Transcript Tumor Radiation Biology

Tumor Radiation Biology
Tumor Radiation Biology
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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?
Tumor Induction
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Mutations or changes in cellular
population control mechanisms
• Proto-oncogenes
• Tumor suppressor genes
• DNA stability genes
Proto-Oncogenes
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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.
Tumor Suppressor Genes
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Negative growth regulators
• Antagonists of proto-oncogenes
• Decreases cell growth potential
• Increase negative growth signals of cell
to cell contact.
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Inactivation of both copies of gene
required to result in complete loss of
function
DNA Stability Genes
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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
Neoplastic Transformation
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Tumor cells typically arise from a
normal cell population. >
Mutation in growth control
mechanism (often more than one) >
Abnormal cells begin to proliferate >
Cells escape detection by body’s
immune system >
Invasion of surrounding tissue.
Mechanisms of Proto-oncogene
Mutation or Expression
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Retroviral integration
• Retroviral genome integrates with DNA
near oncogene and promotes activation
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DNA mutation of regulatory sites
• Mutation reduces regulatory activity by
alteration of protein transcription
• Can be alteration of a single base pair
Mechanisms of Proto-oncogene
Mutation or Expression
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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
Mechanisms of Proto-oncogene
Mutation or Expression
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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
Mechanisms of Proto-oncogene
Mutation or Expression
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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
Inactivation of Tumor-Suppressor
Genes
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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.
Inactivation of Tumor-Suppressor
Genes
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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.
Cancer is a Multi-Step Process
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DNA damage (radiation etc.) >
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
Cancer is a Multi-Step Process
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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.
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Escape from senescence
• Cell aging does not occur.
Cancer is a Multi-Step Process
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Angiogenesis – in order to grow a
tumor must recruit and establish a
blood supply.
• Certain genes promote or inhibit
endothelial cell growth
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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
Cancer is a Multi-Step Process
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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
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.
Tumor Radiation Biology
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Tumor tissue exhibit chaotic growth
and phenotype patterns
• Cells in different areas of tumor may
have different appearances
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Different
Different
Different
Different
size
chromosomal imprints
cytoplasmic and nuclear patterns
adhesion characteristics
• May be unrecognizable from parent cells
or not look like them at all.
Tumor Radiation Biology
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Stromal and other support cells are
poorly developed or not at all.
• Connective tissue lattice
• NO nerve supply
• Poorly developed vascular and lymphatic
system.
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Frequently large #’s of inflammatory
cells due to dying non-viable cells
Tumor Radiation Biology
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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
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Blood flow in tumors while copious is
sluggish
Tumor volume not uniformly vascularized
Tumor cells may use oxygen inefficiently
Tumor Hypoxia
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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
Tumor Hypoxia
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There are two types of hypoxia
• Transient Hypoxia
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Intermittent in nature
Can be quite severe
• Permanent Hypoxia
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Unrelieved hypoxia
Severe to the point of causing cell death
Tumor Hypoxia
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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
Tumor Hypoxia
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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.
Tumor Hypoxia
Tumor Hypoxia
Tumor Hypoxia
Tumor Hypoxia
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Hypoxic cells are radiation resistant
• Decreased Oxygen fixation of injury
• Permits repair to proceed
• Must be relatively profound.
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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
Tumor Hypoxia
Tumor Hypoxia
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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.
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Cell division dependent on normal oxygen
Reoxygenation
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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.
Reoxygenation
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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.
Reoxygenation
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Accomplished by fractionation
• Oxic cells preferentially killed by
radiation
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Cells
Cells
Cells
Cells
in cycling pool
with normal oxygen tension
with normal nutrition
with normal pH
• Poorly oxygenated cells move into oxic
zone.
Normal Tissue Tolerance
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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
Normal Tissue Tolerance
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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
Normal Tissue Tolerance
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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
Normal Tissue Tolerance
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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
Normal Tissue Tolerance
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Repopulation potential of tissue cells
• Tissues with many blast cells have
greater repopulation potential.
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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
Normal Tissue Tolerance
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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.
Normal Tissue Tolerance
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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.
Radiocurability of Tumors
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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
Tumor Curability
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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