Inflammatory Cells and Metastasis Experimentelle Krebsforschung SS 07 Gerhard Christofori Institute of Biochemistry and Genetics Department of Clinical-Biological Sciences Center of Biomedicine University of Basel Multiple Events Underlying Metastatic Tumor Cell Dissemination Alberts et al. 2002
Cell autonomous vs.. host contribution Cancer Cells Cancer Cells Immune Cells Fibroblasts Endothelial Cells Hanahan and Weinberg, Cell 2000 Tumor versus Host Tumor cell intrinsic changes (spontaneous) Loss of tumor suppressor function Gain of oncogene function Host predisposition (inheritable; tumor cell or stroma) Loss of tumor suppressor function Gain of oncogene function Modifier genes Host responses (spontaneous or inherited?) Immune system: immune surveillance (anti-cancer) inflammatory responses (pro-cancer) Fibroblasts Endothelium blood vessel angiogenesis lymphatic vessel angiogenesis other stromal cell types Bone marrow-derived cells!
Tumor versus Host Tumor cell intrinsic: predetermined vs. acquired selection vs. adaption Host predisposition: inherited modifier genes Tumor versus Host
The critical role of the tumor stroma: a key experiment (Cunha, Werb,, Bissell, Weinberg) Xenograft transplantation of prostate cancer cells in immuno-deficient mice: Normal prostate + normal stromal cells epithelial cells no tumorigenesis Cancer cells + normal stromal cells low tumorigenesis Normal prostate + cancer stromal cells epithelial cells high tumorigenesis Cancer cells + cancer stromal cells high tumorigenesis Non-metastatic + mesenchymal stem cells metastasis breast cancer cells Activated fibroblasts
Carcinoma-associated fibroblasts (CAFs( CAFs) Fibroblasts and myoepithelial cells in breast cancer
Single cell versus collective cell migration Single cell invasion (+ EMT) collective cell invasion (- EMT) Courtesy of D. Kerjaschki and N. Wick, MUW
TGFβ signalling TGFβ and EMT
Wound Healing Chronic inflammation and cancer Helicobacter pylori - gastric cancer Crohn s disease - intestinal and colon cancer Pancreatitis - pancreas cancer HBV and HCV - liver cancer
Chronic inflammation and cancer Tumor infiltrating bone marrow-derived cells
Inflammatory responses Growth factors Cytokines Chemokines Receptors on bone marrow-derived cells Examples: VEGF-A Angiopoietins MCP-1 SDF-1/CXCL12 SLC/CCL21 Interleukins VEGFR-1 Tie-2 CCR2 CXCR4 CCR7 Il Rec... Immune cells and cancer
Monocytes/Macrophages/Dendritic cells Tumor-associated Macrophages (TAMs( TAMs)
Leukocytes and tumor cell intravasation Inflammation and cancer: what does it look like?
Effects of the immune system on carcinogenesis in experimental mouse models The immune system and cancer
The immune system and cancer: a model Wound Healing
Organ-specific Metastasis (Kaplan et al., Nature. 2005 Dec 8;438(7069):820-7) Xenograft transplantation of prostate cancer cells in syngeneic mice: Lewis lung carcinoma (LLC) lung metastasis B16 Melanoma (B16) liver metastasis + others Cond. Medium B16 + LLC Cond. Medium LLC + B16 liver metastasis + others lung metastasis Upon injection of conditioned medium, fibronectin appears to be expressed in the respective target organ. Next, VEGF-receptor-1-positive, bone marrow-derived cells infiltrate into target organs, only then first tumor cells appear. Molecular details are not known yet. Therapeutic Targets
Novel drugs Tumor angiogenesis (endothelial cells) Bergers and Benjamin, 2002, Nat. Rev. Cancer
Increased microvessel density in tumors (for example ductal breast carcinoma) Vasculogenesis/Angiogenesis Carmeliet, 2003
Multistage tumorigenesis in Rip1Tag2 transgenic mice The angiogenic switch
Cellular Events in Tumor Angiogenesis VEGF Family Members Clinical Science www.clinsci clinsci.org Clin. Sci.. (2005) 109, 227-241
VEGFs and their Receptors Clinical Science www.clinsci clinsci.org Clin. Sci.. (2005) 109, 227-241 Vascular Endothelial Growth Factors and their Receptors
The Angiogenic Switch VEGF sequestered by ECM VEGF released by MMP activity (mast cells, Vascular Endothelial Growth Factor-A Cross et al., TIBS, 2003
Activation of Vascular Endothelial Growth Factor-A Ferrara et al., 2003 Matrix Metalloproteases (MMPs) in cancer Egeblad and Werb, 2002
Vascular remodelling by tumor cells (genes of the 18 gene lung metastasis cluster) Epiregulin Cox-2 MMP-1 MMP-2 SPARC VCAM-1 IL13Rα2. Two Vascular Systems! Jones et al., 2001
Lymphatic vessels Papoutsi et al. Dev. Dyn. 2001 The regulation of lymphangiogenesis
VEGF Family Members and their Receptors ANGIOGENESIS LYMPHANGIOGENESIS Forced Lymphangiogenesis in Rip1VEGF-C Mice wt Rip1VEGF-C Mandriota et al., 2001
Forced Lymphangiogenesis in Rip1Tag2 Mice Rip1Tag2;Rip1VEGF-C LN MET Mandriota et al., 2001 Distinct Mechanisms of Tumor Metastasis?
Selected Reviews Hunter K. (2006) Host genetics influence tumopur metastasis. Nature Rev. Cancer 6, 141-146. Kalluri R and Zeisberg M. (2006) Fibroblasts in cancer. Nature Rev. Cancer 6, 392-401. De Visser KE, Eichten A and Coussens LM (2006) Paradoxical roles of the immune system during cancer development. Nature Rev. Cancer 6, 24-37. Pollard JW. (2004) Tumor-educated macrophages promote tuymour progression and metastasis. Nature Rev. Cancer 4, 71-78. Joyce JA. (2005) Therapeutic targeting of the tumor microenvironment. Cancer Cell 7, 513-520. Stacker SA, Achen MG, Jussila L, Baldwin ME, Alitalo K. Lymphangiogenesis and cancer metastasis. Nat Rev Cancer. 2002 Aug;2(8):573-83. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003 Jun;3(6):401-10.