Patologia e fisiopatologia generale - infiammazione e tumori seconda parte
insight review articles
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
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
| | | Nature
© 2002 Publishing Group
insight review articles
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
(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-
, 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.
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
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-
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
© 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-
(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
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
NATURE VOL 420 19/26 DECEMBER 2002
| | Nature
© 2002 Publishing Group
+1 anno fa
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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