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Invasion and Metastasis:
The Malignant Phenotype
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Chapter 14: The Biology of Cancer
Moving Out: Invasion and Metastasis
p. 641 Second Edition
Updated: March 29, 2017
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
Slides 4 to 11:
Examples of Metastases
Metastatic non-Hodgkins Lymphoma
CT Scan and PET Scan (positron emission
tomography) of incorporated radioactivelylabelled deoxyfluoroglucose.
(Brain activity is normal, abdominal active is
pathological)
Figure 14.1 The Biology of Cancer (© Garland Science 2007). P. 588; p. 642 2nd edition
Imaging on Metastatic Colon Carcinoma with RadioactiveIodine-Labelled Monoclonal Ab to A33 Ag
Lloyd Old, Scientific American, August, 1996, p. 138)
SeeMets
Arm
Fig. 2.2b and c
Weinberg
p. 27;
p. 33 2nd edition
Colon Carcinoma Metastatic to
Liver
Breast Carcinoma Metastatic to Brain
Multiple Metastatic Lesions of Gastric Adenocarcinoma to Liver
See next slide
Gastric Carcinoma Metastatic to Brain
Primary Glioblastoma Compared to Breast
Carcinoma Metastasis to the Brain
Breast Carcinoma Metastatic to
Draining Lymph Node
Figure 14.2b The Biology of Cancer (© Garland Science 2007). P 589
Carcinoma Metastatic to Bone. Stained for Epithelial Cell Markers
Figure 14.2c The Biology of Cancer (© Garland Science 2007). P. 589
To Here March 22, 2016 Thursday
Slides 13 to 15: Angiogenesis
Growth-associated
Neovascularization of
a tumor xenograft
Human colorectal
adenocarcinoa
implanted subcutaneously as a
xenograft in
immunocompromised
mice.
Viewed through a skin
wndow.
Figure 13.32a The Biology of Cancer (© Garland Science 2007) p. 561
Progressive Steps
in Invasion and Metastasis
Progression in Invasion and Metastasis
Appearance of Primary Tumor (Neoplasia in situ)
Vascularization (Angiogenesis)
Invasion
• Into surrounding tissue
• Into vascular and lymphatic systems
Release of Tumor Emboli (Shedding)
Systemic Transport
• Hematogenous
• Lymphatic
Arrest at Distant Site
Secondary Invasion: Extravasation
Secondary Angiogenesis
Secondary Invasion
Tertiary Spread
Invasion in Cancer
Cancer Invasion
Epithelial to Mesenchymal Transition in Cancer
Detachment and Invasion
Mesenchymal to Epithelial Transition in Establishing
Disseminated Metastases
Epithelial-Mesenchymal Transition
Non-motile Epithelial Cells
Associated with Each Other via E-Cadherin Cell Surface Attachment Receptor
Anchored to Connective Tissue Basement Membrane by E-Cadherin
Tight Association via E-Cadherin
Express 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 Tissue
Express Intermediate Filament Protein Vimentin:
Characteristic of Connective Tissue Cells
Fibroblast and Leucocyte-like Structure and Function
Able 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”
Table 14.2 The Biology of Cancer (© Garland Science 2007)
p. 603
Reversibility of Epithelial-Mesenchymal Transition:
To Invasive Carcinoma and Back to Macrometastasis at Distant Site
Figure 14.17b The Biology of Cancer (© Garland Science 2007)
p. 606; p. 665, 2nd edition
Reversibility of Epithelial –
Mesenchymal Transition:
Epithelial Characteristics of
Distant Metastases of Primary
Carcinoma
(Aberrant epidermal
growth factor receptor)
Figure 14.18 The Biology of Cancer (© Garland Science 2007)
p. 607
Invasive Squamous Cell Carcinoma of Uterine Cervix
Stromal Cells on Uterus
Inflammatory
Cells
Figure 14.5c The Biology of Cancer (© Garland Science 2007) p. 592
Invasive Carcinoma
Active Invasion by Melanoma Emboli
Figure 14.5b The Biology of Cancer (© Garland Science 2007) p. 592
D Detachment and Active Invasion by Renal Adenocarcinoma (Frog)
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Extravasation Facilitated by Clot Formation
Figure 14.9 The Biology of Cancer (© Garland Science 2007) p. 595
Invasion-Metastasis Cascade Adapted from Fidler, Nat. Rev. Cancer
3: 453-458, 2003
Figure 14.4 The Biology of Cancer (© Garland Science 2007) p. 591; Figure 14.4, p. 644, 2nd Edition
Release of Tumor Emboli
and Tumor Cell Shedding
Invasion through thin anaplastic venous walls in tumor
Facilitated by:
• Local trauma
• Diagnostic procedures
• Surgery
• Manipulation
Emboli (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
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 Cavity
Lymphatic Spread:
•
Lymphatic capillaries to regional lymph nodes
Hematogenous Spread: Entry via
• Lymphatic drainage into circulation
• Abnormal blood vessels in tumors
• Tumor cell deformability and motility
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
Association of Normal Melanocyte with Epithelial Keratinocytes
(Epithelial adherens
junction protein)
Figure 14.16a The Biology of Cancer (© Garland Science 2007)
p. 605; p. 662 2nd edition
Epithelial to Mesenchymal Transition in Melanoma Cells:
Facilitation of Detachment and Invasion
(Mesenchymal adherens
junction protein)
Figure 14.16b The Biology of Cancer (© Garland Science 2007)
p. 605; p. 662 2nd edition
Turning Point Questions
Coming Up
Please get stuff off of the
desks.
Non-Response
Response
Counter
Non-Response
Non-Response
Secondary Metastatic Growth
Growth 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
E = endothelial (capillary lining cells)
R = RBC
5 to 7 um
W = whiteblood cells
(leucocytes)
12 to 18 um
RBC’s and WBC’s in capillary circulation
Normal deformable
RBC’s (5 to 7 um)
In circulation
Large tumor cell embolus
surrounded by platelets.
Destruction of connective tissue matrix (blue) by advancing cancer cell
Most Frequent Sites of Metastases for Some
Human Cancer
Breast
Colon
Kidney
Lung
Ovary
Prostate
Axillary lymph nodes, other breast, lung, pleura, liver,
bone brain, spleen, adrenals, ovary
Regional lymph nodes, liver, lung, bladder, stomach
Lung, liver, bone
Regional lymph nodes, pleura, diaphagm, liver, bone,
brain, kidney, adrenal, throid, spleen
Peritoneum, regional lymph nodes, lung, liver
Bones of spine and pelvis, regional lymph nodes
Stomach
Testis
Urinary Bladder
Regional lymph nodes, liver, lung, bone
Regional lymph nodes, lung. liver
Rectum, colon, prostate, ureter, vagina, bone, regional
lymph nodes, lung, peritoneum, pleura, liver, brain
Uterine Lining
Regional lymph nodes, lung, liver, ovary
Primary Tumors and Preferred Sites of Metastatic Spread
Figure 14.42 The Biology of Cancer (© Garland Science 2007)
p. 635
Presence of Micrometastases and Clinical Prognosis: Breast Cancer
Figure 14.50a The Biology of Cancer (© Garland Science 2007)
p. 645
Presence of Micrometastases and Clinical Prognosis: Colon Cancer
Figure 14.50b The Biology of Cancer (© Garland Science 2007)
p. 645
See Slide 48 later on 128
Metastasis-associated genes
Figure 14.51b The Biology of Cancer (© Garland Science 2007)
p. 647; See page 714, 2nd edition
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 Production
Tumor Responses
• Tumor-induced immune suppression
Possible Facilitation of Metastasis by Treatment
• Diagnostic and surgical manipulation
• X-ray Damage
• Immune suppression
by Drug Treatment
by Surgery and Anesthesia
by Stress Hormones
Reciprocal Stimulation of Breast Cancer Cells by Macrophages:
Stimulation of Proliferation and Migration of Carcinoma Cells by Epidermal
Growth Factor (EGF) from Macrophages
p. 673, 2nd edition
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 Factor
CSF-1 = Colony-Stimulating Factor
p. 673, 2nd edition
Size of Primary Breast Cancer and Risk of Metastasis: 46-Year Follow-up
(Figure 14.3, p. 590
Figure 14.3 The Biology of Cancer (© Garland Science 2007)
Factors Hindering Metastatic Spread
Metastasis-Suppressor Genes: See Table 14.4, p. 643
e.g. TIMP: Tissue Inhibitor of Metalloproteinases or
RhoGD1-2: 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
BRMS1 = Breast cancer Metastasis suppressor gene
CDH1 = E-cadherin > epithelial (non-motile) cells
Over- or Under-expression of 128
Metastasis-Associated Genes in
DNA-Array Assay for Potential
Metastatic Progression.
(17 representative
Genes)
.
RNA’s prepared from 64 primary
non-metastatic adenocarcinomas,
and from 12 metastatic
adenocarcinomas
Blue means decreased
expression.
Half of the 128 genes in
the 12 mets were downregulated.
Red means increased
expression.
Half were up-regulated.
Figure 14.51a The Biology of Cancer (© Garland Science 2007)
p. 714, Fig. 14.51, 2nd Edition
Turning Point Questions
Coming Up
Please get stuff off of the
desks.
Non-Response