1. Inflammation and Cancer
Pin Ling (凌 斌), Ph.D.
ext 5632;
References:
“Hallmarks of Cancer: The Next Generation” (Cell, 2011)
“Paradoxical roles of immune system during cancer development” (Nat Rev. Cancer, 2006)
Insight Review on Inflammation (Nature, 2008, July)

2. Outline Roles of the immune system in cancer development
Overview of Inflammation
Inflammation, The NF-kB pathway, and Cancer Development
Tumor-Associated Macrophages and Cancer

3. Cancer development & Microenvironment
Cancers are not only autonomous masses of mutant cells.
=> Composed of other cell types?
=> fibroblasts, epithelial cells, “immune cells”, cells forming blood & lymphatic vessels, & mesenchymal cells.
2. “Tissue homeostasis” is maintained by coordinated interactions between these diverse cell types.
=> How about cancer?
=> Cancerous cells hijack the normal physiological
process to favour their own survival.
3. Most cancers found in clinical are already the outcome of hijacking microenvironment by malignant cells
Here we focus on the relationship between the immune cells and cancers.

4. Paradoxical roles of the immune system in cancer development
The key functions of the mammalian immune system:
(1) Protect from infectious pathogens
(2) Monitor tissue homeostasis => Eliminate damaged
cells or tumor cells
Mechanisms against cancer development:
(1) Cellular immunity- T, NK, & Other innate immune cells
(2) Humoral immunity- Cytokines, Abs, ..etc
3. Mechanisms promoting cancer development:
(1) Inflammation => Angiogenesis & Tissue remodelling
(2) Enhance survival pathways (NF-kB)
(3) Suppression of anti-tumor immune responses

5. Most cancers outplay the immune system
Cancers display the signs of inflammation -infiltration of immune cells
HE Stain
Most cancers outplay the immune system
CD45 Stain
(all immune cells)
=> Escape from cytotoxic T cell attacks => Make other immune cells help their survival

6. The complex relationship between the immune system and cancers-I
1. Adaptive and innate immune cells regulate tissue homeostasis and efficient wound healing
2. Altered interactions between adaptive and innate immune cells can lead to “chronic inflammatory disorders”.
Chronic inflammatory conditions enhance a predisposition to cancer development.
4. In cancers, an abundance of infiltrating innate immune cells (e.g. macrophages, mast cells, and neutrophils) correlates with increased angiogenesis and/or poor prognosis.

7. The complex relationship between the immune system and cancers-II
5. Long-term usage of non-steroidal anti-inflammatory drugs and selective cyclooxygenase 2 (COX2) inhibitors reduces cancer incidence.
6. In cancers, an abundance of infiltrating lymphocytes correlates with favourable prognosis.
7. Activation of anti-tumour adaptive immune responses can suppress tumour growth
8. Polymorphisms in genes that regulate immune balance influence cancer risk.
9. Genetic elimination or depletion of immune cells alters cancer progression in experimental models.

8. Outline Overview of Inflammation
Roles of the immune system in cancer development
Overview of Inflammation
Inflammation, The NF-kB pathway, and Cancer Development
Tumor-Associated Macrophages and Cancer

9. Key Concepts about Inflammation-I
Inflammation- A physiological process whereby tissues respond to infectious & non-infectious insults (also called sterile inflammation, including toxic, traumatic, or autoimmune insults).
2. Four key signs:
(1) Redness (2)Swelling (3) Heat (4)Pain
This process includes several phases:
(1) Initial phase-Changes in local blood flow & accumulation of inflammatory cells (neutrophiles, macrophages, DCs, & lymphocytes)
(2) Middle phase-Resolution of initial insults
(3) Final phase-Termination of inflammation & tissue repair

10. Causes & Outcomes of Inflammation

11. The Inflammatory Pathway

12. Inflammation in innate and adaptive immunity
Inflammatory cells, cytokines, & chemokines are major effectors in this process.

13. PRRs for sensing infectious & endogenous stimuli
1. PRRs (Pattern
Recognition Receptor) for:
(1) PAMPs from pathogens
(2) DAMPs (Danger
Associated Molecular
Patterns) from host cells
2. Deregulated immune
responses to these stimuli
leading to
Infectious diseases
Autoimmune disorders
Allergy
“Cancer development”

14. An infection case of inflammation

15. Macrophages release cytokines and initiate an inflammation response during infection

16. Leukocytes transmigrate to infection sites

17. Trafficking molecules in the multi-step adhesion cascade

18. An overview of leukocyte migration at sites of inflammation

19. Inflammatory cytokines secreted by macrophages
(IL-8)

20. Resolution of acute inflammation
Lipid mediator class switching: PGE2, Leukotrienes => Lipoxins

21. Lipid mediators in Pro- & Anti-inflammatory responses

22. Role of macrophages in resolution of inflammation

23. Key Concepts about Inflammation-II
Dysregulation of any step in the inflammation process leads to diseases.
While acute inflammation is a part of the defense response, chronic inflammation leads to inflammatory disorders, diabetes, atherosclerosis, & “Cancer.”
Malignant cells actively turn the inflammation process to become the chronic status.
Chronic inflammation creates a microenvironment for cancer progression.

24. Outline Roles of the immune system in cancer development
Overview of Inflammation
Inflammation, The NF-kB pathway, and Cancer Development
Tumor-Associated Macrophages and Cancer

25. Question
Q: Whether all the inflammation is the same?

26. Role of chronic inflammation in promoting cancer development

27. Pathways connecting inflammation & cancers

28. Oncogenes & Cancer-related Inflammation

29. Hallmarks of Cancer-2000
Inflammation
Inflammation
Inflammation

30. Inflammation is the 7th hallmark of cancer
Mantovani, A., Nature, 20091

31. Hallmarks of Cancer-2011 Hanahan, D. & Weunberg, RA, Cell , 2011
Emerging Hallmarks and Enabling Characteristics.
An increasing body of research suggests that two additional hallmarks of cancer are involved in the pathogenesis of some and perhaps all cancers. One involves the capability to modify, or reprogram, cellular metabolism in order to most effectively support neoplastic proliferation. The second allows cancer cells to evade immunological destruction, in particular by T and B lymphocytes, macrophages, and natural killer cells. Because neither capability is yet generalized and fully validated, they are labeled as emerging hallmarks. Additionally, two consequential characteristics of neoplasia facilitate acquisition of both core and emerging hallmarks. Genomic instability and thus mutability endow cancer cells with genetic alterations that drive tumor progression. Inflammation by innate immune cells designed to fight infections and heal wounds can instead result in their inadvertent support of multiple hallmark capabilities, thereby manifesting the now widely appreciated tumor-promoting consequences of inflammatory responses.
Hanahan, D. & Weunberg, RA, Cell , 2011

32. Targeting of Hallmarks of Cancer
Therapeutic Targeting of the Hallmarks of Cancer.
Drugs that interfere with each of the acquired capabilities necessary for tumor growth and progression have been developed and are in clinical trials or in some cases approved for clinical use in treating certain forms of human cancer. Additionally, the investigational drugs are being developed to target each of the enabling characteristics and emerging hallmarks depicted in Figure 3, which also hold promise as cancer therapeutics. The drugs listed are but illustrative examples; there is a deep pipeline of candidate drugs with different molecular targets and modes of action in development for most of these hallmarks.
Hanahan, D. & Weunberg, RA, Cell , 2011

33. Inflammatory network in cancer
The NF-kB pathway is the key underlying pathway promoting cancer

34. The NF-kB Pathway
Inflammation
Innate immune
responses
3. Survival

35. NF-kB induces cytokines to promote tumor survival

36. Association of inflammation with cancers

39. Outline Roles of the immune system in cancer development
Overview of Inflammation
Inflammation, The NF-kB pathway, and Cancer Development
Tumor-Associated Macrophages and Cancer

40. A model of innate & adaptive immune cells in cancer development

41. Cancer cell necrosis promotes tumor progression by recruiting macrophages

42. Tumor-associated macrophages in promoting cancer

43. Macrophage polarization during tumor progression

44. The End & Thank You

45. Figure 1 The Hallmarks of Cancer.
This illustration encompasses the six hallmark capabilities originally proposed in our 2000 perspective. The past decade has witnessed remarkable progress toward understanding the mechanistic underpinnings of each hallmark.
Source: Cell , Volume 144, Issue 5, Pages (DOI: /j.cell )
Copyright © 2011 Elsevier Inc. Terms and Conditions

46. Figure 4 The Cells of the Tumor Microenvironment.
(Upper) An assemblage of distinct cell types constitutes most solid tumors. Both the parenchyma and stroma of tumors contain distinct cell types and subtypes that collectively enable tumor growth and progression. Notably, the immune inflammatory cells present in tumors can include both tumor-promoting as well as tumor-killing subclasses.(Lower) The distinctive microenvironments of tumors. The multiple stromal cell types create a succession of tumor microenvironments that change as tumors invade normal tissue and thereafter seed and colonize distant tissues. The abundance, histologic organization, and phenotypic characteristics of the stromal cell types, as well as of the extracellular matrix (hatched background), evolve during progression, thereby enabling primary, invasive, and then metastatic growth. The surrounding normal cells of the primary and metastatic sites, shown only schematically, likely also affect the character of the various neoplastic microenvironments. (Not shown are the premalignant stages in tumorigenesis, which also have distinctive microenvironments that are created by the abundance and characteristics of the assembled cells.)
Source: Cell , Volume 144, Issue 5, Pages (DOI: /j.cell )
Copyright © 2011 Elsevier Inc. Terms and Conditions

48. Lipid mediators in Pro- & Anti-inflammatory responses