Caecinogenesis The Molecular Basis Of

Cancer

Fadwa Jameel Altaf Layalh S. Ab dullah

Osama NassifAli Sawan

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

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

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

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

Tumor Development and Growth

Transformation Growth of transformed cells Invasion of tumor cells into the

surrounding tissues Metastasis of tumor cells to distant

sites

Hallmarks of Cancer

1. Self sufficiency in growth factors2. Insensitivity to growth-inhibitory

signals3. Evasion of apoptosis4. Limitless replicative potential5. Sustained angiogenesis6. Ability to invade and metastasize

Six fundamental changes of cell Six fundamental changes of cell PhysiologyPhysiology

Self-Sufficiency In Growth Signals

Oncogenes

promote autonomous cell growth in cancer cells by:

Point MutationsChromosomal Translocations

Gene Amplification

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.

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

Self-Sufficiency In Growth Signals

(Oncogenes) Growth Factors

Growth Factor Receptors Signal transducing Proteins

Nuclear transcription factors Cyclins & cyclin- dependent

kinases

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

Self-Sufficiency In Growth Signals

(Oncogenes) Growth Factors

Growth Factor Receptors Signal transducing Proteins

Nuclear transcription factors Cyclins & cyclin- dependent

kinases

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

Self-Sufficiency In Growth Signals

(Oncogenes) Growth Factors

Growth Factor Receptors Signal transducing Proteins

Nuclear transcription factors Cyclins & cyclin- dependent

kinases

30% OF ALL TUMORS

Activation of

MAP kinase pathway

BCR-ABL HYBRID GENE

Potenttyrosine kinase activity

Impaired apoptosis

(Gleevec)ST1 571 is effective in treatment of CML

Self-Sufficiency In Growth Signals

(Oncogenes) Growth Factors

Growth Factor Receptors Signal transducing Proteins

Nuclear transcription factors Cyclins & cyclin- dependent

kinases

Self-Sufficiency In Growth Signals

(Oncogenes) Growth Factors

Growth Factor Receptors Signal transducing Proteins

Nuclear transcription factors Cyclins & cyclin- dependent

kinases

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.