Caecinogenesis The Molecular Basis Of Cancer

1
Caecinogenesis The Molecular Basis Of Cancer

• Fadwa Jameel Altaf
• Layalh S. Ab dullah
• Osama Nassif
• Ali Sawan

2
Types of Normal Cellular Genes

• 3 Normal regulatory genes
• Growth promoting protooncogene
• Growth inhibiting tumor suppressor gene
• Gene regulate apoptosis
• 4 the category is DNA repair gene

3
Molecular Basis Of Cancer

• Nonlethal genetic damage lies at the heart of
  carcinogenesis
• Genetic hypothesis of cancer implies that a tumor
  mass result from the clonal expansion of a single
  progenitor cell that incurred the genetic damage

4
Clonality of Neoplastic Cells

• Most tumor cells are monoclonal
• All tumor cells may possess a specific
  chromosomal abnormality.
• Unique rearrangement of immunoglobulin or T-cell
  receptor genes in lymphoid tumors.
• Tumor cell heterogeneity is common
• Clinical behavior is the best definition of
  malignancy

5
Principles of Carcinogenesis

• Neoplastic transformation is a progressive
  process involving multiple hits or genetic
  changes.
• Alterations in DNA cause changes in one or both
  of the following types of genes
• Proto-oncogenes----Oncogene--- (dominant)
• Tumor suppressor genes---TSG---- (recessive)
• Genes regulate apoptosis (dominant or recessive)
• DNA repair genes

6
(No Transcript)
7
Tumor Development and Growth

• Transformation
• Growth of transformed cells
• Invasion of tumor cells into the surrounding
  tissues
• Metastasis of tumor cells to distant sites

8
Hallmarks of Cancer
Six fundamental changes of cell Physiology

• Self sufficiency in growth factors
• Insensitivity to growth-inhibitory signals
• Evasion of apoptosis
• Limitless replicative potential
• Sustained angiogenesis
• Ability to invade and metastasize

9
(No Transcript)
10
Self-Sufficiency In Growth Signals

• Oncogenes
• promote autonomous cell growth in cancer cells
  by
• Point Mutations
• Chromosomal Translocations
• Gene Amplification

11
Activation of Oncogenes

• Point Mutations
• The RAS gene is an oncogene that becomes
  activated by a point mutation.
• Chromosomal Translocations
• Translocation of chromosome 9 and 22 in CML
  creating a fusion gene that produces an activated
  tyrosine kinase.
• Gene Amplification
• Specific oncogenes such as N-myc and C-neu are
  amplified in neuroblastoma and breast cancer
  respectively.

12
Self-Sufficiency In Growth Signals

• Oncogenes
• promote autonomous cell growth in cancer cells
• Their product is called oncoproteins
• Devoid of important regulatory elements
  their production does not depend on growth
  factors or other external signals

13
(No Transcript)
14
Self-Sufficiency In Growth Signals (Oncogenes)

• Growth Factors
• Growth Factor Receptors
• Signal transducing Proteins
• Nuclear transcription factors
• Cyclins cyclin- dependent kinases

15
Growth Factors

• Many cancer cells acquire growth
  self-sufficiency, by acquiring the ability to
  synthesize the same GF to which they are
  responsive.
• The growth factor itself is not altered or
  mutant, but the product of other oncogenes cause
  overexpression of growth factors

16
Self-Sufficiency In Growth Signals (Oncogenes)

• Growth Factors
• Growth Factor Receptors
• Signal transducing Proteins
• Nuclear transcription factors
• Cyclins cyclin- dependent kinases

17
(No Transcript)
18
Growth Factor Receptors

• Mutations pathologic overexpression of normal
  forms of GFR have been detected in several
  tumors.
• Overexpression of GFR render tumor cells
  hyperresponsive to normal level of GF
• EGF receptor seen in 80 of sq cell ca of lung
• HER2 is amplified in 25-30 of adenocarcinoma of
  breast

19
Self-Sufficiency In Growth Signals (Oncogenes)

• Growth Factors
• Growth Factor Receptors
• Signal transducing Proteins
• Nuclear transcription factors
• Cyclins cyclin- dependent kinases

20
(No Transcript)
21
30 OF ALL TUMORS
22
Activation of MAP kinase pathway
23
BCR-ABL HYBRID GENE

• Potenttyrosine kinase activity
• Impaired apoptosis
• (Gleevec)ST1 571 is effective in treatment of CML

24
Self-Sufficiency In Growth Signals (Oncogenes)

• Growth Factors
• Growth Factor Receptors
• Signal transducing Proteins
• Nuclear transcription factors
• Cyclins cyclin- dependent kinases

25
(No Transcript)
26
(No Transcript)
27
(No Transcript)
28
Self-Sufficiency In Growth Signals (Oncogenes)

• Growth Factors
• Growth Factor Receptors
• Signal transducing Proteins
• Nuclear transcription factors
• Cyclins cyclin- dependent kinases

29
(No Transcript)
30
(No Transcript)
31
Cyclins

• CyclinD overexpressed seen in
• -Breast, esophagaus, liver, lymphoma
• . Cyclin CDK4 amplification is seen in
• -Melanoma, sarcoma, glioblastoma.
• . Cyclin B,E, CDKs occur in some malignant
  neoplasm but they are less frequant than cyclin
  D/CDK4.

32
(No Transcript)
33
(No Transcript)
34
(No Transcript)