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Principles of Cancer Biology
P James Villeneuve, MDCM PhD FRCSC
Division of Thoracic SurgeryThe University of OttawaThe Ottawa Hospital
Surgical Foundations 2013.1.22
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Outline
• Basics– Cell cycle– Hallmarks of cancer– Metastasis
• Radiotherapy– Mechanism
• Chemotherapy– Mechanism
• Surgical Oncology• Key points
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Tumourigenesis
Loss of balanceOncogenes > Suppressors
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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
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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
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G1/S: adequate cellular growth to support replication
G2/M: full, accurate DNA replication
Spindle: Chromosomes aligned
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http://www.genome.jp/kegg/pathway/hsa/hsa04110.html
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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’
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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
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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
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Lethal tumour burden(1000g)
30 d
oubl
ing
times
10 doublings
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Hoeijmakers J (2009) NEJM 361:1475-85
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Vogelstein, Science (1991)Gastroenterology (2010) 138(6)2101-14
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Hanahan, Weinberg (2011) Cell 144:646-74
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Hanahan, Weinberg (2011) Cell 144:646-74
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The microenvironment is important
Hanahan, Coussens (2011) Cell 144:646-74
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Hanahan, Coussens (2011) Cell 144:646-74
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Hoeijmakers J (2009) NEJM 361:1475-85
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Radiotherapy
Surgery by non-surgical means
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Medscape
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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
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Delivery methods
• External beam– Most common– Radiation source is at distance from patient
• Brachytherapy– Radiation source is close or within tissue being treated
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Medscape
Deliver higher dosesPrevent tissue damageGreater kill due to redistribution of tumour
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Medscape
Repairable damage
Irreparable damage
Predicting tissue response
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Chemotherapy
Whole-body therapy
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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
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Classes of chemotherapy agents
• Based on cell cycle• Phase-specifc
– Exhibit a dose-plateau• Phase insensitive
– Linear kill kinetics
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Phase insensitive
• Alkylating agents– Platinums– Mustards
• Typically have severe side effects– Bone marrow depression– Emetogenic
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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
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Cancer surgery
Cures most solid tumors
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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
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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
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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
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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
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Key points (3)
• Diagnosis and staging lead to treatment• Understanding the concepts of tumourigenesis will
help understand the approach to cancer care
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Questions?