Biology of Cancer

1. Biology of Cancer 19th Oct. 2010 Hesham Abdelbary MD, MSc, FRCSC

2. Objectives • Normal cell cycle • Concepts in tumorigenesis • Tumor metastasis • Anti-cancer therapeutics • Bisphosphonates • Radiation • Chemotherapy • Biologic therapy • Conclusion

3. 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

4. M Checkpoint G0 phase Rest/Quiescent G1 Checkpoint • Tumor suppressor Genes • Retinoblastoma (Rb) – constitutively expressed • P53 – activated in response to DNA damage • - G1 checkpoint • - triggers apoptosis G2 Checkpoint

5. 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

6. 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)

7. 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

8. 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.

9. Two proposed theories for WHEN metastatic process occurs Late metastasis model (conventional paradigm) Early metastasis model • Clonal evolution • Accumulation of genetic alteration • Super clone cells that can break from restraints of primary tumor • 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

10. The two models may not be mutually exclusive

11. 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

12. Metastatic lytic bone lesionsDo 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

13. 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

14. 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

15. 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

16. 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

17. 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