Transcript Final_TumourBiology_Jan22

Principles of Cancer Biology
P James Villeneuve, MDCM PhD FRCSC
Division of Thoracic Surgery
The University of Ottawa
The 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 balance
Oncogenes > 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
Spindle: Chromosomes aligned
G2/M: full, accurate DNA
replication
G1/S: adequate cellular
growth to support
replication
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
30 doubling times
Lethal tumour burden
(1000g)
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
Deliver higher doses
Prevent tissue damage
Greater kill due to redistribution of tumour
Medscape
Predicting tissue response
Repairable damage
Irreparable damage
Medscape
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?