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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 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) e t a c h m e n t a n d A c t i v e I n v 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