inflammatory cells and metastasis - fmi · inflammatory cells and metastasis experimentelle...
TRANSCRIPT
1
Gerhard ChristoforiGerhard Christofori
Institute of Biochemistry and GeneticsInstitute of Biochemistry and GeneticsDepartment of Clinical-Biological SciencesDepartment of Clinical-Biological Sciences
Center of BiomedicineCenter of BiomedicineUniversity of BaselUniversity of Basel
Inflammatory Cells andInflammatory Cells andMetastasisMetastasis
Experimentelle KrebsforschungExperimentelle KrebsforschungSS 07SS 07
Multiple Events UnderlyingMultiple Events Underlying Metastatic Metastatic Tumor Cell DisseminationTumor Cell Dissemination
Alberts et al. 2002
2
Hanahan and Weinberg, Cell 2000
Cancer CellsCancer Cells Cancer CellsCancer Cells FibroblastsFibroblasts
Endothelial CellsEndothelial Cells
Immune CellsImmune Cells
Cell autonomous Cell autonomous vsvs. host contribution. host contribution
Tumor versus HostTumor versus Host
Tumor cell intrinsic changes (spontaneous)Loss of tumor suppressor functionGain of oncogene function
Host predisposition (inheritable; tumor cell or stroma)Loss of tumor suppressor functionGain of oncogene function“Modifier genes”
Host responses (spontaneous or inherited?)Immune system:
immune surveillance (anti-cancer)inflammatory responses (pro-cancer)
FibroblastsEndothelium
blood vessel angiogenesislymphatic vessel angiogenesis
other stromal cell typesBone marrow-derived cells!
3
Tumor versus HostTumor versus Host
Tumor cell intrinsic:
predetermined vs. acquired selection vs. adaption
Host predisposition:
inheritedmodifier genes
Tumor versus HostTumor versus Host
4
The critical role of the tumor The critical role of the tumor stromastroma::a key experimenta key experiment
((CunhaCunha, , WerbWerb, Bissell, Weinberg), Bissell, Weinberg)
Xenograft transplantation of prostate cancer cells in immuno-deficient mice:
Normal prostate + normal stromal cells no tumorigenesisepithelial cells
Cancer cells + normal stromal cells low tumorigenesis
Normal prostate + cancer stromal cells high tumorigenesisepithelial cells
Cancer cells + cancer stromal cells high tumorigenesis
Non-metastatic + mesenchymal stem cells metastasisbreast cancer cells
Activated fibroblastsActivated fibroblasts
5
Carcinoma-associated fibroblasts (Carcinoma-associated fibroblasts (CAFsCAFs))
Fibroblasts and Fibroblasts and myoepithelial myoepithelial cellscellsin breast cancerin breast cancer
6
Single cell versus collective cell migrationSingle cell versus collective cell migration
Courtesy of D. Kerjaschki and N. Wick, MUW
Single cell invasion(+ EMT)
collective cell invasion(- EMT)
7
TGFTGFββ signalling signalling
TGFTGFββ and EMTand EMT
8
Wound HealingWound Healing
Chronic inflammation and cancerChronic inflammation and cancer
Helicobacter pylori - gastric cancerHelicobacter pylori - gastric cancerCrohnCrohn’’s s disease - intestinal and colon cancerdisease - intestinal and colon cancerPancreatitis Pancreatitis - pancreas cancer- pancreas cancerHBV and HCV - liver cancerHBV and HCV - liver cancer………………
9
Chronic inflammation and cancerChronic inflammation and cancer
Tumor infiltrating bone marrow-derived cellsTumor infiltrating bone marrow-derived cells
10
Inflammatory responsesInflammatory responses
Growth factorsCytokinesChemokines
Receptors on bone marrow-derived cells
Examples:
VEGF-A VEGFR-1Angiopoietins Tie-2MCP-1 CCR2SDF-1/CXCL12 CXCR4SLC/CCL21 CCR7Interleukins Il Rec.……… ……..
Immune cells and cancerImmune cells and cancer
11
Monocytes/Macrophages/Dendritic Monocytes/Macrophages/Dendritic cellscells
Tumor-associated Macrophages (Tumor-associated Macrophages (TAMsTAMs))
12
Leukocytes and tumor cell Leukocytes and tumor cell intravasationintravasation
Inflammation and cancer: what does it look like?Inflammation and cancer: what does it look like?
13
Effects of the immune system on carcinogenesis Effects of the immune system on carcinogenesis in experimental mouse modelsin experimental mouse models
The immune system and cancerThe immune system and cancer
14
The immune system and cancer: a modelThe immune system and cancer: a model
Wound HealingWound Healing
15
Organ-specific MetastasisOrgan-specific Metastasis(Kaplan et al., (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 liver metastasis + others+ LLC
Cond. Medium LLC lung metastasis+ B16
Upon injection of conditioned medium, fibronectin appears to be expressed in the respectivetarget organ. Next, VEGF-receptor-1-positive, bone marrow-derived cells infiltrate into targetorgans, only then first tumor cells appear.Molecular details are not known yet.
Therapeutic TargetsTherapeutic Targets
16
Novel drugsNovel drugs……
Tumor angiogenesis (endothelial cells) Tumor angiogenesis (endothelial cells)
Bergers and Benjamin, 2002, Nat. Rev. Cancer
17
Increased Increased microvessel microvessel density in tumorsdensity in tumors(for example (for example ductal ductal breast carcinoma)breast carcinoma)
Vasculogenesis/AngiogenesisVasculogenesis/Angiogenesis
Carmeliet, 2003
18
Multistage Multistage tumorigenesis tumorigenesis in Rip1Tag2 transgenic micein Rip1Tag2 transgenic mice
““The The angiogenic angiogenic switchswitch””
19
Cellular Events in Tumor Angiogenesis Cellular Events in Tumor Angiogenesis
Clinical Science www.Clinical Science www.clinsciclinsci.org .org ClinClin. . SciSci. (2005) 109, 227-241. (2005) 109, 227-241
VEGF Family MembersVEGF Family Members
20
Clinical Science www.Clinical Science www.clinsciclinsci.org .org ClinClin. . SciSci. (2005) 109, 227-241. (2005) 109, 227-241
VEGFs VEGFs and theirand their ReceptorsReceptors
Vascular Endothelial Growth FactorsVascular Endothelial Growth Factors
and their Receptorsand their Receptors
21
TheThe Angiogenic Angiogenic SwitchSwitch
VEGF sequestered by ECM
VEGF released by MMP activity(mast cells,
Vascular Endothelial Growth Factor-AVascular Endothelial Growth Factor-A
Cross et al., TIBS, 2003
22
Activation ofActivation ofVascular Endothelial Growth Factor-AVascular Endothelial Growth Factor-A
Ferrara et al., 2003
Matrix Matrix Metalloproteases Metalloproteases ((MMPsMMPs)) in cancerin cancer
Egeblad and Werb, 2002
23
Vascular Vascular remodelling remodelling by tumor cellsby tumor cells(genes of the 18 gene lung metastasis cluster)(genes of the 18 gene lung metastasis cluster)
EpiregulinEpiregulinCox-2Cox-2MMP-1MMP-1MMP-2MMP-2
SPARCSPARCVCAM-1VCAM-1IL13RIL13Rαα22…………..
Two Vascular Systems!Two Vascular Systems!
Jones et al., 2001
24
Lymphatic vesselsLymphatic vessels
Papoutsi et al. Dev. Dyn. 2001
The regulation of The regulation of lymphangiogenesis lymphangiogenesis
25
VEGF Family Members and their ReceptorsVEGF Family Members and their Receptors
ANGIOGENESIS LYMPHANGIOGENESIS
Rip1VEGF-C
wt
ForcedForced Lymphangiogenesis Lymphangiogenesis in Rip1VEGF-C Mice in Rip1VEGF-C Mice
Mandriota et al., 2001
26
Rip1Tag2;Rip1VEGF-C
METLN
ForcedForced Lymphangiogenesis Lymphangiogenesis in Rip1Tag2 Mice in Rip1Tag2 Mice
Mandriota et al., 2001
Distinct Mechanisms of Tumor Metastasis? Distinct Mechanisms of Tumor Metastasis?
27
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 immunesystem during cancer development. Nature Rev. Cancer 6, 24-37.
Pollard JW. (2004) Tumor-educated macrophages promote tuymour progression andmetastasis. 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 andcancer 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.