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Biology of Cancer
19th Oct. 2010
Hesham Abdelbary MD, MSc, FRCSC
Objectives
Normal cell cycle
Concepts in tumorigenesis
Tumor metastasis
Anti-cancer therapeutics Bisphosphonates Radiation Chemotherapy Biologic therapy
Conclusion
Cell Cycle
Highly organized, unidirectional process
Objective is to produce exact replica
Consists of 4 main phases: 2 preparation – Growth phase1 (G1), Growth phase 2 (G2) 2 functional – Synthesis (S), Mitosis (M)
3 main checkpoints Triggered by DNA damage / stresses (hypoxia, cell-cell
contact) Halts replication Triggers Apoptosis vs. DNA repair & continuation of cell cycle
G0 phaseRest/Quiescent
G1 Checkpoint
G2 Checkpoint
M Checkpoint
Tumor suppressor Genes
1)Retinoblastoma (Rb) – constitutively expressed
2)P53 – activated in response to DNA damage
- G1 checkpoint - triggers
apoptosis
Concepts in Tumorigenesis
Loss of balance - Oncogenes > tumor suppressor(Ras, Tyr Kinase, Myc) (Rb, p53)
Loss of error correction/checkpoints Increase proliferation Decrease apoptosis Abnormal differentiation
Evasion of Immune system Don’t present tumor antigens for adaptive immune
system Down regulate MHC – evade T cells Cloak themselves with fibrin
Solid tumor made of 2 cell population: i) active cycling
ii) quiescent
Growth fraction – fraction of cells that are actively cycling
Tumor growth depends: 1) growth fraction
2) rate of replication
3) rate of cell loss (differentiation/death)
Gompertzian Tumor Growth Curve
Not an exponential growth curve
Tumor tries to limit its own growth – growth fraction declines by tim
75% of tumor has grown prior to clinical detection
Peak growth rate precedes time of clinical detection
Clinical detection 109 cells = 1 cm3 -- 1-4% of cells are actively dividing
Harriison’s principles of Internal Medicine
Tumor Metastasis
Advanced stage of disease
Tumor cells at metastatic site are the most difficult to target therapeutically – possess different biologic properties
Complex multiple steps process: Loss of cellular adhesion Invasiveness through surrounding tissues (collagenases, proteases) Intravasation and survival in vascular system Extravasation at metastatic site Colonize, survive & proliferation at metastatic site
Established Theory – need a ‘super clone’ cell that had time to evolve at primary site in order to successfully pass all steps needed.
Two proposed theories for WHEN metastatic process occurs
Late metastasis model(conventional paradigm)
Early metastasis model
- In an attempt to explain why patients may present with mets after complete resection of a small primary (ex/ melanoma)
- Migrating Cancer Stem Cell theory (CSC) – highly undifferentaited cells
- Reside at invasive front
- Highly influenced by tumor microenvironment
- Plasticity of CSC
- Clonal evolution
- Accumulation of genetic alteration
- Super clone cells that can break from restraints of primary tumor
The two models may not be mutually exclusive
-What determines tropism of metastatic cells to a distant metastatic site?
- Bone marrow derived progenitors from pre-metastatic niche @ metastatic microenvironment site
- CXCL12 – homing cytokine
- fibronectin – anchoring protein
Metastatic lytic bone lesions
Do tumor cells directly destroy bone matrix?
- Parathyroid hormone related protein (PTHrp)
- Receptor activated NF-kappaB Ligand (RANKL)
- Osteoprotegrin (OPG) – inhibits osteoclastogenesis
- Bisphosphonates – standard of care. Protects against hypercalcemia
Radiation Therapy
X-rays, gamma rays
Part of approach to local tumor control
Neoadjuvant vs adjuvant
Curative vs palliative (SC compression, brain mets, painful bone mets)
Not selective in tissue damaging effects (secondary cancers)
Damages cellular DNA, releases free radicals
Tumor cells are more sensitive – lack of checkpoints to repair DNA damage
Chemotherapy
Harriison’s principles of Internal Medicine
- Phase specific agents- methotrexate- 5 fluorouracil- vincristin
- phase non-specific agents-Cyclophosphamide- Ifosfamide- Cisplastin- Doxorubicin
- Induce necrosis & apoptosis
- Need multiagent regimen to obtain efficacy
Other available therapies
Hormonal (breast, prostate)
Biologic (IFN, TNF) – modulate immune system to stimulate anti-tumor immune response
Targeted therapy – Imatinib (Tyrosine Kinase) Avastin - VEGF antibody
Conclusion
Cancer is a heterogenous dynamic disease with a high propensity of resistance
Biology of macrometastsis differs from primary
Requires a multimodal approach of attack
Significant morbidity with current therapies
Need to tailor targeted therapies for specific cancer
Immune modulation