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clustering by geneThe authors examined 501 genes respon-sible for the 560 genodermatoses defined by a unique OMIM entry. The mismatch is attributable to the possibility that a single gene can cause more than one disease (allelic variants and pleiotropy) and, con-versely, a single disease can be caused by different genes (phenocopies and genetic heterogeneity). Genes operate within intricate pathways and networks, many of which are known. The authors use existing software to map these 501 genes onto these known networks, high-lighting nodes and groups of disorders. This exercise does not take into account variation caused by type of mutation, let alone epigenetic factors. Nonetheless, the authors demonstrate overlapping networks of genes—for example, those causing depigmentation, deafness, or both—and this process will undoubtedly reveal new candidate genes for disorders of unknown cause. This type of analysis could be applied to the 1-2-3-4 ecto-dermal dysplasia classification now that several ectodermal dysplasia genes and pathways are known.

Where does this take us?Despite some intrinsic limitations and simplifications, this analytical approach may help researchers identify candidate disorders and genes for future study. CGenDerm can be improved and extend-ed in the future. It might be adapted to form a searchable database to aid clinicians. It remains to be seen whether the analyti-cal methods will tell us more than existing search engines and Sherlockian deduc-tion—a process that works only because the author already knows the answer.

CONFLICT OF INTERESTThe author states no conflict of interest.

ACKNOWLEDGMENTI am grateful to Robin Ferner and Neil McLellan for their comments on the manuscript.

WEB RESOURCESBritish Association of Dermatologists: http://www.

bad.org.uk/site/920/default.aspx

History of the International Classification of Diseases: http://www.who.int/classifications/icd/en/HistoryOfICD.pdf

National Center for Biotechnology Information Entrez System, National Library of Medicine: http://www.lmdatabases.com/index.html

Online Mendelian Inheritance in Man: http://www.ncbi.nlm.nih.gov/omim

REfERENCESConnor S (2004) The Book of Skin. Reaktion

Books: London

Feramisco JD, Sadreyev RI, Murray ML, Grishin NV, Tsao H (2009) Phenotypic and genotypic analyses of genetic skin disease through the online Mendelian Inheritance in Man (OMIM) database. J Invest Dermatol 129:2628–36

Freire-Maia N, Pinheiro M (1984) Ectodermal Dysplasias: A Clinical and Genetic Study. Liss: New York

Jones KL (2006) Smith’s Recognizable Patterns

of Human Malformation, 6th edn. Elsevier Saunders: Philadelphia, PA

Leech S, Moss C (2007) A current and online genodermatoses database. Br J Dermatol 156: 1115-48

McKusick VA (1966) Mendelian Inheritance in Man: Catalogs of Autosomal Dominant, Autosomal Recessive, and X-Linked Phenotypes. Johns Hopkins University Press: Baltimore, MD

Moss C (1991) Dermatology and the human gene map. Br J Dermatol 124:3–9

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Stromal Collagenase in Melanoma: A Vascular ConnectionVeli-Matti Kähäri1 and Risto Ala-aho1

In this issue, Zigrino et al. report on the role of host-derived mouse collagenase-3 (matrix metalloproteinase (MMP)-13) in melanoma growth and metastasis using a mouse model that lacks MMP-13. The authors demonstrate that vascularization of cutaneous melanomas in these mice is impaired compared with that of controls. This study emphasizes the importance of stromal murine MMP-13, a functional homologue of human MMP-1, in tumor progression.

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Proteinases in tumor growthTumor progression is a multistage pro-cess in which malignant cells invade surrounding tissue and metastasize to dis-tant organs. An important stage of tumor invasion is the loss of an intact basement membrane. Subsequently, malignant cells metastasize to other organs by invading blood or lymphatic vessels. Tumor cells then enter blood or lymph circulation, attach at a distant location, and degrade the basement membranes and extracellular matrix (ECM) at the sites of metastases. Furthermore, angio-genesis is required for tumor growth, and tumor-induced lymphangiogenesis plays an important role in tumor metastasis (Karpanen and Alitalo, 2008).

collagenasesCollagenase-1 (matrix metalloproteinase (MMP)-1), collagenase-2 (MMP-8), and collagenase-3 (MMP-13) are principal

secreted proteinases capable of cleaving native fibrillar collagens of types I, II, III, V, and IX. In addition to MMP-1, MMP-8, and MMP-13, gelatinase-A (MMP-2) has a weak catalytic activity toward fibrillar collagens (Ala-aho and Kähäri, 2005). Furthermore, membrane-type-1 MMP (MMP-14) cleaves fibrillar collagens. Collagenases vary in their ability to cata-lyze fibrillar collagens.

The first MMP to be identified, a col-lagenase, was purified from the tails of tadpoles by Gross and Lapière (1962). The first human MMP to be identified, MMP-1, was cloned from adult skin fibro-blasts (Goldberg et al., 1986). Human MMP-1 is expressed in physio logical pro-cesses, for example, during embryonic development and wound healing, as well as under a number of pathological condi-tions, including chronic cutaneous ulcers and various malignant tumors. MMP-1 is expressed by a variety of normal cells

1Department of Dermatology and MediCity Research Laboratory, University of Turku, Turku, Finland

Correspondence: Veli-Matti Kähäri, Department of Dermatology, University of Turku, P.O.B. 52, FI-20521 Turku, Finland. E-mail:veli-matti.kahari@utu.fi

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in culture, including keratinocytes, fibro-blasts, endothelial cells, monocytes, and macrophages, as well as by several types of tumor-derived cells.

Two closely related mouse coun-terparts of human MMP-1 have been identified: Mcol1-A and Mcol1-B. Both are expressed during embryo implan-tation, but only Mcol-A cleaves fibril-lar collagens (Balbin et al., 2001). The original murine interstitial collagenase (MMP-13) exhibits the highest homol-ogy with human MMP-13, indicating that it represents a counterpart to human MMP-13. Notably, mouse MMP-13 and human MMP-1 are expressed in similar situations—evidence that mouse MMP-13 is also a functional homologue of human MMP-1.

MMP-8 is stored in secretory gran-ules of neutrophils and released in response to extracellular stimuli. MMP-8 is also expressed by chondrocytes and mononuclear fibroblast-like cells in rheumatoid synovium and in bronchial epithelial cells and monocytes during bronchitis. MMP-8 can regulate inflam-mation by cleaving and activating lipopolysaccharide-induced CXC chemo-kine LIX-1, a potent chemoattractant for monocytes and activator of neutrophil functions (Balbin et al., 2003).

Collagenase-3 (MMP-13) was origi-nally cloned from human breast cancer. Compared with other MMPs, MMP-13 has wide substrate specificity. It can inactivate chemokines such as mono-cyte chemoattractant protein-3 and stromal cell-derived factor-1, and it also appears to be involved in the activation of proTGF-β3. Expression of MMP-13 is limited to a few physiologic situations that involve rapid and effective remodel-ing of collagenous ECM (fetal bone devel-opment, postnatal bone remodeling, and gingival and fetal skin wound repair, for example). Mice lacking MMP-13 exhibit delayed formation of long bones, evi-

dence for the role of MMP-13 in skel-etal development (Inada et al., 2004). In humans, MMP-13 expression is detected under pathological conditions character-ized by the destruction of normal tissue architecture, such as osteoarthritic carti-lage, rheumatoid synovium, and chronic cutaneous ulcers (Vaalamo et al., 1997).

collagenases in cancer progressionIt is accepted that collagenases play a role in the initial cleavage of fibrillar col-lagens of types I, II, and III, and it has been suggested that degradation of col-lagenous ECM by these MMPs is impor-tant for tumor invasion. Numerous stud-ies have demonstrated overexpression of collagenases in malignant tumors as compared with normal tissues, suggest-ing a role for collagenases in cancer cell invasion. Beside malignant cells, stromal fibroblasts, vascular endothelial cells, and inflammatory cells produce MMPs, which contribute to proteolytic remod-eling of the peritumoral ECM. However, there is little direct evidence to character-ize the role of distinct collagenases in dif-ferent stages of tumor progression.

MMP-1 is expressed by tumor cells or adjacent stromal fibroblasts in response to stimulating factors produced by tumor cells. In both cases, MMP-1 is expressed at sites of tumor invasion. Overexpression of MMP-1 has been demonstrated in a variety of cancers, and its expression is associated with poor prognosis in colorectal, gastric, and esophageal carc inomas, metastatic melanoma, and pancreatic adenocarci-noma. In head-and-neck squamous-cell carcinomas (SCCs), MMP-1 expression is often localized to stromal cells sur-rounding tumor islands.

MMP-8 is expressed mainly by neu-trophils in inflammatory reactions, but it is also detected in certain malignant tumors, including head-and-neck SCCs and ovarian cancer. MMP-8 might play a dual role in tumor progression because the incidence of chemically induced skin carcinomas is increased in MMP-8-deficient male mice (Balbin et al., 2003).

The expression of MMP-13 has been detected in invasive malignant tumors, including breast carcinomas, SCCs of the head and neck (Johansson et al., 1997), SCCs of the skin (Airola et al., 1997), and primary and metastatic melanoma (Airola

et al., 1999). MMP-13 is not expressed by normal epidermal keratinocytes in culture or in vivo in intact skin or during wound repair (Vaalamo et al., 1997). Therefore, MMP-13 expression appears to be a marker for squamous epithelial cell trans-formation. MMP-13 expression is detect-ed mainly in tumor cells at the invading front of SCCs, but it is also expressed by stromal fibroblasts surrounding tumor cells. MMP-13 expression in SCCs corre-lates with a tumor’s capacity for invasion and metastasis, suggesting that MMP-13 expression levels could be an indica-tor for the invasive capacity of SCCs. Accordingly, the growth of cutaneous SCCs was found to be potently suppressed by MMP-13 targeted antisense ribozyme (Ala-aho et al., 2004).

collagenases in angiogenesisIn this issue, Zigrino et al. study the role of stromal mouse MMP-13 in melanoma growth using a mouse model lacking MMP-13. In this model, the growth of tumors established by intra-dermally injected melanoma cells was significantly impaired, especially at the early stage of tumor growth, compared with that of wild-type mice. Interestingly, the metastasis rate of cutaneous mela-nomas was also reduced, especially the development of metastasis in the heart. The authors demonstrate that vascu-larization of melanomas in MMP-13-deficient mice is impaired compared with that of wild-type mice, providing a possible explanation for impaired tumor growth and metastasis. These findings are consistent with their observation of murine MMP-13 expression in vascu-lar endothelial cells and macrophages within the stromal compartment of the tumors. This expression pattern is simi-lar to that of human MMP-1, provid-ing evidence that in this model murine MMP-13 functions as a homologue of human MMP-1 (Airola et al., 1999).

The results reported in this issue by Zigrino et al. provide direct evidence that murine MMP-13 plays an impor-tant role in new blood vessel formation during melanoma growth. Recent stud-ies have identified a novel mechanism by which MMP-1 promotes angiogen-esis. MMP-1 proteolytically activates protease activated receptor-1 (PAR1), a thrombin receptor that is highly

|Host-derived collagenases play important roles in tumor progression.

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expressed in endothelial cells (Blackburn and Brinckerhoff, 2008). It appears that MMP-1 can act directly on endo-thelial cells as a proangiogenic signaling molecule to complement the effect of thrombin in promoting angiogenesis and tumor progression. Interestingly, it has also been shown in a breast cancer model that stromal fibroblast-derived MMP-1 in the tumor microenvironment can alter the behavior of tumor cells through PAR1 by promoting cell migration and invasion (Boire et al., 2005). These results comple-ment previous findings that expression of MMP-1 serves as a marker for rapid pro-gression in human metastatic melanoma (Nikkola et al., 2002, 2005).

Since the initial identification of collagenase in tadpoles by Gross and Lapière (1962), it has become evident that the role of collagenases is more complex than that of simply promoting turnover of collagenous ECM. MMPs can proteolytically activate and release biologically active fragments from ECM, and they can also process several non-matrix substrates embedded in the ECM or on the cell surface. The results of Zigrino et al. provide direct evidence that host-derived collagenases play an important role in tumor progression and that novel inhibition strategies for stromal collagenases may be an impor-tant approach for targeting vasculariza-tion of invasive malignant tumors.

CONFLICT OF INTERESTThe authors state no conflict of interest.

REfERENCESAirola K, Johansson N, Kariniemi A-L, Kähäri V-M,

Saarialho-Kere UK (1997) Human collagenase-3 is expressed in malignant squamous epithelium of the skin. J Invest Dermatol 109:225–31

Airola K, Karonen T, Vaalamo M, Lehti K, Lohi J, Kariniemi AL et al. (1999) Expression of collagenases-1 and -3 and their inhibitors TIMP-1 and -3 correlates with the level of invasion in malignant melanomas. Br J Cancer 80:733–43

Ala-aho R, Ahonen M, George SJ, Heikkilä J, Grénman R, Kallajoki M et al. (2004) Targeted inhibition of human collagenase-3 (MMP-13) expression inhibits squamous cell carcinoma growth in vivo. Oncogene 23:5111–23

Ala-aho R, Kähäri V-M (2005) Collagenases in cancer. Biochimie 87:273–86

Balbín M, Fueyo A, Knäuper V, López JM, Álvarez J, Sánchez LM et al. (2001) Identification and enzymatic characterization of two diverging murine counterparts of human interstitial collagenase (MMP-1) expressed

at sites of embryo implantation. J Biol Chem 276:10253–62

Balbín M, Fueyo A, Tester AM, Pendás AM, Pitiot AS, Astudillo A et al. (2003) Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nat Genet 35:252–7

Blackburn JS, Brinckerhoff CE (2008) Matrix metalloproteinase-1 and thrombin differentially activate gene expression in endothelial cells via PAR-1 and promote angiogenesis. Am J Pathol 173:1736–46

Boire A, Covic L, Agarwal A, Jacques S, Sherifi S, Kuliopulos A (2005) PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120:303–13

Goldberg GI, Wilhelm SM, Kronberger A, Bauer EA, Grant GA, Eisen AZ (1986) Human fibroblast collagenase. Complete primary structure and homology to an oncogene transformation-induced rat protein. J Biol Chem 261:6600–5

Gross J, Lapière CM (1962) Collagenolytic activity in amphibian tissues: a tissue culture assay. Proc Natl Acad Sci USA 48:1014–22

Inada M, Wang Y, Byrne MH, Rahman MU, Miyaura C, López-Otín C et al. (2004) Critical roles for collagenase-3 (MMP13) in development of growth plate cartilage and in endochondral ossification. Proc Natl Acad Sci USA 101:17192–7.

Johansson N, Airola K, Grénman R, Kariniemi A-L,

Saarialho-Kere U, Kähäri V-M (1997) Expression of collagenase-3 (matrix metalloproteinase-13) in squamous cell carcinomas of the head and neck. Am J Pathol 151:499–508

Karpanen T, Alitalo K (2008) Molecular biology and pathology of lymphangiogenesis. Annu Rev Pathol 3:367–97

Nikkola J, Vihinen P, Vlaykova T, Hahka-Kemppinen M, Kähäri V-M, Pyrhönen S (2002) High expression levels of collagenase-1 and stromelysin-1 correlate with shorter disease-free survival in human metastatic melanoma. Int J Cancer 97: 432–8

Nikkola J, Vihinen P, Vuoristo MS, Kellokumpu-Lehtinen P, Kähäri V-M, Pyrhönen S. (2005) High serum levels of matrix metalloproteinase-9 and matrix metalloproteinase-1 are associated with rapid progression in patients with metastatic melanoma. Clin Cancer Res 11:5158–66

Vaalamo M, Mattila L, Johansson N, Kariniemi A-L, Karjalainen-Lindsberg M-L, Kähäri V-M et al. (1997) Distinct populations of stromal cells express collagenase-3 (MMP-13) and collagenase-1 (MMP-1) in chronic ulcers but not in normally healing wounds. J Invest Dermatol 109:96–101

Zigrino P, Kuhn I, Bäuerle T, Zamek J, Fox JW, Neumann S et al. (2009) Stromal expression of MMP-13 is required for melanoma invasion and metastasis. J Invest Dermatol 109:2686–93

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Cancer Risk Evaluation in Psoriasis: In Search of the Holy Grail?Carle F. Paul1,2 and Pierre-Antoine Gourraud3

Benefit–risk assessment of systemic treatment in psoriasis is a dynamic process. Long-term safety of psoriasis therapies has been questioned, with the spectrum of systemic immunosuppression potentially leading to increased cancer risk. In this issue, Brauchli et al. report on a population-based analysis of cancer risk in a large cohort of psoriasis patients, most of whom had not been treated with systemic agents. The study prepares the ground for future prospective long-term cohort stud-ies in psoriasis patients treated with systemic therapies, including biological agents.

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The association between psoriasis and cancer risk has received considerable attention, as has the role of certain thera-peutic agents used to treat psoriasis in promoting cancer risk. Prospective cohort studies have demonstrated that the risk

of nonmelanoma skin cancer increases linearly with the number of psoralen plus ultraviolet light A (PUVA) sessions in patients with psoriasis (Nijsten and Stern, 2003). In addition, treatment with systemic immunosuppressant agents in

1Paul Sabatier University, Toulouse, France; 2Department of Dermatology, Toulouse University Hospital, Toulouse, France and 3Department of Neurology, University of California, San Francisco, California, USA

Correspondence: Carle F. Paul, Department of Dermatology, Toulouse University Hospital, Place Baylac, 31000 Toulouse, France. E-mail: paul.c@chu-toulouse.fr