Transcript Invasion and Metastasis: The Malignant Phenotype
Invasion and Metastasis: The Malignant Phenotype
Folder Title: Inv&Mets(NoTP) Chapter 14: The Biology of Cancer Moving Out: Invasion and Metastasis p. 641 Second Edition
Updated: March 23, 2015
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 Site Course Web-page (No Password Needed)
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)
Figure 14.1
The Biology of Cancer
(© Garland Science 2007). P. 588; p. 642 2 nd edition
Imaging on Metastatic Colon Carcinoma with Radioactive Iodine-Labelled Monoclonal Ab to A33 Ag Lloyd Old, Scientific American, August, 1996, p. 138) SeeMets Arm
Colon Carcinoma Metastatic to Liver
Fig. 2.2b and c Weinberg p. 27; p. 33 2 nd edition
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
Figure 13.32a
The Biology of Cancer
(© Garland Science 2007) p. 561
Growth-associated Neovascularization of a tumor xenograft
Human colorectal adenocarcinoa implanted sub cutaneously as a xenograft in immunocompromised mice.
Viewed through a skin wndow.
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, 2 nd Edition
Figure 14.2b
The Biology of Cancer
(© Garland Science 2007). P 589
Breast Carcinoma Metastatic to Draining Lymph Node
Carcinoma Metastatic to Bone. Stained for Epithelial Cell Markers Figure 14.2c
The Biology of Cancer
(© Garland Science 2007). P. 589
Turning Point Questions Coming Up Please get stuff off of the desks.
Invasion in Cancer
Cancer Invasion
Invasive Squamous Cell Carcinoma of Uterine Cervix Stromal Cells on Uterus Figure 14.5c
The Biology of Cancer
(© Garland Science 2007) p. 592 Invasive Carcinoma Inflammatory Cells
Active Invasion by Melanoma Emboli Figure 14.5b
The Biology of Cancer
(© Garland Science 2007) p. 592
i v e I n v a s i o D e t a c h m e n t a n d A t c
Detachment and Active Invasion by Renal Adenocarcinoma (Frog)
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
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 and Extravasation
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
Extravasation Facilitated by Clot Formation Figure 14.9
The Biology of Cancer
(© Garland Science 2007) p. 595
Epithelial to Mesenchymal Transition in Cancer Detachment and Invasion Mesenchymal to Epithelial Transition in Establishing Disseminated Metastases
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 2 nd 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 2 nd edition
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, 2 nd edition
Reversibility of Epithelial – Mesenchymal Transition: Epithelial Characteristics of Distant Metastases of Primary Carcinoma
Figure 14.18
The Biology of Cancer
(© Garland Science 2007) (Aberrant epidermal growth factor receptor)
p. 607
Most Frequent Sites of Metastases for Some Human Cancer
Breast Colon Kidney Axillary lymph nodes, other breast, lung, pleura, liver, bone brain, spleen, adrenals, ovary Regional lymph nodes, liver, lung, bladder, stomach Lung, liver, bone Lung Ovary Prostate 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
..
(17 representative Genes)
Over- or Under-expression of 128 Metastasis-Associated Genes in DNA-Array Assay for Potential Metastatic Progression.
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 down regulated.
Red means increased expression.
Half were up-regulated.
Figure 14.51a
The Biology of Cancer
(© Garland Science 2007)
p. 714, Fig. 14.51, 2 nd Edition
Figure 14.51b
The Biology of Cancer
(© Garland Science 2007)
p. 647; See page 714, 2 nd edition
Turning Point Questions Coming Up Please get stuff off of the desks.
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)
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
Extravasation Facilitated by Clot Formation Figure 14.9
The Biology of Cancer
(© Garland Science 2007) p. 595
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, 2 nd 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, 2 nd 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
p. 673, 2 nd edition EGF = Epidermal Growth Factor CSF-1 = Colony-Stimulating Factor
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