tumor radiation biology

Tumor Radiation BiologyTumor Radiation Biology


Tumors represent uncontrolled Tumors represent uncontrolled growth of a cell population.growth of a cell population.• Loss of contact inhibition – Loss of contact inhibition –

overpopulationoverpopulation• Disordered growthDisordered growth• Non-uniform phenotype (cell Non-uniform phenotype (cell

characteristics) Chaotic gene expressioncharacteristics) Chaotic gene expression• Some cells in population hypoxic?Some cells in population hypoxic?

Tumor InductionTumor Induction

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

Proto-OncogenesProto-Oncogenes

Positive grow regulators Positive grow regulators • Promote cell division and decrease Promote cell division and decrease

response to extracellular control signalsresponse to extracellular control signals• Requires only a single copy of the gene Requires only a single copy of the gene

to result in up-regulation.to result in up-regulation.• Blunts cell to cell contact growth Blunts cell to cell contact growth

inhibition.inhibition.

Tumor Suppressor GenesTumor Suppressor Genes

Negative growth regulatorsNegative growth regulators• Antagonists of proto-oncogenesAntagonists of proto-oncogenes• Decreases cell growth potentialDecreases cell growth potential• Increase negative growth signals of cell Increase negative growth signals of cell

to cell contact.to cell contact. Inactivation of both copies of gene Inactivation of both copies of gene

required to result in complete loss of required to result in complete loss of function function

DNA Stability GenesDNA Stability Genes

Monitor and maintain the integrity of Monitor and maintain the integrity of the DNA. the DNA.

Loss of function promotes mutationsLoss of function promotes mutations• Detection of DNA lesions decreasedDetection of DNA lesions decreased• Repair of damage decreased or Repair of damage decreased or

improperimproper• Decreased apoptosisDecreased apoptosis

Neoplastic TransformationNeoplastic Transformation

Tumor cells typically arise from a Tumor cells typically arise from a normal cell population. >normal cell population. >

Mutation in growth control Mutation in growth control mechanism (often more than one) >mechanism (often more than one) >

Abnormal cells begin to proliferate >Abnormal cells begin to proliferate > Cells escape detection by body’s Cells escape detection by body’s

immune system >immune system > Invasion of surrounding tissue. Invasion of surrounding tissue.

Mechanisms of Proto-oncogene Mechanisms of Proto-oncogene Mutation or ExpressionMutation or Expression

Retroviral integrationRetroviral integration• Retroviral genome integrates with DNA Retroviral genome integrates with DNA

near oncogene and promotes activationnear oncogene and promotes activation DNA mutation of regulatory sitesDNA mutation of regulatory sites

• Mutation reduces regulatory activity by Mutation reduces regulatory activity by alteration of protein transcriptionalteration of protein transcription

• Can be alteration of a single base pairCan be alteration of a single base pair


Gene AmplificationGene Amplification• Improper DNA replication leads to Improper DNA replication leads to

multiple copies of genemultiple copies of gene• Increased numbers of copies promotes Increased numbers of copies promotes

up-regulation of oncogene.up-regulation of oncogene.• Seen in leukemia, and breast cancerSeen in leukemia, and breast cancer


Chromosomal translocationChromosomal translocation• Tumor Chromosomes different from Tumor Chromosomes different from

normal cells. normal cells. • Abnormal reproduction (mutation) Abnormal reproduction (mutation)

results in part of one chromosome being results in part of one chromosome being removed and attached to another.removed and attached to another.

• Recombination may promote oncogene Recombination may promote oncogene expression.expression.

• Some recombinations occur repeatedly Some recombinations occur repeatedly


Multiple mechanisms may be present Multiple mechanisms may be present in any given tumor genotype. in any given tumor genotype.

Modified or amplified by mutations in Modified or amplified by mutations in tumor suppressor gene activitytumor suppressor gene activity

Must escape detection by DNA Must escape detection by DNA integrity monitoring and repair integrity monitoring and repair systems. systems.

Clonogenic activity preservedClonogenic activity preserved

Inactivation of Tumor-Suppressor Inactivation of Tumor-Suppressor GenesGenes

These genes provide control of These genes provide control of oncogenes. oncogenes. • Recessive genes but still functionRecessive genes but still function• Loss of both copies of these genes is Loss of both copies of these genes is

generally required to allow tumors to generally required to allow tumors to growgrow

• The effect can be a sporatic mutation in The effect can be a sporatic mutation in and individual cell or in some cases is a and individual cell or in some cases is a heritable disorder.heritable disorder.

Inactivation of Tumor-Suppressor Inactivation of Tumor-Suppressor GenesGenes

Inactivate or lost through somatic Inactivate or lost through somatic homozygosity.homozygosity.• A mutation occurs in the gene on one A mutation occurs in the gene on one

chromosome. chromosome. • The complimentary chromosome is loss The complimentary chromosome is loss

through mitotic misadventurethrough mitotic misadventure• The remaining chromosome self The remaining chromosome self

replicatesreplicates• Daughter cell winds up with a self-copy Daughter cell winds up with a self-copy

of the mutated gene.of the mutated gene.

Cancer is a Multi-Step ProcessCancer is a Multi-Step Process

DNA damage (radiation etc.) >DNA damage (radiation etc.) > DNA damage multipliedDNA damage multiplied Both pro oncogenes and oncogene Both pro oncogenes and oncogene

suppressors affected. suppressors affected. Usually multiple cellular systems Usually multiple cellular systems

affected. affected. Eventually an imortalized clonogenic Eventually an imortalized clonogenic

cell develops and tumor growth cell develops and tumor growth beginsbegins


Deregulation of cellular proliferation Deregulation of cellular proliferation through suppression of many genesthrough suppression of many genes

Failure of cells to respond the growth Failure of cells to respond the growth restrictive signalsrestrictive signals

Failure of excess cells to undergo Failure of excess cells to undergo apoptosis.apoptosis.• Apoptosis is major effect of p53.Apoptosis is major effect of p53.

Escape from senescenceEscape from senescence• Cell aging does not occur. Cell aging does not occur.


Angiogenesis – in order to grow a Angiogenesis – in order to grow a tumor must recruit and establish a tumor must recruit and establish a blood supply. blood supply. • Certain genes promote or inhibit Certain genes promote or inhibit

endothelial cell growth endothelial cell growth Mutation can cause down or up regulation Mutation can cause down or up regulation

Invasion and metastasis occurInvasion and metastasis occur• In metastasis cell adhesion is lostIn metastasis cell adhesion is lost• Sign of a very deranged growth in a cellSign of a very deranged growth in a cell


Lastly cancer cells must possess Lastly cancer cells must possess mechanisms to avoid replication mechanisms to avoid replication arrest at the cell cycle checkpointsarrest at the cell cycle checkpoints• G1- S p53 dependentG1- S p53 dependent• S phase arrest mediated by Cyclin A & ES phase arrest mediated by Cyclin A & E• G2 – M mediated multiple gene productsG2 – M mediated multiple gene products


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


Tumor tissue exhibit chaotic growth Tumor tissue exhibit chaotic growth and phenotype patternsand phenotype patterns• Cells in different areas of tumor may Cells in different areas of tumor may

have different appearanceshave different appearances Different sizeDifferent size Different chromosomal imprintsDifferent chromosomal imprints Different cytoplasmic and nuclear patternsDifferent cytoplasmic and nuclear patterns Different adhesion characteristicsDifferent adhesion characteristics

• May be unrecognizable from parent cells May be unrecognizable from parent cells or not look like them at all. or not look like them at all.


Stromal and other support cells are Stromal and other support cells are poorly developed or not at all. poorly developed or not at all. • Connective tissue latticeConnective tissue lattice• NO nerve supplyNO nerve supply• Poorly developed vascular and Poorly developed vascular and

lymphatic system. lymphatic system. Frequently large #’s of inflammatory Frequently large #’s of inflammatory

cells due to dying non-viable cellscells due to dying non-viable cells


Hypoxia is a feature of tumors not Hypoxia is a feature of tumors not found in normal tissues. found in normal tissues. • Tumor vascularity is primitive and Tumor vascularity is primitive and

growth is not controlled by genetic growth is not controlled by genetic template. template.

• Tumor vascularity tends to be primitiveTumor vascularity tends to be primitive Blood flow in tumors while copious is Blood flow in tumors while copious is

sluggish sluggish Tumor volume not uniformly vascularizedTumor volume not uniformly vascularized Tumor cells may use oxygen inefficiently Tumor cells may use oxygen inefficiently

Tumor HypoxiaTumor Hypoxia

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


There are two types of hypoxiaThere are two types of hypoxia• Transient HypoxiaTransient Hypoxia

Intermittent in natureIntermittent in nature Can be quite severeCan be quite severe

• Permanent HypoxiaPermanent Hypoxia Unrelieved hypoxiaUnrelieved hypoxia Severe to the point of causing cell deathSevere to the point of causing cell death


Intermittent HypoxiaIntermittent Hypoxia• Caused by vascular spasmCaused by vascular spasm• Spasm usually at the arteriole levelSpasm usually at the arteriole level• Due to lack or neurologic control of Due to lack or neurologic control of

vesselsvessels• May be mediated by vasopressors May be mediated by vasopressors

secreted by the tumorsecreted by the tumor• Increases radiation resistanceIncreases radiation resistance• Increase resistance to some drugsIncrease resistance to some drugs


Permanent HypoxiaPermanent Hypoxia• Occurs when tumor growth outstrips Occurs when tumor growth outstrips

vascular supplyvascular supply• Hypoxic cells are physically displaced Hypoxic cells are physically displaced

from vessels.from vessels.• Oxygen diffusion distance varies with Oxygen diffusion distance varies with

metabolism but beyond 100 microns metabolism but beyond 100 microns hypoxia is probably profound. hypoxia is probably profound.

• Tumor pressure on surrounding tissues Tumor pressure on surrounding tissues may further impede blood supply. may further impede blood supply.


Hypoxic cells are radiation resistantHypoxic cells are radiation resistant• Decreased Oxygen fixation of injuryDecreased Oxygen fixation of injury• Permits repair to proceedPermits repair to proceed• Must be relatively profound. Must be relatively profound.

OO22 tension below 3mmHg tension below 3mmHg Present during main phase of repairPresent during main phase of repair

• Hypoxic cell DHypoxic cell D00 2.5-3.0 x oxic cells 2.5-3.0 x oxic cells

• Favors tumors as normal tissue are oxic Favors tumors as normal tissue are oxic


Hypoxia not protective against single Hypoxia not protective against single hit double strand break injury.hit double strand break injury.• Linear part of curve is maintainedLinear part of curve is maintained• Hypoxia less of a concern with high LETHypoxia less of a concern with high LET• Hypoxic cells are not in cycling pool. Hypoxic cells are not in cycling pool.

Cell division dependent on normal oxygenCell division dependent on normal oxygen

ReoxygenationReoxygenation

Refers to reestablishing Oxygen Refers to reestablishing Oxygen supply to hypoxic cells.supply to hypoxic cells.• Occurs spontaneously with transient Occurs spontaneously with transient

hypoxia when vasospasm releaseshypoxia when vasospasm releases• Occurs through oxic cell death in chronic Occurs through oxic cell death in chronic

hypoxia. hypoxia. • Promoted by treatment schemes or drug Promoted by treatment schemes or drug

interventions but mechanism the same.interventions but mechanism the same.


Necessary in Radiation therapyNecessary in Radiation therapy• Normal tissues are oxygenated.Normal tissues are oxygenated.• Oxygenated normal tissues are more Oxygenated normal tissues are more

sensitive to radiation than hypoxic sensitive to radiation than hypoxic tumor cellstumor cells

• Irradiation of tumors usually requires Irradiation of tumors usually requires irradiation of normal tissues. irradiation of normal tissues.

• Normal tissue tolerance limits radiation Normal tissue tolerance limits radiation dose. dose.


Accomplished by fractionationAccomplished by fractionation• Oxic cells preferentially killed by Oxic cells preferentially killed by

radiationradiation Cells in cycling poolCells in cycling pool Cells with normal oxygen tensionCells with normal oxygen tension Cells with normal nutritionCells with normal nutrition Cells with normal pHCells with normal pH

• Poorly oxygenated cells move into oxic Poorly oxygenated cells move into oxic zone. zone.

Normal Tissue ToleranceNormal Tissue Tolerance

Inherent radiosensitivity of cellsInherent radiosensitivity of cells Repair capability of cellsRepair capability of cells Cell cycle time of critical cell lineCell cycle time of critical cell line Repopulation potential of cellsRepopulation potential of cells Size of the radiation fieldSize of the radiation field Finely fractionated dose tolerance Finely fractionated dose tolerance

levels of normal tissues varies from levels of normal tissues varies from about 10 gray to 75 grayabout 10 gray to 75 gray


Inherent radiosensitivity of tissuesInherent radiosensitivity of tissues• Apparent differences in radiosensitivity Apparent differences in radiosensitivity

are largely due to redundancy of cellsare largely due to redundancy of cells• At the cellular level mammalian cells At the cellular level mammalian cells

most have the same sensitivity within a most have the same sensitivity within a fairly narrow range (Dfairly narrow range (D00 ~~ 1.5-2.0 Gy) 1.5-2.0 Gy)

• Hypoxia does not play a significant roleHypoxia does not play a significant role• Other factors such as drugs can modify Other factors such as drugs can modify

the inherent sensitivity of some tissuesthe inherent sensitivity of some tissues


Repair capability of critical lineRepair capability of critical line• Late responding tissues generally more Late responding tissues generally more

repairrepair• Early responding tissues generally less Early responding tissues generally less

repairrepair• Critical cell line may not be early Critical cell line may not be early

responderresponder• Repair capability may be altered by Repair capability may be altered by

outside influences such as hyperthermiaoutside influences such as hyperthermia


Cell cycle time of the critical cell lineCell cycle time of the critical cell line• Apparent tolerance may only be due to Apparent tolerance may only be due to

slow cell cycle timesslow cell cycle times• Dose rate effect may allow tolerance in Dose rate effect may allow tolerance in

rapidly dividing cells do to repopulationrapidly dividing cells do to repopulation• Relative abundance of critical cells may Relative abundance of critical cells may

increase toleranceincrease tolerance


Repopulation potential of tissue cellsRepopulation potential of tissue cells• Tissues with many blast cells have Tissues with many blast cells have

greater repopulation potential.greater repopulation potential. Particularly if dose rate is lowParticularly if dose rate is low

• Tissues composed of hierarchical type Tissues composed of hierarchical type cells usually have greater repopulation cells usually have greater repopulation potentialpotential

• RPM and Flexible type cells may have RPM and Flexible type cells may have limited repopulation potentiallimited repopulation potential


Size of the radiation fieldSize of the radiation field• Small fields allow healing by ingrowth of Small fields allow healing by ingrowth of

cells from non irradiated tissue. cells from non irradiated tissue. • Small fields less likely to irradiate whole Small fields less likely to irradiate whole

organorgan• Small fields permit revascularization by Small fields permit revascularization by

invasion from periphery.invasion from periphery.• Large field increase scatter and dose to Large field increase scatter and dose to

adjacent tissue with potential influence adjacent tissue with potential influence on damage to target tissue. on damage to target tissue.


Dose fractionation schemeDose fractionation scheme• Fractionation favors repairFractionation favors repair• Repair greatest in late responding tissueRepair greatest in late responding tissue• Dose rate effect favors repopulationDose rate effect favors repopulation• Fractionated dose reduces injury in most Fractionated dose reduces injury in most

normal tissues.normal tissues.

Radiocurability of TumorsRadiocurability of Tumors

Tumors display a wide range of apparent Tumors display a wide range of apparent sensitivity to radiation injurysensitivity to radiation injury

Generally speaking the same factors at Generally speaking the same factors at work in normal tissues are also at work in work in normal tissues are also at work in tumorstumors

Hypoxia, if present, will reduce injuryHypoxia, if present, will reduce injury Size and type of tumor also influences the Size and type of tumor also influences the

rate of radiation controlrate of radiation control

Tumor CurabilityTumor Curability

Practices employed in radiation Practices employed in radiation therapy are designed to promote therapy are designed to promote normal tissue survival and increase normal tissue survival and increase tumor tissue death. tumor tissue death. • The difference between normal tissues The difference between normal tissues

and tumor tissue is generally small.and tumor tissue is generally small.• The therapeutic gain is the ratio of The therapeutic gain is the ratio of

tumor death to normal tissue deathtumor death to normal tissue death

tumor radiation biology

Documents

cell division

individual cell

normal cell population

cell contact growth

sporatic mutation

tumor inductionmutations

growth control mechanism

uncontrolled growth