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insight review articles

a b



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


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,


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


NATURE VOL 420 19/26 DECEMBER 2002

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© 2002 Publishing Group

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


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


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-b, PDGF, chemokines (monocyte chemoattractant protein-1, -2 and -3

(MCP-1/CCL2, MCP-2/CCL8 and MCP-3/CCL7), macrophage inflammatory protein-1a and -1b (MIP-1a/CCL3 and MIP-1b/CCL4), and the

cytokines IL-1b and TNF-a. Deployment of monocytes/macrophages to the site of injury peaks as the number of neutrophils decline. Once present,


. After activation, macrophages are the main source of growth factors

however, they differentiate into mature macrophages or immature dendritic cells

and cytokines (TGF-b1, PDGF, bFGF, TGF-a, insulin-like growth factor (IGF)-I and -II, TNF-a and IL-1) that modulate tissue repair. Cells in their local

microenvironment (for example, endothelial, epithelial, mesenchymal or neuroendocrine cells) are profoundly affected by macrophage products.

Macrophages also regulate local tissue remodelling by inducing ECM components, stimulating production of proteolytic enzymes (for example, MMPs

and urokinase-type plasminogen activator (uPA)), clearing apoptotic and necrotic cells, and modulating angiogenesis through local production of

thrombospondin-1 (refs 72, 73).

Following their activation, mast cells are full of stored and newly synthesized inflammatory mediators. This cell type synthesizes and stores

histamine, cytokines and proteases complexed to highly sulphated proteoglycans within granules, and produces lipid mediators and cytokines upon

stimulation. Once activated by complement or by binding of antigens to immunoglobulin E (IgE) bound to high-affinity IgE receptors (Fc;RI), they

degranulate, releasing mediators including heparin, heparanase, histamine, MMPs and serine proteases, and various polypeptide growth factors,


including bFGF and vascular endothelial growth factor . These function both in the early initiation phase of inflammation (for example, vascular reaction

and exudation), and in the late phase where leukocyte accumulation and wound healing takes place.

Chemotactic cytokines

Chemokines are classified into polypeptide groups identified by the location of cysteine residues near their amino termini (for example, C-C, C-X-C, C

and CX C). Chemokines represent the largest family of cytokines (~41 human members), forming a complex network for the chemotactic activation of


all leukocytes. Chemokine receptors, members of the seven-transmembrane-spanning G-protein-coupled receptors, vary by cell type and degree of


cell activation . There is considerable redundancy in chemokine-receptor interaction, as many ligands bind different receptors, or vice versa.

The composition of chemokines produced at sites of tissue wounding not only recruits downstream effector cells (as discussed above), but also

dictates the natural evolution of immune reactivity. For example, MCP-1/CCL2, a potent chemotactic protein for monocytes and lymphocytes,

simultaneously induces expression of lymphocyte-derived IL-4 in response to antigen challenge while decreasing expression of IL-12 (ref. 75). The net

1-type to a T 2-type inflammatory response.

effect of this alteration facilitates a switch from a T


Tissue repair

In response to wounding, fibroblasts migrate into the wound bed and initially secrete collagen type III, which is later replaced by collagen type I.

Synthesis and deposition of these collagens by fibroblasts is stimulated by factors including TGF-b1, -b2 and -b3, PDGF, IL-1a, -1b and -4, and mast

cell tryptase. Once sufficient collagen has been generated, its synthesis is stopped; thus, during wound repair, production as well as the degradation of

collagens is under precise spatial and temporal control.

The final phase of the healing process is re-epithelialization and migration of epithelial cells across this amalgam, in a process that requires both

dissolution of the fibrin clot and degradation of the underlying dermal collagen. Epithelial cells at the leading edge of the wound express the uPA

receptor, which is important for focal activation of uPA, and collagenolytic enzymes of the MMP family. In the absence of the fibrinolytic enzyme


plasmin, derived from plasminogen after activation by uPA and tissue-PA, re-epithelialization is dramatically delayed .

The pro-inflammatory properties of TGF-b, such as leukocyte recruitment, adhesion and regulation of MMP secretion and activation, are balanced


by its ability to also reverse its role, and suppress these events and foster ECM synthesis to mediate tissue repair . As inflammatory cells are activated,


their complement of TGF-b receptors change, resulting in differential susceptibility to TGF-b and enhanced sensitivity to suppression by TGF-b , a

critical event to resolving inflammation.

T cells. During development of melanoma, activated macrophages infiltration is closely associated with the depth of invasion of primary

produce TGF-b, TNF-a, IL-1a, arachidonate metabolites and melanoma due, in part, to macrophage-regulated tumour-associat-

18 19

extracellular proteases ed angiogenesis

. In response, melanocytes express IL-8 and .

vascular endothelial growth factor (VEGF)-A, thereby inducing vas- In addition to altering the local balance of pro-angiogenic factors


cular angiogenesis under paracrine control during melanoma development, during human cervical carcinogen-

. Indeed, macrophage |


NATURE VOL 420 19/26 DECEMBER 2002

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© 2002 Publishing Group insight review articles

mammary epithelium in CSF-1-null/PyMT mice restores

macrophage recruitment, primary tumour development and


metastatic potential . A similar study showed that subcutaneous

op op 22

growth of Lewis lung cancer cells is impaired in Csf1 /Csf1 mice .

In this example, however, tumours displayed a decreased mitotic

index and pronounced necrosis, apparently resulting from dimin-

T 1 cytokines T 2 cytokines ished angiogenesis and impaired tumour-stroma formation. These


(IL-1, TNF-α, IFN-γ, etc.) (IL-1, IL-10, IL-13, etc.) defects were corrected by treatment of tumour-bearing mice with

Pro-inflammatory Anti-inflammatory recombinant CSF-1 (ref. 22). Together, these genetic experiments

provide a causal link between CSF-1-dependent infiltrating

macrophages and the malignant potential of epithelial cells.

Macrophages are not unique among inflammatory cells in poten-

tiation of neoplastic processes. Genetic and functional experiments

indicate that neutrophils, mast cells, eosinophils and activated T

Abundant Altered balance of pro-

Few pro-inflammatory and anti-inflammatory

chemokines lymphocytes also contribute to malignancies by releasing extracellu-

chemokines chemokines

(e.g. ELR(+)CXC) 11,23–26

lar proteases, pro-angiogenic factors and chemokines .

(e.g. ELR(+)CXC) (e.g. ELR(–)CXC)

Limited Cancers associated with chronic inflammation



inflammation How are inflammatory cells co-opted into the neoplastic process? A

inflammation plausible hypothesis is that many malignancies arise from areas of

Restricted Neovascularization Angiostasis

vascularization infection and inflammation, simply as part of the normal host

response. Indeed, there is a growing body of evidence that many

Rapid tumour growth Tumour regression

Restricted 11,27–29

malignancies are initiated by infections (Table 1) — upwards of

tumour growth 15% of malignancies worldwide can be attributed to infections, a


global total of 1.2 million cases per year . Persistent infections within

the host induce chronic inflammation. Leukocytes and other phago-

cytic cells induce DNA damage in proliferating cells, through their

generation of reactive oxygen and nitrogen species that are produced


normally by these cells to fight infection . These species react to form


peroxynitrite, a mutagenic agent . Hence, repeated tissue damage

and regeneration of tissue, in the presence of highly reactive nitrogen

and oxygen species released from inflammatory cells, interacts with

DNA in proliferating epithelium resulting in permanent genomic

alterations such as point mutations, deletions, or rearrangements.

Figure 2 Cytokine and chemokine balances regulate neoplastic outcome. The Indeed, p53 mutations are seen at frequencies similar to those in

balance of cytokines in any given tumour is critical for regulating the type and extent of tumours in chronic inflammatory diseases such as rheumatoid

inflammatory infiltrate that forms. Tumours that produce little or no cytokines or an 31

arthritis and inflammatory bowel disease .

overabundance of anti-inflammatory cytokines induce limited inflammatory and The strongest association of chronic inflammation with malig-

vascular responses, resulting in constrained tumour growth. In contrast, production of nant diseases is in colon carcinogenesis arising in individuals with

an abundance of pro-inflammatory cytokines can lead to a level of inflammation that inflammatory bowel diseases, for example, chronic ulcerative colitis

potentiates angiogenesis, thus favouring neoplastic growth. Alternatively, high levels and Crohn’s disease. Hepatitis C infection in the liver predisposes to

of monocytes and/or neutrophil infiltration, in response to an altered balance of pro- liver carcinoma, an increased risk of bladder and colon carcinoma is

versus anti-inflammatory cytokines, can be associated with cytotoxicity, angiostasis associated with schistosomiasis, whereas chronic Helicobacter pylori

and tumour regression. In tumours, interleukin-10 is generally a product of tumour 32

infection is the world’s leading cause of stomach cancer . The

cells and tumour-associated macrophages. Gram-negative bacterium H. pylori is established as a definite car-

cinogen for the development of gastric cancer — the second most


common type of cancer globally — and DNA damage resulting


from chronic inflammation is believed the mechanism

esis, TAMs express VEGF-C and VEGF-D as well as the VEGF . Exacerbat-

receptor-3 (VEGFR-3), all of which are implicated in formation of ing DNA damage induced by inflammatory cells is expression of


lymphatic vessels and lymphatic metastases macrophage migration inhibitory factor (MIF) from macrophages

. By placing TAMs at the and T lymphocytes. MIF is a potent cytokine that overcomes p53

centre of the recruitment and response to angiogenic and lymphan- 33

function by suppressing its transcriptional activity

giogenic stimuli, they may foster the spread of tumours. TAMs also . Chronic bypass

induce VCAM-1 expression on mesothelial cells, a step also believed of p53 regulatory functions in infiltrated tissues can enhance prolif-


to be key for tumour cell dissemination into the peritoneum eration and extend life span, while also creating an environment with

. a deficient response to DNA damage, amplifying accumulation of

The functional significance of macrophage recruitment to sites of potential oncogenic mutations.

neoplastic growth has been examined by crossing transgenic mice Infectious viral agents, for example, DNA tumour viruses, may

expressing Polyoma virus middle T (PyMT) driven by the mouse also directly transform cells by inserting active oncogenes into the

mammary tumour virus (MMTV) long terminal repeat, which are host genome, although other mechanisms also are responsible.

prone to development of mammary cancer, with mice containing a

op 21 While many types of infectious agents are present in animals, only a

null mutation in the CSF-1 gene (Csf1 ) . Whereas the absence of subset of individuals infected with human papilloma virus, hepatitis

CSF-1 during early neoplastic development is without apparent B virus (HBV) or Epstein-Barr virus develop virus-associated

consequence, development of late-stage invasive carcinoma and pul- malignancies. This may reflect immune suppression, the necessity of

monary metastases are significantly attenuated. The key difference

op op cofactors necessary for promotion or the fact that a neoplasm can

between PyMT mice and PyMT/Csf1 /Csf1 mice is not in the develop only if viral infection has targeted a pluripotent progenitor

apparent proliferative capacity of neoplastic epithelial cells, but in the or stem cell. Such stem cells are typically low in abundance and locat-

failure to recruit mature macrophages into neoplastic tissue in the ed in regions of tissues protected from agents that would otherwise

absence of CSF-1. Targeting CSF-1 expression specifically to

| 863

NATURE VOL 420 19/26 DECEMBER 2002

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© 2002 Publishing Group




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Corso di laurea: Corso di laurea magistrale in medicina e chirurgia (ordinamento U.E. - durata 6 anni) (CASERTA, NAPOLI)

I contenuti di questa pagina costituiscono rielaborazioni personali del Publisher flaviael di informazioni apprese con la frequenza delle lezioni di Patologia e Fisiopatologia Generale e studio autonomo di eventuali libri di riferimento in preparazione dell'esame finale o della tesi. Non devono intendersi come materiale ufficiale dell'università Seconda Università di Napoli SUN - Unina2 o del prof Castoria Gabriella.

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