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Invasion and Metastasis:The Malignant Phenotype
Updated: March 26, 2014
Folder Title: Inv&Mets
Chapter 14: The Biology of CancerMoving Out: Invasion and Metastasis
p. 641 Second Edition
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See Metastasis: Cancer Menacing Ballet
by Jennifer Couzin
(Insert by Robert Weinberg)
Metastasis: Cancer's Menacing Ballet, (MetsScienceFeb1403.pdf) Science, Feb. 14, 2003, Vol 299, p 1003
Linked on “Password” Protected SiteCourse Web-page
(No Password Needed)
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Figure 14.1 The Biology of Cancer (© Garland Science 2007). P. 588
Metastatic non-Hodgkins Lymphoma
CT Scan and PET Scan (positron emission tomography) of incorporated radioactively-labelled deoxyfluoroglucose.
(Brain activity is normal, abdominal active is pathological)
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Imaging on Metastatic Colon Carcinoma with Radioactive-Iodine-Labelled Monoclonal Ab to A33 Ag
Lloyd Old, Scientific American, August, 1996, p. 138)
SeeMets
Arm
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Colon Carcinoma Metastatic to Liver
Breast Carcinoma Metastatic to Brain
Fig. 2.2b and c
Weinberg
p. 27
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Multiple Metastatic Lesion to Liver
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Gastric Carcinoma Metastatic to Brain
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Primary Glioblastoma Compared to Breast Carcinoma Metastasis to the Brain
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Figure 13.32a The Biology of Cancer (© Garland Science 2007) p. 561
Human colorectal adenocarcinoa implanted sub-cutaneously as a xenograft in immunocompromised mice.
Viewed through a skin wndow.
Growth-associated Neovascularization of
a tumor xenograft
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Figure 14.4 The Biology of Cancer (© Garland Science 2007) p. 591
Invasion-Metastasis Cascade Adapted from Fidler, Nat. Rev. Cancer 3: 453-458, 2003
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Figure 14.2b The Biology of Cancer (© Garland Science 2007). P 589
Breast Carcinoma Metastatic to Draining Lymph Node
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Figure 14.2c The Biology of Cancer (© Garland Science 2007). P. 589
Carcinoma Metastatic to Bone. Stained for Epithelial Cell Markers
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Turning Point Questions Coming Up
Please get stuff off of the desks.
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In the previous slide breast carcinoma metastatic to the bone was detected by using stains for epithelial cell
markers. Why does that work?
1 2 3 4 5 6
17% 17% 17%17%17%17%
Rank Responses
1
2
3
4
5
6 Other
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Angiogenesis can promote intravasation.Why do you think that happens?
1 2 3 4 5 6
0% 0% 0%0%0%0%
Rank Responses
1
2
3
4
5
6 Other
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Invasion in Cancer
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Cancer Invasion
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Figure 14.5c The Biology of Cancer (© Garland Science 2007) p. 592
Invasive Squamous Cell Carcinoma of Uterine CervixStromal Cells on Uterus
Inflammatory Cells
Invasive Carcinoma
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Figure 14.5b The Biology of Cancer (© Garland Science 2007) p. 592
Active Invasion by Melanoma Emboli
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Detachment and Active Invasion by Renal
Detachment and Active Invasion by Renal Adenocarcinoma (Frog)
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Progression in Invasion and MetastasisAppearance of Primary Tumor (Neoplasia in situ)Vascularization (Angiogenesis)Invasion• Into surrounding tissue• Into vascular and lymphatic systemsRelease of Tumor Emboli (Shedding)Systemic Transport• Hematogenous• LymphaticArrest at Distant SiteSecondary Invasion: ExtravasationSecondary AngiogenesisSecondary InvasionTertiary Spread
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Release of Tumor Emboli and Tumor Cell Shedding
Invasion through thin anaplastic venous walls in tumor Facilitated by:• Local trauma• Diagnostic procedures• Surgery• ManipulationEmboli (small clumps of cells)• Favored for survival by protection of inner cells• Surrounded by fibrin clot• May protect embolus while in circulation• May facilitate survival of tumor cells at secondary tumor
arrest site
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Routes of Systemic Spread of Tumor Emboli and Tumor Cells
Direct Extension Across Organ and Body Cavities• Peritoneal Cavity• Pleural Linings• Peri-cardial Space• Cerebrospinal CavityLymphatic Spread:• Lymphatic capillaries to regional lymph
nodesHematogenous Spread: Entry via• Lymphatic drainage into circulation• Abnormal blood vessels in tumors• Tumor cell deformability and motility
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Arrest and Extravasation
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Arrest of Tumor Emboli and Tumor Cells at Distant Sites
Predilection for Specific Organ Sites• Depends only partly on anatomical and circulatory
relationships• Specific Organ Homing Based on Cell Adhesion
Recognition
Cell-Cell and Cell-Connective Tissue Adherence• Plasma membrane ligands on metastatic tumor cells• Cell adhesion receptors on endothelial lining of capillaries
in target organs• Binding to laminin and fibronectin in extra-cellular
connective tissue matrix
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Figure 14.9 The Biology of Cancer (© Garland Science 2007) p. 595
Extravasation Facilitated by Clot Formation
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Epithelial to Mesenchymal Transition in Cancer Detachment and Invasion
Mesenchymal to Epithelial Transition in Establishing Disseminated Metastases
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Figure 14.16a The Biology of Cancer (© Garland Science 2007) p. 605
Association of Normal Melanocyte with Epithelial Keratinocytes
(Epithelial adherens junction protein)
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Figure 14.16b The Biology of Cancer (© Garland Science 2007) p. 605
Epithelial to Mesenchymal Transition in Melanoma Cells:
Facilitation of Detachment and Invasion
(Mesenchymal adherens junction protein)
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Epithelial-Mesenchymal Transition
Non-motile Epithelial CellsAssociated with Each Other via E-Cadherin Cell Surface Attachment ReceptorAnchored to Connective Tissue Basement Membrane by E-CadherinTight Association via E-CadherinExpress Intermediate Filament Protein Cytokeratin:
Characteristic of Epithelial Cells.
Invasive Carcinoma Cells: Morphology and Gene-expression Converted to Connective Tissue Type Cells
Express N-Cadherin: Loosely and Reversibly Associated with Each Other and with Connective TissueExpress Intermediate Filament Protein Vimentin:
Characteristic of Connective Tissue CellsFibroblast and Leucocyte-like Structure and FunctionAble to Migrate and to Cross Circulatory and Connective Tissue Barriers
Re-use Gene Expression and Functions from Embryonic and Wound-healing States
Revert back to Epithelial Characteristics after Seeding Distant Site:“Mesenchymal-Epithelial Transition”
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Table 14.2 The Biology of Cancer (© Garland Science 2007) p. 603
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Figure 14.17b The Biology of Cancer (© Garland Science 2007) p. 606
Reversibility of Epithelial-Mesenchymal Transition:
To Invasive Carcinoma and Back to Macrometastasis at Distant Site
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Figure 14.18 The Biology of Cancer (© Garland Science 2007) p. 607
Reversibility of Epithelial – Mesenchymal Transition:
Epithelial Characteristics of Distant Metastases of Primary
Carcinoma
(Aberrant epidermal growth factor receptor)
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Most Frequent Sites of Metastases for Some Human Cancer
Breast
ColonKidney
Lung
OvaryProstate
StomachTestisUrinary Bladder
Uterine Lining
Axillary lymph nodes, other breast, lung, pleura, liver, bone brain, spleen, adrenals, ovaryRegional lymph nodes, liver, lung, bladder, stomachLung, liver, bone
Regional lymph nodes, pleura, diaphagm, liver, bone, brain, kidney, adrenal, throid, spleenPeritoneum, regional lymph nodes, lung, liverBones of spine and pelvis, regional lymph nodes
Regional lymph nodes, liver, lung, boneRegional lymph nodes, lung. liverRectum, colon, prostate, ureter, vagina, bone, regional lymph nodes, lung, peritoneum, pleura, liver, brain
Regional lymph nodes, lung, liver, ovary
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Figure 14.42 The Biology of Cancer (© Garland Science 2007) p. 635
Primary Tumors and Preferred Sites of Metastatic Spread
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Figure 14.50a The Biology of Cancer (© Garland Science 2007) p. 645
Presence of Micrometastases and Clinical Prognosis: Breast Cancer
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Presence of Micrometastases and Clinical Prognosis: Colon Cancer
Figure 14.50b The Biology of Cancer (© Garland Science 2007) p. 645
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Figure 14.51a The Biology of Cancer (© Garland Science 2007)
p. 647
Over- or Under-expression of 128 Metastasis-Associated Genes in DNA-Array Assay for Potential
Metastatic Progression
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Figure 14.51b The Biology of Cancer (© Garland Science 2007) p. 647
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Turning Point Questions Coming Up
Please get stuff off of the desks.
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Primary localized carcinoma cells can become invasive and metastatic by invoking genes, gene products, and functions of mesenchymal
connective tissue type cells (the epithelial-mesenchymal-transition).Name any one feature, molecule, function, or property of
mesenchymal cells that could help to promote invasion and metastasis.
1 2 3 4 5 6
0% 0% 0%0%0%0%
Rank Responses
1
2
3
4
5
6 Other
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The blue line and the red line in the medulloblastoma cancer (panel III) run very close together after 90 months.
What does that tell you about the primary medulloblastoma with no metastasis signature?
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Figure 14.3 The Biology of Cancer (© Garland Science 2007)
Size of Primary Breast Cancer and Risk of Metastasis: 46-Year Follow-up (Figure 14.3, p. 590
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Secondary Metastatic GrowthGrowth at site of secondary arrest• Protection by fibrin clot?
Secondary Invasion• Out of vasculature into target tissue• Active• Passive
Growth of Metastatic Nodules• Angiogenesis• Invasion into metastatic organ site
Potential for Tertiary Invasion
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Factors Contributing to Metastatic Spread
Metastasis-Associated Up-regulated Genes:Promotion of Epitelial-Mesenchymal Transition
Host Responses (not necessarily immunological)• Inflammatory responses: See Macrophages and Promotion of
Metastasis, Figures 14.22 and 14.23, pp. 612-613 At Primary Site At Potential Seeding Site. See Scientific American, March 2007 Article:
“Deadly Dialogue”. (Not required reading but of value now or later)• Clot Formation• Cytokine and Growth Factor ProductionTumor Responses• Tumor-induced immune suppressionPossible Facilitation of Metastasis by Treatment• Diagnostic and surgical manipulation• X-ray Damage• Immune suppression by Drug Treatment by Surgery and Anesthesia by Stress Hormones
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Reciprocal Stimulation of Breast Cancer Cells by Macrophages: Stimulation of Proliferation and Migration of Carcinoma Cells by Epidermal
Growth Factor (EGF) from Macrophages
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Reciprocal Stimulation of Breast Cancer Cells & Macrophages: Recruitment of Macrophages by Colony Stimulating Factor from Cancer Cells,
and Promotion of Entry into Vasculature by Inflammatory Macrophages
Tumor-associated Macrophage
EGF = Epidermal Growth FactorCSF-1 = Colony-Stimulating Factor
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Factors Hindering Metastatic Spread
Metastasis-Suppressor Genes: See Table 14.4, p. 643e.g. TIMP: Tissue Inhibitor of Metalloproteinases orRhoGD1-2: Down-regulates Rho – Stimulator of Actin Polymerization
Host Responses • Activated Macrophages• Natural Killer Cells• Cytotoxic Lymphocytes
Hydrodynamic Effects in Host circulation
Failure to Recognize and Arrest at Secondary Site