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

http://www.cancerresearchuk.org/home/

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?