Tumor I Nvasion A Nd Meta Stasis
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Tumor I nvasion a nd Meta stasis T. Davis 9-25-2009
Neop la sms
????
???
Non-invasive Non-metastatic
Invasive Metastatic or nonmetastatic
Neop la sms
Benig n
Ma lig na nt
Non-invasive Non-metastatic
Invasive Metastatic or nonmetastatic
Ex cep tion s t o th e R ule
Benig n t umors tha t ma y ki ll th e pa tient
Ma lig na nt tumors w it hout meta st asi s
??? ???
??? ???
Ex cep tion s t o th e R ule
Benig n t umors tha t ma y ki ll th e pa tient
Ma lig na nt tumors w it hout meta st asi s
Meningioma Leiomyoma
Glioblastoma multiforme Basal cell carcinoma
Malig nan t Tu mo r Prop er ties
Penetration of the ??? Invasion and destruction of ??? Penetrate ??? or fungate through the ??? Local ???, like ??? is a marker for malignancy See Robbins Table 7-2 for benign vs malignant features
Malig nan t Tu mo r Prop er ties
Penetration of the basement membrane Invasion and destruction of surrounding tissue Penetrate organ walls or fungate through the surface Local invasion, like metastasis is a marker for malignancy See Robbins Table 7-2 for benign vs malignant features
Invasive breast carcinoma
Invasive breast carcinoma
Local invasion by ductal carcinoma
Local invasion by ductal carcinoma
Colon carcinoma invades into surrounding adipose tissue
Colon carcinoma invades into surrounding adipose tissue
???
#1 marker of malignancy Exceptions: ??? of the brain and ??? of the skin RARELY metastasize; also, ??? LOCALLY invade skull bone, but do not metastasize and are considered benign. ** On board exams they sometimes substitute ??? for metastasis
Meta stasis
#1 marker of malignancy Exceptions: gliomas (astrocytomas) of the brain and basal cell carcinomas of the skin RARELY metastasize; also, meningiomas LOCALLY invade skull bone, but do not metastasize and are considered benign. ** On board exams they sometimes substitute inva si ve ness for metastasis
Glioblastoma Multiforme (Astrocytoma III/IV
Glioblastoma Multiforme (Astrocytoma III/IV
Metastatic melanoma
Metastatic melanoma
Ca ncer St at is tics
90 % of cancer deaths are due to ??? 1/3 of ??? and ??? patients have lymph node metastases at diagnosis Frequency overall: ???, ???, ??? #1 endocrine site: ???
Ca ncer St at is tics
90 % of cancer deaths are due to metastases 1/3 of breast and colon cancer patients have lymph node metastases at diagnosis Frequency overall: liver, lung, bone #1 endocrine site: adrenal glands
Stage of tumors at diagnosis listed by organ/site
Pathwa ys of S pread
Direc t s eedin g of body cavities: ??? #1; also pleural, pericardial, subarachnoid, joint Lym phat ic s pr ead : ???> ???; follows natural drainage- breast cancer (Upper-Outer Quadrant) goes 1st to ??? Hemato ge no us spr ead : esp. ???; also ???; usually ??? Ot he r : eg. Perineural spread
Pathwa ys of S pread
Direc t s eedin g of body cavities: peritoneal #1; also pleural, pericardial, subarachnoid, joint Lym phat ic s pr ead : carcinoma> sarcoma; follows natural drainagebreast cancer (Upper-Outer Quadrant) goes 1st to axillary nodes Hemato ge no us spr ead : esp. sarcoma; also carcinoma; usually veins Ot he r : eg. Perineural spread
Breast carcinoma with perineural invasion
Ven ou s D ra in age
Portal: ??? Caval: ??? Paravertebral plexus: ??? and ??? metastasize to the vertebrae Renal Cell CA: invades ??? and grows into the ???
Ven ou s D ra in age
Portal: liver Caval: lungs Paravertebral plexus: thyroid and prostate carcinomas metastasize to the vertebrae Renal Cell CA: invades renal vein and grows into the vena cava
Liver with metastases
????
“The first node in a regional lymphatic basin that receives lymph flow from the primary tumor” Dyes and radiolabeled tracers mark the node Breast, colon and melanomas In breast carcinomas it replaces a total dissection of the axillary lymph nodes and reduces morbidity
Sen tin el L N Bi ops y
“The first node in a regional lymphatic basin that receives lymph flow from the primary tumor” Dyes and radiolabeled tracers mark the node Breast, colon and melanomas In breast carcinomas it replaces a total dissection of the axillary lymph nodes and reduces morbidity
ANGI OGENE SIS
Tumors stimulate the growth of ??? Any tumor >??? mm in diameter must have a vascular supply New ??? supply oxygen and nutrients and ??? secrete growth factors
ANGI OGENE SIS
Tumors stimulate the growth of host blood vessels Any tumor >2 mm in diameter must have a vascular supply New vessels supply oxygen and nutrients and endothelial cells secrete growth factors
Tu mor Blood
Ves sels
??? new capillaries or ??? host endothelial cells Tumor vessels are ??? and ??? due to high levels of ??? Tumor cells can also “mimic” endothelial cells (???)
Tu mor Blood
Ves sels
Sprout new capillaries or “recruit” host endothelial cells Tumor vessels are irregular and leaky due to high levels of VEGF Tumor cells can also “mimic” endothelial cells (vasculogenic mimicry)
Tu mor- associa ted An giog en ic F act ors
??? and ??? are made mostly by tumor cells but also by macrophages and stromal cells
Tu mor- associa ted An giog en ic F act ors
VEGF (vascular endothelial growth factor) and bFGF (basic fibroblast growth factor) are made mostly by tumor cells but also by macrophages and stromal cells
ANGI OGENI C SW ITCH
Angiogenesis is delayed; a minority of the cells become angiogenic ??? inhibits angiogenesis by inducing production of ??? and down-regulating ??? Angiogenesis inhibitors made by tumor cells: ???; and ??? (from plasminogen), ??? (collagen) All are possible therapeutic targets!
ANGI OGENI C SW ITCH
Angiogenesis is delayed; a minority of the cells become angiogenic p53 inhibits angiogenesis by inducing production of thrombospondin-1 and down-regulating VEGF Angiogenesis inhibitors made by tumor cells: thrombospondin-1; and angiostatin (from plasminogen), endostatin/tumstatin (collagen) All are possible therapeutic targets!
In va sion a nd M etastasis
Robbins Figure 7-42 Cells ???, enter and exit ??? and establish a ??? ??? cells are successful at metastasis; Robbins Figure 7-43
In va sion a nd M etastasis
Robbins Figure 7-42 Cells break loose, enter and exit vessels and establish a secondary growth site Rar e malignant cells are successful at metastasis; Robbins Figure 7-43
Steps i n M etas tasi s • ??? of cells from the primary tumor • ??? of the surrounding tissue • ??? to blood and lymphatic vessels • ??? at target sites • ??? (extravasation) • ??? • Establishment of a new ???
Steps i n M etas tasi s • Detachment of cells from the primary tumor • Invasion of the surrounding tissue • Penetration to blood and lymphatic vessels • Arrest at target sites • Egression (extravasation) • Proliferation • Establishment of a new blood supply
Metastatic Cascade
Figs. 1 to 3 – A pair of living squamous epithelial cells from a normal lip being separated from each other by microneedles. In Fig. 1 a needle has been placed in each cell. In Fig. 2 the needles have been moved apart, stretching the cells, which are thereby distorted. Tension lines appear in the cytoplasm as the cells cling to each other tenaciously. In Fig. 3 the cells have finally separated and have retracted into approximately their former shape. The needles are widely separated.
Figs. 4 to 6 – A pair of living squamous epithelial cells from a carcinoma of the lip being separated from each other by microneedles. In Fig. 4 a needle tip has been placed in each cell. In Fig. 5 the needles have been moved only slightly apart and the cells begin to separate. Note the lack of distortion in these cells as compared to Fig. 2. In Fig. 6 the cells have been completely separated by only a slight additional movement of the needles. Notice that the needles in this whole series of manipulations have remained relatively close together as compared with the movements of the needles required to separate the normal cells in Figs. 1 to 3. It is apparent that these carcinomatous cells were far less mutually adherent
In vasi on of the Extr ace llular M atri x (E CM)
Basement membrane Interstitial connective tissue Vessel basement membrane Vessel basement membrane Interstitial connective tissue
St eps in t he I nvas ion
Detachment of cells ??? Attachment to the ECM ??? Degredation of the ECM type IV collagen by serine, cysteine and matrix ??? Migration of tumor cells (chemotaxis due to ???
St eps in t he I nvas ion
Detachment of cells (Ecadherin/catenins) Attachment to the ECM (integrins attach to laminin/fibronectin) Degredation of the ECM type IV collagen by serine, cysteine and matrix METALLOPROTEINASE S (MMPs) Migration of tumor cells (chemotaxis due to MMP cleavage products- growth factors released also
Tu mor Cells Circu la ti on
in
They clump with each other, RBCs and platelets Adhesion to endothelium (integrinslaminin-proteinases)
Tu mor Cells Circu la ti on
in
They clump with each ???, ??? and ??? Adhesion to endothelium (???)
Tu mor Tr op is m
Different ??? in different organs Different ??? on the tumor cells- eg. breast cancers express ??? and ??? receptors and “matching” chemokines are at high levels in lung and lymph nodes “unfertile soil” like ??? without receptors
Tu mor Tr op is m
Different endothelial receptors in different organs Different chemokine receptors on the tumor cells- eg. breast cancers express CXCR4 and CCR7 receptors and “matching” chemokines are at high levels in lung and lymph nodes “unfertile soil” like skeletal muscle without receptors
Met asta ses an d Trop ism Pri mar y S it e and His tol ogy
Or ga n
Clear cell carcinoma (kidney)
???
Cutaneous melanoma
???
Ocular melanoma
???
Adenocarcinomas of the GI tract
???
Follicular carcinoma, thyroid
???
Met asta ses an d Trop ism Pri mar y S it e and His tol ogy
Or ga n
Clear cell carcinoma (kidney)
Thyroid
Cutaneous melanoma
Small bowel/brain
Ocular melanoma
Liver
Adenocarcinomas of the GI tract
Ovary (Kruckenberg tumor)
Follicular carcinoma, thyroid
Bone
Meta stasis Gen es
???: a membrane component required for metastasis in ??? and ??? Anti-metastasis genes: ???
Meta stasis Gen es
Ezrin: a membrane component required for metastasis in osteosarcoma and rhabdomyosarcoma Anti-metastasis genes: NM23
Meta stasis O ncog en es
??? and ??? (breast cancer) ??? transition ??? is down-regulated and ??? is upregulated
Meta stasis O ncog en es
SNAIL and TWIST (breast cancer) Epithelial-to-mesenchymal transition E-cadherin is down-regulated and vimentin is up-regulated
Ta rget ed Th er apy
Signal-transduction Inhibitors
Block enzymes and Growth Factor Receptors ??- GIST and CML (abnormal tumor enzymes); ???- non-small-cell lung cancer (EGFR)
Ta rget ed Th er apy
Signal-transduction Inhibitors
Block enzymes and Growth Factor Receptors GLE EV EC (im at inib) - GIST and CML (abnormal tumor enzymes); IRESSA (ge fetini b) - non-small-cell lung cancer (EGFR)
Ta rget ( 2)
Apoptosis Inducers
??? - multiple myeloma (blocks proteasomes) ??? - leukemias and lymphomas (blocks BCL-2)
Ta rget ( 2)
Apoptosis Inducers
VELCADE - multiple myeloma (blocks proteasomes) GENASE NSE - leukemias and lymphomas (blocks BCL-2)
Ta rget ( 3)
Monoclonal Antibodies
??? - invasive breast carcinomas (that show overexpression of HER-2-neu)
Ta rget ( 3)
Monoclonal Antibodies
Hercept in - invasive breast carcinomas (that show overexpression of HER-2-neu)
Ta rget ( 4)
Anti-angiogenesis
Angiostatin (from plasminogen) Endostatin (from collagen)
Ta rget ( 4)
Anti-angiogenesis
??? (from plasminogen) ??? (from collagen)
Neop la sms
????
???
Non-invasive Non-metastatic
Invasive Metastatic or nonmetastatic
Neop la sms
Benig n
Ma lig na nt
Non-invasive Non-metastatic
Invasive Metastatic or nonmetastatic
Ex cep tion s t o th e R ule
Benig n t umors tha t ma y ki ll th e pa tient
Ma lig na nt tumors w it hout meta st asi s
??? ???
??? ???
Ex cep tion s t o th e R ule
Benig n t umors tha t ma y ki ll th e pa tient
Ma lig na nt tumors w it hout meta st asi s
Meningioma Leiomyoma
Glioblastoma multiforme Basal cell carcinoma
Malig nan t Tu mo r Prop er ties
Penetration of the ??? Invasion and destruction of ??? Penetrate ??? or fungate through the ??? Local ???, like ??? is a marker for malignancy See Robbins Table 7-2 for benign vs malignant features
Malig nan t Tu mo r Prop er ties
Penetration of the basement membrane Invasion and destruction of surrounding tissue Penetrate organ walls or fungate through the surface Local invasion, like metastasis is a marker for malignancy See Robbins Table 7-2 for benign vs malignant features
Invasive breast carcinoma
Invasive breast carcinoma
Local invasion by ductal carcinoma
Local invasion by ductal carcinoma
Colon carcinoma invades into surrounding adipose tissue
Colon carcinoma invades into surrounding adipose tissue
???
#1 marker of malignancy Exceptions: ??? of the brain and ??? of the skin RARELY metastasize; also, ??? LOCALLY invade skull bone, but do not metastasize and are considered benign. ** On board exams they sometimes substitute ??? for metastasis
Meta stasis
#1 marker of malignancy Exceptions: gliomas (astrocytomas) of the brain and basal cell carcinomas of the skin RARELY metastasize; also, meningiomas LOCALLY invade skull bone, but do not metastasize and are considered benign. ** On board exams they sometimes substitute inva si ve ness for metastasis
Glioblastoma Multiforme (Astrocytoma III/IV
Glioblastoma Multiforme (Astrocytoma III/IV
Metastatic melanoma
Metastatic melanoma
Ca ncer St at is tics
90 % of cancer deaths are due to ??? 1/3 of ??? and ??? patients have lymph node metastases at diagnosis Frequency overall: ???, ???, ??? #1 endocrine site: ???
Ca ncer St at is tics
90 % of cancer deaths are due to metastases 1/3 of breast and colon cancer patients have lymph node metastases at diagnosis Frequency overall: liver, lung, bone #1 endocrine site: adrenal glands
Stage of tumors at diagnosis listed by organ/site
Pathwa ys of S pread
Direc t s eedin g of body cavities: ??? #1; also pleural, pericardial, subarachnoid, joint Lym phat ic s pr ead : ???> ???; follows natural drainage- breast cancer (Upper-Outer Quadrant) goes 1st to ??? Hemato ge no us spr ead : esp. ???; also ???; usually ??? Ot he r : eg. Perineural spread
Pathwa ys of S pread
Direc t s eedin g of body cavities: peritoneal #1; also pleural, pericardial, subarachnoid, joint Lym phat ic s pr ead : carcinoma> sarcoma; follows natural drainagebreast cancer (Upper-Outer Quadrant) goes 1st to axillary nodes Hemato ge no us spr ead : esp. sarcoma; also carcinoma; usually veins Ot he r : eg. Perineural spread
Breast carcinoma with perineural invasion
Ven ou s D ra in age
Portal: ??? Caval: ??? Paravertebral plexus: ??? and ??? metastasize to the vertebrae Renal Cell CA: invades ??? and grows into the ???
Ven ou s D ra in age
Portal: liver Caval: lungs Paravertebral plexus: thyroid and prostate carcinomas metastasize to the vertebrae Renal Cell CA: invades renal vein and grows into the vena cava
Liver with metastases
????
“The first node in a regional lymphatic basin that receives lymph flow from the primary tumor” Dyes and radiolabeled tracers mark the node Breast, colon and melanomas In breast carcinomas it replaces a total dissection of the axillary lymph nodes and reduces morbidity
Sen tin el L N Bi ops y
“The first node in a regional lymphatic basin that receives lymph flow from the primary tumor” Dyes and radiolabeled tracers mark the node Breast, colon and melanomas In breast carcinomas it replaces a total dissection of the axillary lymph nodes and reduces morbidity
ANGI OGENE SIS
Tumors stimulate the growth of ??? Any tumor >??? mm in diameter must have a vascular supply New ??? supply oxygen and nutrients and ??? secrete growth factors
ANGI OGENE SIS
Tumors stimulate the growth of host blood vessels Any tumor >2 mm in diameter must have a vascular supply New vessels supply oxygen and nutrients and endothelial cells secrete growth factors
Tu mor Blood
Ves sels
??? new capillaries or ??? host endothelial cells Tumor vessels are ??? and ??? due to high levels of ??? Tumor cells can also “mimic” endothelial cells (???)
Tu mor Blood
Ves sels
Sprout new capillaries or “recruit” host endothelial cells Tumor vessels are irregular and leaky due to high levels of VEGF Tumor cells can also “mimic” endothelial cells (vasculogenic mimicry)
Tu mor- associa ted An giog en ic F act ors
??? and ??? are made mostly by tumor cells but also by macrophages and stromal cells
Tu mor- associa ted An giog en ic F act ors
VEGF (vascular endothelial growth factor) and bFGF (basic fibroblast growth factor) are made mostly by tumor cells but also by macrophages and stromal cells
ANGI OGENI C SW ITCH
Angiogenesis is delayed; a minority of the cells become angiogenic ??? inhibits angiogenesis by inducing production of ??? and down-regulating ??? Angiogenesis inhibitors made by tumor cells: ???; and ??? (from plasminogen), ??? (collagen) All are possible therapeutic targets!
ANGI OGENI C SW ITCH
Angiogenesis is delayed; a minority of the cells become angiogenic p53 inhibits angiogenesis by inducing production of thrombospondin-1 and down-regulating VEGF Angiogenesis inhibitors made by tumor cells: thrombospondin-1; and angiostatin (from plasminogen), endostatin/tumstatin (collagen) All are possible therapeutic targets!
In va sion a nd M etastasis
Robbins Figure 7-42 Cells ???, enter and exit ??? and establish a ??? ??? cells are successful at metastasis; Robbins Figure 7-43
In va sion a nd M etastasis
Robbins Figure 7-42 Cells break loose, enter and exit vessels and establish a secondary growth site Rar e malignant cells are successful at metastasis; Robbins Figure 7-43
Steps i n M etas tasi s • ??? of cells from the primary tumor • ??? of the surrounding tissue • ??? to blood and lymphatic vessels • ??? at target sites • ??? (extravasation) • ??? • Establishment of a new ???
Steps i n M etas tasi s • Detachment of cells from the primary tumor • Invasion of the surrounding tissue • Penetration to blood and lymphatic vessels • Arrest at target sites • Egression (extravasation) • Proliferation • Establishment of a new blood supply
Metastatic Cascade
Figs. 1 to 3 – A pair of living squamous epithelial cells from a normal lip being separated from each other by microneedles. In Fig. 1 a needle has been placed in each cell. In Fig. 2 the needles have been moved apart, stretching the cells, which are thereby distorted. Tension lines appear in the cytoplasm as the cells cling to each other tenaciously. In Fig. 3 the cells have finally separated and have retracted into approximately their former shape. The needles are widely separated.
Figs. 4 to 6 – A pair of living squamous epithelial cells from a carcinoma of the lip being separated from each other by microneedles. In Fig. 4 a needle tip has been placed in each cell. In Fig. 5 the needles have been moved only slightly apart and the cells begin to separate. Note the lack of distortion in these cells as compared to Fig. 2. In Fig. 6 the cells have been completely separated by only a slight additional movement of the needles. Notice that the needles in this whole series of manipulations have remained relatively close together as compared with the movements of the needles required to separate the normal cells in Figs. 1 to 3. It is apparent that these carcinomatous cells were far less mutually adherent
In vasi on of the Extr ace llular M atri x (E CM)
Basement membrane Interstitial connective tissue Vessel basement membrane Vessel basement membrane Interstitial connective tissue
St eps in t he I nvas ion
Detachment of cells ??? Attachment to the ECM ??? Degredation of the ECM type IV collagen by serine, cysteine and matrix ??? Migration of tumor cells (chemotaxis due to ???
St eps in t he I nvas ion
Detachment of cells (Ecadherin/catenins) Attachment to the ECM (integrins attach to laminin/fibronectin) Degredation of the ECM type IV collagen by serine, cysteine and matrix METALLOPROTEINASE S (MMPs) Migration of tumor cells (chemotaxis due to MMP cleavage products- growth factors released also
Tu mor Cells Circu la ti on
in
They clump with each other, RBCs and platelets Adhesion to endothelium (integrinslaminin-proteinases)
Tu mor Cells Circu la ti on
in
They clump with each ???, ??? and ??? Adhesion to endothelium (???)
Tu mor Tr op is m
Different ??? in different organs Different ??? on the tumor cells- eg. breast cancers express ??? and ??? receptors and “matching” chemokines are at high levels in lung and lymph nodes “unfertile soil” like ??? without receptors
Tu mor Tr op is m
Different endothelial receptors in different organs Different chemokine receptors on the tumor cells- eg. breast cancers express CXCR4 and CCR7 receptors and “matching” chemokines are at high levels in lung and lymph nodes “unfertile soil” like skeletal muscle without receptors
Met asta ses an d Trop ism Pri mar y S it e and His tol ogy
Or ga n
Clear cell carcinoma (kidney)
???
Cutaneous melanoma
???
Ocular melanoma
???
Adenocarcinomas of the GI tract
???
Follicular carcinoma, thyroid
???
Met asta ses an d Trop ism Pri mar y S it e and His tol ogy
Or ga n
Clear cell carcinoma (kidney)
Thyroid
Cutaneous melanoma
Small bowel/brain
Ocular melanoma
Liver
Adenocarcinomas of the GI tract
Ovary (Kruckenberg tumor)
Follicular carcinoma, thyroid
Bone
Meta stasis Gen es
???: a membrane component required for metastasis in ??? and ??? Anti-metastasis genes: ???
Meta stasis Gen es
Ezrin: a membrane component required for metastasis in osteosarcoma and rhabdomyosarcoma Anti-metastasis genes: NM23
Meta stasis O ncog en es
??? and ??? (breast cancer) ??? transition ??? is down-regulated and ??? is upregulated
Meta stasis O ncog en es
SNAIL and TWIST (breast cancer) Epithelial-to-mesenchymal transition E-cadherin is down-regulated and vimentin is up-regulated
Ta rget ed Th er apy
Signal-transduction Inhibitors
Block enzymes and Growth Factor Receptors ??- GIST and CML (abnormal tumor enzymes); ???- non-small-cell lung cancer (EGFR)
Ta rget ed Th er apy
Signal-transduction Inhibitors
Block enzymes and Growth Factor Receptors GLE EV EC (im at inib) - GIST and CML (abnormal tumor enzymes); IRESSA (ge fetini b) - non-small-cell lung cancer (EGFR)
Ta rget ( 2)
Apoptosis Inducers
??? - multiple myeloma (blocks proteasomes) ??? - leukemias and lymphomas (blocks BCL-2)
Ta rget ( 2)
Apoptosis Inducers
VELCADE - multiple myeloma (blocks proteasomes) GENASE NSE - leukemias and lymphomas (blocks BCL-2)
Ta rget ( 3)
Monoclonal Antibodies
??? - invasive breast carcinomas (that show overexpression of HER-2-neu)
Ta rget ( 3)
Monoclonal Antibodies
Hercept in - invasive breast carcinomas (that show overexpression of HER-2-neu)
Ta rget ( 4)
Anti-angiogenesis
Angiostatin (from plasminogen) Endostatin (from collagen)
Ta rget ( 4)
Anti-angiogenesis
??? (from plasminogen) ??? (from collagen)
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