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.