1. 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
Folder Title: Inv&Mets
Malignancy is by defintion, the progressive emergence in a developing neoplasm of the ability to invade surrounding tissues and to spread to distant sites. It is these two properties of late-stage cancers that leads to their lethal outcomes. Thus understanding the biology of invasion and metastasis is key to understanding and managing malignant neoplasia.
Updated: March 29, 2017

2. See Metastasis: Cancer Menacing Ballet (Insert by Robert Weinberg)
by Jennifer Couzin
(Insert by Robert Weinberg)
Metastasis: Cancer's Menacing Ballet, (MetsScienceFeb1403.pdf) Science, Feb. 14, 2003, Vol 299, p 1003

3. Examples of Metastases
Slides 4 to 11:
Examples of Metastases

4. 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 The Biology of Cancer (© Garland Science 2007). P. 588; p nd edition

5. Imaging on Metastatic Colon Carcinoma with Radioactive-Iodine-Labelled Monoclonal Ab to A33 Ag Lloyd Old, Scientific American, August, 1996, p. 138)
SeeMets
Arm

6. Colon Carcinoma Metastatic to Liver
Fig. 2.2b and c
Weinberg
p. 27;
p. 33 2nd edition
Colon Carcinoma Metastatic to Liver
Breast Carcinoma Metastatic to Brain

7. Multiple Metastatic Lesions of Gastric Adenocarcinoma to Liver
See next slide

8. Gastric Carcinoma Metastatic to Brain

9. Primary Glioblastoma Compared to Breast Carcinoma Metastasis to the Brain

10. Breast Carcinoma Metastatic to Draining Lymph Node
Figure 14.2b The Biology of Cancer (© Garland Science 2007). P 589

11. Carcinoma Metastatic to Bone. Stained for Epithelial Cell Markers
To Here March 22, 2016 Thursday
Figure 14.2c The Biology of Cancer (© Garland Science 2007). P. 589

12. Slides 13 to 15: Angiogenesis

15. Growth-associated Neovascularization of a tumor xenograft
Human colorectal adenocarcinoa implanted sub-cutaneously as a xenograft in immunocompromised mice.
Viewed through a skin wndow.
Figure 13.32a The Biology of Cancer (© Garland Science 2007) p. 561

16. in Invasion and Metastasis
Progressive Steps
in Invasion and Metastasis

17. 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

18. Invasion in Cancer

19. Cancer Invasion

20. Epithelial to Mesenchymal Transition in Cancer Detachment and Invasion
Mesenchymal to Epithelial Transition in Establishing Disseminated Metastases

21. 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”

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

23. Reversibility of Epithelial-Mesenchymal Transition:
To Invasive Carcinoma and Back to Macrometastasis at Distant Site
p. 606; p. 665, 2nd edition
Figure 14.17b The Biology of Cancer (© Garland Science 2007)

24. Reversibility of Epithelial – Mesenchymal Transition:
Epithelial Characteristics of Distant Metastases of Primary Carcinoma
(Aberrant epidermal growth factor receptor)
p. 607
Figure The Biology of Cancer (© Garland Science 2007)

25. Invasive Squamous Cell Carcinoma of Uterine Cervix
Stromal Cells on Uterus
Inflammatory Cells
Invasive Carcinoma
Figure 14.5c The Biology of Cancer (© Garland Science 2007) p. 592

26. Active Invasion by Melanoma Emboli
Figure 14.5b The Biology of Cancer (© Garland Science 2007) p. 592

27. Detachment and Active Invasion by Renal Adenocarcinoma (Frog)

28. Extravasation Facilitated by Clot Formation
Figure The Biology of Cancer (© Garland Science 2007) p. 595

30. Invasion-Metastasis Cascade Adapted from Fidler, Nat. Rev
Invasion-Metastasis Cascade Adapted from Fidler, Nat. Rev. Cancer 3: , 2003
Figure The Biology of Cancer (© Garland Science 2007) p. 591; Figure 14.4, p. 644, 2nd Edition

31. 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

32. 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

33. 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

34. Association of Normal Melanocyte with Epithelial Keratinocytes
(Epithelial adherens junction protein)
p. 605; p nd edition
Figure 14.16a The Biology of Cancer (© Garland Science 2007)

35. Epithelial to Mesenchymal Transition in Melanoma Cells:
Facilitation of Detachment and Invasion
(Mesenchymal adherens junction protein)
p. 605; p nd edition
Figure 14.16b The Biology of Cancer (© Garland Science 2007)

36. Turning Point Questions Coming Up
Please get stuff off of the desks.

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40. 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

41. E = endothelial (capillary lining cells)
R = RBC
5 to 7 um
W = white-blood cells (leucocytes)
12 to 18 um
RBC’s and WBC’s in capillary circulation

42. Normal deformable RBC’s (5 to 7 um)
In circulation

43. Large tumor cell embolus surrounded by platelets.

45. Destruction of connective tissue matrix (blue) by advancing cancer cell

46. Most Frequent Sites of Metastases for Some Human Cancer
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
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
Regional lymph nodes, lung, liver, ovary
Breast
Colon
Kidney
Lung
Ovary
Prostate
Stomach
Testis
Urinary Bladder
Uterine Lining

47. Primary Tumors and Preferred Sites of Metastatic Spread
Figure The Biology of Cancer (© Garland Science 2007)

48. Presence of Micrometastases and Clinical Prognosis: Breast Cancer
Figure 14.50a The Biology of Cancer (© Garland Science 2007)

49. Presence of Micrometastases and Clinical Prognosis: Colon Cancer
Figure 14.50b The Biology of Cancer (© Garland Science 2007)
p. 645

50. See Slide 48 later on 128 Metastasis-associated genes
p. 647; See page 714, 2nd edition
Figure 14.51b The Biology of Cancer (© Garland Science 2007)

51. 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 and 14.23, pp
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

52. 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

53. EGF = Epidermal Growth Factor CSF-1 = Colony-Stimulating Factor
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

54. Size of Primary Breast Cancer and Risk of Metastasis: 46-Year Follow-up
(Figure 14.3, p. 590
Figure The Biology of Cancer (© Garland Science 2007)

55. 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

56. BRMS1 = Breast cancer Metastasis suppressor gene
CDH1 = E-cadherin > epithelial (non-motile) cells

57. 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
(17 representative
Genes) . .
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 , 2nd Edition

58. Turning Point Questions Coming Up
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59. Non-Response