Patologia e fisiopatologia generale - infiammazione e tumori seconda parte

insight review articles

Inflammation and cancer

Lisa M. Coussens & Zena Werb

*†§ ‡§

*Cancer Research Institute, Departments of †Pathology and ‡Anatomy, and the §UCSF Comprehensive Cancer Center, University of California,

San Francisco, California 94143 USA (e-mail: coussens@cc.ucsf.edu; zena@itsa.ucsf.edu)

Recent data have expanded the concept that inflammation is a critical component of tumour progression.

Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that

the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable

participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells

have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines

and their receptors for invasion, migration and metastasis. These insights are fostering new anti-

inflammatory therapeutic approaches to cancer development.

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reconstitution of the normal microenvironment

he functional relationship between . These

inflammation and cancer is not new. In 1863, steps involve: activation of members of the selectin family of

Virchow hypothesized that the origin of cancer adhesion molecules (L- P-, and E-selectin) that facilitate

was at sites of chronic inflammation, in part rolling along the vascular endothelium; triggering of signals

based on his hypothesis that some classes of that activate and upregulate leukocyte integrins mediated by

irritants, together with the tissue injury and ensuing cytokines and leukocyte-activating molecules; immobiliza-

1

inflammation they cause, enhance cell proliferation tion of neutrophils on the surface of the vascular endotheli-

. a b a b

um by means of tight adhesion through

Although it is now clear that proliferation of cells alone does and

4 1 4 7

not cause cancer, sustained cell proliferation in an integrins binding to endothelial vascular cell-adhesion

environment rich in inflammatory cells, growth factors, molecule-1 (VCAM-1) and MadCAM-1, respectively; and

activated stroma, and DNA-damage-promoting agents, transmigration through the endothelium to sites of injury,

certainly potentiates and/or promotes neoplastic risk. presumably facilitated by extracellular proteases, such as

During tissue injury associated with wounding, cell matrix metalloproteinases (MMPs).

proliferation is enhanced while the tissue regenerates; A family of chemotactic cytokines, named chemokines,

proliferation and inflammation subside after the assaulting which possess a relatively high degree of specificity for

1,6,7

agent is removed or the repair completed. In contrast, chemoattraction of specific leukocyte populations ,

proliferating cells that sustain DNA damage and/or recruits downstream effector cells and dictates the natural

mutagenic assault (for example, initiated cells) continue to evolution of the inflammatory response. The profile of

proliferate in microenvironments rich in inflammatory cells cytokine/chemokines persisting at an inflammatory site is

and growth/survival factors that support their growth. In a important in the development of chronic disease. The pro-

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sense, tumours act as wounds that fail to heal inflammatory cytokine TNF-a (tumour necrosis factor-a)

. controls inflammatory cell populations as well as mediating

Today, the causal relationship between inflammation, many of the other aspects of the inflammatory process.

innate immunity and cancer is more widely accepted; howev- TGF-b1 is also important, both positively and negatively

er, many of the molecular and cellular mechanisms mediating 8

influencing the processes of inflammation and repair

this relationship remain unresolved — these are the focus of . The

this review. Furthermore, tumour cells may usurp key mecha- key concept is that normal inflammation — for example,

nisms by which inflammation interfaces with cancers, to inflammation associated with wound healing — is usually

further their colonization of the host. Although the acquired self-limiting; however, dysregulation of any of the converging

immune response to cancer is intimately related to the inflam- factors can lead to abnormalities and ultimately, pathogenesis

matory response, this topic is beyond the scope of this article, — this seems to be the case during neoplastic progression.

3,4

but readers are referred to several excellent reviews Neutrophils (and sometimes eosinophils) are the first

. recruited effectors of the acute inflammatory response.

An overview of inflammation Monocytes, which differentiate into macrophages in

tissues, are next to migrate to the site of tissue injury, guided

To understand the role of inflammation in the evolution of by chemotactic factors. Once activated, macrophages are

cancer, it is important to understand what inflammation is the main source of growth factors and cytokines, which pro-

and how it contributes to physiological and pathological foundly affect endothelial, epithelial and mesenchymal cells

processes such as wound healing and infection (Fig. 1). In in the local microenvironment. Mast cells are also impor-

response to tissue injury, a multifactorial network of chemi- tant in acute inflammation owing to their release of stored

cal signals initiate and maintain a host response designed to and newly synthesized inflammatory mediators, such as

‘heal’ the afflicted tissue. This involves activation and directed histamine, cytokines and proteases complexed to highly

migration of leukocytes (neutrophils, monocytes and sulphated proteoglycans, as well as lipid mediators.

eosinophils) from the venous system to sites of damage

(Box 1), and tissue mast cells also have a significant role. For Inflammation and neoplastic progression

neutrophils, a four-step mechanism is believed to coordinate

recruitment of these inflammatory cells to sites of tissue Peyton Rous was the first to recognize that cancers develop

injury and to the provisional extracellular matrix (ECM) that from “subthreshold neoplastic states” caused by viral or

9,10

forms a scaffolding upon which fibroblast and endothelial chemical carcinogens that induce somatic changes .

cells proliferate and migrate, thus providing a nidus for These states, now known as ‘initiation’, involve DNA alter-

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a b

Dermis

Fat

Epithelial cell and basement membrane Endothelial cells and capillary support cells Platelets and fibrin clot

(pericytes, smooth muscle cells)

Neutrophils Lymphocytes Mast cells/eosinophils/basophils Cytokines/chemokines

Malignant epithelial cells

Macrophage/monocyte Fibroblasts and fibrillar collagens

Figure 1 Wound healing versus invasive tumour growth. a, Normal tissues have a highly organized and segregated architecture. Epithelial cells sit atop a basement membrane

separated from the vascularized stromal (dermis) compartment. Upon wounding or tissue assault, platelets are activated and form a haemostatic plug where they release vasoactive

mediators that regulate vascular permeability, influx of serum fibrinogen, and formation of the fibrin clot. Chemotactic factors such as transforming growth factor-b and platelet-

derived growth factor, derived from activated platelets, initiate granulation tissue formation, activation of fibroblasts, and induction and activation of proteolytic enzymes necessary

for remodelling of the extracellular matrix (for example, matrix metalloproteinases and urokinase-type plasminogen activator). In combination, granulocytes, monocytes and

fibroblasts are recruited, the venous network restored, and re-epithelialization across the wound occurs. Epithelial and stromal cell types engage in a reciprocal signalling dialogue

to facilitate healing. Once the wound is healed, the reciprocal signalling subsides. b, Invasive carcinomas are less organized. Neoplasia-associated angiogenesis and

lymphangiogenesis produces a chaotic vascular organization of blood vessels and lymphatics where neoplastic cells interact with other cell types (mesenchymal, haematopoietic

and lymphoid) and a remodelled extracellular matrix. Although the vascular network is not disrupted in the same way during neoplastic progression as it is during wounding, many

reciprocal interactions occur in parallel. Neoplastic cells produce an array of cytokines and chemokines that are mitogenic and/or chemoattractants for granulocytes, mast cells,

monocytes/macrophages, fibroblasts and endothelial cells. In addition, activated fibroblasts and infiltrating inflammatory cells secrete proteolytic enzymes, cytokines and

chemokines, which are mitogenic for neoplastic cells, as well as endothelial cells involved in neoangiogenesis and lymphangiogenesis. These factors potentiate tumour growth,

stimulate angiogenesis, induce fibroblast migration and maturation, and enable metastatic spread via engagement with either the venous or lymphatic networks.

well as lymphocytes — all of which are capable of producing an

ations, are irreversible and can persist in otherwise normal tissue assorted array of cytokines, cytotoxic mediators including reactive

indefinitely until the occurrence of a second type of stimulation (now oxygen species, serine and cysteine proteases, MMPs and membrane-

referred to as ‘promotion’). Promotion can result from exposure of perforating agents, and soluble mediators of cell killing, such as

initiated cells to chemical irritants, such as phorbol esters, factors 11,12

TNF-a, interleukins and interferons (IFNs)

released at the site of wounding, partial organ resection, hormones or .

chronic irritation and inflammation (Fig. 1). Functionally, many Monocytes, in the presence of granulocyte–macrophage colony-

promoters, whether directly or indirectly, induce cell proliferation, stimulating factor (GM-CSF) and interleukin (IL)-4, differentiate

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recruit inflammatory cells, increase production of reactive oxygen into immature dendritic cells . Dendritic cells migrate into inflamed

species leading to oxidative DNA damage, and reduce DNA repair. peripheral tissue where they capture antigens and, after maturation,

Subversion of cell death and/or repair programmes occurs in migrate to lymph nodes to stimulate T-lymphocyte activation.

chronically inflamed tissues, thus resulting in DNA replication and Soluble factors such as IL-6 and CSF-1, derived from neoplastic cells,

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proliferation of cells that have lost normal growth control. Normal push myeloid precursors towards a macrophage-like phenotype .

inflammation is self-limiting, because the production of anti- Interestingly, dendritic cells found in neoplastic infiltrates are

inflammatory cytokines follows the pro-inflammatory cytokines frequently immature and defective in T-cell stimulatory capacity.

closely (Fig. 2). However, chronic inflammation seems to be due to Tumour-associated macrophages (TAMs) are a significant

persistence of the initiating factors or a failure of mechanisms component of inflammatory infiltrates in neoplastic tissues and are

required for resolving the inflammatory response. Why does the derived from monocytes that are recruited largely by monocyte

inflammatory response to tumours persist? chemotactic protein (MCP) chemokines. TAMs have a dual role in

neoplasms — although they may kill neoplastic cells following acti-

vation by IL-2, interferon and IL-12 (refs 15, 16), TAMs produce a

Inflammatory cell component of tumours number of potent angiogenic and lymphangiogenic growth factors,

Tumour cells produce various cytokines and chemokines that attract cytokines and proteases, all of which are mediators that potentiate

leukocytes. The inflammatory component of a developing neoplasm 17

neoplastic progression

may include a diverse leukocyte population — for example, neu- . TAMs and tumour cells also produce IL-10,

trophils, dendritic cells, macrophages, eosinophils and mast cells, as which effectively blunts the anti-tumour response by cytotoxic

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insight review articles

Box 1

Wound healing as an example of physiological inflammation

Cellular components a-granule

Platelet activation and aggregation, in addition to accelerating coagulation, provide a bolus of secreted proteins and contents to the

immediate area, all of which help initiate and accelerate the inflammatory response by the host. Examples of such secreted proteins include

arachodonic acid metabolites, heparin, serotonin, thrombin, coagulation factors (factor V), adhesive proteins (fibrinogen and von Willebrand factor),

plasma proteins (immunoglobulin-g and albumin), cell growth factors (platelet-derived growth factor (PDGF), platelet-derived angiogenesis factor,

transforming growth factor-a (TGF-a), TGF-b and basic fibroblast growth factor (bFGF)), enzymes (heparanase and factor XIII) and protease inhibitors

a2-macroglobulin a2-antiplasmin).

(plasminogen activator inhibitor-1, and Following platelet-induced haemostasis and release of TGF-b1 and PDGF,

formation of granulation tissue is facilitated by chemotaxis of neutrophils, monocytes, fibroblasts and myofibroblasts, as well as by synthesis of new

extracellular matrix (ECM) and neoangiogenesis.

Neutrophil chemotaxis is stimulated by factors such as circulating complement factor 5 (C5a), leukotriene B4, kallikrein, bacterial products (if

present) and numerous factors released from platelets at the site (for example, PDGF, TGF-b, platelet-activating factor and platelet factor-4 (PF-4)).

Although terminally differentiated with little biosynthetic machinery, neutrophils are capable of considerable production of cytokines/chemokines

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necessary for effector cell recruitment, activation and response . These phagocytic cells initiate wound healing by serving as a source of early-

68 69

, and interleukin (IL)-1a and IL-1b . These cytokines mediate

response pro-inflammatory cytokines such as tumour necrosis factor-a (TNF-a)

leukocyte adherence to the vascular endothelium, thus targeting and restricting leukocytes to areas of repair, and initiate repair by inducing expression

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of matrix metalloproteinases (MMPs) and keratinocyte growth factor (KGF/FGF-7) by fibroblasts .

In response to tissue injury, mononuclear phagocytes (that is, macrophage progenitors) migrate from the venous system to the site of tissue injury.

They are guided to the site by chemotactic factors, including PF-4, TGF-