(Tumor, neoplasm) - Unregulated cell growth without invasion - Unregulated cell growth with tissue invasion and metastasis 1
Clonal - Tumors arise from a single cell Heterogeneous - Multiple related subclones Tumor, 1cm in size - 10 9 cells Present to physician - 10 10-10 11 cells Cancers of epithelial tissues Carcinoma e.g. adenocarcinoma, squamous cell carcinoma Cancers of nonepithelial (mesenchymal) tissues Sarcoma e.g. rhabdomyosarcoma, osteogenic sarcoma Cancers from hematopoietic or lymphoid cells Leukemias or lymphomas e.g. Acute myeloid leukemia, diffuse large B-cell lymphoma 2
Squamous cell carcinoma Lymphoma Rhabdomyosarcoma Adenocarcinoma Acute leukemia? 3
- - - - -? (Oncogene) (Tumor suppressor gene) 4
Active proliferation ( ) expands cell population Differentiation ( ) to perform specialized process Apoptosis ( ) Culling of unwanted or abnormal cells During development - Positional cues - Cell-cell interactions - Signals from microenvironment After development - An ongoing dynamic process - A response to abnormal conditions resulting in tissue injury 5
Mutations in several different genes that regulate - cell proliferation - cell survival - DNA repair - motility - invasion - angiogenesis Malignant phenotype 6
Cell proliferation Cell survival DNA repair Motility/ Invasion/ Metastasis Angiogenesis Cell signaling Epigenetics Cell proliferation Cell cycles 4 phases G1 phase - determine its readiness S phase - DNA synthesis, genetic material is replicated G2 phase - assess replication and correct errors M-phase - separate duplicated chromosomes 7
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Normal cells - The cell cycle is well regulated - Cyclin, Cyclin-dependent kinase (CDK) Cancer cells - Deregulation of the molecular mechanisms controlling cell cycle progression DNA repair Normal cells Protective mechanisms to repair DNA damage - during DNA synthesis - during mitosis - by environmental mutagens Cancer cells - The repair pathways are often abnormal 9
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Cell survival and death Normal cells Massive irreparable DNA damage Anoxia (extreme oxygen deprivation Severe signaling imbalance Programmed cell death (Apoptosis) 2 distinct pathways - Death-receptor mediated pathway - Mitochondrial-mediated pathway 11
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p53 promote ell cycle arrest, attenuate apoptosis, tumor suppressor Loss of function - Enable tumor cells to escape cell arrest, senescence, or apoptosis Acquired mutation - the most common genetic alteration in human cancer Germline mutation - Li-Fraumeni cancer syndrome 13
Invasion/ metastasis 3 major features of invasion and metastasis - 1, cell adhesion to the basememt membrane - 2, local proteolysis of the membrane - 3, movement through the membrane and extracellular matrix Enter into circulation Find a hospitable niche in a foreign tissue 14
Angiogenesis Tumor growth - Oxygen and nutrition are necessary - The diffusion capacity is limited (oxygen in tissue, ~100 µm). - Require recruitment of neighboring blood vessels (angiogenesis) support their metabolic requirement Stimuli for angiogenesis - Hypoxia, inflammation, genetic lesion 15
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Tumor vessels - Tortuous and dilated with an uneven diameter - Excessive branching and shunting Vessel walls - Numerous openings, widened interendothelial junctions - Discontinuous or absent basement membrane high permeability No functional intra-tumor lymphatics Interstitial hypertension Signal transduction pathways Receptor tyrosine kinase 17
Normally - Tyrosine kinase activity is short-lived, and reversed by protein tyrosine phosphatase In human cancer, tyrosine kinases or downstream pathways are activated by - Mutation - Gene amplification - Chromosome translocation These pathways regulate cell proliferation, survival, and angiogenesis 18
HER Human epithelial growth factor receptor Lung cancer - EGFR mutation 19
Breast cancer CML 20
Cell proliferation Cell survival DNA repair Motility/ Invasion/ Metastasis Angiogenesis Cell signaling Epigenetics DNA RNA Protein 21
Epigenetic changes Epigenetics is defined as - changes that alter the pattern of gene expression, but are not caused by changes in DNA code Epigenetic changes - Methylation of cytosine residues in CpG island - Modification of histone by acetylation or methylation - Changes in higher order chromosome structure 22
Regulatory regions of the genes - contain CpG island - CpG island is unmethylated Hypermethylation in promoter region - silencing of gene Hypermethylation in promoter of tumor suppressor gene Cancer 23
- (Pathology) (Cytology) - 24
(Pathology) - - - - -.. - - - - 25
(Chemotherapy) (Induction or neoadjuvant chemotherapy) - - - (Adjuvant chemotherapy) - (micrometastasis) -.. - - - 26
- - - - - - 27
Chronic myelogenous leukemia (CML) 28
Lung cancer - Geftinib (Iressa ), Erlotinib (Tarceva ) Head and neck cancer - Cetuximab (Erbitux ) Breast cancer - Trastuzumab (Herceptin ), Lapatinib (Tykerb ) HCC - Sorafenib (Nexavar ), Sunitinib (Sutent ) Antiangiogenesis - Bevacizumab (Avastin ) 29
Lung cancer - Target EGFR mutation (+) Iressa ( ) Tarceva ( ) 30
Breast cancer - Target HER2 overexpression HER2 IHC 3+ or FISH (+) Anti-HER2 Ab (Herceptin ) Thanks! 31