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Principles of Cancer Biology P James Villeneuve, MDCM PhD FRCSC Division of Thoracic Surgery The University of Ottawa The Ottawa Hospital Surgical Foundations.

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Presentation on theme: "Principles of Cancer Biology P James Villeneuve, MDCM PhD FRCSC Division of Thoracic Surgery The University of Ottawa The Ottawa Hospital Surgical Foundations."— Presentation transcript:

1 Principles of Cancer Biology P James Villeneuve, MDCM PhD FRCSC Division of Thoracic Surgery The University of Ottawa The Ottawa Hospital Surgical Foundations

2 Outline Basics –Cell cycle –Hallmarks of cancer –Metastasis Radiotherapy –Mechanism Chemotherapy –Mechanism Surgical Oncology Key points

3 Tumourigenesis Loss of balance Oncogenes > Suppressors

4 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

5 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

6 G1/S: adequate cellular growth to support replication G2/M: full, accurate DNA replication Spindle: Chromosomes aligned

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10 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’

11 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

12 Tumour cell kinetics and you 1cm 3 = 1g tumor ( 10 9 ) 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

13 Lethal tumour burden (1000g) 30 doubling times 10 doublings

14 Hoeijmakers J (2009) NEJM 361:

15 Vogelstein, Science (1991) Gastroenterology (2010) 138(6)

16 Hanahan, Weinberg (2011) Cell 144:646-74

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19 The microenvironment is important Hanahan, Coussens (2011) Cell 144:646-74

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22 Hoeijmakers J (2009) NEJM 361:

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25 Radiotherapy Surgery by non-surgical means

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27 Medscape

28 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

29 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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31 Medscape Deliver higher doses Prevent tissue damage Greater kill due to redistribution of tumour

32 Medscape Repairable damage Irreparable damage Predicting tissue response

33 Chemotherapy Whole-body therapy

34 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 to log regrowth between cycles

35 Classes of chemotherapy agents Based on cell cycle Phase-specifc –Exhibit a dose-plateau Phase insensitive –Linear kill kinetics

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37 Phase insensitive Alkylating agents –Platinums –Mustards Typically have severe side effects –Bone marrow depression –Emetogenic

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39 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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41 Cancer surgery Cures most solid tumors

42 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

43 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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47 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

48 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

49 Key points (3) Diagnosis and staging lead to treatment Understanding the concepts of tumourigenesis will help understand the approach to cancer care

50 Questions?


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