Tumor I Nvasion a Nd Meta Stasis

8/14/2019 Tumor I Nvasion a Nd Meta Stasis

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Tumor I nvasion a ndumor I nvasion a ndMeta stasiseta stasisT. DavisT. Davis

9-25-20099-25-2009


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Neop la smseop la sms ??????? Non-invasiveNon-invasive Non-metastaticNon-metastatic

????? InvasiveInvasive Metastatic or non-Metastatic or non-

metastaticmetastatic


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Neop la smseop la sms Benignenign Non-invasiveNon-invasive Non-metastaticNon-metastatic

Malignantalignant InvasiveInvasive Metastatic or non-Metastatic or non-

metastaticmetastatic


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Ex cep tion s t o th e R ulex cep tion s t o th e R ule Benig n t umorsenig n t umorstha t ma y ki ll th eha t ma y ki ll th e

patientatient ??????

??????

Malignantalignanttumors w it houtumors w it houtmeta st asi seta st asi s

??????

??????


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Ex cep tion s t o th e R ulex cep tion s t o th e R ule Benig n t umorsenig n t umorstha t ma y ki ll th eha t ma y ki ll th e

patientatient MeningiomaMeningioma

LeiomyomaLeiomyoma

Malignantalignanttumors w it houtumors w it houtmeta st asi seta st asi s

GlioblastomaGlioblastomamultiformemultiforme

Basal cell carcinomaBasal cell carcinoma


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Malig nan t Tu mo ral ig nan t Tu mo rProp er tiesrop er ties Penetration of thePenetration of the ??????

Invasion and destruction ofInvasion and destruction of??????

PenetratePenetrate ?????? or fungate throughor fungate throughthethe ??????

LocalLocal ??????, like, like ?????? is a marker foris a marker for

malignancymalignancy

See Robbins Table 7-2 for benign vsSee Robbins Table 7-2 for benign vs

malignant featuresmalignant features


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Malig nan t Tu mo ral ig nan t Tu mo rProp er tiesrop er ties Penetration of thePenetration of the basementbasement

membranemembrane

Invasion and destruction ofInvasion and destruction of

surrounding tissuesurrounding tissue

PenetratePenetrate organ wallsorgan walls or fungateor fungate

through thethrough the surfacesurface

LocalLocal invasioninvasion, like, like metastasismetastasis is ais a

marker for malignancymarker for malignancy

See Robbins Table 7-2 for benign vsSee Robbins Table 7-2 for benign vs

mali nant featuresmalignant features


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Invasive breast carcinoma


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Local invasion by ductal carcinoma


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Colon carcinoma invades into surrounding adipose tissue


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Colon carcinoma invades into surrounding adipose tissue


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????? #1 marker of malignancy#1 marker of malignancy

Exceptions:Exceptions: ?????? of the brain andof the brain and ?????? of theof the

skin RARELY metastasize; also,skin RARELY metastasize; also, ??????LOCALLY invade skull bone, but do notLOCALLY invade skull bone, but do not

metastasize and are considered benign.metastasize and are considered benign.

** On board exams they sometimes** On board exams they sometimes

substitutesubstitute ????? for metastasisfor metastasis


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Meta stasiseta stasis #1 marker of malignancy#1 marker of malignancy Exceptions:Exceptions: gliomas (astrocytomas)gliomas (astrocytomas) of theof the

brain andbrain and basal cell carcinomasbasal cell carcinomas of the skinof the skinRARELY metastasize; also,RARELY metastasize; also, meningiomasmeningiomasLOCALLY invade skull bone, but do notLOCALLY invade skull bone, but do notmetastasize and are considered benign.metastasize and are considered benign.

** On board exams they sometimes** On board exams they sometimessubstitutesubstitute inva si ve nessnva si ve ness for metastasisfor metastasis


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Glioblastoma Multiforme (Astrocytoma III/IV


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Glioblastoma Multiforme (Astrocytoma III/IV


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Metastatic melanoma


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Metastatic melanoma


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Ca ncer St at is ticsa ncer St at is tics 90 % of cancer deaths are due to90 % of cancer deaths are due to ??????

1/3 of1/3 of?????? andand ?????? patients havepatients have

lymph node metastases at diagnosislymph node metastases at diagnosis Frequency overall:Frequency overall: ???, ???, ??????, ???, ???

#1 endocrine site:#1 endocrine site: ??????


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Ca ncer St at is ticsa ncer St at is tics 90 % of cancer deaths are due to90 % of cancer deaths are due to

metastasesmetastases

1/3 of1/3 ofbreastbreast andand colon cancercolon cancerpatients have lymph node metastasespatients have lymph node metastases

at diagnosisat diagnosis

Frequency overall:Frequency overall: liver, lung, boneliver, lung, bone #1 endocrine site:#1 endocrine site: adrenal glandsadrenal glands


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Stage of tumors at diagnosis listed by organ/site


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Pathwa ys of S preadathwa ys of S pread Direc t s eedin girec t s eedin g of body cavities:of body cavities: ??????

#1#1; also pleural, pericardial,; also pleural, pericardial,subarachnoid, jointsubarachnoid, joint

Lym phat ic s pr eadym phat ic s pr ead :: ???> ??????> ???;;follows natural drainage- breast cancerfollows natural drainage- breast cancer(Upper-Outer Quadrant) goes 1(Upper-Outer Quadrant) goes 1ststto ???to ???

Hemato ge no us spr eademato ge no us spr ead : esp.: esp. ??????;;alsoalso ??????; usually; usually ??????

Otherther : eg. Perineural spread: eg. Perineural spread


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Pathwa ys of S preadathwa ys of S pread Direc t s eedin girec t s eedin g of body cavities:of body cavities:

peritoneal #1peritoneal #1; also pleural, pericardial,; also pleural, pericardial,subarachnoid, jointsubarachnoid, joint

Lym phat ic s pr eadym phat ic s pr ead :: carcinoma>carcinoma>sarcomasarcoma; follows natural drainage-; follows natural drainage-breast cancerbreast cancer (Upper-Outer Quadrant)(Upper-Outer Quadrant)

goes 1goes 1stst to axillary nodesto axillary nodes

Hemato ge no us spr eademato ge no us spr ead : esp.: esp.sarcomasarcoma; also; also carcinomacarcinoma; usually; usually veinsveins

Otherther : eg. Perineural spread: eg. Perineural spread


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Breast carcinoma with perineural invasion


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Ven ou s D ra in ageen ou s D ra in age Portal:Portal: ??????

Caval:Caval: ??????

Paravertebral plexus:Paravertebral plexus: ?????? andand ??????metastasize to the vertebraemetastasize to the vertebrae

Renal Cell CA: invadesRenal Cell CA: invades ?????? and growsand grows

into theinto the ??????


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Ven ou s D ra in ageen ou s D ra in age Portal:Portal: liverliver

Caval:Caval: lungslungs

Paravertebral plexus:Paravertebral plexus: thyroidthyroid andand

prostate carcinomasprostate carcinomas metastasize tometastasize to

the vertebraethe vertebrae

Renal Cell CA: invadesRenal Cell CA: invades renal veinrenal vein andand

grows into thegrows into the vena cavavena cava


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Liver with metastases


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???????TheThe first nodefirst node in a regionalin a regional

lymphatic basin that receiveslymphatic basin that receiveslymph flow from the primarylymph flow from the primary

tumortumor

Dyes and radiolabeled tracers markDyes and radiolabeled tracers markthe nodethe node

Breast, colon and melanomasBreast, colon and melanomas

InIn breast carcinomasbreast carcinomas it replaces ait replaces atotal dissection of the axillarytotal dissection of the axillary

lymph nodes and reduceslymph nodes and reduces

morbiditymorbidity


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Sen tin el L N Bi ops yen t in el L N Bi ops yThe first node in a regionalThe first node in a regional

lymphatic basin that receiveslymphatic basin that receiveslymph flow from the primarylymph flow from the primary

tumortumor

Dyes and radiolabeled tracers markDyes and radiolabeled tracers markthe nodethe node

Breast, colon and melanomasBreast, colon and melanomas

InIn breast carcinomasbreast carcinomas it replaces ait replaces atotal dissection of the axillarytotal dissection of the axillary

lymph nodes and reduceslymph nodes and reduces

morbiditymorbidity


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Tumors stimulate the growthTumors stimulate the growth of ???of ???

Any tumor >Any tumor >??? mm??? mm in diameter mustin diameter must

have a vascular supplyhave a vascular supply NewNew ?????? supply oxygen and nutrientssupply oxygen and nutrients

andand ?????? secrete growth factorssecrete growth factors


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Tumors stimulate the growthTumors stimulate the growth of hostof host

blood vesselsblood vessels

Any tumor >Any tumor >2 mm2 mm in diameter mustin diameter musthave a vascular supplyhave a vascular supply

NewNew vesselsvessels supply oxygen andsupply oxygen and

nutrients andnutrients and endothelial cellsendothelial cells secretesecretegrowth factorsgrowth factors


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Tu mor Blood Ves selsu mor Blood Ves sels ?????? new capillaries ornew capillaries or ?????? hosthost

endothelial cellsendothelial cells

Tumor vessels areTumor vessels are ?????? andand ?????? due todue tohigh levels ofhigh levels of??????

Tumor cells can also mimicTumor cells can also mimic

endothelial cells (endothelial cells (??????))


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Tu mor Blood Ves selsu mor Blood Ves sels SproutSprout new capillaries ornew capillaries orrecruitrecruithosthost

endothelial cellsendothelial cells

Tumor vessels areTumor vessels are irregularirregular andand leakyleakydue to high levels ofdue to high levels ofVEGFVEGF

Tumor cells can also mimicTumor cells can also mimic

endothelial cells (endothelial cells (vasculogenicvasculogenicmimicrymimicry))


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Tu mor- associa tedu mor- associa tedAn giog en ic F act orsn giog en ic F act ors ?????? andand ?????? are made mostly byare made mostly by tumortumor

cellscells but also bybut also by macrophages andmacrophages and

stromal cellsstromal cells


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Tu mor- associa tedu mor- associa tedAn giog en ic F act orsn giog en ic F act orsVEGF (vascular endothelial growthVEGF (vascular endothelial growth

factor) and bFGF (basic fibroblastfactor) and bFGF (basic fibroblast

growth factor) are made mostly bygrowth factor) are made mostly bytumor cells but also by macrophagestumor cells but also by macrophages

and stromal cellsand stromal cells


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ANGI OGENI C SW ITCHNGI OGENI C SW ITCHAngiogenesis is delayed; a minority ofAngiogenesis is delayed; a minority of

the cells become angiogenicthe cells become angiogenic ?????? inhibits angiogenesis by inducinginhibits angiogenesis by inducing

production ofproduction of?????? and down-regulatingand down-regulating??????

Angiogenesis inhibitors made by tumorAngiogenesis inhibitors made by tumorcells:cells: ??????; and; and ?????? (from(fromplasminogen),plasminogen), ?????? (collagen)(collagen)

All are possible therapeutic targets!All are possible therapeutic targets!


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ANGI OGENI C SW ITCHNGI OGENI C SW ITCHAngiogenesis is delayed; a minority ofAngiogenesis is delayed; a minority of

the cells become angiogenicthe cells become angiogenic p53p53 inhibits angiogenesis by inducinginhibits angiogenesis by inducing

production ofproduction ofthrombospondin-1thrombospondin-1 andanddown-regulatingdown-regulatingVEGFVEGFAngiogenesis inhibitors made by tumorAngiogenesis inhibitors made by tumor

cells:cells: thrombospondin-1thrombospondin-1; and; andangiostatinangiostatin (from plasminogen),(from plasminogen),endostatin/tumstatinendostatin/tumstatin (collagen)(collagen)

All are possible therapeutic targets!All are possible therapeutic targets!


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In va sion a nd M etastasisn va sion a nd M etastasis Robbins Figure 7-42Robbins Figure 7-42

CellsCells ??????, enter and exit, enter and exit ?????? andand

establish aestablish a ?????? ????? cellscells are successful at metastasis;are successful at metastasis;

Robbins Figure 7-43Robbins Figure 7-43


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In va sion a nd M etastasisn va sion a nd M etastasis Robbins Figure 7-42Robbins Figure 7-42

CellsCells break loosebreak loose, enter and exit, enter and exit

vesselsvessels and establish aand establish a secondarysecondarygrowth sitegrowth site

Rarear e malignant cellsmalignant cells are successful atare successful atmetastasis; Robbins Figure 7-43metastasis; Robbins Figure 7-43


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Steps i n Metas tasi steps i n M etas tasi s ?????? of cells from theof cells from the primary tumorprimary tumor

?????? of theof the surrounding tissuesurrounding tissue

??????

toto

bloodblood

andand

lymphatic vesselslymphatic vessels

?????? at target sitesat target sites

?????? (extravasation)(extravasation)

?????? Establishment of a newEstablishment of a new ??????


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Steps i n Metas tasi steps i n M etas tasi s DetachmentDetachment of cells from theof cells from the primaryprimarytumortumor

InvasionInvasion of theof the surrounding tissuesurrounding tissue

PenetrationPenetration toto bloodblood andand lymphatic vesselslymphatic vessels

ArrestArrest at target sitesat target sites

EgressionEgression (extravasation)(extravasation) ProliferationProliferation

Establishment of a newEstablishment of a new blood supplyblood supply


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MetastaticCascade


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Figs. 1 to 3Figs. 1 to 3 A pair of living squamous epithelial A pair of living squamous epithelial

cells from a normal lip being separated from each othercells from a normal lip being separated from each other

by microneedles. Inby microneedles. In Fig. 1Fig. 1 a needle has been placed ina needle has been placed in

each cell. Ineach cell. In Fig. 2Fig. 2 the needles have been moved apart,the needles have been moved apart,

stretching the cells, which are thereby distorted.stretching the cells, which are thereby distorted.Tension lines appear in the cytoplasm as the cells clingTension lines appear in the cytoplasm as the cells cling

to each other tenaciously. Into each other tenaciously. In Fig. 3Fig. 3 the cells have finallythe cells have finally

separated and have retracted into approximately theirseparated and have retracted into approximately their

former shape. The needles are widely separated.former shape. The needles are widely separated.

Figs. 4 to 6Figs. 4 to 6 A pair of living squamous epithelial A pair of living squamous epithelial

cells from a carcinoma of the lip being separated fromcells from a carcinoma of the lip being separated from

each other by microneedles. Ineach other by microneedles. In Fig. 4Fig. 4 a needle tip hasa needle tip has

been placed in each cell. Inbeen placed in each cell. In Fig. 5Fig. 5 the needles havethe needles have

been moved only slightly apart and the cells begin tobeen moved only slightly apart and the cells begin to

separate. Note the lack of distortion in these cells asseparate. Note the lack of distortion in these cells ascompared to Fig. 2. Incompared to Fig. 2. In Fig. 6Fig. 6 the cells have beenthe cells have been

completely separated by only a slight additionalcompletely separated by only a slight additional

movement of the needles. Notice that the needles inmovement of the needles. Notice that the needles in

this whole series of manipulations have remainedthis whole series of manipulations have remained

relatively close together as compared with therelatively close together as compared with the

movements of the needles required to separate themovements of the needles required to separate the

normal cells in Figs. 1 to 3. It is apparent that thesenormal cells in Figs. 1 to 3. It is apparent that thesecarcinomatous cells were far less mutually adherentcarcinomatous cells were far less mutually adherent


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Invasion of thenvasion of theExtr ace l lular M atri x (E CM)xtr ace l lular M atri x (E CM) Basement membraneBasement membrane

Interstitial connective tissueInterstitial connective tissue

Vessel basement membraneVessel basement membraneVessel basement membraneVessel basement membrane

Interstitial connective tissueInterstitial connective tissue


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St eps in t he I nvas iont eps in t he I nvas ion Detachment ofDetachment of

cellscells ?????? Attachment to the ECMAttachment to the ECM

?????? Degredation of theDegredation of the

ECM type IV collagenECM type IV collagenby serine, cysteine andby serine, cysteine andmatrixmatrix ??????

Migration of tumorMigration of tumorcells (chemotaxis duecells (chemotaxis due

toto ??????


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St eps in t he I nvas iont eps in t he I nvas ion Detachment of cellsDetachment of cells (E-(E-

cadherin/catenins)cadherin/catenins) Attachment to the ECMAttachment to the ECM

(integrins attach to(integrins attach tolaminin/fibronectin)laminin/fibronectin)

Degredation of theDegredation of theECM type IV collagenECM type IV collagenby serine, cysteine andby serine, cysteine andmatrixmatrixMETALLOPROTEINASEMETALLOPROTEINASE

S (MMPs)S (MMPs) Migration of tumorMigration of tumor

cells (chemotaxis duecells (chemotaxis duetoto MMP cleavageMMP cleavageproducts- growthproducts- growth

factors released alsofactors released also


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Tu mor Cells inu mor Cells inCircu la ti onircu la ti on They clump with eachThey clump with each other, RBCs andother, RBCs and

plateletsplatelets

Adhesion to endothelium (Adhesion to endothelium (integrins-integrins-laminin-proteinaseslaminin-proteinases))


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Tu mor Tr op is mu mor Tr op is m

DifferentDifferent ?????? in different organsin different organs DifferentDifferent ?????? on the tumor cells- eg.on the tumor cells- eg.

breast cancers expressbreast cancers express ??? and ?????? and ???

receptors and matchingreceptors and matchingchemokineschemokinesare at high levels inare at high levels in lung and lymphlung and lymphnodesnodes

unfertile soil likeunfertile soil like ?????? withoutwithoutreceptorsreceptors


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Tu mor Tr op is mu mor Tr op is m

DifferentDifferent endothelial receptorsendothelial receptors inindifferent organsdifferent organs

DifferentDifferent chemokine receptorschemokine receptors on theon the

tumor cells- eg. breast cancerstumor cells- eg. breast cancersexpressexpress CXCR4 and CCR7CXCR4 and CCR7 receptorsreceptors

and matchingand matchingchemokineschemokines are atare at

high levels in lung and lymph nodeshigh levels in lung and lymph nodes

unfertile soil likeunfertile soil like skeletal muscleskeletal musclewithout receptorswithout receptors


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Met asta ses an d Trop ismet asta ses an d Trop ismPri mar y S it e and His tol ogyri mar y S it e and His tol ogy Or ga nOr ga nClear cell carcinoma (kidney)Clear cell carcinoma (kidney) ??????

Cutaneous melanomaCutaneous melanoma ??????

Ocular melanomaOcular melanoma ??????

AdenocarcinomasAdenocarcinomas ??????of the GI tractof the GI tract

Follicular carcinoma, thyroidFollicular carcinoma, thyroid ??????


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Met asta ses an d Trop ismet asta ses an d Trop ismPri mar y S it e and His tol ogyri mar y S it e and His tol ogy Or ga nOr ga nClear cell carcinoma (kidney)Clear cell carcinoma (kidney) ThyroidThyroid

Cutaneous melanomaCutaneous melanoma Small bowel/brainSmall bowel/brain

Ocular melanomaOcular melanoma LiverLiver

AdenocarcinomasAdenocarcinomas Ovary (KruckenbergOvary (Kruckenbergof the GI tract tumor)of the GI tract tumor)

Follicular carcinoma, thyroidFollicular carcinoma, thyroid BoneBone


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Meta stasis Gen eseta stasis Gen es EzrinEzrin: a: a membranemembrane componentcomponent

required for metastasis inrequired for metastasis in

osteosarcomaosteosarcoma andand rhabdomyosarcomarhabdomyosarcomaAnti-metastasis genes:Anti-metastasis genes: NM23NM23


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Meta stasis O ncog en eseta stasis O ncog en es ??? and ?????? and ??? (breast cancer)(breast cancer)

?????? transitiontransition

?????? is down-regulated andis down-regulated and ?????? is up-is up-regulatedregulated


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Meta stasis O ncog en eseta stasis O ncog en es SNAIL and TWISTSNAIL and TWIST (breast cancer)(breast cancer)

Epithelial-to-mesenchymalEpithelial-to-mesenchymal transitiontransition

E-cadherinE-cadherin is down-regulated andis down-regulated andvimentinvimentin is up-regulatedis up-regulated


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Ta rget ed Th er apya rget ed Th er apy Signal-transduction InhibitorsSignal-transduction Inhibitors

Block enzymes and Growth FactorBlock enzymes and Growth FactorReceptorsReceptors

??-?- GIST and CMLGIST and CML (abnormal tumor(abnormal tumorenzymes);enzymes); ???-??- non-small-cell lung cancernon-small-cell lung cancer(EGFR)(EGFR)


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Ta rget ed Th er apya rget ed Th er apy Signal-transduction InhibitorsSignal-transduction Inhibitors

Block enzymes and Growth FactorBlock enzymes and Growth FactorReceptorsReceptors

GLEEVEC (imatinib)LEEVEC (imatinib) -- GIST and CMLGIST and CML(abnormal tumor enzymes);(abnormal tumor enzymes); IRESSA (ge fetini b)RESSA (ge fetini b) - non-small-cell- non-small-celllung cancer (EGFR)lung cancer (EGFR)


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Ta rget ( 2)a rget ( 2)Apoptosis InducersApoptosis Inducers

????? -- multiple myelomamultiple myeloma (blocks(blocksproteasomes)proteasomes)

????? -- leukemias and lymphomasleukemias and lymphomas(blocks BCL-2)(blocks BCL-2)


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Ta rget ( 2)a rget ( 2)Apoptosis InducersApoptosis Inducers

VELCADEELCADE -- multiple myelomamultiple myeloma (blocks(blocksproteasomes)proteasomes)

GENASE NSEENASE NSE -- leukemias andleukemias andlymphomas (blocks BCL-2)lymphomas (blocks BCL-2)


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Ta rget ( 3)a rget ( 3) Monoclonal AntibodiesMonoclonal Antibodies

????? - invasiveinvasive breast carcinomasbreast carcinomas (that(thatshow overexpression ofshow overexpression ofHER-2-neuHER-2-neu))


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Ta rget ( 3)a rget ( 3) Monoclonal AntibodiesMonoclonal Antibodies

Hercept inercept in - invasiveinvasive breastbreastcarcinomascarcinomas (that show overexpression(that show overexpression

ofofHER-2-neuHER-2-neu))


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Ta rget ( 4)a rget ( 4)Anti-angiogenesisAnti-angiogenesis

Angiostatin (from plasminogen)Angiostatin (from plasminogen) Endostatin (from collagen)Endostatin (from collagen)


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Tumor I Nvasion a Nd Meta Stasis