Principles of Cancer Biology
P James Villeneuve, MDCM PhD FRCSC
Division of Thoracic SurgeryThe University of OttawaThe Ottawa Hospital
Surgical Foundations 2013.1.22
Outline
• Basics– Cell cycle– Hallmarks of cancer– Metastasis
• Radiotherapy– Mechanism
• Chemotherapy– Mechanism
• Surgical Oncology• Key points
Tumourigenesis
Loss of balanceOncogenes > Suppressors
Principles of Cellular Growth• Ability to produce exact replica
– essential component of life• Normal cellular regulation
– Balance between division and death (apoptosis)– Limits on proliferation
• Physical boundaries (e.g. basement membrane)• Tissue pressure contact inhibition
– Cell cycle regulation• Error correction
– Lack of fidelity in cellular reproduction genetic instability– Repair genes– Immune mechanisms: removal of non-self cells– Apoptosis
Cell Cycle
• Organized unidirectional process to achieve identical cellular replicas– Compare to meiosis
• Mitosis– Process of chromosomal segregation and cytoplamic
division• Interphase
– Growth (gap) phases G1, G2 [G0]– Synthesis phase
G1/S: adequate cellular growth to support replication
G2/M: full, accurate DNA replication
Spindle: Chromosomes aligned
http://www.genome.jp/kegg/pathway/hsa/hsa04110.html
Oncogenes : Oncoproteins
• Genetic sequence (gene) that causes cancer– Huebner and Todaro (1969)
• First described Src– Chicken virus causing sarcomas– Martin (1970)
• Proto-oncogene– Arising from mutations, increased expression,
translocations– Bishop and Varmus (1967): Nobel Prize 1989
• RAS, WNT, MYC, ERK, TRK, Ph’
What is cancer then?
• Balance between oncogenic stimulus and tumuor suppressor activity
• Tumours are characterized by– 2 cell populations
• Actively dividing : Quiescent– Growth fraction
• Proportion in active division and proliferation– Growth rate
• Fraction dividing• Rate of division• Rate of attrition
Tumour cell kinetics and you
• 1cm3 = 1g tumor ( 109) cells– 1 cm the limit of clinical detection– 30 doublings occurred prior to clinical detection
• Only 10 more doublings (3 logs)– 1kg of tumor– terminal disease
• 75% of tumour growth occurs prior to clinical detection
Lethal tumour burden(1000g)
30 d
oubl
ing
times
10 doublings
Hoeijmakers J (2009) NEJM 361:1475-85
Vogelstein, Science (1991)Gastroenterology (2010) 138(6)2101-14
Hanahan, Weinberg (2011) Cell 144:646-74
Hanahan, Weinberg (2011) Cell 144:646-74
The microenvironment is important
Hanahan, Coussens (2011) Cell 144:646-74
Hanahan, Coussens (2011) Cell 144:646-74
Hoeijmakers J (2009) NEJM 361:1475-85
Radiotherapy
Surgery by non-surgical means
Medscape
Mechanism of action
• Ionizing radiation– Photon (gamma ray)– Beta particle (electron)– Alpha particle
• Mechanistically, based on tissue-particle interactions– Photoelectric effect– Compton effect
• Depth-energy-particle type dependence
Delivery methods
• External beam– Most common– Radiation source is at distance from patient
• Brachytherapy– Radiation source is close or within tissue being treated
Medscape
Deliver higher dosesPrevent tissue damageGreater kill due to redistribution of tumour
Medscape
Repairable damage
Irreparable damage
Predicting tissue response
Chemotherapy
Whole-body therapy
Principles of Chemotherapy
• Exponential relationship between dose and kill– small decrease in drug dose results in large increase in cell
survival• Cycling cells at greatest risk• Multiple courses of therapy
– each treatment kills same proportion(not number) of cells
– e.g.: 3 log killed 1010 to 107
1 log regrowth between cycles
Classes of chemotherapy agents
• Based on cell cycle• Phase-specifc
– Exhibit a dose-plateau• Phase insensitive
– Linear kill kinetics
Phase insensitive
• Alkylating agents– Platinums– Mustards
• Typically have severe side effects– Bone marrow depression– Emetogenic
Phase-sensitive agents
• S-phase drugs interfere with nucelotide synthesis– ‘false’ nucleotides– Cofactor antimetabolites
• M-phase drugs interfere with chromosomal segregation– Microtubule inhibitors
• G1/G2 phase agents intefere with basal cellular machinery
Cancer surgery
Cures most solid tumors
Surgery : Chemo : Radiotherapy
• Surgery is mostly oncology• Timing of treatment
– Neoadjuvant• Precedes surgical intervention• Aims to improve margins, decrease metabolic burden
– Adjuvant• Follows resection• For nodal disease
Surgical Oncology Terms
• R = residual– R0 = complete resection– R1 = margins are microscopically positive– R2 = margins are grossly positive
• Stage and groupings– Based mostly on TNM classification– Stages are aggregates of TNM variables
Key points
• Cancer arises from– Mutations– Cause dysregulation in key cellular functions– Oncogenes : suppressors
• Presentation of cancer– Depends on tumour burden– Depends on kinetics– Metastasis– Microenvironment
Key points (2)
• Radiotherapy– DNA damage and ROS– Ionizing energy– Damages normal tissues
• Chemotherapy– Depends on agent used– Selective action on more rapidly dividing cells
Key points (3)
• Diagnosis and staging lead to treatment• Understanding the concepts of tumourigenesis will
help understand the approach to cancer care
Questions?
