Principles of cancer biology
Download
1 / 50

Principles of Cancer Biology - PowerPoint PPT Presentation


  • 201 Views
  • Uploaded on

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

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about ' Principles of Cancer Biology' - nitesh


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
Principles of cancer biology

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
Outline

  • Basics

    • Cell cycle

    • Hallmarks of cancer

    • Metastasis

  • Radiotherapy

    • Mechanism

  • Chemotherapy

    • Mechanism

  • Surgical Oncology

  • Key points


Tumourigenesis

Tumourigenesis

Loss of balance

Oncogenes > Suppressors


Principles of cellular growth
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
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



Oncogenes oncoproteins
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
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
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)

10 doublings

30 doubling times



Vogelstein, Science (1991)

Gastroenterology (2010) 138(6)2101-14




The microenvironment is important
The microenvironment is important

Hanahan, Coussens (2011) Cell 144:646-74




Radiotherapy

Radiotherapy

Surgery by non-surgical means



Mechanism of action
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
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
Predicting tissue response

Repairable damage

Irreparable damage

Medscape


Chemotherapy

Chemotherapy

Whole-body therapy


Principles of chemotherapy
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
Classes of chemotherapy agents

  • Based on cell cycle

  • Phase-specifc

    • Exhibit a dose-plateau

  • Phase insensitive

    • Linear kill kinetics


Phase insensitive
Phase insensitive

  • Alkylating agents

    • Platinums

    • Mustards

  • Typically have severe side effects

    • Bone marrow depression

    • Emetogenic


Phase sensitive agents
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

Cancer surgery

Cures most solid tumors


Surgery chemo radiotherapy
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
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
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
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
Key points (3)

  • Diagnosis and staging lead to treatment

  • Understanding the concepts of tumourigenesis will help understand the approach to cancer care



ad