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