Tumor Radiation Biology

1
Tumor Radiation Biology
2
Tumor Radiation Biology

• Tumors represent uncontrolled growth of a cell
  population.
• Loss of contact inhibition overpopulation
• Disordered growth
• Non-uniform phenotype (cell characteristics)
  Chaotic gene expression
• Some cells in population hypoxic?

3
Tumor Induction

• Mutations or changes in cellular population
  control mechanisms
• Proto-oncogenes
• Tumor suppressor genes
• DNA stability genes

4
Proto-Oncogenes

• Positive grow regulators
• Promote cell division and decrease response to
  extracellular control signals
• Requires only a single copy of the gene to result
  in up-regulation.
• Blunts cell to cell contact growth inhibition.

5
Tumor Suppressor Genes

• Negative growth regulators
• Antagonists of proto-oncogenes
• Decreases cell growth potential
• Increase negative growth signals of cell to cell
  contact.
• Inactivation of both copies of gene required to
  result in complete loss of function

6
DNA Stability Genes

• Monitor and maintain the integrity of the DNA.
• Loss of function promotes mutations
• Detection of DNA lesions decreased
• Repair of damage decreased or improper
• Decreased apoptosis

7
Neoplastic Transformation

• Tumor cells typically arise from a normal cell
  population. gt
• Mutation in growth control mechanism (often more
  than one) gt
• Abnormal cells begin to proliferate gt
• Cells escape detection by bodys immune system gt
• Invasion of surrounding tissue.

8
Mechanisms of Proto-oncogene Mutation or
Expression

• Retroviral integration
• Retroviral genome integrates with DNA near
  oncogene and promotes activation
• DNA mutation of regulatory sites
• Mutation reduces regulatory activity by
  alteration of protein transcription
• Can be alteration of a single base pair

9
Mechanisms of Proto-oncogene Mutation or
Expression

• Gene Amplification
• Improper DNA replication leads to multiple copies
  of gene
• Increased numbers of copies promotes
  up-regulation of oncogene.
• Seen in leukemia, and breast cancer

10
Mechanisms of Proto-oncogene Mutation or
Expression

• Chromosomal translocation
• Tumor Chromosomes different from normal cells.
• Abnormal reproduction (mutation) results in part
  of one chromosome being removed and attached to
  another.
• Recombination may promote oncogene expression.
• Some recombinations occur repeatedly

11
Mechanisms of Proto-oncogene Mutation or
Expression

• Multiple mechanisms may be present in any given
  tumor genotype.
• Modified or amplified by mutations in tumor
  suppressor gene activity
• Must escape detection by DNA integrity monitoring
  and repair systems.
• Clonogenic activity preserved

12
Inactivation of Tumor-Suppressor Genes

• These genes provide control of oncogenes.
• Recessive genes but still function
• Loss of both copies of these genes is generally
  required to allow tumors to grow
• The effect can be a sporatic mutation in and
  individual cell or in some cases is a heritable
  disorder.

13
Inactivation of Tumor-Suppressor Genes

• Inactivate or lost through somatic homozygosity.
• A mutation occurs in the gene on one chromosome.
  
• The complimentary chromosome is loss through
  mitotic misadventure
• The remaining chromosome self replicates
• Daughter cell winds up with a self-copy of the
  mutated gene.

14
Cancer is a Multi-Step Process

• DNA damage (radiation etc.) gt
• DNA damage multiplied
• Both pro oncogenes and oncogene suppressors
  affected.
• Usually multiple cellular systems affected.
• Eventually an imortalized clonogenic cell
  develops and tumor growth begins

15
Cancer is a Multi-Step Process

• Deregulation of cellular proliferation through
  suppression of many genes
• Failure of cells to respond the growth
  restrictive signals
• Failure of excess cells to undergo apoptosis.
• Apoptosis is major effect of p53.
• Escape from senescence
• Cell aging does not occur.

16
Cancer is a Multi-Step Process

• Angiogenesis in order to grow a tumor must
  recruit and establish a blood supply.
• Certain genes promote or inhibit endothelial cell
  growth
• Mutation can cause down or up regulation
• Invasion and metastasis occur
• In metastasis cell adhesion is lost
• Sign of a very deranged growth in a cell

17
Cancer is a Multi-Step Process

• Lastly cancer cells must possess mechanisms to
  avoid replication arrest at the cell cycle
  checkpoints
• G1- S p53 dependent
• S phase arrest mediated by Cyclin A E
• G2 M mediated multiple gene products

18
Cancer is a Multi-Step Process

• Radiation injury to the DNA may promote
  neoplastic transformation by either inhibiting or
  damaging genes which control cell growth and
  replication or by causing damage which promotes
  up regulation of genes which actively causes
  uncontrolled cell growth.

19
Tumor Radiation Biology

• Tumor tissue exhibit chaotic growth and phenotype
  patterns
• Cells in different areas of tumor may have
  different appearances
• Different size
• Different chromosomal imprints
• Different cytoplasmic and nuclear patterns
• Different adhesion characteristics
• May be unrecognizable from parent cells or not
  look like them at all.

20
Tumor Radiation Biology

• Stromal and other support cells are poorly
  developed or not at all.
• Connective tissue lattice
• NO nerve supply
• Poorly developed vascular and lymphatic system.
• Frequently large s of inflammatory cells due to
  dying non-viable cells

21
Tumor Radiation Biology

• Hypoxia is a feature of tumors not found in
  normal tissues.
• Tumor vascularity is primitive and growth is not
  controlled by genetic template.
• Tumor vascularity tends to be primitive
• Blood flow in tumors while copious is sluggish
• Tumor volume not uniformly vascularized
• Tumor cells may use oxygen inefficiently

22
Tumor Hypoxia

• Four different subpopulations of tumor cells with
  respect to oxygenation.
• Well oxygenated viable dividing
• Well oxygenated viable non-dividing
• Poorly oxygenated viable non-dividing
• Anoxic and/or necrotic non-viable

23
Tumor Hypoxia

• There are two types of hypoxia
• Transient Hypoxia
• Intermittent in nature
• Can be quite severe
• Permanent Hypoxia
• Unrelieved hypoxia
• Severe to the point of causing cell death

24
Tumor Hypoxia

• Intermittent Hypoxia
• Caused by vascular spasm
• Spasm usually at the arteriole level
• Due to lack or neurologic control of vessels
• May be mediated by vasopressors secreted by the
  tumor
• Increases radiation resistance
• Increase resistance to some drugs

25
Tumor Hypoxia

• Permanent Hypoxia
• Occurs when tumor growth outstrips vascular
  supply
• Hypoxic cells are physically displaced from
  vessels.
• Oxygen diffusion distance varies with metabolism
  but beyond 100 microns hypoxia is probably
  profound.
• Tumor pressure on surrounding tissues may further
  impede blood supply.

26
Tumor Hypoxia
27
Tumor Hypoxia
28
Tumor Hypoxia
29
Tumor Hypoxia

• Hypoxic cells are radiation resistant
• Decreased Oxygen fixation of injury
• Permits repair to procede
• Must be relatively profound.
• O2 tension below 3mmHg
• Present during main phase of repair
• Hypoxic cell D0 2.5-3.0 x oxic cells
• Favors tumors as normal tissue are oxic

30
Tumor Hypoxia
31
Tumor Hypoxia

• Hypoxia not protective against single hit double
  strand break injury.
• Linear part of curve is maintained
• Hypoxia less of a concern with high LET
• Hypoxic cells are not in cycling pool.
• Cell division dependent on normal oxygen

32
Reoxygenation

• Refers to reestablishing Oxygen supply to hypoxic
  cells.
• Occurs spontaneously with transient hypoxia when
  vasospasm releases
• Occurs through oxic cell death in chronic
  hypoxia.
• Promoted by treatment schemes or drug
  interventions but mechanism the same.

33
Reoxygenation

• Necessary in Radiation therapy
• Normal tissues are oxygenated.
• Oxygenated normal tissues are more sensitive to
  radiation than hypoxic tumor cells
• Irradiation of tumors usually requires
  irradiation of normal tissues.
• Normal tissue tolerance limits radiation dose.

34
Reoxygenation

• Accomplished by fractionation
• Oxic cells preferentially killed by radiation
• Cells in cycling pool
• Cells with normal oxygen tension
• Cells with normal nutrition
• Cells with normal pH
• Poorly oxygenated cells move into oxic zone.

35
Normal Tissue Tolerance

• Inherent radiosensitivity of cells
• Repair capability of cells
• Cell cycle time of critical cell line
• Repopulation potential of cells
• Size of the radiation field
• Finely fractionated dose tolerance levels of
  normal tissues varies from about 10 gray to 75
  gray

36
Normal Tissue Tolerance

• Inherent radiosensitivity of tissues
• Apparent differences in radiosensitivity are
  largely due to redundancy of cells
• At the cellular level mammalian cells most have
  the same sensitivity within a fairly narrow range
  (D0 1.5-2.0 Gy)
• Hypoxia does not play a significant role
• Other factors such as drugs can modify the
  inherent sensitivity of some tissues

37
Normal Tissue Tolerance

• Repair capability of critical line
• Late responding tissues generally more repair
• Early responding tissues generally less repair
• Critical cell line may not be early responder
• Repair capability may be altered by outside
  influences such as hyperthermia

38
Normal Tissue Tolerance

• Cell cycle time of the critical cell line
• Apparent tolerance may only be due to slow cell
  cycle times
• Dose rate effect may allow tolerance in rapidly
  dividing cells do to repopulation
• Relative abundance of critical cells may increase
  tolerance

39
Normal Tissue Tolerance

• Repopulation potential of tissue cells
• Tissues with many blast cells have greater
  repopulation potential.
• Particularly if dose rate is low
• Tissues composed of hierarchical type cells
  usually have greater repopulation potential
• RPM and Flexible type cells may have limited
  repopulation potential

40
Normal Tissue Tolerance

• Size of the radiation field
• Small fields allow healing by ingrowth of cells
  from non irradiated tissue.
• Small fields less likely to irradiate whole organ
• Small fields permit revascularization by invasion
  from periphery.
• Large field increase scatter and dose to adjacent
  tissue with potential influence on damage to
  target tissue.

41
Normal Tissue Tolerance

• Dose fractionation scheme
• Fractionation favors repair
• Repair greatest in late responding tissue
• Dose rate effect favors repopulation
• Fractionated dose reduces injury in most normal
  tissues.

42
Radiocurability of Tumors

• Tumors display a wide range of apparent
  sensitivity to radiation injury
• Generally speaking the same factors at work in
  normal tissues are also at work in tumors
• Hypoxia, if present, will reduce injury
• Size and type of tumor also influences the rate
  of radiation control

43
Tumor Curability

• Practices employed in radiation therapy are
  designed to promote normal tissue survival and
  increase tumor tissue death.
• The difference between normal tissues and tumor
  tissue is generally small.
• The therapeutic gain is the ratio of tumor death
  to normal tissue death