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

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)

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)

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

Breast Carcinoma Metastatic to Brain

Fig. 2.2b and c

Weinberg

p. 27

Multiple Metastatic Lesion to Liver

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

Human colorectal adenocarcinoa implanted sub-cutaneously as a xenograft in immunocompromised mice.

Viewed through a skin wndow.

Growth-associated Neovascularization of

a tumor xenograft

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

Figure 14.2b The Biology of Cancer (© Garland Science 2007). P 589

Breast Carcinoma Metastatic to Draining Lymph Node

Figure 14.2c The Biology of Cancer (© Garland Science 2007). P. 589

Carcinoma Metastatic to Bone. Stained for Epithelial Cell Markers

Turning Point Questions Coming Up

Please get stuff off of the desks.

In the previous slide breast carcinoma metastatic to the bone was detected by using stains for epithelial cell

markers. Why does that work?

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Angiogenesis can promote intravasation.Why do you think that happens?

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Invasion in Cancer

Cancer Invasion

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

Figure 14.5b The Biology of Cancer (© Garland Science 2007) p. 592

Active Invasion by Melanoma Emboli

Detachment and Active Invasion by Renal

Detachment and Active Invasion by Renal Adenocarcinoma (Frog)

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

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

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

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

Figure 14.9 The Biology of Cancer (© Garland Science 2007) p. 595

Extravasation Facilitated by Clot Formation

Epithelial to Mesenchymal Transition in Cancer Detachment and Invasion

Mesenchymal to Epithelial Transition in Establishing Disseminated Metastases

Figure 14.16a The Biology of Cancer (© Garland Science 2007) p. 605

Association of Normal Melanocyte with Epithelial Keratinocytes

(Epithelial adherens junction protein)

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)

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”

Table 14.2 The Biology of Cancer (© Garland Science 2007) p. 603

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

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)

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

Figure 14.42 The Biology of Cancer (© Garland Science 2007) p. 635

Primary Tumors and Preferred Sites of Metastatic Spread

Figure 14.50a The Biology of Cancer (© Garland Science 2007) p. 645

Presence of Micrometastases and Clinical Prognosis: Breast Cancer

Presence of Micrometastases and Clinical Prognosis: Colon Cancer

Figure 14.50b The Biology of Cancer (© Garland Science 2007) p. 645

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

Figure 14.51b The Biology of Cancer (© Garland Science 2007) p. 647

Turning Point Questions Coming Up

Please get stuff off of the desks.

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.

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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?

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

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

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

Reciprocal Stimulation of Breast Cancer Cells by Macrophages: Stimulation of Proliferation and Migration of Carcinoma Cells by Epidermal

Growth Factor (EGF) from Macrophages

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

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