Cancer Biology Course. Invasion and Metastasis
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1 Cancer Biology Course Invasion and Metastasis 2016 Lu-Hai Wang NHRI
2 Cancer metastasis Major problem: main reason for killing cancer patients, without it cancer can be cured or controlled. Challenging questions: Why cancer cells decide to move out? When do they move out? How do they do it? Where do they go and why? Cancer stem cells and metastasis Driving force? Timing? Mechanism? organtropism? role of stem cells?
3 Activity asso with brain is normal. Disseminated tumors Non-Hodgkin s lymphoma CAT :computed x-ray tomography plus PET: positron-emission tomography (FDG) Tumor cells take up FDG more than normal cells. Figure 14.1 The Biology of Cancer ( Garland Science 2007)
4 Pancreatic islet tumor cells from Rip-tag transgenic mouse metastasize to a lymphati c vessel Lymphatic vessel Figure 14.2a The Biology of Cancer ( Garland Science 2007)
5 Human breast cancer cells metastasize to a lymph node Figure 14.2b The Biology of Cancer ( Garland Science 2007)
6 Wright Giemsa stain of epithelial cancer cells in bone marrow Figure 14.2c The Biology of Cancer ( Garland Science 2007)
7 Figure 14.3 The Biology of Cancer ( Garland Science 2007) Primary tumor size and risk of metastasis
8 Figure 14.4 The Biology of Cancer ( Garland Science 2007) The invasion-metastasis cascade
9 Process of metastasis
10 more differentiated colorectal ca less differentiated colorectal ca Intact BM (green) (Basement membrane) lack BM (green)
11 Rectal carcinoma
12 The invasion pattern (migrating from left to right) of lobular mammary carcinoma cells Figure 14.5a The Biology of Cancer ( Garland Science 2007)
13 Pink/brown: Invading cervix squamous carcinoma cells into stroma Green: inflammatory cells Figure 14.5c The Biology of Cancer ( Garland Science 2007) pink arrows popint o basement membrane
14 Breast cancer line MCF-7 co-cultured with fibroblasts in 3-D gel Green: collagen matrix The migrating Cell cluster: Red: e-cadherin Green: actin Blue: cancer cells nuclei
15 Seen here is melanoma cancer cells migrating as a group. (confocal microscope image) Red: E-cadherin; green: beta-integrin Black: matrix digested away Figure 14.5b The Biology of Cancer ( Garland Science 2007)
16 Oral squamous carcinoma cells and ca-asso fibroblasts
17 Rip-Tag transgenic mouse pancreatic ca model Yellow: Macrophages stimulated by IL-4 and secreting cathepsins (red) at invasion front
18 Apc mutant mouse: intestinal carcinogenesis model CD34+ myeloidderived cells are recruited to cap the cancer cells at invasion front and secrete mmp2 and mmp9
19 Mena+ carcinoma cell, endothelial cell and macrophage from triad in tumor microenvironment for metastasis
20 Counting number of triad for prognosis
21 Intra-vitsal microscopy of caplillary and cells inside E: endothelial cell (capillary wall) R: erythrocyte W: leukocyte Figure 14.7a The Biology of Cancer ( Garland Science 2007)
22 Green: Capillary Red: erythrocyte Figure 14.7b The Biology of Cancer ( Garland Science 2007)
23 Figure 14.8 The Biology of Cancer ( Garland Science 2007) Cancer cells grow in the lumen of a microvessel.
24 Figure 14.6 The Biology of Cancer ( Garland Science 2007) Blood flow
25 Steps leading to extravasation Proteases digest away platelets. Cancer cells grow inside vessel. Cancer cells break through the capillary basement membrane Figure 14.9 The Biology of Cancer ( Garland Science 2007)
26 Colon carcinoma cells detected in bone marrow by anti-cytokeratin antibody Figure 14.10a The Biology of Cancer ( Garland Science 2007)
27 Breast cancer cells as micrometastasis detected in bone marrow Figure 14.10b The Biology of Cancer ( Garland Science 2007)
28 Two mouse lung adenocarcinoma micrometastases in a lymh node Figure 14.10c The Biology of Cancer ( Garland Science 2007)
29 Breast cancer Cytokeratin+ cells in marrow as prognosis indicator
30 Single cancer cells CGH to assess genetic heterogeneity of cancer cells from initial minimal residual diseases and those from subsequent metastatic relapse (from bone marrow) Figure 14.11a, b The Biology of Cancer ( Garland Science 2007)
31 Early stage: Heterogeneous micrometastases Late stage: Homogeneous metastases Figure 14.11c The Biology of Cancer ( Garland Science 2007)
32 ouse breast cancer cells injected into mesenteric vein traveled to liver, stayed dormant for weeks. Figure The Biology of Cancer ( Garland Science 2007)
33 EMT epithelial mesenchymal transition * EMT transcriptional factors: Twist, Snail, slug, Zeb1, Zeb2 etc *TGF-beta *Canonical Wnt signaling: E-Cadherin/beta-catenin *Non-canonical Wnt pathway: Win5a; Wnt/Ca signaling
34 Three types of EMT Kaluri and Weinberg, JCI (2009)
35 EMT Kaluri and Weinberg, JCI (2009)
36 Xin Ye and Robert A. Weinberg Trend in cell Biol,(2015)
37 Table 14.1 The Biology of Cancer ( Garland Science 2007)
38
39 Scanning E/M Sea urchin embryo Ectoderm cells migrate interially. Figure 14.13a The Biology of Cancer ( Garland Science 2007)
40 Figure 14.13b The Biology of Cancer ( Garland Science 2007)
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