Inflammation & Cancer 1. Chronic Inflammation 2 3.

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Presentation transcript:

Inflammation & Cancer 1

Chronic Inflammation 2

3

Ulcerative Colitis 4

5

6

Why would chronic inflammation lead to cancer? The pathogen (e.g., virus) carries an oncogene that is inappropriately expressed. Infection leads to cell death that requires rapid proliferation that is associated with an accumulation of replication-induced mutations. In its effort to clear the infectious agent, the immune system causes some undesirable side-effects. 7

8 Inactive Trypsin

9

Why would chronic inflammation lead to cancer? The pathogen (e.g., virus) carries an oncogene that is inappropriately expressed. Not all chronic inflammation is due to an infectious agent. For those that are, no oncogenes have been identified. Infection leads to cell death that requires rapid proliferation that is associated with an accumulation of replication-induced mutations. The rate of replication-induced mutations is 1:10 9, assuming the repair mechanisms are working properly. In its effort to clear the infectious agent, the immune system causes some undesirable side-effects. 10

11

NSAID Use 12

75 mg aspirin/day for 10 years 13

14

15

16

17

Mouse Models 18

19

20

21

22 Target Genes of NF-kB Cytokines/Chemokines and their Modulators Immunoreceptors Proteins Involved in Antigen Presentation Cell Adhesion Molecules Acute Phase Proteins Stress Response Genes Cell Surface Receptors (-) Regulators of Apoptosis Growth Factors, Ligands and their Modulators Early Response Genes Transcription Factors Enzymes

HOW? 23 DOES?

Paracrine signaling Autocrine signaling cox2 Autocrine signaling through PGE 2 24 ROS/RNS?

25

Paracrine signaling Autocrine signaling cox2 Autocrine signaling through PGE 2 NSAIDs 26

MAPKKK Pathway 27

28 Tumor- Infiltrating Lymphocytes (TILs)

29

Macrophages 30

31 Tumor- Associated Macrophages (TAMs)

CSF-1 = M-CSF

CSF-1

35 CSF-1/M-CSF MCP-1/CCL2 RANTES/CCL5 VEGF PDGF CSF-1

36 MIP-1 

37

38 TNF-  Growth Survival More inflammatory cells COX-2/PGE 2

39 Matrix Metalloproteinases (MMPs)

41

42

43

44

45

47 Lack paracrine support Hydrodynamic sheer forces

48

49