Patologia e fisiopatologia generale - infiammazione e tumori seconda parte

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 mastcell 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 factors¹⁸.cular angiogenesis under paracrine control during melanoma development, during human cervical carcinogen-. Indeed, macrophage |862 www.nature.com/natureNATURE VOL 420 19/26 DECEMBER 2002| |Nature© 2002 Publishing Group insight review articlesmammary epithelium in CSF-1-null/PyMT mice restoresmacrophage recruitment, primary tumour development and¹²metastatic potential . A similar study showed that subcutaneousop op ²²growth of Lewis lung cancer cells is impaired in Csf1 /Csf1 mice .In this example, however, tumours displayed a decreased mitoticindex and pronounced necrosis, apparently resulting from dimin-T 1 cytokines T 2 cytokines ished angiogenesis and impaired tumour-stroma formation. TheseH H(IL-1, TNF-α, IFN-γ, etc.) (IL-1, IL-10, IL-13, etc.) defects were corrected by treatment of tumour-bearing mice withPro-inflammatory Anti-inflammatory recombinant CSF-1 (ref. 22). Together, these genetic experimentsprovide

A causal link between CSF-1-dependent infiltrating macrophages and the malignant potential of epithelial cells. Macrophages are not unique among inflammatory cells in potentiating neoplastic processes. Genetic and functional experiments indicate that neutrophils, mast cells, eosinophils and activated T lymphocytes also contribute to malignancies by releasing extracellular proteases, pro-angiogenic factors and chemokines.

Abundant Altered balance of pro-inflammatory and anti-inflammatory chemokines lymphocytes also contribute to malignancies by releasing extracellular proteases, pro-angiogenic factors and chemokines (e.g. ELR(+)CXC) 11,23–26.

Limited Cancers associated with chronic inflammation Excessive 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 malignancies are initiated by infections (Table 1) — upwards of 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.

Indeed, p53

Mutations are seen at frequencies similar to those inbalance of cytokines in any given tumour is critical for regulating the type and extent of tumours in chronic inflammatory diseases such as rheumatoidinflammatory infiltrate that forms. Tumours that produce little or no cytokines or an 31arthritis 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 withan abundance of pro-inflammatory cytokines can lead to a level of inflammation that inflammatory bowel diseases, for example, chronic ulcerative colitispotentiates angiogenesis, thus favouring neoplastic growth. Alternatively, high levels and Crohn’s disease. Hepatitis C infection in the liver predisposes toof monocytes and/or neutrophil infiltration, in response

To an altered balance of pro- versus anti-inflammatory cytokines, can be associated with cytotoxicity, angiostasis associated with schistosomiasis, whereas chronic Helicobacter pylori infection is the world's leading cause of stomach cancer. The Gram-negative bacterium H. pylori is established as a definite carcinogen for the development of gastric cancer - the second most common type of cancer globally - and DNA damage resulting from chronic inflammation is believed to be the mechanism. In tumours, interleukin-10 is generally a product of tumour cells and tumour-associated macrophages. TAMs express VEGF-C and VEGF-D as well as the VEGF receptor-3 (VEGFR-3), all of which are implicated in formation of lymphatic vessels and lymphatic metastases. Exacerbating DNA damage induced by inflammatory cells is expression of macrophage migration inhibitory factor (MIF) from macrophages.

By placing TAMs at the centre of the recruitment and response to angiogenic and lymphan-33giogenic stimuli, they may foster the spread of tumours. TAMs also induce VCAM-1 expression on mesothelial cells, a step also believed to be key for tumour cell dissemination into the peritoneum. The functional significance of macrophage recruitment to sites of potential neoplastic growth has been examined by crossing transgenic mice expressing Polyoma virus middle T (PyMT) driven by the mouse 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 aop 21 While many types of infectious agents are present in animals, only anull mutation in the CSF-1 gene (Csf1 ) . Whereas the absence of subset of individuals infected with human papilloma virus, hepatitisCSF-1 during early neoplastic development is without apparent B virus (HBV) or Epstein-Barr virus develop virus-associatedconsequence, development of late-stage invasive carcinoma and pul- malignancies. This may reflect immune suppression, the necessity ofmonary metastases are significantly attenuated. The key differenceop op cofactors necessary for promotion or the fact that a neoplasm canbetween PyMT mice and PyMT/Csf1 /Csf1 mice is not in the develop only if viral infection has targeted a pluripotent progenitorapparent proliferative capacity of neoplastic epithelial cells, but in the or stem cell. Such stem cells are typically

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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 otherwiseabsence of CSF-1. Targeting CSF-1 expression specifically to| 863www.nature.com/natureNATURE VOL 420 19/26 DECEMBER 2002| | Nature© 2002 Publishing Groupinsight review articles34harm them . In Rous sarcoma virus infections, inflammation is

Pathologic condition	Associated neoplasm(s)	Aetiologic agent
Asbestosis, silicosis	Mesothelioma, lung carcinoma	Asbestos fibres, silica35 carcinoma particles
Bronchitis	Lung carcinoma	Silica, asbestos, smoking (nitrosamines, peroxides)

inflammatory cells . Epstein-Barr virus also causes sustained proliferation of B lymphocytes, which, when coupled with a secondary mutation, can result in neoplastic

progression and malignant Cystitis, bladder Bladder carcinoma Chronic indwelling, urinaryconversion to give rise to Burkett’s lymphoma. inflammation catheters

The molecular mechanism behind the associated risk of hepato- Gingivitis, lichen planus Oral squamous cellcellular carcinoma resulting from HBV and/or hepatitis C virus carcinoma(HCV) infection is uncertain. Although there is evidence for clonal Inflammatory bowel Colorectal carcinomadisease, Crohn’s disease,integration of viral DNA in tumours and surrounding parenchyma chronic ulcerative colitiscells, there are no defined transforming sequences found within the Lichen sclerosus Vulvar squamous cellviral genomes that can act as viral oncogenes. Moreover, there is no carcinomaevidence to suggest that viral integration activates either a classical Chronic pancreatitis, Pancreatic carcinoma Alcholism, mutation incellular oncogene or inactivates a cellular tumour suppressor gene. hereditary pancreatitis