Bone Small Intestine Lymph Node Lung or Lymph Node INVASION METASTASIS Activated Platelets (Protection from NK cell lysis) MMP-2, MMP-9, Other Proteases CAF Breast or Prostate Cancer Cell Breast Cancer Cell Melanoma Cell Carcinoma-associated Fibroblast (CAF) Developing Primary Tumor CXCR4 CXCR4 CXCL12 CXCL12 CXCL12 CCL19, CCL21 CCL25 Th0 CD8 + T Cell CD8 + T Cells MHCII MHCI B7 CD4 CD8 Apoptotic/Necrotic Bodies TUMOR REJECTION Perforin-/Granzyme-mediated Tumor Cell Death Recruitment of Angiogenesis-promoting Cell Types Tumor-derived Factors Stimulate Endothelial Cell Proliferation & Migration iDC NK NKT (Type I) CCR7 M1 Macrophage Monocyte TCR-CD3 TCR-CD3 CD28 IL-12, IFN-γ IL-12 IL-2, IFN-γ IFN-γ IFN-γ IL-12, TNF-α, NO IFN-γ , LPS Chemokines Th1 Th1 Draining Lymph Node CCR7 CCR7 CCR9 CXCR4 CCL19, CCL21 Dendritic Cell IFN-γ iDC Accumulation Th0 T reg Treg Treg CD8 + T Cell CD8 + T Cells Dendritic Cell B7 CD4 CD8 TCR-CD3 TCR-CD3 CD28 IL-4 IL-4, IL-5, IL-10, IL-13 IL-4 IL-10 IL-13 TGF-β TGF-β, IL-2 TGF-β, IL-10 TGF-β, IL-10 Th2 Th2 MDSC MDSC CCR7 Draining Lymph Node MHCII MHCI NK NK Apoptotic/Necrotic Bodies M2 Macrophage IL-1β, IL-6, IL-10, IL-12 low Arginase, IL-10, NO Angiogenesis Tumor/Stromal Cell CXCL9 CXCL10 CXCL11 NKT (Type II) TUMOR ESCAPE M2 Macrophage IL-10 IL-12 low TGF-β CCL2 Mast Cells Monocyte Eosinophils CXCR1/2 CXCR4 NFκB HIF-1 HIF-1 IL-8 COX2 MMPs VEGF, CXCL12 VEGF VEGF IL-8 CXCL12 PGE 2 IL-8 CXCL12 PGE 2 EP2 CXCR1/2 CXCR4 EP2 VEGF R2 VEGF R2 M2 Macrophage IL-1β, IL-6,TNF-α MMPs, uPA VEGF, PDGF, bFGF, EGF bFGF, VEGF ECM Degradation Myeloid Progenitor Cell iDC IL-8, TNF-α, Osteopontin TGF-β, MMPs, PGE 2 , VEGF VEGF, MMP-9, Oncostatin M VEGF, bFGF, MMP-9, TNF-α, IL-8, Histamine CXCL1, CXCL12, IL-6, IL-8, MMPs, PGE 2 , VEGF Extracellular Matrix CXCL12 Neutrophils IL-6, IL-8, VEGF, bFGF TUMOR GROWTH/ANGIOGENESIS bFGF, VEGF Tumor/Stromal Cell Invading Tumor Cell Tumor or Stromal Cell Endothelial Cell CAF CCL19 CCL21 CCL19 CCL21 TUMOR-DERIVED CHEMOKINES/CYTOKINES RECRUIT IMMUNE EFFECTOR CELLS THAT MAY PROMOTE TUMOR GROWTH Cell Type – Tumor-promoting Effects Receptors Tumor-derived Chemokines/Cytokines Monocytes/Macrophages (Type 2) – Immunosuppression, proliferation & angiogenesis CCR1, CCR5 CCL3/MIP-1a, CCL4/MIP-1b, CCL5/RANTES, CCL8/MCP-2 CCR2 CCL2/MCP-1 M-CSF R M-CSF Dendritic Cells – Immunosuppression, tumor antigen tolerance, angiogenesis CCR1, CCR5 CCL3/MIP-1a, CCL4/MIP-1b, CCL5/RANTES CCR6 CCL20/MIP-3a, b-Defensin CXCR1, CXCR2 CXCL8/IL-8 CXCR4 CXCL12/SDF-1 Regulatory T Cells (T reg ) & Th2 Cells – Immunosuppression CCR4 CCL17/TARC, CCL22/MDC Myeloid-derived Suppressor Cells – Immunosuppression, proliferation & angiogenesis CCR2 CCL2/MCP-1 CXCR2 CXCL5 CXCR4 CXCL12/SDF-1 Mast Cells – Immunosuppression, proliferation & angiogenesis CCR3 CCL11/Eotaxin CCR5 CCL5/RANTES CXCR4 CXCL12/SDF-1 SCF R/c-kit SCF/c-kit Ligand Neutrophils – Proliferation & angiogenesis CXCR1 CXCL6/GCP-2, CXCL8/IL-8 CXCR2 CXCL1/GROa, CXCL2/GROb, CXCL3/GROg, CXCL5, CXCL8/IL-8 Eosinophils – Angiogenesis CCR3 CCL11/Eotaxin Global [email protected] [email protected] North America TEL 800 343 7475 Europe | Middle East | Africa TEL +44 (0)1235 529449 China [email protected] TEL +86 (21) 52380373 Rest of World bio-techne.com/find-us/distributors TEL +1 612 379 2956 Learn more | rndsystems.com/tumormicroenvironment NOTE: This poster conveys a general overview and should be considered neither comprehensive nor definitive. The details of this information are understood to be subject to interpretation. © 2017 Bio-Techne Microenvironmental Regulation of Tumor Growth & Metastasis bio-techne.com rndsystems.com/ TumorMicroenvironment