Analysis of Melanoma Secretome for Factors That Directly Disrupt the Barrier Integrity of Brain Endothelial Cells
Abstract
:1. Introduction
2. Results
2.1. Effect of Melanoma Conditioned Media on Brain Endothelium
2.2. Characterisation of Melanoma Conditioned Media
2.3. Common Mediators in Oncology and Inflammation
2.4. Effect of Selected Secretory Molecules on the Brain Endothelium
3. Materials and Methods
3.1. Culture of the Melanoma Cells
3.2. Collection of the Conditioned Media
3.3. Culture of the Brain Endothelial Cells
3.4. ECIS Technology Assessment of Conditioned Media
3.5. Cytokine Measurements Using CBA and Luminex
3.6. NanoString nCounter Analysis
3.7. Cytokine Screening Using Proteome Profiler Arrays
3.8. Assessment of Recombinant Cytokines on Barrier Integrity
3.9. Statistical Analysis
4. Discussion
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Appendix A
Array/Set | Aliases | Assay | Company | Catalogue No. | Standard Curve (pg/mL) |
---|---|---|---|---|---|
Secreted proteins tested | |||||
Human IL-8 | CXCL8 | CBA | BD Bioscience | 558277 | 0–5000 |
Human MCP-1 | CCL2 | CBA | BD Bioscience | 558287 | 0–5000 |
Human MIP-1α | CCL3 | CBA | BD Bioscience | 558325 | 0–5000 |
Human VEGF | - | CBA | BD Bioscience | 558336 | 0–5000 |
Human IL-4 | BSF-1 | CBA | BD Bioscience | 558272 | 0–5000 |
Human MIP-1β | CCL4 | CBA | BD Bioscience | 558288 | 0–5000 |
Human IL-6 | BSF-2/HGF | CBA | BD Bioscience | 558276 | 0–5000 |
Human IP-10 | CXCL10 | CBA | BD Bioscience | 558280 | 0–5000 |
Human ANGPTL-4 | HFARP | Luminex | R&D Systems | LXSAH-4 | 0–360810 |
Human Osteopontin | OPN/SPP-1 | Luminex | R&D Systems | LXSAH-4 | 0–636310 |
Human SDF-1α | CXCl12 | Luminex | R&D Systems | LXSAH-4 | 0–36870 |
Human IFNγ | IFG | CBA | BD Bioscience | 558269 | 0–5000 |
Human IL-1β | - | CBA | BD Bioscience | 558279 | 0–5000 |
TGFβ-1 | CBA | BD Bioscience | 560429 | 0–10000 | |
Secreted proteins tested | |||||
Human XL Cytokine Array Kit | Proteome Profiler | R&D Systems | ARY022B | ||
Human XL Oncology Array Kit | Proteome Profiler | R&D Systems | ARY026 |
Protein | Gene | Probe NSID |
---|---|---|
TGFβ-1 | TGFB1 | NM_000660.3:1260 |
VEGF-A | VEGFA | NM_001025366.1:1325 |
Osteopontin | SPP1 | NM_000582.2:760 |
MCP-1 | CCL2 | NM_002982.3:123 |
IL-8 | CXCL8 | NM_000584.2:25 |
Treatment | Company | Catalogue No. |
---|---|---|
Angiogenin | R&D | 265-AN-050/CF |
GDF-15 | R&D | 8146-GD/CF |
Progranulin | R&D | 2420-PG-050 |
SPARC | R&D | 941-SP-050 |
SPARC Like-1 | R&D | 2728-SL-050 |
Tenascin C/Cytotactin | R&D | 3358-TC-050 |
IGFBP-2 | R&D | 674-B2-025 |
Cystatin C | Biolegend | 756202 |
DKK-1 | Biolegend | 778602 |
Galectin-3 | Biolegend | 599704 |
MIF | Biolegend | 599404 |
Osteopontin | Biolegend | 557102 |
TGFβ-1 | Biolegend | 580702 |
CXCL-1 | Biolegend | 574402 |
ANGPTL-4 | R&D | RDS4487AN050 |
cANGPTL-4 | R&D | RDS3485AN050 |
IL-8 | PrimeGene | 101-08A |
VEGF | PrimeGene | 105-16Y |
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Secretory Molecule | Common Alias | Function (Relevant to Metastasis or Vascular Modulation) | References |
---|---|---|---|
ANGPTL-4 | HFARP | TJ disruption | [24] |
IFN-γ | - | Lymphocyte extravasation (Thelper17) | [2,3,25] |
IL-1β | - | Influences VE-Cadherin arrangement and increases vascular permeability | [26,27] |
IL-4 | BSF-1 | Vascular hyperpermeability | [28] |
IL-6 | BSF-2 | Elevated in metastatic melanoma | [29,30] |
IL-8 | CXCL8 | Elevated expression closely associated with melanoma invasion and metastasis | [20,31] |
IP-10 | CXCL10 | Lymphocyte extravasation (T-cell) | [4,32] |
MCP-1 | CCL2 | Induces endothelial TJ opening. Vascular permeability | [33,34] |
MIP-1α | CCL3 | Leukocyte extravasation (Dendritic cell) | [4,35] |
MIP-1β | CCL4 | Lymphocyte extravasation (T-Cell CD4+) | [4,36] |
Osteopontin (OPN) | BSP-1 | Expression associated with tumour invasion. | [37,38] |
SDF-1α | CXCL12 | Melanoma matrix invasion | [39] |
TGFβ-1 | - | Cancer progression, angiogenesis, invasion and metastasis. Osteolytic metastasis in melanoma | [12,40] |
VEGF | VPF | Elevated expression closely associated with metastasis. Increases endothelial permeability. Reversible VE-Cadherin endocytosis | [26,41,42,43,44] |
Secretory Molecule | Function (Relevant to Metastasis or Vascular Modulation) | References |
---|---|---|
Angiogenin | Associated with metastatic potential | [52] |
Cystatin C | Implicated in melanoma brain metastasis | [53] |
CXCL-1 | Tumorigenesis Endothelial activation and leukocyte recruitment | [54,55] |
DKK-1 | Inhibits melanoma invasiveness Increases platelet mediated endothelial activation | [56,57] |
Galectin-3 | Contributes to metastasis. Induces endothelial angiogenesis | [58,59] |
GDF-15 | High expression correlated with reduced overall survival in patients with melanoma | [60] |
IGFBP-2 | Increased in malignancy | [61] |
MIF | Tumour survival Endothelial permeability | [62,63] |
Progranulin | VEGF independent angiogenesis. Correlated with melanoma survival | [64,65] |
SPARC | Highly implicated in EMT processes and overexpression in melanoma Mediates invasiveness | [66,67] |
Tenascin C | Upregulated in melanoma but likely supportive only to cellular adhesion and ECM movement. | [68] |
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Anchan, A.; Martin, O.; Hucklesby, J.J.W.; Finlay, G.; Johnson, R.H.; Robilliard, L.D.; O’Carroll, S.J.; Angel, C.E.; Graham, E.S. Analysis of Melanoma Secretome for Factors That Directly Disrupt the Barrier Integrity of Brain Endothelial Cells. Int. J. Mol. Sci. 2020, 21, 8193. https://doi.org/10.3390/ijms21218193
Anchan A, Martin O, Hucklesby JJW, Finlay G, Johnson RH, Robilliard LD, O’Carroll SJ, Angel CE, Graham ES. Analysis of Melanoma Secretome for Factors That Directly Disrupt the Barrier Integrity of Brain Endothelial Cells. International Journal of Molecular Sciences. 2020; 21(21):8193. https://doi.org/10.3390/ijms21218193
Chicago/Turabian StyleAnchan, Akshata, Olivia Martin, James J. W. Hucklesby, Graeme Finlay, Rebecca H. Johnson, Laverne D. Robilliard, Simon J. O’Carroll, Catherine E. Angel, and E Scott Graham. 2020. "Analysis of Melanoma Secretome for Factors That Directly Disrupt the Barrier Integrity of Brain Endothelial Cells" International Journal of Molecular Sciences 21, no. 21: 8193. https://doi.org/10.3390/ijms21218193