Download Biology of Cancer

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
M Checkpoint
G0 phase
Rest/Quiescent
G1 Checkpoint
Tumor suppressor Genes
1)Retinoblastoma (Rb) –
constitutively expressed
G2 Checkpoint
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
Harriison’s principles of Internal Medicine
 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
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)
- Clonal evolution
- Accumulation of genetic alteration
- Super clone cells that can break
from restraints of primary tumor
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
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
 Three methods of delivery: 1) External beam (most common)
2) Brachytherapy
3) Systemic radionuclides
 Efficacy requires good tissue oxygenation
 Resistant cells (hypoxic, G1/S phases)
 Optimum beam distance from the target that
maximizes tumor damage but minimizes skin damage
 Beam intensity α (1 / distance2)
 Scenario- if tumor 5 cm underneath skin
• Beam 5cm from skin – 75% absorbed by skin
• Beam 10cm from skin – 5% absorbed by skin
 Acts synergistically with chemotherapy
Chemotherapy
- Phase specific agents
- methotrexate
- 5 fluorouracil
- vincristin
- phase non-specific agents
-Cyclophosphamide
- Ifosfamide
- Cisplastin
- Doxorubicin
- Induce necrosis & apoptosis
- Need multiagent regimen to
obtain efficacy
Harriison’s principles of Internal Medicine
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