20.GEM GEM4 Summer School: Cell and Molecular Biomechanics in Medicine: Cancer Summer 2007
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1 MIT OpenCourseWare 20.GEM GEM4 Summer School: Cell and Molecular Biomechanics in Medicine: Cancer Summer 2007 For information about citing these materials or our Terms of Use, visit:
2 From Cell Physiology and Biology to Cellular Biomechanics: Role of Hydrodynamics, Chemokines and Adhesion in Leukocyte-mediated Melanoma Extravasation Cheng Dong, Ph.D. Professor of Bioengineering & Engineering Science and Mechanics Department of Bioengineering & The Huck Institutes for the Life Sciences The Pennsylvania State University University Park, PA 16802, USA Courtesy of Cheng Dong. Used with permission.
3 USA Today (Nov. 10, 2004) interviewed leading medical experts about the relationship between inflammation and cancer: Doctors believe that inflammation is involved in a wide variety of cancers. Image removed due to copyright restrictions. Scan of USA Today article. Scientists say they can t be sure whether inflammation produces cancer; or cancer leads to inflammation; or the two processes interact. Doctors suspect that longterm inflammation or infection is involved in up to 20% of cancers, including those of the esophagus, colon, skin, stomach, liver, bladder, breast and some kinds of lymphoma.
4 Cancer Metastasis Cascade Tumor in epithelium Break through basal lamina Invade capillary Connective tissue Capillary Less than 1 in 1000 cells will survive to form metastasis Adhere to capillary wall Extravasation Proliferation Illustration by MIT OpenCourseWare. After Alberts, et al., BMES Conference 2001 Alberts et al., 1994
5 Inhibiting V600E B-Raf reduced melanoma lung metastasis in vivo Images removed due to copyright restrictions. A, sirna-mediated inhibition of V600EB- Raf inhibits melanoma lung metastasis. Left panel, 1205 Lu cell; right panel, UACC 903M cell. Number of tumors within particular size ranges (<1500 or >1500 pixels) were quantified in a minimum of 6 fields per lung from 5 to 10 animals. Values are means ± SEM. B, co-localization of human melanoma cells and mouse PMNs in vivo.
6 On-going Studies Overall Hypothesis : Tumor cells elicit a sequence of signaling events to facilitate their transendothelial migration via immunoediting Melanoma MAPK IL-8 NF-κB PMN Protein secretion PKC Junction regulation Ca 2+ EC PMN : polymorphonuclear neutrophils
7 Working Hypothesis: Neutrophils (PMN) facilitate melanoma adhesion leading to increased migration under flow conditions an important step in tumor cell extravasation during metastasis. ICAM-1 Melanoma PSGL-1 Sle x E-selectin Neutrophil β 2 integrins L-selectin ICAM-1 P-selectin Image removed due to copyright restrictions. Endothelium
8 Flow-Migration Assay Figure by MIT OpenCourseWare. A Filter Cell monolayer Chemoattractant Images removed due to copyright restrictions. 5 cm Inlet Gasket Outlet B Modified top plate Filter Gasket Gopalan et al J. Immunol. Top Plate 10 cm Flow Cellular Monolayer Porous membrane Wells for Chemoattractant WBC melanoma Bottom Plate Flow
9 PMN Facilitates Melanoma Cell Migration Under Flow Conditions NHEM only - Static C8161 only - Static C PMN - Static p=0.47 p=0.47 C8161 only - Dynamic C PMN - Dynamic p= Cells Migrated per mm 2 Dynamic: shear stress = 0.4 dyn/cm 2
10 To Clarify The Signaling Events Of Cytokine/Chemokine Induction Mediated By PMN-melanoma Interaction Hypothesis : Tumor cells modulate protein secretion through activation of transcription factor signaling in PMNs Melanoma MAPK IL-8 NF-κB PMN Protein secretion PMN : polymorphonuclear neutrophils
11 IL-8 Secretions from PMN, Melanoma Cells and Co-cultures * * * * * * IL-8, pg/ml Images removed due to copyright restrictions. Western blot results. 0 WM35 C8161 WM9 1205Lu PMN only Melanoma cell only PMN + Melanoma cell transwell co-culture PMN + Melanoma cell contact co-culture ELISA data Figure by MIT OpenCourseWare. WM35 : low metastatic potential Increased IL-8 in co-cultures of C PMNs WM9 - PMNs 1205Lu - PMNs Western blots Increased IL-8 from PMNs (Transwell) co-cultured with C8161, WM9, 1205Lu Constant IL-8 from melanoma cells
12 Mac-1 Expression after Melanoma-PMN Co-culture 6 Fold Induction Mac-1 expression on PMN PMN Co-culture Transwell 0 Untreated CXCR 1/2 Ab blocked Figure by MIT OpenCourseWare.
13 Blocking Intercellular IL-8 Signaling Affects PMN-facilitated Melanoma Extravasation Melanoma cell extravasation increased in response to IL-8- stimulated PMNs compared with non-stimulated PMN groups. Melanoma extravasation decreased significantly in the presence of CXCR1/CXCR2- blocked PMNs or anti-il-8 neutralizing antibody compared with unstimulated PMNs. Image removed due to copyright restrictions. Graph showing results of treatment with CXCR1/2- and IL-8-blockers.
14 Inhibiting V600E B-Raf Reduced Melanoma Cell Extravasation in vitro B-Raf encodes a RAS-regulated kinase that mediates cell growth and malignant transformation kinase pathway activation. As the most mutated gene in malignant melanomas, B-Raf has raised questions whether targeting B-Raf might effectively reduce melanoma metastasis. Graphs removed due to copyright restrictions. Inhibition of mutant V600E B-Raf greatly reduced melanoma extravasation compared with non-inhibited melanoma cells (untransfected, nucleofected with buffer only or scrambled sirna) under both static and dynamic flow conditions.
15 Inhibiting V600E B-Raf reduced IL-8 production Graphs removed due to copyright restrictions. A, Inhibition of mutant V600E B-Raf significantly reduced the IL-8 production from melanoma cells (1205 Lu and UACC 903M) cultured alone compared with the control melanoma cells (untransfected melanoma and melanoma nucleofected with buffer only or scrambled sirna). B, IL-8 production from tumor microenvironment (including both PMN and melanoma cells) increased after PMN co-cultured with control melanoma cells (~1.5 fold), whereas IL-8 production either kept the same or even reduced after PMN co-culture with melanoma cells treated with sirna against mutant V600E B-Raf. Values were normalized to the summed background level of PMN and melanoma cell cultured alone.
16 Mac-1 expression on PMN after coculture with melanoma cells Graphs removed due to copyright restrictions. Mac-1 expression on PMN increased significantly after PMN co-cultured with control melanoma cells (untransfected melanoma and melanoma nucleofected with buffer only or scrambled sirna). However, the co-culture between PMN and melanoma cells treated with sirna against V600E B-Raf did not significantly increase Mac-1 expression on PMN.
17 Disruption of ICAM-1/β 2 integrin binding inhibited melanoma cell extravasation Graphs removed due to copyright restrictions. A, ICAM-1 expression on melanoma cells (1205 Lu and UACC 903M) was reduced after knockdown of mutant V600E B-Raf and ICAM-1 using sirna; B, knockdown of mutant V600E B-Raf and ICAM-1 inhibited PMN-mediated melanoma extravasation, values are mean ± SEM;
18 Inhibiting V600E B-Raf disrupts NF-κB activity Graphs removed due to copyright restrictions. A, NF-κB activity is reduced after inhibition of mutant V600E B-Raf in 1205 Lu (lane 10) compared with control cases (untransfected 1205 Lu, lane 1; 1205 Lu nucleofected with scrambled sirna, lane 4 or buffer only, lane 7). The complexes were supershifted by polyclonal antibodies against p50 (lanes 2, 5, 8 and 11) and p65 (lanes 3, 6, 9 and 12). B, PDTC treatment reduced IL-8 secretion and ICAM-1 expression on melanoma cells Lu cells were treated with PDTC (100µM) for 1hr. After twice washing, 1205 Lu cells were cultured using fresh culture media. Left panel: supernatant after 4h was collected and IL-8 secretion was detected by ELISA; right panel: ICAM-1 expression on 1205 Lu was examined by flow cytometry.
19 Mechanism of inhibiting V600E B-Raf to disrupt melanoma extravasation β 2 integrins ICAM-1 IL-8 sle x E-selectin B-Raf NF-κB Melanoma nucleus IL-8 ICAM-1 PMN EC
20 PMN-facilitated Melanoma Extravasation PMN-C8161 = f (1/γ) * C8161 EC SLe x E-Selection PMN ICAM-1 β 2 Integrins ICAM-1 PMN-EC = f (τ) Figure by MIT OpenCourseWare.
21 Parallel-Plate Flow Assay Figures removed due to copyright restrictions. Please see: FMLP-stimulated neutrophils were injected together with tumor cells at a very low flow rate (0.004 ml/min) for 2 min to accumulate cells within the flow chamber. After the initial accumulation, a step increase in flow rate was applied to the cells. BMC Immunology. 2:9, 2001.
22 TC-PMN Collision and Aggregation Near the Endothelium in a Shear Flow The following parameters were measured and found to be influenced by shear conditions: Image removed due to copyright restrictions. the number of TC-PMN collisions; the number of TCs captured by PMNs; and the number of TCs adhered to ECs as a result of TC-PMN collision/aggregation. Adhesion Efficiency Number of TC adhered to EC monolayer as a result of collisions = Total number of collisions
23 Two Different Types of Cell Aggregation Are Examined: Tumor Cell to PMN & PMN to Endothelial Cell α τ PMN τ = µγ& α 1/γ C8161 EC Normalized tethering frequency events/mm 2 /min Two different cell aggregations are examined: tumor cell to PMN and PMN to endothelial cell. PMN tethering data indicates that PMN adhesion to endothelial cells follows a more traditional hydrodynamic relationship and is proportional to shear stress and contact duration. The adhesion and migration data reveal that tumor cell to PMN adhesion varies inversely to shear rate and is dependant on contact duration while independent of shear stress Figures by MIT OpenCourseWare. 1.0 cp 2.0 cp 3.2 cp C8161 Migration per mm Shear rate (sec -1 ) Shear rate (sec -1 ) WM9 Adhesion Efficiency cp 3.2 cp 7.0 cp cp 1.0 cp 3.2 cp Shear rate (sec -1 )
24 Effects of Shear Rate and Shear Stress on PMN-Melanoma Interactions Experimental and Computational Approach Focus on interactions between PMN and melanoma cell Model second step: melanoma cell colliding and adhering to a tethered PMN on EC by capturing: Deformation Collision Adhesion kinetics
25 Side-View PIV System Images removed due to copyright restrictions.
26 Velocity Profiles Interrogation windows: 30 x 20 pixels (W x H), 0.23 µm/pixel Stream lines over an adhered 16-µm bead near the microslide wall. Velocity vectors over an adhered 16-µm bead near the microslide wall.
27 Computational Fluid Dynamics and Statistic Population Balance Model Images removed due to copyright restrictions. Cell population studies CFD studies Micro-PIV experimental studies
28 Simulation of a melanoma cell binding to a PMN
29 Cancer Immunoediting in Leukocyte-mediated Melanoma Extravasation Flow Shear rate vs. Shear stress PMN collision frequency adhesion efficiency tumor PMN cell-cell signaling, chemokine secretion adhesion molecule expression tumor PMN Endothelial junction regulation: phosphorylation state - tumor cell extravasation model Tumor cell extravasation
30 Acknowledgement Photographs removed due to copyright restrictions. Shile Liang Hsin H. Peng Meghan Hoskins Chong-Haw Kwang Sharad Gupta Payal Khanna Patricia Groleau Tara Yunkuins Maggie Slattery Louis Hodgson Jun You Xiao X. Lei Jian Cao Karen Perkowski Brad Rank Jordan Leyton-Mange Desiree Wagner Dr. Andrew Henderson (BU) Dr. Jeffery Zahn (Rutgers ) Dr. Gavin Robertson (PSU) Dr. Elise Kohn (NIH) Dr. Lance Liotta (NIH) Dr. Danny Welch (UAB) Dr. Avery August (PSU) Dr. Mike Lawrence (UVA) Supported by NIH and NSF grants.
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