Patologia bilogia del cancerPresentation Transcript
Tumorigenesis Kastan MB. Cancer: Principles & Practice of Oncology. 5th ed. 1997;121-134. Initial genetic change (eg, loss of function of pRb or overexpression of c-myc) Decrease in apoptosic cell death Subsequent genetic change Normal cell Increase in cell proliferation and apoptosic cell death Secondary genetic change (eg, dysfunction of p53 or overexpression of bcl-2) Further alterations in phenotype (eg, invasiveness and metastasis)
Emergence of tumor cell heterogeneity Primary Neoplasm Metastases TRANSFORMATION TUMOR EVOLUTION METASTASIS TUMOR EVOLUTION AND PROGRESSION AND PROGRESSION
Host influences on metastatic disease Fidler IJ. Cancer: Principles & Practice of Oncology. 5th ed. 1997;135-147.
CANCER CELLS NORMAL CELLS Loss of contact inhibition Increase in growth factor secretion Increase in oncogene expression Loss of tumor suppressor genes Neovascularization Oncogene expression is rare Intermittent or coordinated growth factor secretion Presence of tumor suppressor genes Frequent mitoses Nucleus Blood vessel Abnormal heterogeneous cells Normal cell Few mitoses Cancer cells vs normal cells
Precancerous conditions Stedman’s Medical Dictionary. 26th ed. 1995;1182,1405, 279.
Growth factor Growth factor receptor Paracrine (adjacent cells) Growth factor and receptor synthesis Post receptor signal transduction pathways Gene activation Oncogenes Autocrine stimulation The role of oncogenes
Pathogenesis TRANSFORMATION ANGIOGENESIS MOTILITY & INVASION Capillaries, Venules, Lymnphatics ADHERENCE ARREST IN CAPILLARY BEDS EMBOLISM & CIRCULATION EXTRAVASATION INTO ORGAN PARENCHYMA RESPONSE TO MICROENVIRONMENT TUMOR CELL PROLIFERATION & ANGIOGENESIS METASTASES METASTASIS OF METASTASES TRANSPORT Multicell aggregates (Lymphocyte, platelets)
Establishment of a capillary network from the surrounding host tissue
A series of processes originating from microvascular endothelial cells
Mediated by multiple molecules released by both tumor and host cells [eg, fibroblastic growth factor (FGF), vascular endothelial growth factor (VEGF), vascular permeability factor (VPF), angiogenin, epidermal growth factor (EGF)]
Angiogenesis Fidler IJ. Cancer: Principles & Practice of Oncology. 5th ed. 1997;135-147.
Cell cycle CELL DIFFERENTIATION CELL LIFE CYCLE TIME CELL DIVISION G 2 PERIOD (CHROMOSOME REPLICATION) S-PHASE G 1 PERIOD
The doubling process Normal cell Dividing Malignant transformation 2 cancer cells Doubling 4 cells Doubling 8 cells Doubling 16 cells 1 million cells (20 doublings) undetectable 1 billion cells (30 doublings) lump appears 1 trillion cells (40 doublings – 2 lb/1kg) 41 – 43 doublings — Death
Tumor growth and detection 10 12 10 9 time Diagnostic threshold (1cm) Undetectable cancer Detectable cancer Limit of clinical detection Host death Number of cancer cells
Malignant tumor cells can remain dormant yet viable for years
Emergence from dormancy can lead to disease recurrence
Cells may arrest in G 0 phase
Rate of cell death counterbalances rate of cell division
Dormancy of tumor cells Fidler IJ. Cancer: Principles & Practice of Oncology. 5th ed. 1997;141.