and fatty food . Consume food rich in antioxidants.

• Routine Screening of Cancer: PAP smear (Ca Cervix), Mammography  (Ca Breast).

• Genetic testing: Prophylactic mastectomy for BRCA1,2 gene mutations.

•Vaccination: Effective for Specific type of cancers HPV – cervical cancer, HBV- liver cancer