Inflammation and Cancer: Is the Link as Simple as We Think?
2005; Elsevier BV; Volume: 124; Issue: 6 Linguagem: Inglês
10.1111/j.0022-202x.2005.23724.x
ISSN1523-1747
AutoresBrian J. Nickoloff, Yinon Ben‐Neriah, Eli Pikarsky,
Tópico(s)Skin Protection and Aging
Resumonuclear factor-κB transforming growth factor β tumor necrosis factor-α For investigative cutaneous biologists a link between inflammation and skin cancer is a topic frequently discussed when multi-stage chemical carcinogenesis and photocarcinogenesis models are presented. Indeed, the inflammatory process includes the release of cytokines, growth factors, chemotactic polypeptides, and prostaglandins, which have become favorite targets for prevention of chemical induced as well as UV-light-induced skin cancer (Marks and Furstenberger, 2000Marks F. Furstenberger G. Cancer chemoprevention through interruption of multistage carcinogenesis. The lessons learnt by comparing mouse skin carcinogenesis and human large bowel cancer.Eur J Cancer. 2000; 36: 314-329Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar; Tripp et al., 2003Tripp C.S. Blomme E.A. Chinn K.S. Hardy M.M. LaCelle P. Pentland A.P. Epidermal COX-2 induction following ultraviolet irradiation: Suggested mechanism for the role of COX-2 inhibition in photoprotection.J Invest Dermatol. 2003; 121: 853-861Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar; Wilgus et al., 2003Wilgus T.A. Koki A.T. Zweifel B.S. Kusewitt D.F. Rubal P.A. Oberyszyn T.M. Inhibition of cutaneous ultraviolet light B-mediated inflammation and tumor formation with topical celecoxib treatment.Mol Carcinogen. 2003; 38: 49-58Crossref PubMed Scopus (128) Google Scholar; Bowden, 2004Bowden G.T. Prevention of non-melanoma skin cancer by targeting ultraviolet-B-light signalling.Nat Rev Cancer. 2004; 4: 23-35Crossref PubMed Scopus (319) Google Scholar). Dissecting the mediators of inflammation in cutaneous carcinogenic pathways has revealed key roles for prostaglandins, cyclooxygenase-2, tumor necrosis factor-α (TNF-α), AP-1, nuclear factor-κB (NF-κB), signal transducer and activator of transcription (STAT)3, and others (Buckman et al., 1998Buckman S.Y. Gresham A. Hale P. Hruza G. Anast J. Masferrer J. Pentland A.P. COX-2 expression is induced by UVB exposure in human skin: Implications for the development of skin cancer.Carcinogenesis. 1998; 19: 723-729Crossref PubMed Scopus (491) Google Scholar; Moore et al., 1999Moore R.J. Owens D.M. Stamp G. et al.Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis.Nat Med. 1999; 5: 828-831Crossref PubMed Scopus (723) Google Scholar; Suganuma et al., 1999Suganuma M. Okabe S. Marino M.W. Sakai A. Sueoka E. Fujiki H. Essential role of tumor necrosis factor alpha (TNF-alpha) in tumor promotion as revealed by TNF-alpha-deficient mice.Cancer Res. 1999; 59: 4516-4518PubMed Google Scholar; Young et al., 1999Young M.R. Li J.J. Rincon M. Flavell R.A. Sathyanarayana B.K. Hunziker R. Colburn N. Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion.Proc Natl Acad Sci USA. 1999; 96: 9827-9832Crossref PubMed Scopus (365) Google Scholar; Chan et al., 2004Chan K.S. Sano S. Kiguchi K. Anders J. Komazawa N. Takeda J. DiGiovanni J. Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis.J Clin Invest. 2004; 114: 720-728Crossref PubMed Scopus (296) Google Scholar; Lind et al., 2004Lind M.H. Rozell B. Wallin R.P. van Hogerlinden M. Ljunggren H.G. Toftgard R. Sur I. Tumor necrosis factor receptor 1-mediated signaling is required for skin cancer development induced by NF-kappaB inhibition.Proc Natl Acad Sci USA. 2004; 101: 4972-4977Crossref PubMed Scopus (87) Google Scholar). Besides these experimental results, several clinical conditions associated with inflammation appear to predispose the patient to increased susceptibility for skin cancer including discoid lupus erythematosus, dystrophic epidermolysis bullosa, and chronic wound sites. Despite this vast collection of data and clinical observations, however, there are several dermatological settings in which chronic, and even lifelong, skin diseases associated with inflammation do not predispose to conversion of lesions into malignancies such as psoriasis, atopic dermatitis, and Darier's disease. The purpose of this commentary is to summarize a rapidly accumulating body of evidence providing new molecular insights linking inflammation with the promotion of tumorigenesis, and to remind the reader that such a link may not be as simple as currently portrayed because certain types of inflammatory processes in skin (and possibly other tissues as well) may also serve a tumor suppressor function. Here we focus on such a dualistic viewpoint, and offer a new perspective on potential molecular mechanisms that regulate the pro-oncogenic, as well as the tumor suppressor, effects of chronic inflammation, and tumor development using psoriasis as our primary disease model. Over the past few months, several publications in leading biomedical journals grappled with an important issue in oncology, namely, defining potential links between chronic tissue damage, inflammation, and the development of cancer (Beachy et al., 2004Beachy P.A. Karhadkar S.S. Berman D.M. Mending and malignancy.Nature. 2004; 431: 402Crossref PubMed Scopus (48) Google Scholar; Bhowmick et al., 2004Bhowmick N.A. Chytil A. Plieth D. et al.TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia.Science. 2004; 303: 848-851Crossref PubMed Scopus (1076) Google Scholar; Greten et al., 2004Greten F.R. Eckmann L. Greten T.F. et al.IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer.Cell. 2004; 118: 285-296Abstract Full Text Full Text PDF PubMed Scopus (1944) Google Scholar; Pikarsky et al., 2004Pikarsky E. Porat R.M. Stein I. et al.NF-kappaB functions as a tumour promoter in inflammation-associated cancer.Nature. 2004; 431: 461-466Crossref PubMed Scopus (2008) Google Scholar). In an essay concept entitled "Mending and Malignancy,"Beachy et al., 2004Beachy P.A. Karhadkar S.S. Berman D.M. Mending and malignancy.Nature. 2004; 431: 402Crossref PubMed Scopus (48) Google Scholar point out the clinical link between persistent heartburn and adenocarcinoma of the esophagus. They focus on injured epithelium and highlight molecular pathways contributing to an expanded stem cell pool that, together with mutagenic agents, contribute to carcinogenesis. They conclude that understanding the response to epithelial injury may lead to useful strategies for cancer prevention and therapy. In addition,Balkwill and Coussens, 2004Balkwill F. Coussens L.M. Cancer: An inflammatory link.Nature. 2004; 431: 405-406Crossref PubMed Scopus (541) Google Scholar reviewed the role of the NF-κB signal transduction pathway that can regulate inflammation and also promote malignancy. Their review summarized the latest findings revealed in a letter to Nature byPikarsky et al., 2004Pikarsky E. Porat R.M. Stein I. et al.NF-kappaB functions as a tumour promoter in inflammation-associated cancer.Nature. 2004; 431: 461-466Crossref PubMed Scopus (2008) Google Scholar. Using Mdr2 knockout mice in which hepatitis is followed by hepatocellular carcinoma (HCC), Pikarsky et al implicated TNF-α upregulation in tumor promotion of HCC, and suggest that TNF-α and NF-κB are potential targets for cancer prevention in the context of chronic inflammation. A similar conclusion was reached with respect to NF-κB by an independent group of investigators using a model of experimental dextran sodium sulfate-induced colitis, in which inactivation of the IκB kinase resulted in reduced colorectal tumors (Greten et al., 2004Greten F.R. Eckmann L. Greten T.F. et al.IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer.Cell. 2004; 118: 285-296Abstract Full Text Full Text PDF PubMed Scopus (1944) Google Scholar). Way before the molecular clues for cancer had been investigated,Hawkins, 1835Hawkins C. Cases of warty tumors in cicatrices.Med Chir Trans. 1835; 19: 19Crossref PubMed Google Scholar made the clinical observation that squamous cell carcinoma can be a long-term sequela of chronic osteomyelitis in the overlying skin. Furthermore, it has been argued that the immune response contributes significantly to fostering a tumorigenic process through CD4+ T cells, or other inflammatory links (Daniel et al., 2003Daniel D. Meyer-Morse N. Bergsland E.K. Dehne K. Coussens L.M. Hanahan D. Immune enhancement of skin carcinogenesis by CD4+ T cells.J Exp Med. 2003; 197: 1017-1028Crossref PubMed Scopus (138) Google Scholar; Vakkila and Lotze, 2004Vakkila J. Lotze M.T. Inflammation and necrosis promote tumour growth.Nat Rev Immunol. 2004; 4: 641-648Crossref PubMed Scopus (487) Google Scholar). Although there are many other clinical conditions supporting the concept that inflammation is a critical component of tumor progression (e.g., reflux esophagitis/esophageal cancer; inflammatory bowel disease/colorectal cancer) (Coussens and Werb, 2002Coussens L.M. Werb Z. Inflammation and cancer.Nature. 2002; 420: 860-867Crossref PubMed Scopus (10054) Google Scholar), there is at least one notable example that does not fit this paradigm. As described below, psoriasis is a chronic cutaneous inflammatory disease, which is seldom if ever accompanied by cancer, suggesting the relationship between tissue repair, inflammation, and development of cancer may not be as simple as portrayed by the aforementioned reviews and experimental results. Besides psoriasis, other noteworthy observations pointing to more complexity include the observation that in the Mdr2 knockout mice, we rarely detect bile duct tumors despite extensive inflammation, NF-κB activation, and abundant proliferation of bile ducts in portal spaces (Pikarsky et al., 2004Pikarsky E. Porat R.M. Stein I. et al.NF-kappaB functions as a tumour promoter in inflammation-associated cancer.Nature. 2004; 431: 461-466Crossref PubMed Scopus (2008) Google Scholar). Moreover, in a skin cancer mouse model, NF-κB was shown to inhibit tumor formation (Dajee et al., 2003Dajee M. Lazarov M. Zhang J.Y. et al.NF-kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia.Nature. 2003; 421: 639-643Crossref PubMed Scopus (462) Google Scholar). Thus, the composition of inflammatory mediators, or the properties of the responding epithelial cells (e.g. signaling machinery, metabolic status), may dictate either tumor promotion or tumor suppression, as summarized in Figure 1. As highlighted in Figure 1, we suggest that chronic inflammation and tissue repair can trigger pro-oncogenic events, but also that tumor suppressor pathways may be upregulated at various sites of injury and chronic cytokine networking. The principal support for such a dualistic viewpoint is based on both clinical and biochemical characteristics of psoriatic plaques. Psoriatic plaques represent a common tissue response to injury in genetically predisposed individuals (approximately 2%–3% of the population worldwide) with prominent and persistent inflammation that does not lead to cancer development (Nickoloff, 2001Nickoloff B.J. Creation of psoriatic plaques: The ultimate tumor suppressor pathway. A new model for an ancient T-cell-mediated skin disease. Viewpoint.J Cutan Pathol. 2001; 28: 57-64Crossref PubMed Scopus (63) Google Scholar). Moreover, conversion from clinically symptomless skin to thick, erythematous scaling plaques includes a remodeling of both epidermal and dermal compartments with neovascularization accompanied by activation of CD4+ T cells and other immunocytes (Nickoloff and Nestle, 2004Nickoloff B.J. Nestle F.O. Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities.J Clin Invest. 2004; 113: 1664-1675Crossref PubMed Scopus (447) Google Scholar). The psoriatic plaque is further interrogated because STAT3 signaling, which is important in cutaneous carcinogenesis, is also dramatically increased in lesional keratinocytes (Chan et al., 2004Chan K.S. Sano S. Kiguchi K. Anders J. Komazawa N. Takeda J. DiGiovanni J. Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis.J Clin Invest. 2004; 114: 720-728Crossref PubMed Scopus (296) Google Scholar; Sano et al., 2005Sano S. Chan K.S. Carbajal S. et al.Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model.Nat Med. 2005; 11: 43-49Crossref PubMed Scopus (541) Google Scholar). This remarkable set of cellular changes is entirely reversible, particularly when agents that neutralize TNF-α are administered to patients with psoriasis (Nickoloff and Nestle, 2004Nickoloff B.J. Nestle F.O. Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities.J Clin Invest. 2004; 113: 1664-1675Crossref PubMed Scopus (447) Google Scholar). Perhaps of greatest interest to this topic is that lesional keratinocytes are characterized by a high resistance to apoptosis, and yet only rarely, if ever, become converted to carcinomas (Wrone-Smith et al., 1997Wrone-Smith T. Mitra R.S. Thompson C.B. Jasty R. Castle V.P. Nickoloff B.J. Keratinocytes derived from psoriatic plaques are resistant to apoptosis compared with normal skin.Am J Pathol. 1997; 151: 1321-1329PubMed Google Scholar; Nickoloff, 2001Nickoloff B.J. Creation of psoriatic plaques: The ultimate tumor suppressor pathway. A new model for an ancient T-cell-mediated skin disease. Viewpoint.J Cutan Pathol. 2001; 28: 57-64Crossref PubMed Scopus (63) Google Scholar). NF-κB has also been implicated in psoriatic lesions, as agents targeting this signal transduction pathway have shown pre-clinical efficacy (Zollner et al., 2002Zollner T.M. Podda M. Pien C. Elliott P.J. Kaufmann R. Boehncke W.H. Proteasome inhibition reduces superantigen-mediated T cell activation and the severity of psoriasis in a SCID-hu model.J Clin Invest. 2002; 109: 671-679Crossref PubMed Scopus (104) Google Scholar). Furthermore, in this issue,Lizzul et al., 2005Lizzul P.F. Aphale A. Malaviya R. Sun Y. Masud S. Dombrovskiy V. Gottlieb A.B. Differential expression of phosphorylated NF-κB in normal and psoriatic epidermis and down regulation of NF-κB in response to treatment with etanercept.J Invest Dermatol. 2005; 124: 1275-1283Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar demonstrate NF-κB signaling is activated in psoriatic plaques and is downregulated following administration of a TNF-α targeting agent (e.g., etanercept). TNF-α signaling is of particular relevance to this topic of inflammation and skin cancer. On the one hand, psoriatic plaques are dependent on TNF-α signaling, as agents that block TNF-α are highly effective in treating psoriatic patients (Nickoloff and Nestle, 2004Nickoloff B.J. Nestle F.O. Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities.J Clin Invest. 2004; 113: 1664-1675Crossref PubMed Scopus (447) Google Scholar). TNF-α also appears to be essential for skin carcinogenesis, however, as mice genetically engineered to be deficient in TNF-α are resistant to skin carcinogenesis (Moore et al., 1999Moore R.J. Owens D.M. Stamp G. et al.Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis.Nat Med. 1999; 5: 828-831Crossref PubMed Scopus (723) Google Scholar). Furthermore, TNF-α receptor 1-mediated signaling is required for skin cancer development in mice when accompanied by NF-κB inhibition (Lind et al., 2004Lind M.H. Rozell B. Wallin R.P. van Hogerlinden M. Ljunggren H.G. Toftgard R. Sur I. Tumor necrosis factor receptor 1-mediated signaling is required for skin cancer development induced by NF-kappaB inhibition.Proc Natl Acad Sci USA. 2004; 101: 4972-4977Crossref PubMed Scopus (87) Google Scholar). Thus, the interplay between inflammatory cytokines such as TNF-α and the NF-κB signaling pathway must be taken into consideration when attempting to link inflammation and skin cancer (Pasparakis et al., 2002Pasparakis M. Courtois G. Hafner M. et al.TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2.Nature. 2002; 417: 861-866Crossref PubMed Scopus (383) Google Scholar). One cannot easily dismiss the many dilemmas raised by the psoriatic plaque that confound a simple link between tissue repair, inflammation, and carcinogenesis. Since it is easily visible to the naked eye, and patients may suffer from such lesions for decades, it is difficult to argue that various skin cancers such as squamous cell carcinoma, basal cell carcinoma, or melanoma actually do develop within plaques but are being overlooked by patients and dermatologists (Nickoloff, 2004Nickoloff B.J. The skin cancer paradox of psoriasis: A matter of life and death decisions in the epidermis.Arch Dermatol. 2004; 140: 873-875Crossref PubMed Scopus (14) Google Scholar). Remarkably, psoriatic plaques are intentionally exposed to mutagenic agents including excessive sunlight, topical administration of crude coal tar, or parenteral DNA cross-linking agent-psoralen followed by ultraviolet light (i.e. PUVA). Moreover, these treatments are known to induce skin cancer in non-lesional skin (Nijsten and Stern, 2003Nijsten T.E. Stern R.S. The increased risk of skin cancer is persistent after discontinuation of psoralen+ultraviolet A: A cohort study.J Invest Dermatol. 2003; 121: 252-258Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). To add insult to injury, prior to the use of new and effective biological agents selectively targeting TNF-α, thousands, if not tens of thousands, of patients were and are being treated with immunosuppressive agents such as corticosteroids, or cyclosporine A. Thus, since psoriatic skin is characterized by altered differentiation, angiogenesis, increased telomerase activity, proliferative changes, and apoptosis resistance (McKenzie and Sabin, 2003McKenzie R.C. Sabin E. Aberrant signalling and transcription factor activation as an explanation for the defective growth control and differentiation of keratinocytes in psoriasis: A hypothesis.Exp Dermatol. 2003; 12: 337-345Crossref PubMed Scopus (47) Google Scholar), one would expect that each and every psoriatic plaque would be converted to cancer, or at least serve as fertile soil for the presence of non-epithelial skin cancers over time (Nickoloff, 2001Nickoloff B.J. Creation of psoriatic plaques: The ultimate tumor suppressor pathway. A new model for an ancient T-cell-mediated skin disease. Viewpoint.J Cutan Pathol. 2001; 28: 57-64Crossref PubMed Scopus (63) Google Scholar,Nickoloff, 2004Nickoloff B.J. The skin cancer paradox of psoriasis: A matter of life and death decisions in the epidermis.Arch Dermatol. 2004; 140: 873-875Crossref PubMed Scopus (14) Google Scholar). How can one reconcile the key characteristics of psoriatic lesions with the paucity of cancers that arise within such plaques? There is a biological context requiring consideration in which cells can simultaneously resist apoptosis and transformation—namely the senescent state (Campisi, 2001Campisi J. Cellular senescence as a tumor-suppressor mechanism.Trends Cell Biol. 2001; 11: S27-S31Abstract Full Text PDF PubMed Scopus (479) Google Scholar). Using normal keratinocytes in culture and exposing these cells to cytokines that are present in psoriatic plaques such as TNF-α or interferon-γ, the keratinocytes become irreversibly growth arrested and acquire a resistance to apoptosis (Chaturvedi et al., 1999Chaturvedi V. Qin J.Z. Denning M.F. Choubey D. Diaz M.O. Nickoloff B.J. Apoptosis in proliferating, senescent, and immortalized keratinocytes.J Biol Chem. 1999; 274: 23358-23367Crossref PubMed Scopus (187) Google Scholar,Chaturvedi et al., 2003Chaturvedi V. Cesnjaj M. Bacon P. Panella J. Choubey D. Diaz M.O. Nickoloff B.J. Role of INK4a/Arf locus-encoded senescent checkpoints activated in normal and psoriatic keratinocytes.Am J Pathol. 2003; 162: 161-170Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar). Many biochemical features are present in keratinocytes undergoing accelerated senescence including induction of senescence-associated β-galactosidase and cyclin-dependent kinase inhibitors such as members of the INK4a/Arf locus (p12, p14ARF, p16) as well as p21WAF1 (Healy et al., 1995Healy E. Reynolds N.J. Smith M.D. Harrison D. Doherty E. Campbell C. Rees J.L. Up-regulation of p21WAF1/CIP1 in psoriasis and after the application of irritants and tape stripping.J Invest Dermatol. 1995; 105: 274-279Crossref PubMed Scopus (34) Google Scholar). Several senescence markers can also be found within psoriatic plaques in vivo (Chaturvedi et al., 2003Chaturvedi V. Cesnjaj M. Bacon P. Panella J. Choubey D. Diaz M.O. Nickoloff B.J. Role of INK4a/Arf locus-encoded senescent checkpoints activated in normal and psoriatic keratinocytes.Am J Pathol. 2003; 162: 161-170Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar; Elias et al., 2004Elias A.N. Barr R.J. Nanda V.S. p16 expression in psoriatic lesions following therapy with propylthiouracil, an antithyroid thioureylene.Int J Dermatol. 2004; 43: 889-892Crossref PubMed Scopus (15) Google Scholar; Nickoloff, 2004Nickoloff B.J. The skin cancer paradox of psoriasis: A matter of life and death decisions in the epidermis.Arch Dermatol. 2004; 140: 873-875Crossref PubMed Scopus (14) Google Scholar). Thus, we postulate that chronic inflammation in psoriatic skin induces a state of "tumor demotion" possibly through triggering premature, or accelerated, cell senescence. There may also be paracrine effects emanating from lesional keratinocytes or underlying fibroblasts that could effectively suppress neighboring non-epithelial cells, such as melanoma cells, as well. Secreted proteins over-produced by senescent keratinocytes potentially mediating an anti-tumorigenic response include maspin and transforming growth factor β (TGFβ) isoforms (Tremain et al., 2000Tremain R. Marko M. Kinnimulki V. Ueno H. Bottinger E. Glick A. Defects in TGF-beta signaling overcome senescence of mouse keratinocytes expressing v-Ha-ras.Oncogene. 2000; 19: 1698-1709Crossref PubMed Scopus (84) Google Scholar; Nickoloff et al., 2004Nickoloff B.J. Lingen M.W. Chang B.D. et al.Tumor suppressor maspin is up-regulated during keratinocyte senescence, exerting a paracrine antiangiogenic activity.Cancer Res. 2004; 64: 2956-2961Crossref PubMed Scopus (53) Google Scholar). As regards TGFβ,Bhowmick et al., 2004Bhowmick N.A. Chytil A. Plieth D. et al.TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia.Science. 2004; 303: 848-851Crossref PubMed Scopus (1076) Google Scholar described the phenotype of Tgfbr2fspKO mice in which TGFβ receptor type II is selectively inactivated in fibroblasts, resulting in intraepithelial neoplasia in prostate and invasive squamous cell carcinoma of the forestomach. In addition,Becker et al., 2004Becker C. Fantini M.C. Schramm C. et al.TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling.Immunity. 2004; 21: 491-501Abstract Full Text Full Text PDF PubMed Scopus (581) Google Scholar reported that TGFβ suppresses colon cancer progression in an injury/inflammation model via inhibition of interleukin-6 trans signaling. Thus, a keratinocyte senescence program culminating in TGFβ may, through autocrine and paracrine mechanism, play a major role in suppressing tumorigenesis at or around the psoriatic plaque (Campisi, 2001Campisi J. Cellular senescence as a tumor-suppressor mechanism.Trends Cell Biol. 2001; 11: S27-S31Abstract Full Text PDF PubMed Scopus (479) Google Scholar). Perhaps the presence of senescent keratinocytes restricts expansion of transformed stem cells from small clones to large clones, which could account for the lack of tumorigenesis (Hennings et al., 1990Hennings H. Robinson V.A. Michael D.M. Pettit G.R. Jung R. Yuspa S.H. Development of an in vitro analogue of initiated mouse epidermis to study tumor promoters and antipromoters.Cancer Res. 1990; 50: 4794-4800PubMed Google Scholar); or the clonal expansion of keratinocytes in psoriatic plaques does not include a stem cell component (Chaturvedi et al., 2002Chaturvedi V. Chu M.S. Carrol B.M. Brenner B.S.J.W. Nickoloff B.J. Estimation of size of clonal unit for keratinocytes in normal human skin.Arch Pathol Lab Med. 2002; 126: 420-424PubMed Google Scholar). It should also be noted that in the case of psoriasis, epidemiological data on cancer incidence indicate there is no general skin protection as revealed by PUVA-induced lesions that occur on non-plaque containing skin (Nijsten and Stern, 2003Nijsten T.E. Stern R.S. The increased risk of skin cancer is persistent after discontinuation of psoralen+ultraviolet A: A cohort study.J Invest Dermatol. 2003; 121: 252-258Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). Thus, whatever the mechanism by which plaques resist transformation, it must be confined to the lesional skin itself, and not necessarily protect surrounding skin or create a more generalized field effect. An alternative consideration mediating tumor suppression within psoriatic plaques is that the inflammatory infiltrate generates anti-infectious factors such as β-defensins (Harder et al., 1997Harder J. Bartels J. Christophers E. Schroder J.M. A peptide antibiotic from human skin.Nature. 1997; 387: 861Crossref PubMed Scopus (1162) Google Scholar), which compensates for barrier disruption by inhibiting invasion of various pathogenic organisms such as bacterial, fungal, and viral infections (Henseler and Christophers, 1995Henseler T. Christophers E. Disease concomitance in psoriasis.J Am Acad Dermatol. 1995; 32: 982-986Abstract Full Text PDF PubMed Scopus (573) Google Scholar). The presence of such factors that sterilize lesions could serve to target and suppress potentially transforming infectious agents. In addition, factors like β-defensins may serve to bridge innate and adaptive immune responses, thereby combating neoplastic cells as they initially appear (Ganz, 2003Ganz T. Defensins: Antimicrobial peptides of innate immunity.Nat Rev Immunol. 2003; 3: 710-720Crossref PubMed Scopus (2155) Google Scholar). Interactions between epithelial cells and microflora are gaining increasing attention in the gastrointestinal tract as resident commensal bacteria may activate cell survival signals via Toll-like receptors and enhanced NF-κB signaling (Clevers, 2004Clevers H. At the crossroads of inflammation and cancer.Cell. 2004; 118: 671-674Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar; Rakoff-Nahoum et al., 2004Rakoff-Nahoum S. Paglino J. Eslami-Varzaneh F. Edberg S. Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.Cell. 2004; 118: 229-241Abstract Full Text Full Text PDF PubMed Scopus (3030) Google Scholar). The role of NF-κB signaling within keratinocytes may serve as a tumor suppressor by inducing growth arrest via p21WAF (Zhang et al., 2004Zhang J.Y. Green C.L. Tao S. Khavari P.A. NF-kappaB RelA opposes epidermal proliferation driven by TNFR1 and JNK.Genes Dev. 2004; 18: 17-22Crossref PubMed Scopus (116) Google Scholar), or as a tumor promoter by enhancing their survival and resistance to apoptosis. Thus, just as we have come to appreciate that AP-1 and Notch signaling may be double-edged swords when it comes to tumor promotion versus tumor suppression, so too may inflammatory reactions that activate such signaling pathways have dualistic, and perhaps even directly opposing influences depending on the cellular context, strength and persistence of signals, and other microenvironmental factors (Eferl and Wagner, 2003Eferl R. Wagner E.F. AP-1: A double-edged sword in tumorigenesis.Nat Rev Cancer. 2003; 3: 859-868Crossref PubMed Scopus (1490) Google Scholar; Radtke and Raj, 2003Radtke F. Raj K. The role of notch in tumorigenesis: Oncogene or tumour suppressor?.Nat Rev Cancer. 2003; 3: 756-767Crossref PubMed Scopus (679) Google Scholar). 1Nickoloff BJ, et al: JID—Montagna Symposium, 2004, submitted.1Nickoloff BJ, et al: JID—Montagna Symposium, 2004, submitted. As suggested byRadisky et al., 2001Radisky D. Hagios C. Bissell M.J. Tumors are unique organs defined by abnormal signaling and context.Semin Cancer Biol. 2001; 11: 87-95Crossref PubMed Scopus (144) Google Scholar, anti-cancer research might be more effective if aimed at eradicating the cause or signaling context of abnormality, rather than just treating the end result. Devoting efforts at unraveling the signaling pathways and cellular context of keratinocytes within psoriatic plaques could provide novel insights into potent tumor suppressive pathways that lie within a chronic inflammatory network. It is likely that all inflammatory conditions are not alike, whether afflicting the skin or extra-cutaneous sites, and we need to distinguish between those chronic inflammatory sites that predispose to cancer development, and those that may prevent tumor formation. In any event, exploring and discovering the essential elements mediating inflammation-induced tumor suppression may pay dividends beyond the heartbreak of psoriasis in skin to many other organ systems such as the liver, respiratory, and gastrointestinal tracts, in which the response to tissue injury is repair and chronic inflammation. In conclusion, it would seem prudent to remember the paradigm proposed byWeiss, 1971Weiss P.A. A cell is not an island entire of itself.Perspect Biol Med. 1971; 14: 182-205Crossref PubMed Scopus (10) Google Scholar in which he suggested that pre-malignant cells do not comprise an isolated island, but are rather a focus of intense tissue interactions. The myriad inflammatory effects of the tumor microenvironment are important for understanding tumor development, as well as tumor suppression and senescence, and for the design of efficacious prevention strategies against inflammation-associated cancer. This work was supported by NIH Grant AR 40065, AR 47814 (B. J. N.) and Prostate Cancer Foundation Israel-Center of Excellence (E. P. and Y. B. N.). The authors thank Drs J. Robinson, F. Bennett, J. Krueger, K. Gordon, B. Bonish, J. DiGiovanni, M. Denning, and L. Miele for helpful suggestions.
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